Risk factors for lung cancer: a systematic review · Web viewEach section is completed with summary conclusions describing the risk of lung cancer from the evidence located and analysed

RISK FACTORS FOR LUNG CANCER: A SYSTEMATIC REVIEW

FINAL REPORT

2014

Risk factors for Lung cancer: a systematic review was prepared and produced by:

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ForewordLung cancer is the fourth most common cancer diagnosed in both men and women in Australia and the leading cause of cancer death.

Risk factors for lung cancer: a systematic review is a comprehensive systematic review of the international literature commissioned by Cancer Australia.

This systematic review provides a detailed analysis of the key lifestyle, environmental and occupational factors that affect lung cancer risk, in addition to the role of family history. The systematic review also highlights factors where the evidence is either limited or inconsistent in relation to risk of lung cancer.

We anticipate the systematic review and the Risk factors for lung cancer: an overview, a summary of the systematic review, will be a valuable resource to support health professionals, policy makers and the community with evidence about exposure to risk factors for lung cancer, to increase understanding of those who may be at greatest risk of lung cancer and to inform interventions to ultimately reduce the burden of lung cancer.

Helen Zorbas AOCEOCancer Australia

Risk factors for lung cancer: A systematic review i

ContentsForeword........................................................................................................ i

Acknowledgments........................................................................................xxResearch Team from the Joanna Briggs Institute, University of Adelaide.................xxProject Working Group.............................................................................................xxCancer Australia.......................................................................................................xxFunding...................................................................................................................xxi

1 Introduction................................................................................................1

2 Methods.....................................................................................................22.1 Inclusion criteria..................................................................................................2

2.1.1 Types of participants................................................................................22.1.2 Types of intervention/Exposures of interest.............................................22.1.3 Types of outcome....................................................................................22.1.4 Types of studies.......................................................................................3

2.2 Search strategy and study selection....................................................................52.3 Critical appraisal..................................................................................................52.4 Data extraction and synthesis.............................................................................62.5 Use of the IARC monographs...............................................................................7

3 Results.......................................................................................................83.1 Introduction.........................................................................................................83.2 Results of database search, study selection and inclusion.................................13

4 Risk factor: Active smoking and passive smoking........................................164.1 Introduction.......................................................................................................164.2 Results...............................................................................................................24

4.2.1 Active smoking and risk of lung cancer..................................................244.2.2 Active smoking, gender and risk of lung cancer.....................................244.2.3 Passive smoking and risk of lung cancer................................................254.2.4 Other forms of tobacco smoking............................................................26

4.3 Summary...........................................................................................................264.4 Conclusions........................................................................................................27

4.4.1 Hazard identification..............................................................................274.4.2 Risk assessment....................................................................................27

4.5 Methodological quality of studies.......................................................................28Akl et al. 2010.................................................................................................29Boffetta et al. 2000.........................................................................................29Boffetta 2002..................................................................................................29Lee 2011.........................................................................................................29Stayner et al. 2007.........................................................................................29Taylor et al. 2007............................................................................................30

5 Risk factor: Asbestos exposure..................................................................315.1 Introduction.......................................................................................................315.2 Results...............................................................................................................38

5.2.1 Occupational exposure to asbestos and risk of lung cancer...................385.2.2 Non-occupational exposure to asbestos and risk of lung cancer............455.2.3 Asbestos exposure, gender and risk of lung cancer...............................465.2.4 Asbestos exposure, smoking status and risk of lung cancer..................475.2.5 Asbestosis, asbestos exposure and risk of lung cancer..........................505.2.6 Type of asbestos and risk of lung cancer...............................................50

Risk factors for lung cancer: A systematic review ii

5.3 Summary...........................................................................................................515.4 Conclusion.........................................................................................................52


5.5 Methodological quality of studies.......................................................................53Lenters et al. 2011..........................................................................................54Reid et al. 2005...............................................................................................54Reid et al. 2006...............................................................................................54Frost et al. 2011..............................................................................................54Wang et al. 2012.............................................................................................54Yano et al. 2010..............................................................................................55

6 Risk factor: Radon exposure......................................................................566.1 Introduction.......................................................................................................56

6.1.1 Occupational exposure to radon in Australia..........................................566.1.2 Residential exposure to radon in Australia.............................................57

6.2 Results...............................................................................................................686.2.1 Occupational radon exposure and risk of lung cancer............................686.2.2 Occupational radon exposure and risk of lung cancer: Joint effects with smoking..........................................................................................................696.2.3 Residential radon exposure and risk of lung cancer...............................716.2.4 Residential radon exposure and risk of lung cancer in Europe...............716.2.5 Residential radon exposure and risk of lung cancer in the US................726.2.6 Residential radon exposure and risk of lung cancer in China.................726.2.7 Level of residential radon exposure and risk of lung cancer..................736.2.8 Residential radon exposure, smoking status and risk of lung cancer.....736.2.9 Residential radon exposure, gender and risk of lung cancer..................74

6.3 Summary...........................................................................................................756.4 Conclusion.........................................................................................................75


6.5 Methodology quality of studies..........................................................................77Darby et al. 2001............................................................................................78Darby et al. 2004............................................................................................78Grosche et al. 2006.........................................................................................78Jonsson et al. 2010..........................................................................................78Kreuzer et al. 2003.........................................................................................78Krewski et al. 2005.........................................................................................79Legarde et al. 2001.........................................................................................79Leurand et al. 2011.........................................................................................79Lubin et al. 2003.............................................................................................79Lubin et al. 2004.............................................................................................79Pavia et al. 2003.............................................................................................79Pisa et al. 2001...............................................................................................80Schnelzer et al. 2010......................................................................................80Tomasek et al. 2008.......................................................................................80

7 Risk factor: Arsenic exposure.....................................................................817.1 Introduction.......................................................................................................817.2 Results...............................................................................................................87

7.2.1 Inhalational arsenic exposure and risk of lung cancer............................877.2.2 Smelter workers and living near smelters..............................................887.2.3 Miners....................................................................................................927.2.4 Smelter workers and miners..................................................................957.2.5 Fertiliser manufacturing plant, stoking, pesticide and refinery workers.967.2.6 Inhalational arsenic exposure and risk of lung cancer by smoking status.......................................................................................................................98

Risk factors for lung cancer: A systematic review iii

7.2.7 Inhalational arsenic exposure and risk of lung cancer by gender...........997.2.8 Ingested arsenic exposure (drinking water) and risk of lung cancer....1007.2.9 Ingested arsenic exposure (drinking water) and risk of lung cancer by smoking status..............................................................................................1027.2.10 Ingested arsenic exposure (drinking water) and risk of lung cancer by gender..........................................................................................................103

7.3 Summary.........................................................................................................1047.4 Conclusion.......................................................................................................105

7.4.1 Hazard identification............................................................................1057.4.2 Risk assessment..................................................................................105

Methodological quality of studies...........................................................................106Baastrup et al. 2008.....................................................................................107Ferreccio et al. 1998.....................................................................................107Frost et al. 1987............................................................................................107Hughes et al. 1988........................................................................................107Lundstrom et al. 2006...................................................................................107Pershagen 1985............................................................................................107Qiao et al. 1997............................................................................................107‘t Mannetje et al. 2011..................................................................................108Taylor et al. 1989..........................................................................................108Tsuda et al. 1989..........................................................................................108

8 Risk factor: Polycyclic aromatic hydrocarbons (PAHs)................................1098.1 Introduction.....................................................................................................1098.2 Results.............................................................................................................117

8.2.1 Occupational exposure to PAH and risk of lung cancer........................1178.2.2 Occupational PAH exposure and risk of lung cancer in coal gasification workers.........................................................................................................1198.2.3 Occupational exposure to PAHs and risk of lung cancer in coke production workers.......................................................................................1218.2.4 Occupational PAH exposure and risk of lung cancer in creosote workers.....................................................................................................................1228.2.5 Occupational PAH exposure and risk of lung cancer in aluminium production workers.......................................................................................1228.2.6 Occupational PAH exposure and risk of lung cancer in chimney sweeps and in workers exposed to soot....................................................................1248.2.7 Occupational PAH exposure, smoking status and risk of lung cancer. .1248.2.8 Occupational PAH exposure, gender and risk of lung cancer...............125

8.3 Summary.........................................................................................................1258.4 Conclusion.......................................................................................................126


8.5 Methodological quality of studies.....................................................................127Armstrong et al. 1994...................................................................................128Armstrong et al. 2009...................................................................................128Bertrand et al. 1987......................................................................................128Bosetti et al. 2007.........................................................................................128Olsson et al. 2010.........................................................................................128Pastorino et al. 1984.....................................................................................129Veglia et al. 2007..........................................................................................129

9 Risk factor: Family history.......................................................................1309.1 Introduction.....................................................................................................1309.2 Results.............................................................................................................133

9.2.1 Family history and risk of lung cancer..................................................1339.2.2 Family history, smoking status and risk of lung cancer........................1339.2.3 Family history, gender and risk of lung cancer.....................................134

Risk factors for lung cancer: A systematic review iv

9.2.4 Risk of lung cancer by family member affected...................................1349.3 Summary.........................................................................................................1349.4 Conclusion.......................................................................................................135


9.5 Methodological quality of studies.....................................................................136Lissowska et al. 2010....................................................................................137

10 Risk factor: Iron and steel founding........................................................13810.1 Introduction...................................................................................................13810.2 Results...........................................................................................................142

10.2.1 Overall risk of lung cancer in iron and steel foundry workers.............14210.2.2 Risk of lung cancer for workers in iron and steel foundries, by exposure to specific agents..........................................................................................14310.2.3 Risk of lung cancer in iron and steel foundry workers, by job category.....................................................................................................................14410.2.4 Risk of lung cancer in iron and steel foundry workers, by duration of employment..................................................................................................14510.2.5 Risk of lung cancer in iron and steel foundry workers by smoking status.....................................................................................................................14710.2.6 Risk of lung cancer in iron and steel foundry workers by gender.......148

10.3 Summary.......................................................................................................14810.4 Conclusion.....................................................................................................149

10.4.1 Hazard identification..........................................................................14910.4.2 Risk assessment................................................................................149

10.5 Methodological quality of included studies....................................................150Ahn et al. 2010.............................................................................................151Bourgkard et al. 2009...................................................................................151Bosetti et al. 2007.........................................................................................151

11 Risk factor: Silica exposure....................................................................15211.1 Introduction...................................................................................................15211.2 Results...........................................................................................................159

11.2.1 Occupational silica exposure and risk of lung cancer.........................15911.2.2 Duration of silica exposure and risk of lung cancer............................16211.2.3 Intensity of silica exposure and risk of lung cancer............................16311.2.4 Silica exposure and risk of lung cancer in people with silicosis..........16311.2.5 Silica exposure, smoking status and risk of lung cancer....................165



11.5 Methodological quality of studies...................................................................167Erren et al. 2011...........................................................................................168Lacasse et al. 2009.......................................................................................168Lacasse et al. 2005.......................................................................................168Pelucchi et al. 2005.......................................................................................168Preller et al. 2005..........................................................................................168Smith et al.1995...........................................................................................168Steenland et al. 2001....................................................................................169Vida et al. 2010.............................................................................................169Yu et al. 2007................................................................................................169

12 Risk factor: Nickel exposure...................................................................17012.1 Introduction.....................................................................................................17012.2 Results...........................................................................................................177

12.2.1 Occupational nickel exposure and risk of lung cancer.......................177

Risk factors for lung cancer: A systematic review v

12.2.2 Duration of nickel exposure and risk of lung cancer..........................17812.2.3 Cumulative exposure to nickel...........................................................17812.2.4 Occupational nickel exposure, smoking status and risk of lung cancer.....................................................................................................................17912.2.5 Occupational nickel exposure, type of nickel compound and risk of lung cancer...........................................................................................................180



12.5 Methodological quality of studies...................................................................182Beveridge et al. 2010....................................................................................183Lightfoot et al. 2010......................................................................................183

13 Risk factor: Painting as an occupation....................................................18413.1 Introduction...................................................................................................18413.2 Results...........................................................................................................190

13.2.1 Overall lung cancer risk associated with any duration of work as a painter/various levels of exposure................................................................19013.2.2 Wood and gypsum paints and overall risk of lung cancer..................19113.2.3 Dose response for painting as an occupation and lung cancer risk....19213.2.4 Risk of lung cancer from occupational exposure to paint by gender. .193



13.5 Methodological quality of studies...................................................................195Guha et al. 2010...........................................................................................196Bachand et al. 2010......................................................................................196Ramanakumar et al. 2011.............................................................................196Tse et al. 2011..............................................................................................197

14 Risk factor: Cadmium exposure..............................................................19814.1 Introduction...................................................................................................19814.2 Results...........................................................................................................204

14.2.1 Occupational exposure to cadmium and risk of lung cancer..............20414.2.2 Duration and intensity of occupational cadmium exposure and risk of lung cancer...................................................................................................20614.2.3 Residential exposure to cadmium and risk of lung cancer.................20814.2.4 Cadmium exposure, smoking status and risk of lung cancer.............209



14.5 Methodological quality of studies...................................................................211Adams et al. 2011.........................................................................................212Beveridge et al. 2010....................................................................................212Navarro Silvera et al. 2007...........................................................................212Nawrot et al. 2006........................................................................................212t’Mannetje et al. 2011...................................................................................212

15 Risk factor: Air pollution........................................................................21315.1 Introduction...................................................................................................21315.2 Results...........................................................................................................220

15.2.1 Risk of lung cancer associated with exposure to fine particulate matter (PM2.5)...........................................................................................................220

Risk factors for lung cancer: A systematic review vi

15.2.2 Risk of lung cancer associated with exposure to fine particulate matter (PM2.5) and gender.........................................................................................22015.2.3 Risk of lung cancer associated with exposure to sulphur dioxide (SO2).....................................................................................................................22115.2.4 Risk of lung cancer associated with exposure to sulphur dioxide (SO2) and gender...................................................................................................22115.2.5 Risk of lung cancer associated with exposure to nitrogen dioxide (NO2).....................................................................................................................22215.2.6 Risk of lung cancer associated with exposure to nitrogen oxides (NOx).....................................................................................................................22215.2.7 Risk of lung cancer associated with exposure to nitrogen oxides (NOx) and smoking status.......................................................................................22215.2.8 Risk of lung cancer associated with exposure to vehicular traffic......22315.2.9 Risk of lung cancer associated with exposure to vehicular traffic and smoking status..............................................................................................224



15.5 Methodological quality of studies...................................................................226Beelen et al. 2008.........................................................................................227Chen et al. 2008...........................................................................................227Pope et al. 2011............................................................................................227Raaschou-Nielsen et al. 2011........................................................................227Turner et al. 2011.........................................................................................227

16 Risk factor: Chromium exposure.............................................................22816.1 Introduction...................................................................................................22816.2 Results...........................................................................................................235

16.2.1 Occupational exposure to chromium and risk of lung cancer.............23516.2.2 Duration of chromium exposure and risk of lung cancer....................23716.2.3 Chromium exposure, smoking status and risk of lung cancer............238



16.5 Methodological quality of studies...................................................................241Beveridge et al. 2010....................................................................................242Birk et al. 2006.............................................................................................242Cole et al. 2005.............................................................................................242Hara et al. 2010............................................................................................242‘t Mannetje et al. 2011..................................................................................242

17 Risk factor: Beryllium exposure..............................................................24317.1 Introduction...................................................................................................24317.2 Results...........................................................................................................251

17.2.1 Occupational beryllium exposure and overall risk of lung cancer......25117.2.2 Dose response for occupational beryllium exposure and risk of lung cancer...........................................................................................................25417.2.3 Beryllium exposure, gender, smoking status and risk of lung cancer 256



17.5 Methodological quality of studies...................................................................258Hollins et al. 2009.........................................................................................259Levy et al. 2009............................................................................................259

Risk factors for lung cancer: A systematic review vii

Schubauer-Berigan et al. 2011a212................................................................259Schubauer-Berigan et al. 2011b213................................................................259

18 Risk factor: Red meat and processed meat consumption.........................26118.1 Introduction...................................................................................................26118.2 Results...........................................................................................................268

18.2.1 Red meat consumption and overall risk of lung cancer......................26818.2.2 Red meat consumption, smoking status and risk of lung cancer.......26918.2.3 Red meat consumption and risk of lung cancer by gender................26918.2.4 Processed meat consumption and risk of lung cancer.......................27118.2.5 Processed meat consumption, smoking status and risk of lung cancer.....................................................................................................................27218.2.6 Processed meat consumption and risk of lung cancer by gender.......272



18.5 Methodology quality of studies......................................................................274Alavanja et al. 2001......................................................................................275Cross et al. 2006...........................................................................................275De Stefani et al. 1997...................................................................................275De Stefani et al. 2002...................................................................................275De Stefani et al. 2009...................................................................................275Hu et al. 2011...............................................................................................276Lam et al. 2009.............................................................................................276Linseisen et al. 2011.....................................................................................276Tasevska et al. 2009.....................................................................................276Tasevska et al. 2011.....................................................................................276

19 Risk factor: Alcohol consumption............................................................27719.1 Introduction...................................................................................................27719.2 Results...........................................................................................................285

19.2.1 Alcohol consumption and risk of lung cancer in the general population.....................................................................................................................28519.2.2 Alcohol consumption, smoking status and risk of lung cancer...........28619.2.3 Alcohol consumption, gender and lung cancer risk............................28719.2.4 Types of alcoholic beverage consumed and risk of lung cancer.........28819.2.5 Alcohol consumption and risk of lung cancer in alcoholics.................289



19.5 Methodological quality of studies...................................................................292Bagnardi et al. 2011.....................................................................................293Balder et al. 2005.........................................................................................293Boffetta et al. 2001.......................................................................................293Breslow et al. 2000.......................................................................................293Chao et al. 2007............................................................................................293Djousse et al. 2002.......................................................................................294Korte et al. 2002...........................................................................................294Mayne et al. 1994.........................................................................................294Pierce et al.1989...........................................................................................294Rachtan & Sokolowski 1997..........................................................................294Shimazu et al. 2008......................................................................................295Sorensen et al. 1998.....................................................................................295Stemmermann et al. 1990............................................................................295Toriola et al. 2009.........................................................................................295

Risk factors for lung cancer: A systematic review viii

20 Risk factor: Dietary cholesterol and blood cholesterol.............................29620.1 Introduction...................................................................................................29620.2 Results...........................................................................................................305

20.2.1 Dietary cholesterol intake and overall risk of lung cancer..................30520.2.2 Risk of lung cancer and dietary cholesterol intake by smoking status30520.2.3 Dietary cholesterol intake, gender and risk of lung cancer................306Men...............................................................................................................306Women.........................................................................................................308

20.3 Risk of lung cancer and blood cholesterol concentration...............................30920.4 Risk of lung cancer and blood cholesterol by gender.....................................31020.5 Summary.......................................................................................................311

20.5.1 Dietary cholesterol and risk of lung cancer........................................31120.5.2 Blood cholesterol concentration and risk of lung cancer....................311

20.6 Conclusion.....................................................................................................31120.6.1 Hazard identification..........................................................................31120.6.2 Risk assessment................................................................................311

20.7 Methodological quality of studies...................................................................312Ahn et al. 2009.............................................................................................314Alavanja et al. 1996......................................................................................314Byers et al. 1987...........................................................................................314Chang et al. 1995.........................................................................................314De Stefani et al. 2002...................................................................................314Eichholzer et al.2000....................................................................................314Goodman et al.1988.....................................................................................315Hinds et al. 1983a.........................................................................................315Hinds et al. 1983b.........................................................................................315Hu et al. 2011...............................................................................................315Jain et al. 1990..............................................................................................315Keys et al. 1985............................................................................................315Knekt et al. 1991...........................................................................................316Kucharska-Newton et al. 2008......................................................................316Law 1991......................................................................................................316Shekelle et al. 1991......................................................................................316Smith-Warner et al. 2002..............................................................................316Steenland et al. 1995....................................................................................316Swanson et al.1997.......................................................................................317Veierod et al.1997........................................................................................317Wu et al.1994...............................................................................................317

21 Risk factor: Avian exposure....................................................................31821.1 Introduction...................................................................................................31821.2 Results...........................................................................................................321

21.2.1 Avian exposure and risk of lung cancer.............................................32121.2.2 Duration of avian exposure and risk of lung cancer...........................32221.2.3 Avian exposure, smoking status and risk of lung cancer....................32221.2.4 Avian exposure, gender and risk of lung cancer................................322



21.5 Methodological quality of studies...................................................................324Alavanja et al. 1996......................................................................................325Gardiner et al. 1992......................................................................................325Jöckel et al. 2002..........................................................................................325Kohlmeier et al. 1992....................................................................................325Morabia et al. 1998.......................................................................................325

Risk factors for lung cancer: A systematic review ix

22 Risk factor: Wood dust...........................................................................32622.1 Introduction...................................................................................................32622.2 Results...........................................................................................................332

22.2.1 Wood dust exposure and risk of lung cancer.....................................33222.2.2 Wood dust exposure and risk of lung cancer by gender.....................33222.2.3 Wood dust exposure and risk of lung cancer by smoking status........33322.2.4 Dose response relationship between wood dust exposure and lung cancer...........................................................................................................333


22.4.1 Hazard Identification..........................................................................33422.4.2 Risk assessment................................................................................334

22.5 Methodological quality of included studies....................................................335Bhatti et al. 2010..........................................................................................336Innos et al. 2000...........................................................................................336Jayaprakash et al. 2008................................................................................336Laakkonen et al (2006).................................................................................336Stellman et al. 1998......................................................................................336Szadkowska-Stanczyk & Szymczak et al. 2001.............................................337

23 Risk factor: Physical activity..................................................................33823.1 Introduction...................................................................................................33823.2 Results...........................................................................................................342

23.2.1 Physical activity and risk of lung cancer............................................34223.2.2 Physical activity, gender and risk of lung cancer...............................34423.2.3 Physical activity, smoking status and risk of lung cancer...................346



23.6 Methodological quality of studies...................................................................347Alfano et al. 2004..........................................................................................348Bak et al. 2005..............................................................................................348Lee et al. 1994..............................................................................................348Leitzmann et al. 2009...................................................................................348Sinner et al. 2006..........................................................................................348Steindorf et al. 2006.....................................................................................348Tardon et al. 2005.........................................................................................349

24 References............................................................................................350

25 Appendices...........................................................................................37125.1 Appendix A NHMRC Levels of Evidence19 – Aetiology.....................................37125.2 Appendix B Search history.............................................................................371

25.2.1 PubMed Cancer Lit.............................................................................37125.2.2 Embase..............................................................................................37425.2.3 Lung Cancer search histories (minor databases)...............................377

25.3 Appendix C Critical appraisal instruments.....................................................37925.3.1 JBI Critical Appraisal Checklist for Comparable Cohort/ Case Control. 37925.3.2 JBI Critical Appraisal Checklist for Systematic Reviews......................380

25.4 Appendix D Excluded studies.........................................................................38125.4.1 Risk factor – Asbestos........................................................................38125.4.2 Risk factor – Avian exposure..............................................................38125.4.3 Risk factor – Red meat and processed meat consumption.................38225.4.4 Risk factor – Family history................................................................38325.4.5 Risk factor – Wood dust......................................................................383

25.5 Appendix E Tables of included studies...........................................................384

Risk factors for lung cancer: A systematic review x

25.5.1 Air Pollution........................................................................................38425.5.2 Alcohol Consumption.........................................................................38825.5.3 Arsenic exposure...............................................................................39625.5.4 Asbestos............................................................................................40025.5.5 Avian Exposure..................................................................................40525.5.6 Beryllium exposure............................................................................40725.5.7 Cadmium...........................................................................................41125.5.8 Chromium IV......................................................................................41625.5.9 Dietary Cholesterol and Blood Cholesterol.........................................42125.5.10 Family history..................................................................................42825.5.11 Iron and Steel...................................................................................42925.5.12 Red Meat and Processed Meat Consumption...................................43225.5.13 Nickel...............................................................................................43825.5.14 Polycyclic Aromatic Hydrocarbons (PAH) exposure..........................44325.5.15 Painting as an occupation................................................................44925.5.16 Physical Activity...............................................................................45225.5.17 Radon...............................................................................................45725.5.18 Silica................................................................................................46725.5.19 Smoking: Active and passive smoking.............................................47325.5.20 Wood Dust.......................................................................................478

Risk factors for lung cancer: A systematic review xi

TablesTable 3.1 Summary of results of database searching, papers retrieved based on eligibility criteria and number of included studies...........................................................................15Table 4.1 Study characteristics relevant to the association between smoking and lung cancer...............................................................................................................................18Table 4.2 Risk of lung cancer due to smoking in current and former smokers. Referent category of never smokers31.............................................................................................24Table 4.3 Differences in RR estimate of lung cancer in current smokers dependent on the study design used31..........................................................................................................24Table 4.4 Dose response RR estimates for lung cancer in current smoking men and women31...........................................................................................................................24Table 4.5 Risk of lung cancer with workplace exposure to environmental tobacco smoke32

.........................................................................................................................................25Table 4.6 Relative risk of lung cancer in never smoking men alone and both genders when exposed to environmental smoke from their spouse33......................................................25Table 4.7 Second hand smoke (ETS) exposure during childhood and risk of lung cancer 34

.........................................................................................................................................26Table 4.8 Active smoking and passive smoking: Methodological quality of included studies.........................................................................................................................................28Table 5.1 Study characteristics relevant to the association between asbestos exposure and lung cancer................................................................................................................33Table 5.2 Risk estimates of lung cancer due to occupational asbestos exposure – Mining worker cohort studies, IARC monograph 40.......................................................................39Table 5.3 Occupational asbestos exposure and risk estimates of lung cancer from manufacturing worker cohort studies, IARC monograph40 unless otherwise stated..........39Table 5.4 Relative risk estimates of lung cancer due to occupational asbestos exposure – Case controls with exposure measured in number of years, IARC monograph40...............43Table 5.5 Case controls with exposure measured in number of hours, IARC monograph40

.........................................................................................................................................43Table 5.6 Risk estimates of lung cancer due to occupational asbestos exposure – case-controls with categorical exposure, IARC monograph40 unless otherwise stated..............45Table 5.7 Non-occupational asbestos exposure and risk of lung cancer, IARC monograph40

.........................................................................................................................................46Table 5.8 Asbestos exposure, gender and risk of lung cancer , IARC monograph40..........47Table 5.9 Occupational exposure to asbestos, smoking status and risk of lung cancer....48Table 5.10 Asbestosis and risk of lung cancer..................................................................50Table 5.11 Asbestos exposure: Methodological quality of included studies......................53Table 6.1 Study characteristics relevant to the association between radon exposure and lung cancer.......................................................................................................................58Table 6.2 Occupational radon exposure and risk of lung cancer in Europe (cohort studies).........................................................................................................................................68Table 6.3 Level of occupational radon exposure and risk of lung cancer in German uranium miners, (Schnelzer et al. 2010)69........................................................................68Table 6.4 Occupational radon exposure and risk of lung cancer in haematite/iron miners, IARC monograph55............................................................................................................69Table 6.5 Occupational radon exposure and risk of lung cancer in Swedish iron ore miners, (Jonsson et al. 2010)............................................................................................69Table 6.6 Occupational radon exposure, smoking and risk of lung cancer in miners, IARC monograph 55....................................................................................................................70Table 6.7 Occupational radon exposure and risk of lung cancer in German uranium miners: risk to smokers compared with non-smokers, (Schnelzer et al. 2010)69...............70Table 6.8 Occupational radon exposure, smoking status and risk of lung cancer in German, French and Czech uranium miners, Leuraud et al. 201171..................................70Table 6.9 Residential radon exposure and risk of lung cancer, IARC monograph55...........71Table 6.10 Duration of residential radon exposure in Germany, (Kreutzer et al. 2003) 72.72

Risk factors for lung cancer: A systematic review xii

Table 6.11 Residential radon exposure and risk of lung cancer in the US, ( Krewski et al. 2005)66..............................................................................................................................72Table 6.12 Residential radon exposure and lung cancer risk in China,(Lubin et al. 2004)73

.........................................................................................................................................73Table 6.13 Residential radon exposure and risk of lung cancer - a synthesis of data from different exposure levels, (Pavia et al. 2003)75.................................................................73Table 6.14 Residential radon exposure, smoking status and risk of lung cancer in Sweden, (Lagarde et al. 2001)........................................................................................................74Table 6.15 Residential radon exposure of 100 Bq/m3 for at least five years, smoking status and risk of lung cancer, (Lubin et al. 2004)......................................................................74Table 6.16 Residential radon exposure, gender and risk of lung cancer in Italy (Pisa et al. 2001)................................................................................................................................75Table 6.17 Radon exposure: Methodological quality of included studies..........................77Table 7.1 Study characteristics relevant to the association between arsenic exposure and lung cancer.......................................................................................................................83Table 7.2 Risk estimates for ever exposed versus non-exposed, before and after adjustment for metals and other occupational exposures (‘t Mannetje et al. 2011).........87Table 7.3 Risk estimates for lung cancer according to exposure-response analyses for arsenic dust and arsenic fumes/mist in terms of duration (years) (‘t Mannetje et al. 2011).........................................................................................................................................87Table 7.4 Risk estimates of lung cancer due to occupational arsenic exposure – Smelter studies; IARC monograph80 unless otherwise stated.........................................................89Table 7.5 Risk estimates of lung cancer due to occupational arsenic exposure – Mining studies, IARC monograph80 unless otherwise stated.........................................................93Table 7.6 Risk of lung cancer, by occupation in smelters or mines...................................96Table 7.7 Risk estimates of lung cancer due to occupational arsenic exposure – Fertilisation plant, stoking, pesticides and refinery studies, IARC monograph80 unless otherwise stated...............................................................................................................97Table 7.8 Risk estimates for lung cancer due to arsenic exposure among men living near arsenic-emitting smelters, by smoking status (Pershagen et al. 1985).............................98Table 7.9 Cumulative air arsenic exposure index* (CAAEI) in all male primary smelter workers and in primary smelter workers who were current smokers (Lundstrom et al. 2006)................................................................................................................................99Table 7.10 Age-adjusted relative risks for ever and current tobacco use in male tin miners at high risk for lung cancer (Qiao et al. 1997)...................................................................99Table 7.11 Lung cancer mortality in male and female workers.......................................100Table 7.12 Risk estimates of lung cancer due to arsenic exposure from drinking water, IARC monograph 80 unless otherwise stated...................................................................101Table 7.13 Risk estimates for lung cancer mortality according to arsenic concentration of well water, by smoking status (Tsuda et al. 1989)..........................................................102Table 7.14 Risk of lung cancer and exposure to arsenic in drinking water by smoking status..............................................................................................................................102Table 7.15 Risk of lung cancer and exposure to arsenic in drinking water in males and females, IARC monograph80............................................................................................103Table 7.16 Arsenic exposure: Methodological quality of included studies.......................106Table 8.1 Study characteristics relevant to the association between PAH exposure and lung cancer.....................................................................................................................111Table 8.2 Overall SMR and pooled RR with 95% CI for exposure to PAH in various industries and occupations96...........................................................................................117Table 8.3 Risk estimates for lung cancer from occupational exposure to PAHs..............118Table 8.4 Occupational exposure to PAHs and risk of lung cancer in coal gasification workers...........................................................................................................................120Table 8.5 Occupational PAH exposure and risk of lung cancer in coke production workers.......................................................................................................................................121Table 8.6 Occupational PAH exposure and risk of lung cancer in creosote workers. 97. . .122Table 8.7 Occupational PAH exposure and risk of lung cancer in aluminium production workers...........................................................................................................................123

Risk factors for lung cancer: A systematic review xiii

Table 8.8 Occupational PAH exposure, smoking status and risk estimates for lung cancer.......................................................................................................................................125Table 8.9 Occupational PAH exposure, gender and hazard ratio and 95% CI for lung cancer 103........................................................................................................................125Table 8.10 PAH exposure: Methodological quality of included studies............................127Table 9.1 Study characteristics relevant to the association between family history and lung cancer.....................................................................................................................131Table 9.2 Pooled analysis of the overall risk of lung cancer associated with family history114.........................................................................................................................133Table 9.3 Risk of lung cancer associated with family history, by smoking status – and affected family member (case-control)...........................................................................133Table 9.4 Family history and the risk of lung cancer by gender114..................................134Table 9.5 Risk of lung cancer associated with family history, by family member type, from the Lissowska et al. (2010) 114 case-control study...........................................................134Table 9.6 Family history: Methodological quality of included studies.............................136Table 10.1 Study characteristics relevant to the association between iron and steel founding and lung cancer...............................................................................................139Table 10.2 Iron and steel foundry workers and overall risk of lung cancer.....................142Table 10.3 Risk estimates of lung cancer in iron and steel foundry workers, by specific exposure to silica and formaldehyde124...........................................................................143Table 10.4 Risk estimates of lung cancer in iron and steel foundry workers, by job category.........................................................................................................................144Table 10.5 Risk of lung cancer in iron and steel foundry workers, by duration of employment, IARC monograph108....................................................................................146Table 10.6 Risk of lung cancer in iron and steel foundry workers, by smoking status....147Table 10.7 Risk of lung cancer in iron and steel foundry workers; by gender and job, (Ahn et al. 2010).....................................................................................................................148Table 10.8 Iron and steel founding: Methodological quality of included studies.............150Table 11.1 Study characteristics relevant to the association between silica exposure and lung cancer.....................................................................................................................153Table 11.2 Overall risk of lung cancer associated with exposure to silica.......................159Table 11.3 Risk estimates of lung cancer due to occupational silica exposure – Ore mining; cohort & case-control studies, IARC Monograph (1997)128..................................160Table 11.4 Risk estimates of lung cancer due to occupational silica exposure – Ceramics, pottery, refractory brick and diatomaceous earth; cohort & case-control studies, IARC Monograph (1997)128.......................................................................................................161Table 11.5 Risk estimates of lung cancer due to occupational silica exposure – Quarries and granite production and foundry workers; IARC Monograph (1997)128.......................162Table 11.6 Duration of silica exposure and risk of lung cancer.......................................163Table 11.7 Cumulative silica exposure and risk of lung cancer.......................................163Table 11.8 Intensity of silica exposure and risk of lung cancer.......................................163Table 11.9 Lung cancer risk associated with silica exposure in silicotic patients............164Table 11.10 Risk estimates of lung cancer due to occupational silica exposure in silicotics, case-control studies, IARC Monograph (1997)128.............................................................164Table 11.11 Silica exposure, smoking status and risk of lung cancer135..........................165Table 11.12 Silica exposure: Methodological quality of included studies........................167Table 12.1 Study characteristics relevant to the association between nickel exposure and lung cancer.....................................................................................................................172Table 12.2 Occupational exposure to nickel and overall lung cancer risk; all studies included in the IARC monograph139 except for where denoted........................................177Table 12.3 Duration of nickel exposure and risk of lung cancer......................................178Table 12.4 Cumulative exposure to water soluble nickel and Ni oxide and risk of lung cancer; IARC 2012.139......................................................................................................178Table 12.5 Risk resulting from exposure to nickel and smoking status...........................179Table 12.6 Type of nickel compound and lung cancer risk, (Grimsrud et al. 2002).........180Table 12.7 Nickel exposure: Methodological quality of included studies.........................182

Risk factors for lung cancer: A systematic review xiv

Table 13.1 Study characteristics relevant to the association between painting as an occupation and lung cancer............................................................................................186Table 13.2 Overall lung cancer risk for painting as an occupation, any duration............190Table 13.3 Lung cancer risk for exposure to wood and gypsum paints, (Ramanakumar et al. 2011)157......................................................................................................................191Table 13.4 RR of lung cancer and occupational exposure to paint by duration of employment, (Guha et al. 2010)153.................................................................................192Table 13.5 Lung cancer risk for general painting work (not spraying) and spray painting in Chinese non-smoking men by duration of employment (Tse et al. 2011).......................192Table 13.6 Lung cancer risk for painting as an occupation and exposure to wood and gypsum paints by duration of employment157.................................................................193Table 13.7 Lung cancer risk for painting as an occupation by gender153.........................193Table 13.8 Painting as an occupation: Methodological quality of included studies.........195Table 14.1 Study characteristics relevant to the association between cadmium exposure and lung cancer..............................................................................................................200Table 14.2 Risk estimates of lung cancer due to occupational cadmium exposure; research synthesis148......................................................................................................204Table 14.3 Risk estimates of lung cancer due to occupational exposure to cadmium, case-control study (t Mannetje et al. 2011)92..........................................................................204Table 14.4 Risk estimates of lung cancer due to occupational cadmium exposure, cohort studies – IARC monograph160..........................................................................................205Table 14.5 Duration of occupational cadmium exposure and risk of lung cancer...........206Table 14.6 Risk of lung cancer resulting from occupational cadmium exposure by weighted duration or cumulative exposure (t Mannetje et al. 2011)92............................207Table 14.7 Risk of lung cancer from occupational cadmium exposure, by exposure intensity160......................................................................................................................207Table 14.8 Residential cadmium exposure and risk of lung cancer................................208Table 14.9 Risk of lung cancer resulting from any level of cadmium exposure in non-smokers vs smokers.......................................................................................................209Table 14.10 Cadmium exposure: Methodological quality of included studies.................211Table 15.1 Study characteristics relevant to the association between air pollution and lung cancer.....................................................................................................................215Table 15.2 Risk of lung cancer associated with exposure to fine particulate matter (PM2.5).......................................................................................................................................220Table 15.3 Risk of lung cancer associated with exposure to fine particulate matter (PM2.5) and gender, (Chen et al.)188............................................................................................221Table 15.4 Sulphur dioxide (SO2) exposure and risk of lung cancer................................221Table 15.5 Risk of lung cancer associated with exposure to sulphur dioxide (SO2) and gender, (Chen et al. 2008)..............................................................................................221Table 15.6 Risk of lung cancer associated with exposure to nitrogen dioxide (NO2).......222Table 15.7 Risk of lung cancer associated with exposure to nitrogen oxides (NOx).......222Table 15.8 Risk of lung cancer associated with a 20yr exposure to nitrogen oxides (NOx) and smoking status, (Raaschou-Nielsen et al.)194............................................................223Table 15.9 Risk of lung cancer associated with a 20 yr exposure to nitrogen oxides (NOx) and gender, (Raaschou-Nielsen et al.)194........................................................................223Table 15.10 Risk of lung cancer associated with exposure to vehicular traffic...............223Table 15.11 Risk of lung cancer associated with exposure to vehicular traffic and smoking status195..........................................................................................................................224Table 15.12 Air pollution: Methodological quality of included studies.............................226Table 16.1 Study characteristics relevant to the association between chromium (VI) exposure and lung cancer..............................................................................................230Table 16.2 Risk estimates of lung cancer due to occupational Cr VI exposure, research syntheses.......................................................................................................................235Table 16.3 Risk estimates of lung cancer due to occupational Cr VI exposure, cohort studies - IARC monograph (2012f) and Hara et al. (2010)..............................................236Table 16.4 Lung cancer risk resulting from occupational Cr VI exposure - by duration...237

Risk factors for lung cancer: A systematic review xv

Table 16.5 Risk of lung cancer resulting from occupational Cr VI exposure by weighted duration or cumulative exposure, (‘t Mannetje et al 2011).............................................238Table 16.6 Risk of lung cancer resulting from occupational Cr VI exposure, 211..............238Table 16.7 Overall risk of lung cancer resulting from occupational Cr VI exposure and smoking,148.....................................................................................................................238Table 16.8 Chromium exposure: Methodological quality of included studies..................241Table 17.1 Study characteristics relevant to the association between beryllium exposure and lung cancer..............................................................................................................245Table 17.2 Occupational beryllium exposure and overall risk of lung cancer..................251Table 17.3 Quantified levels of occupational beryllium exposure and overall risk of lung cancer.............................................................................................................................253Table 17.4 SMRs for lung cancer in US male beryllium workers employed 1940-1969 by latency and employment duration (Ward et al. 1992)....................................................254Table 17.5 Lung cancer risk estimates by cumulative occupational beryllium exposure, (Sanderson et al. 2001)..................................................................................................255Table 17.6 Lung cancer risk estimates by cumulative occupational beryllium exposure (lagged 10 years), Schubauer-Berigan et al (2011a)......................................................255Table 17.7 Beryllium exposure: Methodological quality of included studies...................258Table 18.1 Study characteristics relevant to the association between red/processed meat consumption and lung cancer.........................................................................................262Table 18.2 Red meat consumption, smoking status and risk of lung cancer...................269Table 18.3 Risk of lung cancer with processed meat consumption by smoking status (De Stefani et al. 2009).........................................................................................................272Table 18.4 Risk of lung cancer with processed meat consumption for women...............273Table 18.5 Red and processed meat consumption: Methodological quality of included studies............................................................................................................................274Table 19.1 Study characteristics relevant to the association between alcohol consumption and lung cancer..............................................................................................................278Table 19.2 Risk of lung cancer incidence in general population by lowest and highest alcohol intake categories................................................................................................285Table 19.3 Risk ratios for alcohol consumption and lung cancer risk in non-smokers (Korte et al. 2002).....................................................................................................................286Table 19.4 Multivariate adjusted Hazard ratio for lung cancer incidence by smoking status (Shimazu et al 2008)......................................................................................................286Table 19.5 Relative risk of lung cancer in women by smoking status (Rachtan & Sokolowski 1997)............................................................................................................287Table 19.6 Odds ratio for alcohol consumption and lung cancer risk by smoking status (Pierce et al 1989)..........................................................................................................287Table 19.7 Binge drinking and risk of lung cancer according to smoking status (Toriola et al 2009)..........................................................................................................................287Table 19.8 Relative risk of lung cancer among binge drinkers compared with non-binge drinkers in men with no history of lung cancer at baseline (Toriola et al 2009)..............288Table 19.9 Increased risk of lung cancer in men with increasing amount of alcohol (Balder et al 2009)......................................................................................................................288Table 19.10 Risk of lung cancer with consumption of vodka in women (Rachtan et al 1997)..............................................................................................................................288Table 19.11 Relative risk for alcoholic beverage types and lung cancer risk (Chao et al. 2007)..............................................................................................................................289Table 19.12 Odds ratio for beer consumption and risk of lung cancer (Mayne et al. 1994).......................................................................................................................................289Table 19.13 Alcohol consumption: Methodological quality of included studies...............292Table 20.1 Study characteristics relevant to the association between cholesterol and lung cancer.............................................................................................................................297Table 20.2 Risk of lung cancer and dietary cholesterol intake in quartiles of consumption.......................................................................................................................................305Table 20.3 Pooled multivariate-adjusted RRs and 95% CIs of lung cancer for dietary cholesterol (for 100mg/day increases), (Smith Warner et al. 2002)................................305

Risk factors for lung cancer: A systematic review xvi

Table 20.4 RRs and 95% CIs of lung cancer by smoking status according to quartile intake of dietary cholesterol among postmenopausal women (Wu et al. 1994)........................306Table 20.5 ORs and 95% CIs for the development of lung cancer among males, by quartiles of cholesterol consumption, (Goodman et al. 1988).........................................306Table 20.6 ORs and 95% CIs for lung cancer risk with highest quartile of cholesterol intake compared to other quartiles in men, (Steenland et al. 1995).........................................307Table 20.7 Risk of lung cancer and dietary cholesterol consumption in quartiles...........307Table 20.8 Risk of lung cancer and dietary cholesterol consumption in tertiles for men. No CIs reported, (Shekelle et al. 1991)................................................................................308Table 20.9 Risk of lung cancer and dietary cholesterol consumption in women in quintiles.......................................................................................................................................308Table 20.10 Risk of lung cancer and dietary cholesterol consumption in quartiles.........308Table 20.11 ORs and 95% CIs for lung cancer risk with highest quartile of cholesterol intake compared to other quartiles in women (Steenland et al. 1995)...........................309Table 20.12 RRs and 95% CIs of lung cancer in relation to serum total cholesterol (mg/dL) in quintiles (Ahn et al. 2009)...........................................................................................309Table 20.13 Association of plasma HDL-cholesterol quartiles with incidence of lung cancer (RRs & 95% CIs) (Kucharska-Newton et al. 2008)...........................................................309Table 20.14 Lung cancer risk and serum cholesterol level (Keys et al. 1985).................310Table 20.15 Relative Hazards and 95% CIs of lung cancer mortality by low plasma cholesterol (<160mg/dl) compared with all other cholesterol levels (Chang et al. 1995).......................................................................................................................................310Table 20.16 RRs and 95% CIs of low plasma cholesterol compared with higher concentrations for lung cancer (Eichholzer et al. 2000)..................................................310Table 20.17 Cholesterol: Methodological quality of included studies..............................312Table 21.1 Study characteristics relevant to the association between avian exposure and lung cancer.....................................................................................................................319Table 21.2 Risk of lung cancer due to avian exposure....................................................321Table 21.3 Risk of lung cancer with long duration of avian exposure.............................322Table 21.4 Lung cancer risk by smoking status, (Morabia et al. 1998)...........................322Table 21.5 Lung cancer risk for women by smoking status (Alavanja et al., 1996).........322Table 21.6 Avian exposure: Methodological quality of included studies.........................324Table 22.1 Study characteristics relevant to the association between wood dust exposure and lung cancer..............................................................................................................327Table 22.2 Risk of lung cancer due to wood dust exposure............................................332Table 22.3 Risk of lung cancer due to wood dust exposure for males............................332Table 22.4 Risk of lung cancer due to wood dust exposure for females.........................333Table 22.5 Risk of death among men by duration (yrs) of wood dust exposure, (Stellman 1998)..............................................................................................................................333Table 22.6 Lung cancer risk among pulp and paper industry workers exposed to wood dust by cumulative dose (Szadkowska-Stanczyk & Szymczak 2001)..............................334Table 22.7 Wood dust: Methodological quality of included studies.................................335Table 23.1 Study characteristics relevant to the association between physical activity and lung cancer.....................................................................................................................339Table 23.2 Leisure time physical activity (LPA) and lung cancer (Tardon et al. 2005)....342Table 23.3 Relative Risk of lung cancer at different levels of physical activity (Lee et al. 1994)..............................................................................................................................342Table 23.4 Relative Risk of lung cancer according to frequency of physical activity/week (Leitzmann et al. 2009)...................................................................................................343Table 23.5 Lung cancer risk in women with different measures of leisure time physical activity (LPA) (Sinner et al. 2006)...................................................................................343Table 23.6 Incident rate ratios (IRR) for lung cancer in relation to categories according to time spent on each of the different types of physical activity in leisure time (Bak et al. 2005)..............................................................................................................................344Table 23.7 Risk of lung cancer by type of physical activity (PA) and by gender (Steindorf et al. 2006).....................................................................................................................345Table 23.8 Physical activity: Methodological quality of included studies........................347

Risk factors for lung cancer: A systematic review xvii

Risk factors for lung cancer: A systematic review xviii

FiguresFigure 5.1 Meta-analysis of effect estimates of cohort studies presenting risk of lung cancer with occupational exposure in crocidolite miners, IARC monograph40...................38Figure 5.2 Meta-analysis of effect estimates of cohort studies presenting risk of lung cancer with occupational exposure in manufacturing workers, IARC monograph40...........41Figure 5.3 Meta-analysis of effect estimates of cohort studies presenting risk of lung cancer with occupational exposure in shipyard, rail yard workers and plumbers, IARC monograph40.....................................................................................................................42Figure 5.4 Meta-analysis of effect estimates of case control studies presenting risk of lung cancer with occupational exposure to asbestos (a) < 7-10 years, (b) > 8-10 years.........44Figure 8.1 Occupational exposure to PAHs and risk of lung cancer, by longest duration of exposure (≥30 years).....................................................................................................119Figure 8.2 Occupational exposure to PAHs and risk of lung cancer in coal gasification workers...........................................................................................................................120Figure 8.3 Occupational cumulative PAH exposure (BaP) and risk of lung cancer in aluminium production workers.......................................................................................123Figure 8.4 Occupational PAH exposure and risk of lung cancer in chimney sweeps and in workers exposed to soot.................................................................................................124Figure 10.1 Iron and steel foundry workers and overall risk of lung cancer....................143Figure 10.2 Risk of lung cancer in iron and steel foundry workers employed for more than 30 years..........................................................................................................................145Figure 10.3 Risk of lung cancer in iron and steel foundry workers employed for less than 10 years..........................................................................................................................146Figure 11.1 Overall risk of lung cancer due to occupational silica exposure in workers in ore mining industry........................................................................................................159Figure 11.2 Risk estimates of lung cancer due to occupational silica exposure in workers in Ceramics, Pottery and Diatomaceous earth industries...............................................161Figure 18.1 Meta-analysis of risk of lung cancer with red meat consumption including all cohorts...........................................................................................................................268Figure 18.2 Risk of lung cancer associated with red meat consumption for men...........270Figure 18.3 Red meat consumption and risk of lung cancer in women...........................270Figure 18.4 Meta-analysis of risk of lung cancer with processed meat consumption in 11 included cohorts.............................................................................................................271Figure 18.5 Risk of lung cancer with processed meat consumption for men..................272Figure 19.1 Meta-analysis of risk of lung cancer (RR) in individuals with high alcohol consumption...................................................................................................................285Figure 19.2 Risk of lung cancer among alcoholic male and female patients...................290Figure 20.1 Risk of lung cancer and dietary cholesterol intake by highest tertile of consumption in men.......................................................................................................306Figure 21.1 Meta-analysis of risk of lung cancer (RR) and avian exposure.....................321Figure 21.2 Meta-analysis of risk of lung cancer (RR) in never smoking women from avian exposure.........................................................................................................................323

Risk factors for lung cancer: A systematic review xix

AcknowledgmentsCancer Australia gratefully acknowledges the following contributions to the development of Risk factors for lung cancer: a systematic review.

Research Team from the Joanna Briggs Institute, University of AdelaideDr Edoardo Aromataris, Director, Synthesis Science

Mr Sandeep Moola, Research Fellow

Dr Sarahlouise White, Research Fellow

Dr Judith Gomersall, Research Fellow

Dr Aye Aye Gyi, Research Fellow

Ms Dagmara Riitano, Research Assistant

Dr Matthew Stephenson, Research Fellow

Prof Alan Pearson AM, Executive Director

Project Working GroupMr Andrew Bowen, consumer

Professor Kwun Fong, Thoracic and Sleep Physician; Professor School of Medicine, University of Queensland

Professor Don Iverson, Behavioural Scientist; Executive Dean, Faculty of Science, Medicine & Health, University of Wollongong

Professor Bernard Stewart, Cancer Cell Biologist; School of Medicine, School of Women's and Children's Health, University of New South Wales

Professor David Roder, Cancer Epidemiologist; Chair of Cancer Epidemiology and Population Health, University of South Australia

Cancer AustraliaMs Sue Sinclair, General Manager, Service Development and Clinical Practice

Dr Vivienne Milch, Medical Officer, Cancer Australia

Ms Liz King, Manager, Lung Cancer

Ms Kathleen Mahoney, Senior Project Officer, Lung Cancer

Dr Rona Hiam, Clinical and Primary Care Adviser, Lung Cancer

Risk factors for lung cancer: A systematic review xx

Julie Mueller, Project Manager, Lung Cancer

FundingThe development of this systematic review was funded by the Australian Government through Cancer Australia.

Risk factors for lung cancer: A systematic review xxi

1 IntroductionIn Australia, lung cancer is the fourth most common cancer in both men and women, and the fifth most commonly diagnosed cancer overall.1 Lung cancer causes more deaths than any other cancer, accounting for 18.9% of all cancer deaths.2 Lung cancer is a disease where cells in the lungs become abnormal and grow out of control, forming a malignant tumour, or cancer. As the cancer grows, it can impair lung function and spread to other parts of the body through a process known as metastasis.

In the case of most risk factors for human diseases, an increase in risk depends on intensity, frequency and duration of exposure, as well as other contextual factors. The interaction of these risk and contextual factors can affect the risk estimate. A person can be exposed to a risk factor, or several risk factors, and not develop lung cancer during their lifetime. On the other hand, a person may never have been exposed to any known risk factors, but they might develop lung cancer. In addition, even if a person with lung cancer has a risk factor, it is usually hard to know how much that risk factor contributed to the development of the cancer.

A person’s chance of developing lung cancer may be increased by a number of factors, known as risk factors. Risk factors can include behaviours (such as tobacco smoking), chemical agents in the environment or the workplace (such as asbestos, arsenic or radon) or a family history of cancer. Some risk factors are modifiable, meaning the risk can be altered by changing behaviour or adopting safety measures. Other risk factors, such as age, are regarded as non-modifiable.

This report presents the detailed outcomes of a systematic review conducted by the Joanna Briggs Institute for Cancer Australia. The systematic review examined the published research on lung cancer up to April 2011. This large-scale, multi-focused systematic review set out to identify, from the existing epidemiological research literature in a systematic way, where associations between specified risk factors and lung cancer exist and to quantify this relationship where possible. The International Agency for Research on Cancer (IARC) Monographs on the Evaluation of Carcinogenic Risks to Humans published to 2011 were used as a main source of evidence and guided the identification of risk factors to be studied in this review. In addition, a multidisciplinary expert advisory group assisted in the prioritisation of risk factors to be studied. In guiding this process, the group considered the likelihood of exposure to respective risk factors in Australia, the likely population exposures to these risk factors, the likely risks associated with these exposures, the quality of available evidence from which to draw robust conclusions, and the potential for modifiability.

Cancer Australia has also developed a short summary report of key information from the systematic review. Risk factors for lung cancer: an overview of the evidence (the overview) has been developed to provide consumers, health professionals and policy makers with a comprehensive, evidence-based summary of factors related to a person’s risk of developing lung cancer. The overview is available on the Cancer Australia website (http://canceraustralia.gov.au/).

2 MethodsThe scope of this project was to identify, from existing research literature, where associations between specified risk factors and lung cancer exist and to quantify this relationship where possible.

Risk factors for lung cancer: A systematic review 1

http://canceraustralia.gov.au/

2.1 Inclusion criteria2.1.1 Types of participants

The systematic review included studies with participants who were:

patients diagnosed with primary lung cancer of any age or sex, and unaffected participants (i.e. retrospective cohort studies, case–control studies)

healthy males and females of all ages independent of their exposure to any risk factors (i.e. prospective cohort studies)

patients at risk of developing primary lung cancer (clinical trials).

2.1.2 Types of intervention/Exposures of interest

Studies were included on any factors associated with primary lung cancer risk in a group or cohort who had been exposed to them. Modifiable risk factors included:

Environmental, occupational and lifestyle factors3-10 —smoking and second-hand smoke (including marijuana use), alcohol consumption, air pollution, radiation (radon, diagnostic radiographies), cooking oil vapours, pet birds, asbestos (and/or other human-made mineral fibres), silica and physical activity.

Nutritional and dietary factors—use of antioxidants, nutritional supplements such as carotenoid sources of vitamin A, vitamin C, vitamin E, selenium, zinc, consumption of fruits and vegetables, coffee, green tea and black tea. Where the research indicated that dietary factors protected against rather than increased the risk of lung cancer, this research was excluded from the review.

Reproductive and hormonal factors11-18 —any factors associated with cancer risk in women, such as oestrogen exposure, menstrual cycle, parity.

Viral factors—including human papillomavirus, herpes simplex, hepatitis B and C, and others.

Non-modifiable risk factors included:

Family history and previous respiratory diseases — studies that related to other non-modifiable risk factors with well-established links to lung cancer (such as age) were excluded.

2.1.3 Types of outcome

Studies had to report a numerical measure of risk, either absolute or relative. Because cancer is a relatively rare disease, odds ratios (OR), rate ratios, standardised incidence ratios (SIR), hazard ratios (HR) and risk ratios were all interpreted as relative risk (RR). Mortality data (standardised mortality ratio, SMR) and incidence data were considered to be synonymous, given that lung cancer is generally a terminal disease.

Preferred outcomes were data that could be categorised into one or more of the following categories: smokers, non-smokers and former smokers, or where the data had been adjusted (particularly for smoking). Systematic reviews that reported on both adjusted


and unadjusted data were included; studies that presented only unadjusted data were excluded.

Preference was given to studies that focused on an identifiable risk factor as opposed to studies that treated ‘occupation’ as a risk factor. Where the research suggested that a particular occupation presented a greater risk for a particular risk factor, this was highlighted in the systematic review.

2.1.4 Types of studies

Most studies of risk factors for lung cancer were non-experimental epidemiological studies, including prospective and retrospective cohort studies, nested case-control studies and case-control studies. Data from clinical trials (randomised and quasi-randomised controlled trials) were available mainly for studies exploring potential protective factors against lung cancer; however, if trials suggested a harmful interaction, they were included.

The specific types of studies considered for inclusion in the systematic review were:

other systematic reviews, pooled analyses and meta-analyses of epidemiological studies, and clinical studies that determined a precise estimation of the association

primary research studies—both non-experimental intervention studies and clinical trials.

Levels of evidence

For each risk factor, the inclusion and presentation of the findings has been broadly ordered according to the National Health and Medical Research Council (NHMRC) levels of evidence:19

Level I—a systematic review of Level II studies

Level II—a prospective cohort study

Level III-1—an ‘all or none’ study

Level III-2—a retrospective cohort study

Level III-3—a case–control study

Level IV—a cross-sectional study or case series.

Research syntheses (Level I)

Pooled analyses, systematic reviews with meta-analyses, and meta-analyses that were not systematic reviews (collectively known as ‘research syntheses’) were identified for each risk factor as a priority.

When multiple research syntheses addressing the same risk factor were located, they were ranked based on the following criteria:

recency (date of completion of search or publication if search date not reported)

inclusion criteria (wide scope specified for the population of interest, and relevance to the overall Australian population)


quality (critical appraisal)

precision of effect estimate.

The results of the research syntheses have been presented according to these criteria. Additional research syntheses are reported if they offer further information on a specific population (e.g. by occupation) and there is no overlap of included studies (to avoid data repetition).

Where possible, data are presented according to subgroups of interest—that is, smoking, non-smoking, former-smoker, or if solely adjusted for smoking. Where possible, data across these subgroups have also been presented stratified by sex.

If a good-quality research synthesis (according to inclusion and ranking criteria) was located, this represented the complete data presented for the risk factor.

Primary research (Levels II–IV)

Primary research (evidence levels II–IV) was included if no adequate research syntheses were located, or if the available research syntheses were undertaken before 2008. In the latter case, included primary studies were limited to those published since the end date of the research synthesis search or, where this was not reported, the year before the research synthesis was published. Primary studies that overlapped with the research syntheses were not included.

Primary research was selected based on:

the scope of inclusion criteria specified for the population (i.e. most expansive/most relevant to the Australian population) if no research syntheses were identified; or studies that correspond to the specific population already referred to in the research syntheses, to ensure congruency of data presented

congruency in the definition of exposure/risk factor

quality (critical appraisal).

If more than one systematic review relevant to the risk factor (based on the criteria already stipulated) was identified, a decision was made on which population(s) (or other defining characteristics) to address with the subsequent analyses of primary research. This decision was based on:

the largest number of studies that corresponded to any defining difference among the included research syntheses

relevance to the Australian population.

2.2 Search strategy and study selectionThe search aimed to identify published and unpublished studies relating to risk factors for lung cancer that were written in English. A broad, four-step search strategy was therefore used to identify as many relevant studies as possible:

The PubMed database (through CancerLit) was initially searched to identify optimal search terms.


All key words and index terms identified from step 1 were used to search the following databases during March–April 2011, based on the Scottish Intercollegiate Guidelines Network cancer search filter (2004):

PubMed through CancerLit

Embase

The Cochrane Library

The Joanna Briggs Institute Library of Systematic Reviews

ACP Journal Club (ACP)

EBM Reviews (Evidence Based Medical Reviews).

Citations were entered into citation management software (EndNote), duplicates were removed and studies were selected for initial inclusion or exclusion by scanning titles and abstracts.

Each identified risk factor was searched again using the simple search string ‘[risk factor]’ AND ‘lung cancer’ in both PubMed and the International Agency for Research on Cancer (IARC) website (http://monographs.iarc.fr).

Reference lists of all identified publications were searched for additional studies. The process of screening reference lists of papers was repeated until no new research that met the protocol criteria was identified.

Following this process of searching and study selection, full-text papers that were considered applicable were retrieved for analysis.

2.3 Critical appraisalEach research paper selected for inclusion in the review was critically appraised (assessed for risk of bias) in an effort to identify and select papers of the highest quality and to establish a clear indication of the degree to which included studies were at risk of bias.

Studies were appraised using the standardised critical appraisal instruments for systematic reviews (research syntheses), randomised controlled trials, comparable cohort studies and case–control studies, available in the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (see Appendix C). Studies were classified as low quality (critical appraisal score 1–3), moderate quality (4–6) or high quality (7+).

2.4 Data extraction and synthesisRelative risk and other measures of association were abstracted and transformed into log(ln) relative risk, and the corresponding standard error calculated from available data using the method of Greenland20 for use in meta-analysis. Where effect estimates and standard errors were not available, they were calculated from crude data and 95% confidence intervals (95% CIs). Measures of association adjusted for the maximum number of covariates were preferentially abstracted. Unadjusted results were included only where no others were provided.


http://monographs.iarc.fr/

Where possible, the results were pooled in statistical meta-analysis using a random effects model (RevMan 5.1, The Cochrane Collaboration). Heterogeneity was assessed using standard chi2 and I2 tests, and subgroup (sensitivity) analysis was used to explore possible sources of heterogeneity based on the study design used in the included studies. Further analyses investigated the risk of exposure by sex or smoking status (e.g. among smokers, former smokers and never-smokers) if the data were available and appropriate. If statistical pooling was not possible, the findings were presented in narrative form.

For prospective studies with different follow-up periods, the time point for follow-up meta-analysis was ranked according to the most frequently reported time, then by the longest follow-up.

The principal aim of the analysis was to report on incidence and calculated risk estimates of lung cancer overall. The type of lung cancer was not considered as a separate outcome measure in meta-analyses or reporting of results. The broad scope of the review provided sufficient basis to combine all types of lung cancer, where possible. Where the evidence clearly suggested a specific type of lung cancer was associated with a risk factor, this evidence is highlighted in the systematic review.

Meta-analysis of observational studies can be a complex task and it was thought unlikely at the outset that all included studies would be able to be statistically analysed. Meta-analysis required the extraction of effect estimates and their standard error from each study.

For binary data:

Where study measures of risk were expressed differently (e.g. odds ratios, rate ratios, risk ratios, hazard ratios), differences in these measures were ignored and all were treated simply as measures of risk.20

Where confidence intervals were provided rather than standard errors, the method of Greenland20 was used to calculate the standard errors. No attempt was made to calculate the standard error from reported p values.

In some cases, effect estimates in primary studies were encountered where data were presented in such a way as to preclude the simple comparison of one level of the exposure variable on the incidence of cancer. Examples include presentation of data across categorical classes or across quantiles of a continuous variable. In these cases, where possible, data from the highest category or quantile, or the most consistently reported, were combined in ‘high–low’ meta-analysis.

Results of statistical analysis of primary studies were interpreted in the text with potential discussion of limitations, methodological issues, and so on. Where statistical analysis was not possible across the subgroups of interest for a particular risk factor, results were discussed in narrative form with particular emphasis on the discussion of the results of prospective studies.

2.5 Use of the IARC monographsThroughout the evidence review, an effort was made to maximise the use of relevant, high-quality information already available and provided by IARC. Therefore, where a monograph identified and addressed a risk factor for lung cancer to be covered in the systematic review, any included individual research reports were not retrieved and appraised, as was done with research papers. Rather, the study details and risk estimates were extracted directly from the published monograph. Details of the methods used by


the IARC working groups can be accessed at http://monographs.iarc.fr/ENG/Preamble/CurrentPreamble.pdf. Individual studies included in the monographs were only retrieved if clarification or extra detail was necessary.


http://monographs.iarc.fr/ENG/Preamble/CurrentPreamble.pdf

3 Results3.1 IntroductionIdentified risk factors for lung cancer are addressed individually in the remainder of the report. As much as possible, the order of presentation of exposures or risk factors in the report has been organised to reflect the descending order of risk across all of those identified. Therefore ‘causal’ risk factors for lung cancer are presented first, followed by exposures that increase risk to an extent sufficient to classify them as risk factors for lung cancer, and finally exposures where the evidence available, or lack thereof in some cases, suggests no increased risk of lung cancer is attributable to exposure to the agent or occupation in question. For each risk factor, details of the evidence located from the search as a whole and the evidence included and reported on is first introduced and accompanied by a table detailing important characteristics of each of the included studies. After this, the risk of lung cancer attributable to the risk factor is presented across the general included population, by gender where possible and also by smoking status where possible. Each section is completed with summary conclusions describing the risk of lung cancer from the evidence located and analysed.

Each risk factor is also accompanied by a list of references and results of the critical appraisal process. Where reference is made throughout the text to low, moderate and high quality studies, this corresponds to scores on the critical appraisal instruments of 1-3, 4-6 and 7+ respectively.

When considering the results presented in this report it is useful to understand different measures of risk estimate and some considerations that are encountered throughout; including the repeated issue of confounding factors and their impact when interpreting the results of such research. Further information is also provided in this section regarding key definitions used across all risk factors with regards to their presentation throughout this report, specifically smoking status of included participants.

Epidemiologists and researchers use a variety of study designs to establish the risk represented by exposure to a particular “risk factor”. The study designs encountered are most commonly referred to as “observational”, in that they do not involve researcher control of an intervention, but rather record an outcome, such as the incidence of lung cancer, potentially due to a natural ‘exposure’ to a factor such as smoking or asbestos. The varying study designs are organised hierarchically according to their internal validity, or the capacity within the type of study design to limit bias. Where a study design has a greater inherent capacity to limit bias (if well conducted of course!), the more credible the results. This is particularly important when the attempt is being made to claim causality; for example, that being exposed to radon or any other risk factor, “causes” lung cancer.

The hierarchical organisation of study designs places retrospective studies, or those that look back in time, beneath prospective designs or those that plan to assess an outcome forward in time. Experimental designs (clinical trials) and systematic reviews lie at the top of the evidence hierarchy. The most common study designs encountered in this review are described below; starting from the base of the evidence hierarchy, with case control studies, and moving up through cohort studies, both prospective and retrospective, clinical trials and experimental studies and ultimately syntheses of existing research such as meta-analyses, systematic reviews and pooled analyses.

Case control studies are often used as a rapid means of the study of risk factors and as such are some of the most common type of studies encountered when investigating risk


of lung cancer due to an exposure. Case-control studies identify patients who have an existing specific condition (cases), such as lung cancer, and match them with people who do not have the disease (controls). The main purpose of matching is to control for confounding (see below) and it is often done, at a minimum, for characteristics such as age and sex. Case-control studies look back, normally by assessing patient history, to see if there are characteristics of these afflicted patients that differ from those who don’t have the disease. As case control studies look backwards in time to establish association between exposure and disease they are also termed retrospective studies and are subject to particular biases, such as a recall bias (relying on participant memory of an exposure) that does not impact on prospective study designs. Despite the retrospective, non-randomised nature of a case-control study limiting the conclusions that can be drawn, this study design has claim to a number of important discoveries and advances in medical research, including demonstrating the link between tobacco smoking and lung cancer.

Cohort studies are also frequently used to investigate the risk of an outcome such as lung cancer, attributable to an exposure. Cohort studies commonly investigate a large population of subjects over time that have an exposure of interest, for example a group of miners exposed to coal dust in the ambient air, and compare them with another group that has not been exposed. Unlike the case control study, participants do not have the disease of interest at the start of the study, such as lung cancer, but are followed prospectively through time and the outcome is measured in both groups, which are then compared. Incidence of the disease under investigation is commonly determined in key subgroups; for example when investigating risk of lung cancer, smoking status of participants is a common and important subgroup reported on. Cohort studies are often referred to as the gold standard of observational epidemiological designs as they are less prone to bias, recall error and have higher validity than other observational study designs. They are however often expensive to conduct due to the large sample sizes and long duration of many studies of this type.

Cohort studies may also be retrospective in design. A retrospective cohort study is quite different from a prospective cohort study in the manner in which it is conducted. Also called a historic cohort study, all the events – exposure to the risk factor, latent period, and subsequent development of disease have already occurred in the past. Data is simply collected in the present, and the risk of developing a disease established if subjects appear to have been exposed to a particular risk factor, such as excessive air pollution for example.

Observational studies strongly aide in studying causal associations between an exposure and disease such as lung cancer, though distinguishing true causality generally requires corroboration from experimental research. In terms of primary research, randomised controlled trials - well controlled research studies performed with human participants - represent the studies that carry the most reliability and weight. This study design necessarily includes methods that reduce the potential for bias (e.g. randomisation and blinding where possible). Though most clinical trials are directed towards informing the effectiveness of an intervention or therapy, they also, though not as frequently, have the capacity to also provide valuable information related to harms or adverse effects from due to an intervention administered or to evaluate removal of exposure to potential risk factors or assess protective effects. Many risk factors cannot be addressed in clinical trials due to ethical reasons, some however, particularly those hypothesised to have potential protective effects of dietary factors such as carotenoids, have been assessed experimentally.

Research syntheses including pooled analyses, systematic reviews and meta-analyses all summarise the findings from a number of existing, related studies. The power of research syntheses lies in this analysis and presentation of the results of a number of similar


studies - which is considered to be of greater value than accepting the information derived from simply one or two identified studies as the ‘truth’. Systematic reviews, for example, take the form of an exhaustive search of the scientific literature, usually focusing on a specific aspect of a clinical topic, to identify all relevant and methodologically sound studies. The studies are appraised and reviewed, and the results summarised. A systematic review of quantitative evidence may also contain a meta-analysis, though this is not the defining feature of any systematic review. In a meta-analysis the results of sufficiently similar studies can be statistically combined and analysed, and the overall result interpreted as if derived from one large study. Pooled analyses in epidemiology are distinguished from systematic reviews in that they do not rely solely on identified and abstracted published data available, but rather use the raw, individual data from a number of studies and combine all into a single analysis. For many of the risk factors identified and reported on in the current report, there are existing syntheses of the literature, particularly systematic reviews and meta-analyses that have been reported on.

Throughout the report, different measures of association, or estimates of effect, are often used, most commonly standardised mortality ratios (SMRs) and in some cases relative risks (RRs) or odds ratios (ORs). Absolute risk is a person’s chance of developing a specific disease over a particular period of time. A person’s absolute risk of disease is estimated by examining a large number of people similar in some respect (such as age or gender) and counting the number of individuals in this group who develop the disease within a defined period. Relative risk, which is the most common metric of risk reported throughout this report, compares the absolute risk of a group of people who are exposed to a risk factor with the absolute risk of a group of people who are not exposed to the risk factor. An OR uses the odds of developing a disease in both groups to calculate a relative measure between two groups rather than the risk. As a rule, retrospective study designs, such as case control studies, will only report ORs, whereas prospective study designs, like the cohort study, will generally report a RR estimate. Where an absolute risk of the exposed group is presented relative to available existing data for a population group, for example adult males, this is referred to as a standardized ratio. the reporting of results as a standardised incidence ratio (SIR) or SMR will depend on whether incidence or mortality data is used is used throughouit the study. Although there are fundamental differences between these types of risk measures, for the purposes of meta-analyses conducted and reported in this review, irrespective of the study designs included and various measures of association, all were considered estimates of the RR. A RR can be reported in a variety of ways. For example, RR of 1.37 could be expressed as a “37% increase in risk”, “a relative risk of 1.37” or “an increase in risk of 1.37 times.”

Another useful metric to assess the impact or burden of a disease such as lung cancer is the ‘population attributable risk’ (PAR) or proportion of lung cancer in a population that could be avoided by reducing or eliminating exposure to the agent, or causal risk factor, in question. Limited published data is available quantifying the PAR for causal risk factors for lung cancer in Australia; however, where possible and applicable, PAR for risk factors in this report has been reported either for Australia or countries with an exposure profile considered similar to that in Australia, particularly the United States, where some estimates of PAR are available for individual risk factors. Steenland and colleagues21 estimate that the PAR for exposure to occupational lung carcinogens including arsenic, asbestos, beryllium, cadmium, chromium, nickel, silica, environmental tobacco smoke at work, exposure to radon progeny (all addressed in this report) and diesel fumes is between 8 – 19% for males and 2% for females. Considering data from the US at the time, elimination of exposure to these risk factors would reduce the number of lung cancer deaths in the US by approximately 10,000 – 20,000 per year21.

An important metric also encountered in the research literature alongside the majority of effect estimates (SMR, SIR, OR, RR) presented in this review are confidence intervals


(CIs). Confidence intervals reflect the precision of the measured estimate of effect. Confidence intervals are inferred for a population from the sample investigated. A confidence interval is defined by the upper and lower limits (or reported confidence limits) about the point estimate of effect. A confidence interval represents the range of values that has a specified probability of containing the true point estimate of effect. The most common specified probability is 95%, akin to p=0.05, and this is used exclusively for reported CIs in this review. The most common interpretation of a 95% CI is that we are 95% confident that the true value of the estimate of interest lies within the specified range. The correct statistical interpretation of a 95% CI is slightly different from this common understanding and specifies that if 100 random samples are taken from the population of interest, 95/100 would contain the true value of the estimate of interest. In practice, there is little difference between these interpretations of CIs. In short, if the CI about a measure is narrow, it is a precise measure; where CIs are large, it is indicative of imprecision in the measure. Confidence intervals can be used a useful guide as to whether or not differences between studies are due to chance variation or some other, potentially hypothesised factor. Where confidence intervals overlap, the differences between measures is considered too small to differentiate between a difference as a result of chance, or sampling variation, and a true difference. If CIs do not overlap than differences between estimates are greater than what would be expected by chance alone and can be regarded as statistically significant. For example, when interpreting a meta-analysis combining the data of multiple, similar studies that are considered representative of the same population (for example if exposed to the same risk factor) presented diagrammatically in a forest plot, CIs that do not overlap indicate that some difference beyond chance variation underlies the observed difference. Such divergence between CIs of individual studies is indicative of significant heterogeneity in an analysis.

Heterogeneity is an important aspect of any interpretation of overall RR estimates derived from meta-analyses or when considering risk estimates presented from individual studies. Ideally, studies that are combined in meta-analysis should be homogeneous, or similar. If not heterogeneity, or differences, between studies, will impact on the interpretation of the results and the ability to draw any legitimate or meaningful conclusions. For example, if one study investigating exposure to radon in uranium miners reports a much greater risk than a similar study, this will impact on the overall effect estimate calculated, and will appear as a significant (p<0.05) Chi2 statistic (Cochran’s Q) between studies in the analysis. In such an example, careful analysis of the reported publication may reveal that the study reporting the greater risk estimate, also reported recording much greater levels of radon in the air – a feasible explanation for the difference. A remarkable feature of many of the included studies for the various risk factors investigated in this report was the large range of exposures and in many cases the rudimentary means of measuring exposure. In many cases, exposures reported by the different studies varied by orders of magnitude from each other. Similarly, often exposure was determined solely by length of time an individual was employed at a particular site, such as a mine for example – established by a questionnaire, no more objective means of quantifying exposure was attempted. When a meta-analysis is performed, another metric encountered to assess heterogeneity is the I2 statistic. I2 describes the percentage of total variation across studies that is due to heterogeneity rather than chance; in effect it quantifies the inconsistency between studies in a meta analysis and is a more robust statistic than the Chi2. I2 values of 25%, 50%, and 75% can be considered as low, moderate, and high.

Confounding is an important consideration and occurs when the apparent effect or process that is recorded or observed is, in reality, not the true effect, but rather there are one or more other processes at play – potentially unknown processes – resulting from differences between comparison groups. This leaves any interpretation of the results potentially erroneous, with the risk established by a study between an exposure and disease state potentially over- or under-estimating the size of the effect or even the


direction of the relationship. For example, any study investigating the risk of a particular factor and its impact on the development of lung cancer should take into account the smoking status of included participants. Smoking is well established as a cause of lung cancer and hence, is an important confounding factor to consider. Confounding may impact any type of research study and often there will be attempts by the researchers in the methods of the study reported to limit or account for confounding. Sometimes this may occur in the design phase of the study where for example, a confounding factor may be ‘standardised’ in groups by deliberate selection of subjects based on levels of the confounder. This may occur in both cohort and case control designs. Most commonly however, confounding factors are addressed during data analysis, with adjustments made for such ‘confounding factors’ and other covariates in the estimation of the overall association. Statistical adjustment relies on measuring these confounding factors and covariates, in essence, correcting for them to remove or lessen their impact on the observed results. This is most commonly done by statistical modelling using regression techniques such as multiple linear or logistic regressions.

If a study has adjusted the analysis for a confounding factor it is important to be aware that if the factor either hasn’t been, or cannot be measured with sufficient precision it will still remain a threat to the validity of the results. As a result, despite the best efforts of researchers to adjust and correct for potential confounding factors, residual confounding, where the effect of the confounding variable is not completely removed, may still remain an issue in these research studies. For example, in many case-control studies, often 90 – 100% of cases with lung cancer are also smokers, irrespective of the risk factor being investigated. This should be kept in consideration when considering the results presented in this review.

Beyond smoking, some of the covariates and factors commonly measured and corrected for include: occupational exposures to carcinogens, education, race, socio economic status, a range of dietary factors and passive smoking. Whether some factors that are adjusted for are encountered depends on the risk factor being addressed. For example, studies investigating dietary or other lifestyle risk factors, such as meat consumption, cholesterol intake or physical activity, will also commonly adjust for participant factors such as Body Mass index (BMI) or energy intake.

In the literature an “ever smoker” is defined as a person who has ever smoked tobacco. In some studies a more precise definition is used - a person who has smoked at least one hundred cigarettes and cigars during the course of his or her life. A person who has never been a cigarette smoker or cigar smoker is defined as a “never smoker”.22 Multiple terms are used in the literature to describe light or intermittent smokers, moderate smokers and heavy smokers but these terms are not defined consistently. They are generally categorised by number of cigarettes and number of days smoked.22 For example, ‘light smoking’ has the widest set of definitions, ranging from “denied ever smoking regularly and denied any smoking within the past 30 days” to smoking 1–39 cigarettes per week, to smoking 10–20 cigarettes per day.22 Some studies have classified smoking into two categories: low level of smoking is by and large defined as <20 cigarettes per day, and high level of use as beyond 20 cigarettes per day.23 Current or former smokers are also often defined as having ever smoked at least 100 cigarettes in the lifetime and never smoked daily.22 According to the AIHW, males are more likely to be daily smokers (18.0%) than females (15.2%). More than half of the population have never smoked (55.4%), and around a quarter of the population are former smokers, with males were more likely to be ex-smokers (27.9%) than females (22.4%).2

For some risk factors, studies investigate and report the joint effect of the risk factor and smoking on risk of lung cancer, in other words, the risk of the two factors combined. For outcomes such as incidence or mortality due to cancer, models of these joint effects are described as either additive, or multiplicative. The assumption underlying additive and


multiplicative risk models is that the risk factors or causal agents do not interfere with each other’s basic mechanism of causing disease. The basic premise of the additive model is that the causal agents do not collaborate to cause additional cases of disease in combination and is indicative of an ‘absence of synergism’. In contrast, a multiplicative model is a measure of interaction of risk factors and if there is a positive interaction, it is interpreted as synergism.24

Relative risk estimates were often found to vary widely between studies included in this review; however, this was unsurprising considering the wide variation encountered between studies in the level of exposure, the level and adjustment of confounders, selection and measurement biases, and variation in period of follow-up. In many instances, the RR estimates reported are not related to any absolute measures of cumulative exposure, as the necessary data were not available and also not based on any consistent or comparable duration of exposure across relevant populations. Almost all of the exposures and risk factors addressed in this review have a long latency, or lag period, between exposure and development of lung cancer. Therefore, many of the estimates of risk reported by studies reflect effects of both past and present exposures, which many have changed over time and may not have the same associated risks. Despite these variations and the realisation that for the most part RRs are simply calculated on the exposed compared to non-exposed populations, without detailed consideration of aspects of exposure such as duration or intensity, analysis and, where possible, statistical combination of data from included studies to present summary RRs still provides a good approximation of the ‘likely’ RR for the exposures of interest. Application of these statistical methods where possible to combine data derived from epidemiological studies has the added advantage of ultimately preventing underestimation of risk of lung cancer.

3.2 Results of database search, study selection and inclusionTable 3.1 summarises the results of the search, selection and inclusion process for the review. The included flow diagram indicates the results of the first search of databases as detailed in the methods section above using the search strategies detailed in Appendix B. In total, 1752 citations were selected from the initial scan of titles and abstracts of the search results on the basis of review eligibility criteria. During this scan, citations were concomitantly organised into broad categories of risk factors based on the information contained in their titles and abstracts. The number of potentially relevant citations identified from the first search is presented beneath each of the risk factors addressed in chapters of this review in Table 3.1. Further information pertinent to each identified risk factor was then subsequently searched for in PubMed and the IARC Monographs presented by the WHO (see methods).

The values presented in Table 3.1 represent the results of the review database search; the number of citations recorded for each identified risk factor and exposure are not indicative of either the nature or the actual volume of literature related to each risk factor, nor are they intended to be. These values solely reflect the sensitivity of the search strategy used (Appendix B) and the subsequent selection processes used by the reviewers involved.

Studies that matched the eligibility criteria specified for the review were retrieved and included for subsequent appraisal. Where studies were excluded during appraisal, full details of the decisions made based on the appraisal criteria are presented in Appendix C. The final column in Table 3.1 represents the total number of studies ultimately reported from to inform each of the risk factors for lung cancer in this report. Tables of characteristics of studies included throughout the series of reviews in this report are


presented in Appendix E. For ease of reference, risk factors in Appendix E are arranged in alphabetical order.


Table 3.1 Summary of results of database searching, papers retrieved based on eligibility criteria and number of included studies

Main search N = 59506Duplicates removed N = 3173Scanned titles and abstracts N = 5633Identified as potentially relevant N = 1752

Eligibility criteria

Air pollution

Alcohol Arsenic Asbestos

Avian Exposure

Beryllium

Cadmium

Chromium

Dietary & Blood Cholesterol

Family History

Iron & Steel Foundry

Meat Red & processed

Nickel PAH Painting as occupation

Physical Activity

Radon Silica Smoking

Wood Dust

# Potentially relevant citations

42 19 111 66 11 19 18 7 16 24 124 13 5 130 45 13 124 43 349 8

Identified by 2nd search*

— 19 3 14 0 3 — — 21 20 — 10 2 — 0 0 108 8 18 2

Retrieved articles

11 32 39 13 11 12 5 7 35 9 21 14 7 53 4 11 56 23 17 10

Appraised articles

5 15 10 10 7 4 5 7 21 1 3 11 7 7 4 7 13 9 7 8

Included articles

5 14 9 (21) 6 (56) 5 3 (2) 5 (11) 5 (11) 21 1 3 (10) 11 6 7 (12) 4 7 13(4) 9(20) 7 6

*Identified risk factors from the primary literature search were searched again through PubMed and the WHO IARC monographs to maximise sensitivity. Value in brackets indicates the number of studies for which data was derived from the IARC monograph. Refer to methods for further details


4 Risk factor: Active smoking and passive smoking4.1 IntroductionSmoking tobacco accounts for approximately 85% of new cases of lung cancer in Australia, and over 80% of deaths from lung cancer are thought to result from cigarette smoking Table 10.7;25.25

Measurements of the prevalence of smoking in Australia first became available in 1945. Historically, a clear majority of males aged 16 and over were smokers, compared to about one quarter of females.26 However, prevalence of smoking among adults has declined steadily since the early 1980s,27 particularly amongst men. 28 The difference in smoking rates observable between the sexes has also continued to close (while remaining statistically significant), largely due to greater numbers of males quitting smoking during the mid-to-late 1980s.27 Comparatively, Australia’s level of smoking is among the lowest for OECD (The Organisation for Economic Co-operation and Development) countries, with about one in six (approximately 2.9 million) Australians aged 14 years and over now smoking daily, compared with about half of all adults in the 1950s.28

Even though the epidemiology of lung cancer associated with tobacco smoke has been extensively investigated for 50 years, there continue to be active areas of research due to changes in smoking patterns and changing trends in design and constituents of smoking tobacco products on the world market.29 For example, in addition to cigarettes, the other major means of smoking tobacco include cigars, pipes, bidis and water pipes such as hookahs or narghiles. Smoking of these other tobacco products and forms is much less common than cigarettes, though in some countries, such as India, bidis are the predominant form of tobacco smoked and water pipes are common throughout North Africa and the Middle East. These other forms of tobacco smoking have become increasingly popular in the USA and some European countries.29 Importantly, the introduction of manufactured cigarettes with addictive properties (e.g. tar and nicotine) may cause exposures to new etiologic agents and changes in lung cancer epidemiology.

During the past quarter of a century it has also become increasingly clear that, although the main hazard is to the individual smoker, there is an associated risk to non-smokers (including former smokers) from exposure to tobacco smoke. The most common terms used to describe exposure to tobacco smoke in non-smokers are passive smoking, environmental tobacco smoke (ETS), second-hand smoke (SHS) and tobacco smoke pollution.30

The initial search of the literature identified 349 citations, whilst the second search identified a further 18 potentially relevant studies. Of the initial citations identified during initial study selection, 350 citations were excluded. Seven research syntheses that sought to establish if active and/or passive smoking are independent risk factors for lung cancer were included. Of these, one was a meta-analysis of all of the included studies in the IARC research Monograph29 on active smoking.31 IARC reviewed all significant published evidence related to tobacco smoking (both active and passive smoking) and cancer29 published until and including 2002. The remaining six syntheses include four meta-analyses23, 32-35 investigating passive smoking in the workplace and by participants’ spouses, and two systematic reviews investigating other forms of tobacco smoking, including water pipe smoking and the risk imposed by the addition of menthol to cigarettes.36-38 Table 4.1 summarises the characteristics of studies relevant to an association between smoking and lung cancer risk.


Table 4.1 Study characteristics relevant to the association between smoking and lung cancer

Citation Sample demographics

Study method Exposure Type of Lung Cancer

Analyses Association/Risk

Gandini et al. 2008Meta-analysis

21 studies (26 cohorts) contribute to data for lung cancer in current smokers. 20 studies for former smokers.

Meta analysis of 216 reports incl. in 2004 IARC monograph Tobacco Smoke and Involuntary Smoking. Report on 13 different cancer sites.

Active tobacco smoking investigated in former and current smokers with never smokers as the referent category.

Lung cancer. Not specified.

Random effects model.Subgroup analyses used to investigate heterogeneity incl. Study design, gender, ethnicity, country and whether risk estimates adjusted or unadjusted.

RR (95%CI)current smokers8.96 (6.73 – 12.1)Former smokers3.85 (2.77 – 5.34)Difference in study design was most important explanatory factor for heterogeneity observed. Case control studies combined resulted in significantly greater risk estimate than cohort studies.

Boffetta et al. 2000Meta-analysisAnalysis of 11 case control studies of multiple location worldwide; Hong Kong, Sweden, Japan, USA and Russia

2834 lung cancer cases; adult never-smokers; exposed to tobacco smoke during childhood. Both genders included; age range from 0-16 years.

Meta-analysis of the studies of childhood exposure to passive smoke identified from Medline database. The search covered the publications up to the year 1998.

Exposure to second hand smoke in adult never-smokers exposed during childhood. Self reported exposure to maternal or paternal smoking during preconceptional, transplancental and direct smoke. Passive smoke exposure quantitatively measured as number of cigarettes/day smoked by the parents (smoker-years or pack-years). Duration of exposure not clearly reported.

Description unclear. Random-effects model was used for meta-analysis.Potential confounding factors adjusted include: drugs and chemicals, parental occupational exposures, prenatal exposure to ionizing radiation, diet, and socioeconomicstatus.

Overall risk resulting from childhood exposure to passive smokeRR (95%CI)RR 0.91 (0.80 - 1.05)Risk resulting from childhood exposure to passive smoke by parentMother: RR 0.99 (0.78 - 1.26)Father: RR 0.83 (0.72 - 0.95)





Boffetta 2002Meta-analysis51 epidemiological studies in total. This includes 6 cohort and 45 case-control studies from several countries.However studies from China (including Hong Kong and Taiwan) and those from the USA each contributed more than one-third of total cases.

7369 lifelong non-smokers of adult lung cancer who were exposed to second hand smoke from spouse and/or other cohabitants.Cases: 7369Males: 661Females: 6708Controls: 13281Males: 801Females: 12480661 male and 6708 female.

Meta-analysis.Only one database (Medline) was searched. The most recent date of publication included was December 2000.

Exposure to environmental tobacco smoke exposure (ETS) in a home environment resulting from a spouse at home and/or other cohabitants.

All histological types of lung cancer; squamous cell carcinoma, adenocarcinoma, non-adenocarcinoma, small cell carcinoma carcinoma

Random-effects model was used for meta-analysis. Combine studies with different levels of adjustment for confounding. No sensitivity analysis conducted.Both adjusted and unadjusted results were used in the analysis.Potential confounding factors adjusted include age, gender, occupation, diet, but not reported.

Overall risk resulting from ETS resulting from a spouseRR (95%CI)RR 1.25 (1.15 - 1.37)Risk by genderMale:RR 1.25 (0.95 - 1.65)Female:RR 1.25 (1.14 – 1.38)Histological type by exposureAdenocarcinomaRR 1.28 (1.13 - 1.44)Non AdenocarcinomaRR 1.14 (1.14 - 1.79)Squamous cell carcinomaRR 1.38 (0.87 - 2.20)Non squamous cell carcinomaRR 1.38 (0.87 - 2.20)Duration of exposure /dose response relationshipNo dose response relationship of exposure was apparent.Positive and cumulative relationship with estimated cumulative exposure; however; data was not clearly presented.

Stayner et al. 2007Meta-analysis

4305 persons categorised as being never smokers

Meta-analysis of 22 studies from multiple locations

Exposure to environmental tobacco smoke exposure (ETS) in a

All histological types of lung cancer; squamous cell carcinoma,

Fixed-effects model and Random-effects model were used for meta-analysis.Meta-regression analyses

Overall workplace exposure RR (95%CI)Workers exposed to ETS have an increased risk of lung





Analysis of 22 case control studies from several countries: USA, Canada, Europe (Germany, Sweden, Spain Italy, France, Portugal; Russia Greece), Hong Kong, Russia, India, and Taiwan.

exposed to second hand smoke at the workplace.Both genders included; however number of male and female not reported separately.No information on ages, but all cases were non-smokers who had exposed to environmental tobacco smoke at workplace.

worldwide of workplace environmental tobacco smoke exposure and lung cancer risk published in Medline and Embase databases. The search time frame covered up to January 2003.

workplace context.(Excluding ETS from having a smoking spouse)Years of workplace exposure was determined as the total number of years in which the subject reported working in an environment where others were smoking.

adenocarcinoma, small cell carcinoma.

were also conducted to evaluate exposure–response analyse results.Sensitivity analyses were also conducted to evaluate the impact of combining studies with different levels of adjustment for confounding.Potential confounding factors adjusted for: age, diet, race, exposure to ETS from a spouse, other occupational carcinogens.

cancer RR 1.24 (1.18 - 1.29) compared with those not exposed.The measure of exposure used to categorise at work place ETS varied from study to study. Total number of years of exposure weighted for the number of hours of exposure per day and for a subjective index of level of smokiness at the workplace. Actual values of these figures were not available.Dose–Response Analyses RR 2.01 (1.33 - 2.60)(Analysis of 7 case control studies)“highly exposed” exposure used to categorise varied across studies as judged by the authors. Highly exposed reported in the included studies varied from >4 co-workers smoked, cumulative exposures measured as >100.6 level×hours per day ×years; > 89 level×hours per day ×years; >64 smokers ×years.Duration of workplace exposureRR (95%CI)Workers exposed to ETS over a 45 year period had an elevated risk of lung cancer





RR 1.63 (1.45 - 1.82)(Analysis of 7 case control studies)Results were not reported by gender.

Taylor et al. 2007Meta-analysisAnalysis of 55 studies from several countries worldwide; US, Canada, Japan, China, India, Taiwan, Singapore, Hong Kong, Europe (Germany, Sweden, Netherlands, Greece, Prague)7 cohort, 25 population-based case-control and23 non-population-based case-control studies

Never smoking women exposed to second hand smoke from spouses.Number of women included not reported. No age estimate provided.

Meta-analysis of papers published between 1981 and 2006. Medline and Embase databases were searched.

Exposure to environmental tobacco smoke exposure (ETS) resulting from a spouse.Context of exposure not reported

Confirmation of diagnosis not clear.

Fixed and random effect models and meta regression used for meta-analysis.Adjusted estimates relative risks or odds ratios were extracted. Unadjusted estimates were only included if adjusted results were not available.Potential confounding factors adjusted varied across the included studies.

Overall risk resulting from ETS resulting from a spouseRR (95%CI)RR 1.27 (1.17 - 1.37).Overall risk resulting from ETS resulting from a spouse by geographical regionRR (95%CI)North America and EuropeRR 1.31 (1.24 – 1.52).AsiaRR 1.31 (1.16 – 1.48).Duration of exposure /dose response relationshipDose–response relationship data not clearly reported.

Lee 2011Systematic reviewIn total, eight epidemiological studies included. These include 2 prospective

Lung cancer cases in mentholated cigarette smokers (current smokers, ever smokers, and former

Meta-analysis. Database search included Medline, Google Scholar, Scopus, Scirus, Science Direct and Academic search

Smoking mentholated cigarettesExposure measured by self reported brand name of cigarettes and duration of exposure

Cases were generally histopathologically confirmed.

Fixed-effects model and random-effects model were used for meta-analysis.Adjusted for age, gender, race and smoking.(Smoking habits, such as daily cigarette consumption and duration of smoking).

Overall risk resulting from actively smoking mentholated cigarettesRR (95%CI)In ever smokers, and current smokersEver users vs no use





cohort studies, 3 hospital-based case control studies and 3 population cases control studies.One case-control study was conducted in Germany, all studies were conducted in the USA

smokers) in both genders of African-Americans population.Age ranged from 30-84 years.Cases= 5806Male =3856Female=1950Controls=8939Male =3765Female=4628

complete. Publication up to the year 2008. Source of data on mentholation status reported in the studies were largely self-reported.

varied as reported by the subjects (range from 15-20 years)

Not attempted to account for the possibility that switching from non-mentholated to mentholated cigarettes, occupation or diet.Although length of use of mentholated cigarettes was investigated, brands smoked years ago was largely unclear.

RR 0.93 (0.84 - 1.02)Current smokers onlyEver users vs no useRR 0.92 (0.84 - 1.02)Former smokers onlyEver users vs no useRR 0.99 (0.62 - 1.56)GenderRR (95%CI)Males: RR 1.01 (0.84 - 1.22)Females: RR 0.80 (0.67 - 0.95)Duration of useLong term use (>15+ years use of mentholated cigarettes) vs <15 years useRR (95%CI)RR 0.95 (0.80 - 1.13).GenderLong term use (>15+ years use of mentholated cigarettes) vs <15 years useRR (95%CI)Males: RR 1.13(0.86 - 1.47)Females: RR 0.78 (0.60 - 1.01)

Akl et al. 2010Systematic reviewAnalysis of 5 case control studies and 1cohort study

Total Cases=983Control=1827Male and female data not reported clearly

Systematic reviewDatabase search included Medline (1950 to 2009), EMBASE (1980

Exposure to water pipe tobacco smoke self reported by the subjects no standardised measures reported. Consumption

Diagnosis varied from radiology and confirmed by histology, panel of pathologist,

Regression models used for analysis.Adjusted for age, gender, other types of inhaled tobacco, cigarettes

Overall risk resulting from water pipe tobacco smoking OR (95%CI)2.12 (1.32 - 3.42).





from India, Eastern Mediterranean (Tunisia) and China

but majority of them were males.

to 2009) and ISI the Web of Science (no search time frame reported)

calculated varied across the studies- the number of pipe years or pack years equivalent of cigarettes or in cumulative dose quartiles.


4.2 Results4.2.1 Active smoking and risk of lung cancer

Meta-analysis of all studies contributing to the 2004 IARC monograph “Tobacco Smoke and Involuntary Smoking” that directly address active smoking clearly indicate a significant risk of lung cancer31. Dose response RR estimates revealed that overall, the risk of lung cancer increases by 7% for each additional cigarette smoked per day with a RR (95% CI) of 1.07 (1.06 – 1.08). The overall RR (95% CI) of lung cancer in current and former smokers is presented in Table 4.2. Details as to the length of time elapsed since participants stopped smoking was unavailable.

Table 4.2 Risk of lung cancer due to smoking in current and former smokers. Referent category of never smokers31

Smoking status RR (95% CI) I2

Current 8.96 (6.73 – 12.1) 75%

Former 3.85 (2.77 – 5.34) 51%I2 represents the % of total variation across studies attributable to heterogeneity rather than chance.

Exploration of the heterogeneity of the analysis indicated the study design used to contribute the data to inform the relationship between smoking and lung cancer had a significant impact on the overall risk estimate. These differences in risk estimate are illustrated in Table 4.3. Where adjusted values were reported, pooled RR were significantly greater than unadjusted values.31

Table 4.3 Differences in RR estimate of lung cancer in current smokers dependent on the study design used31

Study design No. Studies RR (95% CI) P

Cohort studies 11 14.02 (9.64 – 20.4) —

Case control 10 6.29 (4.49 – 8.82) P<0.01

4.2.2 Active smoking, gender and risk of lung cancer

The same authors report on risk of lung cancer by gender from analysis of the included cohorts within studies. Comparison between men and women showed no significant difference in risk of lung cancer with the RR (95% CI) in men reported to be 9.87 (6.85 – 14.24) and in women 7.58 (5.36 – 10.73) (p=0.36). Dose response data with separate pooled RR estimates for men and women are presented in Table 4.4.

Table 4.4 Dose response RR estimates for lung cancer in current smoking men and women31

Cigarette Consumption Men (33 studies) Women (25 studies)

1-9 cig/day 1.39 (1.28-1.50) 1.49 (1.37-1.61)

10-19 cig/day 2.67 (2.11-3.37) 3.30 (2.59-4.20)

≥20 cig/day 13.70 (7.4-25.50) 24.10 (12.70-45.90)


Estimates based on median values of each interval of exposure. Reference category to no smoking. Adj. For study design.

4.2.3 Passive smoking and risk of lung cancer

Workplace exposure

A meta-analysis by Stayner et al.32 showed workplace exposure to second hand smoke was associated with a 24% increase in lung cancer risk in both genders. Where possible, included studies all adjusted for age, exposure to occupational carcinogens and exposure to environmental tobacco smoke as a result of the smoking habits of the subject’s spouse. The results of environmental exposure to tobacco smoke in the workplace are summarised in Table 4.5. Meta regression of data using a linear model suggested RR (95% CI) of lung cancer following 45 years of exposure to environmental tobacco smoke was 1.63 (1.45 – 1.82).

Table 4.5 Risk of lung cancer with workplace exposure to environmental tobacco smoke32

Category No. Studies RR (95% CI)

Passive smoke in workplace 22 1.24 (1.17 – 1.31)

Highly exposed in workplace 7 2.01 (1.33 – 2.60)Random effect model used. Studies selected on basis of adjusting for age, spousal exposure and occupational carcinogens. Highest exposure categories vary significantly between studies.

Exposure from spouse

The majority of studies investigating the effects of passive smoking as a result of spousal exposure include female participants that were never smokers exposed to smoke from their husbands. A recent meta-analysis by Taylor et al.35 included 55 primary studies and also reviewed previously published meta analyses. Of the 55 studies, including both cohort and case control designs, 82% reported an increased risk of lung cancer among non-smoking women whose spouses smoked. The overall RR (95% CI) reported in women was 1.27 (1.17 – 1.37). Bofetta33 addressed the same issue in their meta-analysis, however, they examined the effect in studies including only men, and those that examined both genders. The results are summarised in Table 4.6.

Table 4.6 Relative risk of lung cancer in never smoking men alone and both genders when exposed to environmental smoke from their spouse33

Category No. Studies RR (95% CI)

Male 9 1.25 (0.95 – 1.65)

Both genders 3 1.34 (0.72 – 2.49)

Exposure from parents during childhood

Risk of lung cancer in adulthood after passive smoke exposure from parents during childhood has also been reported in 10 case control studies and one cohort study.34 Irrespective of which parent smoked, there was little evidence of increased risk of lung cancer. Details are summarised in Table 4.7. No indication was given on duration of exposure or latency of cancer development.


Table 4.7 Second hand smoke (ETS) exposure during childhood and risk of lung cancer 34

Category No. Studies Relative risk (95% CI)

Exposure to ETS during childhood 8 0.91 (0.80–1.05)

Exposure to ETS during childhood from mother 4 0.99 (0.78–1.26)

Exposure to ETS during childhood from father 5 0.83 (0.72–0.95)

4.2.4 Other forms of tobacco smoking

A recent systematic review investigated risk of lung cancer due to smoking of mentholated cigarettes by comparison to smokers of un-mentholated cigarettes.36 Including eight (8) relevant studies, the data suggested no risk of lung cancer attributable to the mentholation of cigarettes with a combined RR (95% CI) estimate (across race and gender) for long-term use of 0.93 (0.84 – 1.02).

Another recent and well-conducted systematic review reported on the risk of lung cancer as a result of water pipe smoking37 A total of six retrospective studies were included, (from China, India and Tunisia) and all studies were judged to be of low quality. Overall, the pooled OR (95% CI) for water pipe smoking was 2.12 (1.32-3.42). Analysis of crude, unadjusted measures and reporting from the one good quality study both showed an increase in risk of lung cancer attributable to water pipe smoking.

4.3 SummaryThere is clear evidence to suggest smoking of cigarettes causes the development of lung cancer. Current smokers are approximately nine times more likely to develop lung cancer than people who have never smoked, and former smokers are approximately four times more likely to develop lung cancer than people who have never smoked. Information is not available regarding the amount smoked by current smokers, or the length of time since quitting smoking. However, dose response data does suggest the risk of lung cancer increases from 6-8%, in both men and women, for each additional cigarette smoked per day.31

Passive smoking does not represent as pronounced a risk as active smoking, though the risk remains significant. The evidence suggests an increase in risk, compared with those not exposed to cigarette smoke, ranges from 24% up to twice the increase in risk where intensity of exposure is greatest– either due to duration, frequency of exposure, or a combination of the two factors. A similar increase in risk of approximately 27% is reported from a number of studies that investigated passive exposure in women as a result of their spouse’s smoking habits. The effect on men from the smoking habits of their wives was similar though not significant, potentially due to the small number of studies that contributed data. There is little evidence to suggest exposure to tobacco smoke during childhood increases risk of lung cancer in adulthood. Steenland et al.21 estimate the population attributable risk (PAR) of environmental tobacco smoke in the USA to be approximately 5.7%. This value is based on a RR for lung cancer for passive smoking in never smokers of 1.3, similar to that reported above of 1.24. A similar estimate of PAR for Australia was not available, however, this data suggests 5.7% of lung cancer deaths per year could be alleviated by removal of exposure to environmental tobacco smoke.

Evidence of the different forms of tobacco smoking was also identified. The evidence suggests mentholation of cigarettes represents no difference in risk beyond that imposed


by the smoking of normal, un-mentholated cigarettes. Conversely, the available evidence suggests water pipe smoking represents an increased risk of lung cancer. However, the evidence upon which this conclusion is based is not strong.

All of the results, particularly those where the result is not as pronounced as it is for active smoking, must be considered in light of the quality of evidence it is based upon. Most of the information is based upon retrospective case control studies, which the meta-analysis by Gandini et al.31 showed to be a significant source of heterogeneity in results that tended to overestimate reported values of risk. In most of these studies, information is dependent on subject recall and on the investigators accurately being able to record the smoking status of individuals, both now and in the past. For example, almost all referent categories in the analyses used never-smokers, however, it was unclear in most reports whether passive smoking had been adjusted for in these groups, and the extent to which other potential risk factors for lung cancer had been taken into account.

4.4 Conclusions4.4.1 Hazard identification

Tobacco smoking is carcinogenic to humans (Group 1 carcinogen). There is sufficient evidence to suggest that as well as cancer of the lung, tobacco smoking also causes cancer of the oral cavity, naso-, oro- and hypopharynx, nasal cavity and paranasal sinuses, larynx, oesophagus, stomach, pancreas, colorectum, liver, kidney (body and pelvis), ureter, urinary bladder, uterine cervix and ovary (mucinous), and myeloid leukaemia. Also, a positive association has been observed between tobacco smoking and breast cancer in women. Parental smoking causes hepatoblastoma in children. Also, a positive association has been observed between parental smoking and childhood leukaemia (particularly acute lymphocytic leukaemia).39

Second-hand tobacco smoke is carcinogenic to humans (Group 1 carcinogen). Second-hand tobacco smoke causes cancer of the lung. Also, a positive association has been observed between exposure to second-hand tobacco smoke and cancers of the larynx and the pharynx.39

4.4.2 Risk assessment

Evidence indicates smoking, both active and passive, causes lung cancer. Active smoking of cigarettes imposes a significant increase in the risk of lung cancer in individuals, with current smokers approximately nine times and former smokers approximately four times more likely to develop lung cancer than people who have never smoked.

Passive smoking also increases the risk of lung cancer, whether people are exposed to ambient smoke in the work place, or by their spouse. Despite the increase in risk reported due to passive smoking of tobacco, it still only represents approximately 7% of the risk of that imparted by active smoking.


4.5 Methodological quality of studiesIndividual critical appraisal checklist items are shown below in Table 4.8

Table 4.8 Active smoking and passive smoking: Methodological quality of included studies

Study Study Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Total (Y) Include/exclude

Akl et al. 2010 Systematic review Y Y Y Y Y Y Y Y Y Y 10 Include

Boffetta et al. 2000 Meta-analysis Y U N/A U Y Y Y Y Y Y 7 Include

Boffetta 2002 Meta-analysis Y N U Y U U U Y Y Y 5 Include

Gandini et al. 2008 Meta analysis Y U Y Y Y Y Y Y Y Y 9 Include

Lee 2011 Systematic review Y Y Y Y Y Y Y Y Y Y 10 Include

Stayner et al. 2007 Meta-analysis Y Y Y Y Y U U Y Y N 7 Include

Taylor et al. 2007 Meta-analysis Y N U Y Y Y Y Y Y Y 10 Include


Akl et al. 2010

The objective of this systematic review was clearly stated. The search explicitly covered Medline (1950 onwards), EMBASE (1980 onwards) and ISI the Web of Science. This review followed Cochrane Collaboration methodology for conducting systematic reviews, i.e. using a very sensitive and comprehensive search strategy, a duplicate and independent selection process, a duplicate and independent data abstraction process, and a rigorous appraisal of the methodological quality of included studies. Data analysis was adequately described with appropriate methods to combine studies. Recommendations were supported by the data presented and the authors provided clear directives for future research.

Boffetta et al. 2000

The objective of this meta-analysis was clearly reported. The search strategy was not reported; in addition, the sources of studies were inadequate with only one database (Medline) searched. The search did not include language restriction or year of publication. Assessing the eligibility of each article for inclusion in meta-analysis was not clearly reported; and also for data extraction process. Appropriate methods were used to combine the studies for a pooled RR. The recommendations provided were congruent with the data reported; and the authors also provided specific directives for further research.

Boffetta 2002

The objective of this meta-analysis was clearly stated. The search strategy was not reported, and only one database (Medline) was searched. The most recent date of publication included was December 2000. Inclusion and exclusion criteria were described adequately; however, details were lacking on criteria for appraising studies. It is unclear whether the appraisal was conducted by two independent reviewers. The methods used to minimise errors in data extraction were not provided. Data analysis was adequately described with appropriate methods to combine studies and methods to investigate heterogeneity when detected. Recommendations were supported by the data presented and the authors provided specific directives for future research.

Lee 2011

The objective of this systematic review was clearly stated. In addition to Medline database the searched was also extended to Scopus, Scirus, Science Direct, Academic Search Complete, and Google Scholar. This review followed the PRISMA guideline for reporting systematic reviews; the appraisal was conducted by two independent reviewers. The methods used to minimise errors in data extraction were provided. Data analysis was adequately described with appropriate methods to combine studies and methods to investigate heterogeneity when detected. Recommendations were supported by the data presented and the authors provided specific directives for future research.

Stayner et al. 2007

The objective of this meta-analysis was clearly stated and described with justification for updating the earlier meta-analyses, which did not include exposure-response analyses and no clear differentiation between smokers and never smokers. The search strategy was appropriate; and the sources of studies were adequate because two major databases (Medline and Embase) searched. The criteria for including studies were adequate; however, the search was restricted to English language publications. Assessing the


eligibility of each article for inclusion in meta-analysis was clearly reported; however cross checking process to minimise errors was largely unclear. Also the methods used to minimise errors in data extraction were not clear. Appropriate methods were used to combine the studies for a pooled RR. The recommendations provided were congruent with the data reported; however, the authors did not provide any specific directives for further research.

Taylor et al. 2007

The objective of this meta-analysis was clearly stated and described with justification for updating as earlier meta-analyses according to continent and study type. The search strategy was appropriate. The sources of studies were adequate with two major databases (Medline and Embase). Publications during 1981 - 2006 were included. The most recent date of publication included was the year 2006. All citations in each study were reviewed. Moreover, to capture further articles relevant to the topic, experts in the field of passive smoking were approached. However, the language restriction was not reported. Inclusion and exclusion criteria were explicitly reported in terms of definition of never smokers, spousal exposure. The appraisal was conducted by two independent reviewers. The methods used to minimise errors in data extraction were not provided. Data analysis was adequately described with appropriate methods to combine studies and methods to investigate heterogeneity when detected. Recommendations were supported by the data presented and the authors provided specific directives for future research.


5 Risk factor: Asbestos exposure5.1 IntroductionAsbestos is the collective name of a group of six naturally-occurring silicate minerals that are made up of fine, fibrous crystals. These six different minerals appear in two types based on their physical characteristics, including diameter and length. There is the longer and narrower serpentine mineral chrysotile (also known as ‘white asbestos’), and the five amphibole minerals, which are comparatively shorter and wider: amosite and actinolite (‘brown asbestos’); anthophyllite and crocidolite (‘blue asbestos’); and tremolite.40

Asbestos fibres have many useful qualities: they are strong and flexible, resistant to fire and chemical attack, and have good insulating properties. Asbestos is also relatively cheap to mine and process.40 Despite its once common use, particularly in building materials, asbestos is now recognised as a toxic material responsible for the development of a number of illnesses. Inhalation of asbestos, in sufficient doses, causes three serious health disorders: asbestosis, lung cancer and mesothelioma.41 It is worth noting that mesothelioma is the disorder most commonly associated with exposure to asbestos. As mesothelioma is confined to the lung pleura, or the lining of the lung, it is not considered as lung cancer. It usually takes 20-40 years between exposure to asbestos fibres and the onset of lung cancer.41 Due to the recognised health risks associated with asbestos, there has been a general decline in world production and consumption of asbestos since the peak of its use in the 1970s. However, this is not the case in all countries, with asbestos use actually on the increase in some Latin American and Asian countries (including China), in particular, the use of chrysotile or white asbestos (IARC 2009 cited in IARC 2012).40

Chrysotile is the most common type of asbestos currently produced and used globally.42 However, as chrysotile persists for less time in the environment, there has been some debate regarding whether it poses as significant a risk of lung cancer as exposure to the amphibole series of minerals. In China, chrysotile continues to be mined extensively, and large numbers of workers remain exposed to high levels of chrysotile in factories and industry.43

In Australia, asbestos was used throughout the 20th Century and most extensively between 1945 and 1980.44 During this period, most public buildings and about one third of private dwellings contained asbestos in the form of concrete, asbestos cement sheeting, vinyl floor coverings, lagging of pipes and boilers, and insulation. Asbestos has also been mined, if only for brief periods, in Australia. Up until 1939, more chrysotile than amphibole asbestos was mined.45 All asbestos mining in Australia ended in 1983 and its use was generally phased out from 1980. Asbestos was banned from use in building products in 1989, though it remained in gaskets and brake linings until more recently. Asbestos was prohibited completely from 31 December 2003, and cannot be imported, used or recycled.44 Strict precautions now govern the removal and disposal of asbestos and asbestos-containing materials in Australia.

Despite the phasing out of asbestos in Australia, research on the relationship between asbestos and lung cancer, and how to mitigate these effects, remains a priority. This is primarily due to the apparent long latency between exposure and disease,46 and also the risk of exposure associated with home renovation, building demolition work and construction. The common use of asbestos in building materials means that even people who have never worked in mines or industry may be at risk of exposure.


There is a substantial body of epidemiological research on the association between asbestos exposure and lung cancer, the focus of which has changed over time. Early studies concentrated on whether asbestosis is a necessary precursor condition for asbestos exposure to result in tumour development in the lungs, how risk differs in populations with and without asbestosis and the magnitude of risk in populations with occupational exposure. More recently, research has focused on whether non-occupational environmental exposure presents a risk, the risk in smokers compared with non-smokers, and the interaction between asbestos exposure, smoking and lung cancer risk. The question of whether chrysotile exposure presents as significant a risk of lung cancer as exposure to the amphibole series of minerals remains an area of research and debate.

In the initial search of the literature undertaken for this risk factor, 66 studies were identified as potentially relevant to understand and quantify the relationship between asbestos exposure and lung cancer risk. In second and third searches, 14 additional studies were identified. This brought the total to 80 studies, 64 of which were included in the recently released IARC monograph.40 Following the review protocol, the IARC 2012 monograph was used as the core source of abstracted data and the studies included in the monograph were not retrieved unless required. Overall, data from 56 of the studies referred to in the IARC 2012 monograph is included here. Upon full text analysis, four of the additional 14 studies identified were excluded for not meeting the eligibility criteria, which left ten studies for critical appraisal. Of the ten studies critically appraised, four47-50 were excluded due to low methodological quality (see Table 5.11, see Appendix E). The review for this risk factor is therefore based on six studies42, 43, 46, 51-53 plus the IARC 2012 monograph, which represent a variety of study types. The majority of studies reported on occupational exposure as opposed to non-occupational exposure. The review with a meta-analysis by Lenters et al.46 focuses on differences in the quality of exposure measurement as a source of variation in lung cancer risk estimates (per 100 fibre-years/mL of exposure) using 19 cohort studies on occupational asbestos exposure offering lung cancer risk quantification. The Yano et al.42 study is a nested case control study presenting data from a cohort of workers exposed to chrysotile asbestos whilst working in an asbestos textile factory in China. The remaining four studies are cohort studies, two of which52, 53 report data drawn from workers and residents of the crocidolite mine and mill in Wittenoom, Western Australia. The Wang et al.43 study presents data from a cohort of factory workers exposed to chrysotile asbestos in China. Frost et al.51 is based on asbestos exposure data drawn from a survey of asbestos workers in the United Kingdom. Table 5.1 presents the main characteristics of the included studies.


Table 5.1 Study characteristics relevant to the association between asbestos exposure and lung cancer



Analysis Association/Risk

IARC Monograph – 100C/ IARC Review (2012)

Presents lung cancer risk estimates from 64 studies (case control and cohort studies) published through 2009. Most (not all) all use all male samples. Multi-country coverage.Data included here from 56 studies.

Review of existing evidence on lung cancer risk from asbestos exposure by expert panel with objective of identifying lung cancer risk estimates from case control and cohort studies. Based on this conclusion drawn on whether asbestos causes lung cancer.

Non occupational and occupational exposure but mostly latter. Occupational exposure cohort studies grouped by occupation type. Exposure measured in various ways across studies. Exposure categories (duration and intensity) relating to risk estimates also different across studies. Type of asbestos exposure stated for some studies.

Studies cover a range of lung cancers. For most type not stated.

No pooled or meta-analysis.7 studies reported RR by gender status. No risks by smoking status presented aside from Gustavsson et al (2002).

Range in risk estimates reported for occupational and non-occupational exposure.Overall risk occupational exposure from cohort studies – RR (95% CI)Lowest risk: 1.12 (0.56-2.0). Highest risk: 4.2 (p<0.01)Overall risk occupational exposure from case controls – OR (95% CI)≥ 10 yrs exposure – lowest risk: 1.5 (1.0-2.4); highest risk 2.1 (1.6-2.9)Overall risk non-occupational exposure from case controls and cohort studiesLowest risk: SMR 0.99 (95% CI 0.78-1.25); Highest risk: OR 6.8 (95% CI 2.0-23.1)Risk estimates for gender and smoking status are reported in the text.

Lenters et al. 2011Review with meta-analysis

19 cohort studies with quantitative estimates of cumulative asbestos exposure. Studies incrementally excluded based on different aspects of quality of exposure measurement.

Cumulative exposure categories and corresponding risks extracted from 19 studies. The relative risk and exposure response slope are calculated for each 100 fibre/years/mL of exposure. Stratification by

Occupational exposure. Not stated. Liner regression modelling and meta-regression models were fitted using restricted maximum likelihood (REML) estimation with SAS PROC MIXED).Exposure-response slopes (or relation denoted KL in asbestos literature) calculated

Meta-analysisRR (95% CI)1.66 (1.53-1.79) for each 100 fibre-years/mL of exposure.Meta-KL X 100 (95% CI)0.13 (0.04 – 0.22)Meta-analysis based on the two highest quality exposure measurement studies:





exposure measurement quality undertaken to determine whether source of difference in the exposure response slope.

using linear relative risk regression models. KL is slope of exposure response relationship, or lung cancer potency factor.

Meta-KL X 100 (95% CI)0.55 (0.11-0.99)Suggests that higher quality exposure measurement increases lung cancer risk estimates.

Yano et al. 2010Nested case control study/China

41 male textile worker cases from seven workshops (90% smokers all died from lung cancer) 205 male controls (73% smokers). Matched for age (+-5 yrs). Ave age (cases and controls) 66 yrs. Worked (1972-1976) in a textile plant where high chrysotile exposure. Cohort recruitment over same period.

Incidence density sampling used to identify controls. Smoking information by interview. Exposure in 3 groups based on job categories and measurement of levels at job/work stations. Risk by smoking status. Smokers defined as smoking at least 1 cig/day for 6 months. Dose response and smoking asbestos interaction.

Occupational exposure to chrysotile. Mean duration of exposure 25 yrs. Overall subjects heavily exposed: Measures suggest total dust concentrations in work areas always exceeded 3mg/m3 and personal samples taken for fibre analysis exceeded 3 fibres/ml except in the cement workshop where fibre count was low. Three exposure categories: low, medium and high (no more details on exposure level in each).

Not stated. ORs (adjusted for smoking and age) estimated using conditional logistic regression.Joint effect of asbestos exposure and smoking on lung cancer analysed using a conditional logistical model.

Overall OR (95% CI)Low exposure: 1.00 (reference)Medium exposure1.25 (0.47-3.31)High exposure3.66 (1.61-8.29)Risk by smoking status OR (95% CI)Low-exposure non-smoking group used as reference.Smoking group high exposure 10.39 (1.34-82.4)Non-smoking group high exposure 5.23 (0.50 -54.58)Synergy index (S) 1.55 (95% CI 0.43-5.67) implying a combined effect that is greater than additive.No exposure duration effect except for smokers in high exposure category.

Reid et al. 2005Prospective cohort study/Wittenoom Western

Former male and female workers (n=1196) and residents (n=792) of the crocidolite mining and milling town of Wittenoom who were

Primary objective of study to examine lung cancer risk from exposure in subjects with asbestosis and without asbestosis. Variation in risk by

Occupational and non-occupational exposure to crocidolite. Cumulative exposure measured in fibre-years per ml. Used data from

Not stated. Cox proportional hazards used to model risk of lung cancer incidence.

Risk by smoking status (OR 95% CI)Never-smoker1.00 (ref)Past smoker (no. cigs per day not stated)





Australia also participants in a cancer prevention programme (1990-1996).

smoking also examined.Smoking information by interview.

measurement of dust in mine and mill and job history records. Cumulative exposure on average 11 fibre/ml-year.

9.53 (1.29-70.6) p = 0.027Current smoker (no. cigs per day not stated)26.5 (3.54-198.5) p= 0.001

Reid et al. 2006Retrospective cohort study/Wittenoom Australia

2935 former workers of the crocidolite mine and mill at Wittenoom Western Australia

Participants responded to a questionnaire on smoking issued in 1979 and for whom there were estimates of asbestos exposure.

Occupational exposure to crocidolite asbestos. Cumulative exposure measured in fibre-years per ml. Used data from measurement of dust in mine and mill and job history records. No further details provided.

Not stated. Conditional logistic regression used to relate asbestos exposure, smoking and risk of lung cancer.

Risk by smoking status OR (95% CI)Never smokers used as the comparator.Past smokers (ceased smoking within 6 years of survey)22.1 (5.6-87.0)Past smokers (ceased smoking 20 yrs or more ago)1.9 (0.50-7.2)Current smokers (<20 cigs per day)6.8 (2.0-22.7)Current smokers (>20 cigs per day)13.2 (4.1-42.5)

Wang et al. 2012Prospective cohort study/China

577 asbestos (chrysotile) factory workers and 435 controls (no work with asbestos) followed up from 1972-2008. Males.

Air samples taken in 1999 from the workshops in factory to measure chrysotile fibre and dust concentrations. Personal and area samples taken in 2002. > exposure in raw material and textile sections relative to rubber and cement. Data used to classify workers into 3 exposure

Occupational chrysotile exposure. Risks for 3 categories of exposure: low medium; high. Defined based on measures of exposure in different job categories and stations. No further details provided.Ave. exposure duration 25 years.

Lung cancer type not stated.

Overall lung cancer risk and by smoking status computed. Interaction between asbestos exposure and lung cancer examined using synergy index.Cox proportional hazard models constructed to estimate HRs of cause-specific mortality taking into account age, asbestos exposure level and smoking.

Overall risk HR (95% CI)Control workers (smokers and non-smokers) used as reference.All exp. categories: 3.31(1.60-6.87)Low exp.: 1.94 (0.84-4.46)Med exp.: 3.49 (1.41- 8.67)High exp.: 6.01 (2.74-13.19)Risk by smoking status HR (95% CI)Non-smoking control workers used as reference: 1.00 (ref)Non smokers





categories. All exp categories: 7.52 (0.9-62.79)Smokers (1 cig/day for six years)All exp. categories: 17.35 (2.38-126.57)Exposure-response trend found in smokers and non-smokers.Synergy index 1.4 (95% CI 0.73-3.98)

Frost et al. 2011Retrospective cohort study

98 912 asbestos workers recruited into asbestos worker survey in the UK from 1971 and followed up to December 2005.

Risk of lung cancer estimated using cause of mortality data and general population as a reference. Risk by smoking status (former, current never) calculated. Interaction between smoking and asbestos exposure.Smoking information by interview.

3 occupational (various duration) exposure categories:Low < 10 yrs low exposure jobs;Medium 10-29 yrs;High ≥ 30 yrs.Average exposure for cohort 11 years.

Type of lung cancer not stated.

Poisson regression used to estimate risk of lung cancer mortality. Interaction between smoking and asbestos exposure examined using synergy index and multiplicatively indices, which test the hypothesis of additive and multiplicative interaction respectively.

Risk by smoking status (RR 95% CI)Never smokersLow exp.:1.00Medium exp.: 1.9 (0.8-4.3)High exp.: 1.6 (0.6-4.2)Former smokers (1 pack/day on average for 17 yrs)Low exp.: 5.6 (2.7-11.7)Medium exp.: 6.5 (3.2-13.3)High exp.: 9.7 (4.7-20.0)Current smokers (1 pack/day on average for 35 yrs)Low exp.: 18.8 (9.4-37.9)Medium exp.: 22.7 (11.3-45.6)High exp.: 26.2 (13.0-53.1)Synergy index 1.4 (95% CI 1.2-1.6)


5.2 Results5.2.1 Occupational exposure to asbestos and risk of lung cancer

Lung cancer risk estimates associated with occupational asbestos exposure extracted from the IARC monograph40 plus two other identified studies are presented.42, 43 Where identifiable in the IARC monograph,40 both asbestos type and details of exposure intensity and duration are presented. As dose response relationships were presented for the majority of case control studies, for this risk factor, the results have been separated by study design. In some instances CIs are also missing from the data source. Many studies from which the risk estimates are drawn included only male subjects.

Cohort studies

Included studies provide lung cancer risk estimates from studies of several types of occupational exposure. This includes workers exposed in asbestos mines, various forms of manufacturing, and those exposed in other occupations such as shipbuilding, railway construction and plumbing. Extracted risk estimates are presented despite the IARC40 report not explicitly stating whether included studies adjusted for smoking. Similarly, information on the duration and intensity of exposure for the cohort studies was difficult to ascertain in most cases, however, most of the included cohorts report on participants exposed during the 1940s through to the late 1980s when asbestos mining and use was commonplace internationally. Follow up was variable and ranged from 1 to more than 30- years across studies.

Analysis of the included studies presenting SMR data clearly indicate exposure to asbestos whilst mining crocidolite significantly increases risk of lung cancer mortality compared to population standard (Figure 5.1).

Figure 5.1 Meta-analysis of effect estimates of cohort studies presenting risk of lung cancer with occupational exposure in crocidolite miners, IARC monograph40

Armstrong et al from Wittenoom, WA; Sluis-Cremer et al, South Africa.

Lack of reported variance data precluded meta-analysis of data pertinent to chrysotile miners. The values reported by the included studies indicate it may represent a significant risk factor for lung cancer, however, it does not represent as great a risk of lung cancer as crocidolite (blue asbestos), Table 5.2. It is unclear whether the risk values presented are of statistical or clinical significance, though the inverse relationship with duration of minimum exposure highlights that heterogeneity will impact any consideration of combined studies.


Table 5.2 Risk estimates of lung cancer due to occupational asbestos exposure – Mining worker cohort studies, IARC monograph 40

Reference Exposure and cohort population Risk estimate(95% CI not reported)

Liddell et al. 1997Quebec, Canada

Chrysotile asbestos miners (males)>1 month work in the mine

SMR1.37

Piolatto et al. 1990Balangero, Italy

Chrysotile and balangeroite miners (sex not specified) >1 yr work in the mine

SMR1.1

Overall, workers exposed to asbestos (various types) in the manufacturing industry are at significantly greater risk of lung cancer than manufacturing workers not exposed to asbestos (Table 5.3; Figure 5.2). Risk estimates reported by individual studies was variable, ranging from no significant risk amongst workers exposed to chrysotile in the US (Table 5.3 c.f. Parnes et al. 1990 cited in IARC monograph)40 to increased relative risk of three to four times (c.f. Table 5.3).

Unfortunately, lack of available exposure data in many cases makes any thorough consideration of sources of heterogeneity difficult to achieve. Meta-analysis of subgroups of manufacturing workers suggests risk of lung cancer is similar irrespective of industry type, be it exposure in textile, insulation or working with cement production (Figure 5.2). Only one included study provided sufficient data for inclusion in meta-analysis related to risk of lung cancer resulting from exposure in insulation manufacturing (Figure 5.2; Levin et al. 1998 cited in IARC 2012).40 Despite this, consideration of the elevated relative risk estimates from the remaining studies presented in Table 5.3 from insulation workers (Selikoff & Seidman 1991; Acheson et al.1994 and Berry et al. 2000 cited in IARC 2012).40 would indicate that this sub-group of manufacturing workers may be at greater risk than their counterparts who encounter asbestos in the manufacture of textiles and cement.

Table 5.3 Occupational asbestos exposure and risk estimates of lung cancer from manufacturing worker cohort studies, IARC monograph40 unless otherwise stated

Reference Exposure and cohort population Risk estimate

Selikoff & Seidman 1991Canada, United States.

Insulation workers (males) exposed to asbestos (type not stated) in factory

RR 4.35 (p < 0.001)

Acheson et al. 1984Uxbridge, United Kingdom

Insulation workers (males) exposed to asbestos (type not stated) in factory

RR 2.0

Berry et al. 2000East London, UK

Asbestos insulation factory workers (males) exposed to crocidolite, amosite and chrysotile >1 month work in factory

RR 3.6

Peto et al. 1985Rochdale, England

Asbestos (chrysotile and crocidolite) textile workers (males and females)

RR 1.31 (p < 0.01)

Hughes et al. 1987New Orleans, LA, USA

Asbestos (chrysotile, crocidolite & amosite) cement workers (sex not stated)

RR 1.34

Finkelstein 1989Ontario, Canada

Friction material workers exposed to asbestos (type not stated, females and males) >1 yr work in factory (NB. Incl. mesothelioma)

RR 1.4



Parnes 1990New York, USA

Friction (males and females) material workers exposed to asbestos (chrysotile)

RR 0.95

Zhu & Wang 1993China

Generic asbestos workers (males & females): from 8 factories (chrysotile exposure) >15 yr exposure

RR 4.2 (p < 0.01)

Acheson et al. 1982Lancashire, UK

Generic asbestos workers (females) exposed to chrysotile and crocidolite

RR 2.0

Hodgson & Jones 1986England and Wales, UK

Generic asbestos workers (males) exposed to various types of asbestos

RR 1.30 (p < 0.01)

Enterline et al. 1987USA

Generic asbestos workers (males) exposed to amosite, chrysotile and crocidolite (NB. Incl. mesothelioma)

RR 2.71 (p < 0.01)

Other studies (not in the IARC Monograph40


Wang et al. 2012China

Male workers in an chrysotile manufacturing factory. Air samples showed fibre and dust concentrations high. 3 categories of exposure: low; medium; high. Classification based on job category. No further exposure details provided.Average exposure duration 25 years.

HRControl workers (smokers and non-smokers) the reference.All exp. categories: 3.31(1.60-6.87)Low exp.: 1.94 (0.84-4.46)Med exp.: 3.49 (1.41- 8.67)High exp.: 6.01 (2.74-13.19)Risk by smoking status (see below).Exposure-response trend found in smokers and non-smokers.


Figure 5.2 Meta-analysis of effect estimates of cohort studies presenting risk of lung cancer with occupational exposure in manufacturing workers, IARC monograph40

Levin et al amosite, Texas, USA.Pira et al > 1 mth exposure, Italy. Hein et al chrysotile USA. Loomis et al USA,Raffn et al, chrysotile and lesser amosite, crocidolite, Denmark. Giaroli et al & Botta et al, chrysotile, crocidolite, Italy. Albin et al chrysotile, crocidolite, Sweden.

Workers exposed to asbestos in other sectors of manufacturing, including rail, shipyard workers and plumbers, also show a significantly increased risk of lung cancer of some 34% compared with non-exposed workers (Figure 5.3). Beyond the differences in worker type, the significant heterogeneity observed may be due to differences in other determinants of risk such as duration, intensity and type of exposure.

Figure 5.3 Meta-analysis of effect estimates of cohort studies presenting risk of lung cancer with occupational exposure in shipyard, rail yard workers and plumbers, IARC monograph40

Finkelstein and Verma in plumbers and pipe fitters no detail of exposure or asbestos typeBattista et al in Railway workers exposed to Chrysotile and crocidolite


The remainder of studies in shipyard workers. Tola et al >1yr; Sanden & Jarvholm exposed to Chrysotile crocidolite and amosite. Other details not provided.

The risk estimates presented in Figure 5.2 and Figure 5.3 can be considered alongside the results of a recent meta-analysis by Lenters et al.46 Using many of the same studies presented here amongst the 19 included cohort studies, these authors report a RR for lung cancer of 1.66 (95% CI 1.53-1.79) for each 100 fibre-years/mL of exposure. Using sensitivity analysis, studies were excluded based on aspects of exposure measurement. This revealed a clear trend to indicate that as studies with poorer exposure measurement were excluded, lung cancer risk per unit of asbestos exposure increased. This raises the possibility of different approaches to exposure measurement and rigour in this regard, as a further potential explanation for the variation in estimates of lung cancer risk found in the literature.

Exposure response relationship of risk of lung cancer from case control studies

Case control studies were identified that informed the effect of different levels of exposure to asbestos, both of duration and intensity. All the studies matched cases and controls on the basis of age and sex at minimum and adjusted for smoking as well as a range of other potential confounders including socio-economic status, air pollution and radon. In almost all studies, assessment of exposure was done by interviewer assisted questionnaire. Data was extracted only from those studies in the 2012 monograph for which it was explicitly stated that smoking status of participants had been addressed in some way. Yano et al.42 report on subjects exposed to chrysotile asbestos whilst the 2012 monograph did not provide detail concerning type of asbestos exposure in most cases. Duration of exposure was reported in a number of ways by the included studies, including in years and number of hours of work, or lifetime exposure categories. Those studies that reported on intensity of exposure used categories, low to high, often poorly defined.

The data in Table 5.4 details risk estimates across years of occupational exposure to asbestos. Close consideration of the exposure categories presented would suggest that onset of a statistically significant increase in risk of lung cancer requires approximately 10 years of occupational exposure to asbestos. Risk increases concomitant with increased duration of exposure. This relationship is confirmed by those studies measuring duration of exposure in lifetime hours of exposure to asbestos (Table 5.5). No data was available to allow consideration of the impact of any variations in intensity or level of exposure across these studies.

Table 5.4 Relative risk estimates of lung cancer due to occupational asbestos exposure – Case controls with exposure measured in number of years, IARC monograph40

Reference Exposure Risk Estimate OR (95% CI)

Morabia et al. 1992Sex not stated. 9 metropolitan areas/ US

Never: 1.00< 10 yrs≥ 10 yrs

1.002.0 (1.4-2.8)2.1 (1.6-2.9)

Parkin et al. 1994Male sample. South Africa.

NeverEver< 6 yrs≥ 6 yrs

1.000 0.8 (0.5-1.0)0.7 (0.4-1.0)0.8 (0.4-1.2)



Wilkinson et al. 1995Sex not stated. London/England

Never<5 yrs<10 yrs≥10 yrs

1:001.6 (0.9-2.8)2.2 (1.2-4.3)1.5 (1.0-2.4)

Bruske-Hohlfeld et al. 2000Sex not stated. Bremen & Frankfurt/Germany.

Ever>0-3 yrs>3-10 yrs>10-20 yrs>20-30 yrs>30 yrs

1.4 (1.2-1.6)1.2 (0.9-1.7)1.2 (1.0-1.5)1.5 (1.2-1.8)1.5 (1.1-1.9)1.9 (1.4-2.4)

Hauptmann et al. 2002Males and females. Bremen & Frankfurt / Germany.

0-1 yrs1-2 yrs3-7 yrs≥8 yrs

1.01.1 (0.8-1.5)1.0 (0.7-1.4)1.3 (0.9-1.8)

Pohlabeln et al. 2002Males. Bremen & Frankfurt/Germany

0≤1 yrs1≤10 yrs10 plus yrs

0.9 (0.6-1.3)1.3 (0.8-2.2)1.9 (1.1-3.4)

Pintos et al. 20082 studies both male samples. Montreal. Pooled analysis using data from both studies.

AnyNon substantialSubstantial levelSubstantial < 20 yrsSubstantial > 20 yrs

1.21 (0.98-1.49)1.14 (0.91-1.42)1.90 (1.11-3.24)1.37 (0.69-2.74)2.98 (1.28-6.96)

Table 5.5 Case controls with exposure measured in number of hours, IARC monograph40


Ahrens et al. 1993Male sample. Bremen & Frankfurt Main/Germany

0- ≤ 282 lifetime hrs283-≤1400 lifetime hrs1400-≤5 580 lifetime hrs>5 580 lifetime hrs

1.1 (0.6-1.9)1.1 (0.6-2.1)1.9 (1-3.5)1.9 (1-3.4)

Jockel et al. 1998Sex not sated. Bremen & Frankfurt Main/Germany

≤940 lifetime working hrs940 ≤5 280 lifetime working hrs>5 280 lifetime working hrs

1.0 (0.7-1.4)1.4 (1.0-2.0)1.5 (1.0-2.1)

In the absence of duration response meta-analyses, combination of comparable exposure data across the included studies of periods of less than 10 years and also greater than 10 years (Table 5.4) indicated a significant increase in risk of lung cancer that appeared to increase with greater duration of exposure (Figure 5.4 a & b). However, data less than 10 years appeared heterogeneous (Figure 5.4a) and must be interpreted with caution, whereas the data for periods greater than 10 years is remarkably homogeneous (Figure 5.4b). This result appears consistent with those from the pooled analysis by Pintos et al. 2008 cited in IARC 201240 of substantial exposure for <20 years.


Figure 5.4 Meta-analysis of effect estimates of case control studies presenting risk of lung cancer with occupational exposure to asbestos (a) < 7-10 years, (b) > 8-10 years.

(a)

For all studies exposure category of less than 10 years has been combined except Hauptmann et al where exposure was <7 yrs.

(b)

For all studies exposure category of greater than 10 years has been combined except Hauptmann et al where exposure was ≥8 yrs. Only data from Bruske-Hohlfeld et al had a defined upper limit of 20 years.

Those studies reporting simply outright exposure to asbestos and the association with risk of lung cancer suggest similar results. Minowa et al. 1991 cited in IARC 201240 report what appears to be a marked increase in risk with a reportedly ‘suspected’ exposure. Whilst Kreuzer et al. (1991 cited in IARC 2012)40 clearly indicates an increased risk relative to those never exposed, however no details of exposure are provided. Few studies provided informative detail related to intensity of exposure to asbestos. A study of exposure to chrysotile in industry workers in China42 with extended follow-up revealed a marked, though imprecise, increase in risk in textile workers with increasing intensity of exposure (Table 5.6).

Table 5.6 Risk estimates of lung cancer due to occupational asbestos exposure – case-controls with categorical exposure, IARC monograph40 unless otherwise stated


Minowa et al. 1991Male sample. Naval factory workers/ Yokosuka City Japan

Not exposedSuspectedExposed

1.001.72.5 (p<0.05)

Kreuzer et al. 1999Male sample. Bremen &Frankfurt Main/Germany

Ever vs Never: Age < 45yrs OR 2.4 (1.4-4.0)Age 55-69 OR 1.5 (1.2-1.7)


Additional study, not in IARC monograph 40


Yano et al. 2010Case control study nested in a cohort study/China.

Exposure classified into 3 groups based on job types and dust/fibre concentration measured in work locations. Low (reference); Medium (those in rubber section and maintenance and cleaning); High (workers in the raw material and textile sections)Ave exposure duration 24.8 yrs.Total dust concentrations in work areas > 3 mg/m3 and personal samples taken for fibre analysis > 3 fibres/ml except for cement workshops.

Low: 1.0 (reference; smokers & non-smokers)Medium: 1.25 (0.47-3.31)High: 3.66 (1.61-8.29)No effect of age or exposure duration observed.

5.2.2 Non-occupational exposure to asbestos and risk of lung cancer

Non-occupational exposure includes exposure through inhalation of asbestos fibres from outdoor air and, to a lesser extent, indoor air. It also includes exposure through ingestion of drinking water that has been contaminated by asbestos through erosion of natural deposits, erosion of asbestos-containing cement pipes, or filtering through asbestos-containing pipes. Relative to the studies that have quantified the risk of lung cancer associated with occupational asbestos exposure, there have been few studies that have quantified lung cancer risk from exposure beyond the workplace. The results of three identified studies (Camus et al.1998; Luce 2000 and Mzileni, 1999 cited in IARC 2012)40 are presented in Table 5.7.

Two studies investigated exposure from air due to living in close proximity to asbestos mines (Table 5.7). Increased risk of lung cancer in males was reported with high exposure to crocidolite and amosite (amphibole asbestos) and for females exposed to moderate levels (Mzileni, 1999 cited in IARC 2012).40 In contrast, no increase in risk was observed amongst a cohort working in and living in close proximity to a chrysotile mine who may be exposed to fibres in the ambient air (Table 5.7; Camus et al. 1998 cited in IARC 2012.40

Exposure to asbestos due to living in homes with whitewash containing tremolite did not appear to increase risk of lung cancer. Risk did appear to increase in both sexes, and particularly in women, with more than 20 years exposure, however the imprecision of results reported, more than likely due to a low number of observed cases, does not allow any definitive indication of the magnitude of risk (Luce et al. 2000 cited in IARC 2012).40


Table 5.7 Non-occupational asbestos exposure and risk of lung cancer, IARC monograph40

Reference Exposure Risk estimate (95% CI)

Mzileni et al. 1999Case controlNorthern Province Garankua Hospital South Africa

Exposure to crocidolite and amosite due to living close to mine. Males and females. Three categories of exposure: none, moderate, heavy. No further definitions of categories (i.e. no details on duration or level of exposure).

Study found a significant positive association. Separate measures for males and females. Association highest in females.FemalesNo exposure: 1.0 (ref)Moderate exposure: OR 1.1 (0.3-3.9)Heavy exposure: OR 5.4 (1.3-22.5)Test for trend: p=0.02MalesNo exposure: 1.0 (ref)Moderate exposure: OR 2.1 (1.0-4.4)Heavy exposure: OR 2.8 (0.7-10.4)Test for trend: p=0.2

Camus et al. 1998Cohort study Quebec Canada.

Exposure due to living close near chrysotile mine and with mine workers. Risk estimate developed for an estimated average cumulative exposure in the population. Cumulative exposure = mean intensity and duration of exposure. Range of estimated cumulative exposure 5-125 fibre-yr/ml 1970 - 1989. mean 25 fibre-yr/ml

Risk of mortality from lung cancer in exposed compared to that of women in 60 control areas with normal/low exposure.No association found:SMR 0.99 (0.78-1.25)

Luce et al. 2000Case controlNew Caledonia

Exposure to tremolite due to living in homes with whitewash containing tremolite. Exposure categories by number of yrs of exposure.

FemalesEver vs never: OR 2.5 (1.0-6.2)< 20 yrs: OR 0.6 (0.2-2.6)≥ 20 yrs OR 6.8 (2.0-23.1)MalesEver vs never: OR 0.9 (0.5-1.5)< 20 yrs: OR 0.4 (0.2-1.0)≥20 yrs OR 1.4 (0.7-2.8)

5.2.3 Asbestos exposure, gender and risk of lung cancer

Eight studies were identified (two case controls and six cohort studies) that reported lung cancer risk estimates by gender. The studies informing non-occupational exposure have been detailed in Table 5.7.

The remainder of prospective studies investigated differences in risk amongst males and females exposed to asbestos at work (Table 5.8). Within the individual study cohorts that investigated males and females, risk estimates appear to be generally similar between sexes except for Berry et al. 2000 cited in IARC 201240 in a cohort of English factory workers where female workers appeared to be a greater risk from exposure to asbestos. Considering the differences between study cohorts, three of the studies investigating exposure to chrysotile reported no significantly increased risk of lung cancer in either sex. The study by Pang et al. 1997 cited in IARC 201240 in China was markedly different from the other studies reporting a high risk for both females and males exposed to chrysotile.


Table 5.8 Asbestos exposure, gender and risk of lung cancer , IARC monograph40

Reference Exposure Risk estimate (95% CI)Females

Risk estimate (95% CI)Males

Meurman et al. 1994Cohort study/Finland

Occupational exposure:, Paakkila and Maljasalmi asbestos miners exposed to anthophyllite. ≥3 month exposure.

SMR2.22 (0.06-12.4)

SMR2.88 (2.27-3.60)

Smailyte et al. 2004Cohort study/Lithuania

Occupational exposure: Asbestos cement workers, mainly chrysotile exposure.

RR0.7 (0.1-4.6)

RR0.9 (0.7-1.3)

Kogan et al. 1993Cohort study/USSR

Friction products worker exposed to chrysotile asbestos. > 3 years exposure.

RR0.33

RR0.14

Pang et al. 1997Cohort study/Qingdao, China

Workers exposed to chrysotile asbestos in manufacturing. Kind of work not clear. > 1 year exposure.

RR6.8 (p < 0.01)

RR5.1 (p < 0.01)

Berry 1994Cohort Study/Feroda, UK

Workers (males and females) at a friction materials factory exposed to asbestos (chrysotile).

RR0.57 (0.29-0.99)

RRRR 1.03 (0.9-1.18)

Berry et al. 2000Cohort study, East London, UK

Male and female asbestos factory workers

RR2.55

RR7.46

5.2.4 Asbestos exposure, smoking status and risk of lung cancer

Five located studies presented risk estimates as a result of exposure to asbestos by smoking statusFADDIN EN.CITE 42, 43, 51-53 Data from a further study presented by the IARC monograph was provided by Gustavsson et al. (2002).40 Risk estimates are presented in Table 5.9.


Table 5.9 Occupational exposure to asbestos, smoking status and risk of lung cancer

Reference Exposure Risk estimate(95% CI)

Gustavsson et al. 2002 cited in IARC 2012Population based case control study/ Stockholm County Sweden.

Type of asbestos not stated. Exposure categorised in fibre/ml*yrs:>0-0.99;1-2.49;≥2.5.

Never smokers>0-0.99: 1.8 ( 0.6-5.5)1-2.49: 2.7 (0.7-9.5)≥2.5: 10.2 (2.5-41.2)Smokers 1-10cigs/day>0-0.99: 18.1 (8.2-40.4)1-2.49: 12.1 (5.1-29.3)≥2.5: 13.6 (4.6-40.0)Smokers 11-20cigs/day>0-0.99: 17.0 (8.8-32.7)1-2.49: 29.8 (15.1-58.6)≥2.5: 86.2 (28.8-258.2)Smokers >20cigs/day>0-0.99: 38.5 17.7-83.4)1-2.49: 36.8 (11.9-113.7)≥2.5: 80.6 (20.2-322.0)

Reid et al. 2005Cohort study/Wittenoom Western Australia

Occupational and residential exposure (crocidolite) due to working in mine or living near the mine (males and females). Av 330 work days of exposure. Intensity on av 12 fibre/ml. Cumulative exposure on av 11 fibre/ml-year.

RRNever-smoker1.00 (ref)Past smoker (no. cigs per day not stated)9.53 (1.29-70.6) p value 0.027Current smoker (no. cigs per day not stated)26.5 (3.54-198.5) p value 0.001

Yano et al. 2010Case control study nested within a cohort study/China

Males exposed to chrysotile in a textile factory. Classified as low (reference), medium and high based on job categories and fibre/dust concentration levels. Av. duration of exposure 24.8 yrs. Total dust concentrations in work areas > 3 mg/m3

, personal samples taken for fibre analysis > 3 fibres/ml except for in the cement workshops.

ORLow exposure non smoking group used as referenceNon smokersLow exposure: 1.00Medium exposure: not reportedHigh exposure: 5.23 (0.50-54.58)Ever smokers (defined as having smoked at least 1 cig per day for 6 months)low exposure: 3.04 (0.36-25.71)medium exposure: 4.34 (0.52-36.53)high exposure: 10.39 (1.34-82.45)


Reference Exposure Risk estimate(95% CI)

Wang et al. 2012Cohort study/China

Males exposed to chrysotile in factory. Air sample measurement showed high fibre concentrations. Three exposure categories: high; medium; low. No details on levels of exposure. Av. exposure duration 25 yrs.

HRNon-smoking control workers the reference: 1.00 (ref)Non smokersOverall (all 3 exp categories): 7.52 (0.9-62.79)Smokers (at least 1 cig/day for six years)Overall (all 3 exposure categories):17.35 (2.38-126.57)

Frost et al. 2011Cohort study/Great Britain

Various kinds of asbestos workers exposed in factories in Great Britain. Low exposure < 10 yrs; medium 10-29 yrs; high ≥ 30 yrs. Average exposure for cohort 11 years.

RRNever smokersLow exposure:1.00Medium exposure: 1.9 (0.8-4.3)High exposure: 1.6 (0.6-4.2)Former smokers (on ave 1 pack / day for 17 yrs)Low exposure: 5.6 (2.7-11.7)Medium exposure: 6.5 (3.2-13.3)High exposure: 9.7 (4.7-20.0)Current smokers (on ave 1 pack / day for 35 yrs)Low exposure: 18.8 (9.4-37.9)Medium exposure: 22.7 (11.3-45.6)High exposure: 26.2 (13.0-53.1)

Reid et al. 2006Retrospective Cohort study/Wittenoom Western Australia

Crocidolite asbestos. Cumulative exposure measured in fibre-years per ml. Used data from measurement of dust in mine and mill and job history records. No further details provided.

ORNever smokers used as the comparator.Past smokers (ceased smoking within 6 years of survey)22.1 (5.6-87.0)Past smokers (ceased smoking 20 yrs or more ago)1.9 (0.50-7.2)Current smokers (<20 cigs per day)6.8 (2.0-22.7)Current smokers (>20 cigs per day)13.2 (4.1-42.5)

The interaction between asbestos exposure and smoking has been the topic of much investigation, potentially because smoking was more prevalent during the period of greatest exposure (1943 to 1985) and particularly among the occupational groups exposed. The interaction between asbestos exposure and smoking has been reported as between additive and multiplicative. Indeed, in all of the included studies, a history of smoking significantly increased risk of disease, and data for current smokers suggests a marked and significant increased risk of lung cancer in asbestos workers who smoke.

5.2.5 Asbestosis, asbestos exposure and risk of lung cancer

As explained in the introduction, difference in the magnitude of lung cancer risk amongst exposed cohorts with and without asbestosis has been the focus of research and debate.


Table 5.10 provides risk estimates for subjects with confirmed asbestosis from two studies reported in IARC monograph40 and additional information from Reid, et al 2005.53 All of the studies reported in Table 5.10 are cohort studies that investigate the effects of occupational exposure to asbestos. The results are indicative of a significant association between asbestos exposure and lung cancer in sufferers of asbestosis. The risk appears elevated when comparison is made to risk estimates of nonsufferers.

Table 5.10 Asbestosis and risk of lung cancer

Studies in the IARC monograph 40

Reference Exposure Risk (95% CI)

Germani et al. 1999Cohort study /Italy.

Occupational exposure (textile and cement workers) mainly to chrysotile and crocidolite. Females with confirmed asbestosis.

SMR4.8 (2.7-7.8)

Szeszenia-Dabrowska et al. 2002Cohort study/Poland

Occupational exposure (monograph does not state occupations of workers). Males and females with confirmed asbestosis.

SMRMales1.68 (1.2-2.3)Females6.21 (3.3-10.6)

Additional studies not in the IARC monograph 40

Reference Exposure Risk (95% CI)

Reid et al. 2005Cohort study/Wittenoom Western Australia

Occupational exposure (crocidolite) amongst miners (males).OR presented per f/ml-year of exposure.

ORSubjects with asbestosis1.94 (1.09-3.46)Subjects without asbestosis1.21 (1.02-1.42)

5.2.6 Type of asbestos and risk of lung cancer

No attempt was made to combine studies separately on the basis of asbestos type in this review beyond Figure 5.1, which presents the combined results from two cohorts of crocidolite miners alone. For the most part this was due to the fact that many studies included exposure to multiple forms of asbestos, particularly chrysotile and crocidolite. Furthermore, the range of diverse occupational exposures, durations of exposure and methods of exposure measurement across included studies, none of which specifically attempted to establish clear differences between the two types, would make any such analysis in this review misleading.

Research has attempted to establish whether there are differences in risk based on the type of asbestos fibres to which people are exposed, in particular whether chrysotile is less potent than the amphibole forms of asbestos (of which crocidolite appears the most common). Marked differences between the two fibre types have already been established with regards to the risk of mesothelioma as a result of exposure; amphibole fibres show remarkable potency in comparison to chrysotile.46 The findings of previous meta-analyses investigating the relationship between asbestos exposure and lung cancer risk found that heterogeneity in results could be attributed to occupational category, methods of exposure measurement, smoking habits and standardisation procedures between studies, but not fibre type (Lash et al. 1997 cited in IARC 2012)40 Another research synthesis revealed similar significant heterogeneity between studies investigating various cohorts exposed to chrysotile (Hodgson & Darton 2000 cited in IARC 2012).40


In detailed analysis of the existing literature, Berman & Crump 2008 cited in IARC 201240 matched electron micrographic literature of chrysotile and amphibole fibre characteristics from identified sites to individual epidemiological studies. From these measures, meta-analysis of modelled potency for lung cancer data for the appropriate fibre characteristic was performed. As with the previous two meta-analyses, these authors found substantial variation in lung cancer risk from exposure. In a comparison across all widths or for thick mineral fibres, both chrysotile and amphibole asbestos exposure resulted in similar risk estimates, though chrysotile was generally less potent than amphiboles depending on fibre dimension. For thin fibres, there was statistically significant evidence that chrysotile fibres were less potent than amphiboles. Whilst evidence is still inconclusive to suggest significant differences in lung cancer risk dependent on type of exposure, recent research from Chinese cohorts after more than 30- years of follow-up suggests that exposure to chrysotile may take longer to appear in subjects42, 43, and that establishing any difference between the two requires accurate and detailed assessment of exposure characteristics,46

two features that are not commonly encountered in much of the available epidemiological research.

5.3 SummaryResearch identified and synthesised in this review offers clear indication of an increased risk of lung cancer following exposure to asbestos. Meta-analysis of data from occupational exposure suggests that workers exposed to asbestos are 1.3 – 2 times more likely to develop lung cancer than workers not exposed to asbestos. Whilst there was variation in the risk estimates across studies as well as within studies across the exposure categories, the majority of studies suggest occupational asbestos exposure imparts a lung cancer risk. The results suggest that risk increases with duration of occupational exposure.

However, any consideration of the results of such analysis based on published research should consider relevant issues and limitations encountered during detailed analysis of the literature. It is clear that different and often rudimentary means of measuring and reporting exposure make it difficult to draw firm conclusions about the intensity or level of exposure that presents a lung cancer risk or the duration of exposure required for exposure to present a risk. For example, many studies simply collected relevant exposure data by asking subjects participating in studies how long they had worked at a particular site. Similarly, variation in risk estimates between studies that were observed could be due to differences in occupational groups or even geographical location. For example, insulation workers may be at greater risk than other manufacturing industry workers, while cohorts exposed in China tend to report higher risk estimates than those in other countries.

Although it is clear that asbestos causes lung cancer in humans, the results presented here for the most part are limited to those people exposed to asbestos in mining and industry over the last century. While both activities have been banned in Australia for some 30 and 20 years respectively, the effect of exposure to asbestos as a result of existing products in our ambient environment, for example, those materials already in our homes, remains a topic of great interest. Only three studies were located that examined non-occupational exposure to asbestos, and these presented mixed results of lung cancer risk. Furthermore, of these, only one study represented residential exposure in the sense of having asbestos in the home, as opposed to living near asbestos industries. More research is required on the risk of lung cancer presented by residential exposure to asbestos before a firm conclusion can be drawn on this issue.

The majority of existing studies on lung cancer risk and asbestos exposure have been undertaken on all male populations, more than likely due to the propensity for males to


dominate employment in industry and mining, particularly during the period when most of the study cohorts used here were exposed (1940s – 1980s). Data presented on risk separately in males and females were variable. However, this may in part be due to the fact that cohorts of female participants were often small and risk estimates were based on only limited observations by nearly all studies included.

The risk estimates of lung cancer by smoking status confirmed that risk is highest amongst current smokers and higher among past than never smokers. The literature suggests that the relationship between asbestos exposure and smoking in lung cancer is more than additive. Similarly, the results highlight increased lung cancer risk estimates in subjects with confirmed asbestosis relative to those without. However, the evidence also suggests that asbestosis is not necessary for asbestos exposure to present a significant risk of lung cancer in individuals.

Considering fibre type, the evidence suggests chrysotile exposure presents a risk of lung cancer as do amphibole asbestos types. Recent evidence points to the possibility that hypothesised differences between the two types of asbestos may be due to longer latency for development of the disease following exposure to chrysotile asbestos than observed following exposure to amphibole fibres.

5.4 Conclusion5.4.1 Hazard identification

IARC indicates that all forms of asbestos (chrysotile, crocidolite, amosite, tremolite, actinolite and anthophyllite) are Group 1 carcinogens in humans.40 Consideration of available research also suggests that there is sufficient evidence to conclude that asbestos causes mesothelioma, and cancer of the larynx and ovary.40


There is sufficient evidence to suggest an increased risk of lung cancer of some 1.3 – 2 times following exposure to asbestos. This evidence is derived almost exclusively from studies investigating occupational exposure. Risk is increased in sufferers of asbestosis and smokers. The evidence suggests that chrysotile and amphibole fibres both increase risk of lung cancer development.


5.5 Methodological quality of studiesIndividual critical appraisal checklist items are shown below in Table 5.11.

Table 5.11 Asbestos exposure: Methodological quality of included studies

Study Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Total (Y)

Include

Weiss 1999 Review with pooled analysis Y U Y U U U. U Y Y Y 5 Exclude*

Lenters et al. 2011 Meta-analysis Y Y Y Y U U. Y Y Y Y 8 Include

Reid et al. 2005 Cohort study U U N N Y Y U Y Y N 4 Include

Reid et al. 2006 Retrospective cohort study U U N N Y Y U Y Y N 4 Include

Pira et al. 2009 Prospective cohort study N Y N U Y Y U Y Y N 5 Exclude**

Yano et al. 2010 Case control nested in cohort study N Y Y Y Y N U Y Y N 6 Include

Finkelstein 2010 Cohort study U U N N Y Y N Y Y N 4 Exclude**

Wang et al. 2012 Prospective cohort study N Y N Y Y Y U Y Y N 6 Include

Frost et al. 2011 Cohort study Y U N U Y Y U. Y Y N 5 Include

Menegozzo et al. 2011 Cohort study N Y N N Y Y U. U Y N 4 Exclude**


Lenters et al. 2011

The objective of this meta-analysis was clearly stated and was to examine difference in quality of asbestos exposure measurement as a factor explaining heterogeneity in lung cancer risk measures across cohort studies. The search strategy used to identify studies for the meta-analysis was explained and appropriate. The inclusion criteria were appropriate. However, it needs to be noted that the very recent cohort study by Wang et al.43 based on data gathered from a factory in China was not included. Appropriate methods were used for the data synthesis. The conclusions drawn were based on the results of the analysis. This is a high quality study that scored 8 on the JBI critical appraisal test. Two weaknesses are: that it is unclear whether one or more reviewers were involved in critical appraisal and whether any methods were used to minimise errors in data extraction in the process of the extraction of data from the 19 primary studies used for the meta-analysis.

Reid et al. 2005

Weaknesses include concerns over the accuracy of exposure measurement, limited adjustment for confounding factors (only smoking addressed) and the making of assumptions about smoking behaviour due to missing data (though this is on a small scale).

Reid et al. 2006

One weakness is that due to missing data – some participants not completing the more recent survey designed to gather information on smoking – assumptions had to be made for some subjects about smoking behaviour/quitting smoking. Another is limited addressing of confounding factors, aside from smoking.

Frost et al. 2011

This was a large cohort study on the risk of lung cancer mortality amongst asbestos workers in Great Britain. Ninety five percent of the study sample for whom data was gathered between the years 1971-2005, were males and just over half reported asbestos removal work as their main occupation during the study. The study had two main aims: to shed light on the nature of the interaction between smoking and asbestos exposure in the production of lung cancer risk; second to examine the effect of smoking and smoking cessation among asbestos exposed workers. The population used in the study consisted of 98 912 asbestos workers recruited into the Great Britain Asbestos Survey from 1971, followed-up to December 2005. In total 1 780 233 person years are followed in the study. Poisson regression was used in the study to estimate relative risk of lung cancer mortality associated with smoking habits of the asbestos workers and to assess whether these effects differed within various categories of asbestos exposure. The interaction between asbestos exposure and smoking was examined using the Synergy (S) and Multiplicativity (V) indices, which test the hypotheses of additive and multiplicative interaction respectively.

Wang et al. 2012

This paper presents the results of a thirty seven year prospective study undertaken in an asbestos manufacturing factory in China. The objective of the study is clearly stated and is to provide additional evidence for mortality risks associated with exposure to chrysotile asbestos. This is a high quality cohort study with a long observation and follow up time. This study is particularly useful for shedding light on the debate over whether chrysotile


elevates lung cancer risk because the subjects in this study are known to have been exposed overwhelmingly to chrysotile and there are very few studies on cohorts with pure chrysotile exposure (as opposed to chrysotile with a bit of other asbestos types). Smoking was addressed as a confounder in the study and risk measures were disaggregated by smoking status. Interaction between smoking and asbestos exposure was explored and exposure-response trend between asbestos exposure and lung cancer mortality was examined.

Yano et al. 2010

Nested case control study that focused on lung cancer risk from occupational exposure to chrysotile asbestos in seven workshops in a textile plant in China. Cohort recruitment for the cohort study began in 1972 and closed in November 1996. The final cohort, comprised of 1139 males was followed up for the occurrence of lung cancer until 2001. The objectives of the study were well stated and were to shed light on the debate over whether occupational chrysotile asbestos is a risk factor for lung cancer and the combined effect of smoking and asbestos exposure in lung cancer risk. Cases comprised 41 subjects who had died of lung cancer by the end of 2001. There was a good matching of cases and controls in the study: each case was matched by age (+-5 years) with five controls. Controls were selected from the cohort using the incidence density sampling method. Smoking was adjusted for as a confounding factor as was, age when cases died and exposure duration. This is a high quality case control study. A limitation of this study was small sample size limiting the statistical power available in sub-group analysis.


6 Risk factor: Radon exposure6.1 IntroductionRadon is a naturally occurring, radioactive noble gas that originates from the decay of either uranium-238 (238U), a radioactive mineral found in the earth’s crust with a half-life 4.56109 years, or the radioactive decay of thorium. Two isotopes are of particular interest with respect to the risk of lung cancer; Radon222 and Radon220. Radon222 (222Rn) results from the radioactive decay of uranium (238U) and is therefore present in uranium mines. Radon220 (220Rn or thoron), results from the radioactive decay of thorium and is not present in appreciable levels in uranium mines.

Radon has a half-life of 3.82 days and decays within hours to form short-lived radionuclides and other radioactive progeny with the release of alpha and beta particles. Radon forms underground disperses into the atmosphere where it can be inhaled in the air. Although radon itself is inert gas, its short-lived progeny are electrically charged particles that can attach to natural aerosol and dust, and if inhaled, tend to deposit into the lungs, thus exposing the sensitive bronchial epithelial cells to alpha radiation.54

Alpha particles emitted as a result of the radioactive decay of radon have been linked with disease, including lung cancer. Alpha particles are comprised of two protons and two neutrons and as such are a densely ionising type of radiation, with high energy and mass that can cause cellular damage to the respiratory epithelium once inside the body. Exposure to internalised alpha particles can lead to a variety of molecular lesions and complex DNA damage, which in turn leads to cellular responses such as: cell death, chromosomal abnormalities and genomic instability – all of which are able to contribute to carcinogenesis. IARC considers all types of ionising radiation to be carcinogenic to humans,55 with compounds emitting alpha particles (such as radon), categorised as Group 1carcinogens.

6.1.1 Occupational exposure to radon in Australia

Australia's uranium reserves are the world's largest, comprising 23% of the world total.56 In 2010-2011 Australia produced over 7000 tonnes of uranium oxide and was the world’s third largest producer of uranium (19.2% of world production) behind Kazakhstan and Canada. The majority of the uranium produced in 2010-2011 (6950 tonnes) was exported and was worth approximately 610 billion $AUD.57 Australia's uranium has been mined since 1954, and four mines are currently operating, with more planned and Australia’s uranium production forecast to more than double by 2030. Uranium ores were mined and treated in Australia from the 1950s until 1971. Radium Hill, South Australia, Rum Jungle, Northern Territory, and Mary Kathleen, Queensland, were the largest producers of uranium (as yellowcake). Production ceased either when ore reserves were exhausted or contracts were filled.

In 2011, there were approximately 8000 occupationally exposed individuals working in the uranium mining and milling industry in Australia.58, 59 These workers have their radiological doses assessed and recorded regularly by their mining operator and the Australian National Radiation Dose Register (ANRDR) has been established as the centralised database to capture all radiological doses received in the uranium mining and milling industry. The register is managed by the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA).58


Occupational exposure to radon is of concern for those engaged in the mining industry, specifically those involved in the underground mining of uranium ore. The International Commission on Radiological Protection Statement on Radon recommends 1000 (Becquerel) Bq m3 as the entry point for applying occupational radiological protection requirements in existing exposure situations.60 In 2009, the Commission reaffirmed its policy that, for planned exposure situations, any workers’ exposure to radon incurred as a result of their work, however small, is considered as occupational exposure to radon.

One of the challenges when interpreting research examining exposure with measurements made over time, is how measurements are made and how the time component is integrated. Often exposure estimates do not consider both duration and intensity. An attempt to address this was the adoption of working level (WL) and working level month (WLM), which are time integrated measures of exposure. A WL is defined as 130000 MeV of potential alpha energy per litre of air. A WLM is equal to exposure calculated on the basis of 170 hours being the length of a typical working month. Consequently, one WLM is equal to 2.08 x 10-5 J/m3 x 170 hours = 3.5 x 10-3 J-hours/m3.60

6.1.2 Residential exposure to radon in Australia

In 1990, scientists from the Australian Radiation Laboratory (now part of the Australian Radiation Protection and Nuclear Safety Agency) conducted a nationwide survey of more than 3300 Australian homes to determine the average annual radiation dose to the Australian population from exposure to natural background radiation.61 The survey data revealed that radon levels varied across the continent from one – two to over 400 Becquerels per cubic metre (Bq m3), with the average concentration of radon in Australian homes approximately 11 Bq m3.61, 62 This is approximately 75% lower than the reported global average indoor value of 40 Bq m3.61, 62 The 1990 radon survey revealed average radon levels in homes along the Great Dividing Range are typically higher than levels in homes on the coastal plain, mainly due to differences in the nature of the underlying rock and soil. For example, the average indoor radon level for the Australian Central Territory is 16 Bq m3, compared with the New South Wales average of nine Bq m3.61, 62 The 2009 International Commission on Radiological Protection Statement on Radon revised the upper level for radon gas in dwellings from the 2007 recommended level of 600 Bq m3 to 300 Bq m3. In Australia, ARPANSA recommends that householders with an annual average radon exposure in excess of 200 Bq m3 should reduce this radon exposure. Remedial action is not considered necessary where the annual average radon concentration in a dwelling is below 200 Bq m3. Only a very small fraction of Australian homes (less than 0.1%) have been found to exceed the Action Level of 200 Bq m3.62

The search identified an IARC monograph published originally in 200163 which was revised and updated in 2012.55 The 2012 IARC monograph included studies published until 2009 that considered the occupational or residential exposure to radon. In addition to the 2012 monograph, a further seven syntheses, three cohort studies and three case control studies were included following critical appraisal. A further two syntheses of research64, 65 were excluded due to a significant overlap of included studies with a research synthesis already included.66 Care was taken to avoid duplication of risk estimates and only studies that were not included in either monograph were considered for inclusion. The important characteristics of included studies are detailed in Table 6.1. Studies that examined the lung cancer risk associated with uranium processing and exposure to uranium in nuclear facilities were not included for consideration with this risk factor.


Table 6.1 Study characteristics relevant to the association between radon exposure and lung cancer




Darby et al. 2004Sweden, Finland, Austria, Czech republic, France, Germany, Italy, Spain, & UK.Meta-analysis

7148 cases and 14,208 controlsMales = 5521 cases, 10388 controlsFemales = 1627 cases, 3820 controlsGeneral population controls matched on gender and age.Age range from <55 – 65+ yrs.

Combination of 13 previously published case control studies conducted in 9 countries.Search or inclusion details not reported. Included studies range from 1992 - 2004

Residential exposureBetween 5 – 34 years.Estimates of radon (and radon progeny) exposure was detected using both air and surface monitors for a 12 month period.

All types of lung cancer.

Association examined in two ways:1) Model of proportionate increase in risk per unit increase in measured radon.2) RR across different categories of radon concentration plotted against estimated mean exposure levels in categories.Confounding adjusted through stratification in both analysesRisk was adjusted for gender, age, smoking status, region of residence and exposure time.

General Exposure for both genders combinedOdds ratio (95%CI)<25 Bq/m3 OR 1.00 (0.87 – 1.15)25 - 49 Bq/m3 OR 1.06 (0.98 – 1.15)50 - 99 Bq/m3 OR 1.03 (0.96 – 1.10)100 - 199 Bq/m3OR 1.20 (1.08 – 1.32)200 - 399 Bq/m3OR 1.18 (0.99– 1.42)400 - 799 Bq/m3OR 1.43 (1.06 – 1.92)>800 Bq/m3 OR 2.02 (1.24 – 3.31)Risk was not presented by gender, smoking status or exposure duration.

Grosche et al. 2006GermanyCohort study

59,001 former male employees of the Wismut Company.Mean duration of follow-up: 30.5 yrs

Cohort was identified via company records.Stratified based on high, medium, and low exposures, based on job category.Deaths were identified via district death certificates.

Occupational exposureMean age at first exposure: 24.6 yrs (33% exposed for the first time < 20 yrs old).Mean duration of exposure: 11.3 yrs, 40% of cohort had worked 5–14 yrs.~33% of workers

Not specified. Cumulative radon exposure calculated as the sum of annual radon exposures. 0 WLM was defined as unexposedMajority had worked underground.Overall mean exposure was 241 WLM with 332 WLM among underground workers and 235 WLM among

Overall exposureRR (95%CI)2.08 (1.08–2.79) for exposed, compared with unexposed miners.Risk estimates not presented by smoking status.





exposedbelow 10 WLM; 9.3 % exposed exceeded1000 WLM.

those at different work places.For the other exposed workers, mean exposures were below 10 WLMPoisson regression assuming a linear relation between exposure and risk. Risk adjusted for age, smoking and calendar period.

IARC 2012 monographGlobalResearch syntheses

No detailed sample demographics provided. Populations of interest were:Miners (specifically uranium miners) and people residing in regions where they were exposed to radon.

MonographDerived from expert panel discussionSearch terms or selection criteria not detailed.Research syntheses, cohort and case control studies addressing bothResidential exposure and occupational exposure (5-30 yrs) included.No inclusion criteria or search strategy was detailed

Most studies reported at 100 Bqm3 for >5 yrs

All types of lung cancer

Overall risk estimates calculated, however the models and adjustment factors are not detailed.

Occupational exposure to radonNo risk estimates providedOccupational exposure risk to underground iron ore miners (SMR)USA haematite (ferric oxide) 1.00UK iron ore(type not specified)1.53 (1948 -67)1.13 (1967+)China haematite (ferric oxide)3.7Radon level and exposure duration not reported.Residential exposureRisk for 5-30 year, 100 Bqm3 radon exposure. OR (95%CI)USA - 1.11 (1.00 – 1.28)China - 1.33 (1.01–1.36)Europe – ERR 0.16 (0.05 – 0.31)(adj for random uncertainties in measurement)No reported risk estimates for either





type of exposure by smoking status or gender. Confounders not reported.

Jonsson et al. 2010SwedenCohort study

5486 male workers who had worked for at least 1 year in a Swedish iron ore mine.

Exposure data collected from company records.Lung cancer deaths derived from national register.

Occupational exposureBased on WLM of 166.67 hours of usual work per month.Assessments based on data from 5481 radon measurements carried out during 1969-1998.

Adenocarcinoma Cumulative exposed lagged by 5 yrs and stratified by radon dose, calendar year and attained age.For each category, the mean exposure was calculated by summing the cumulative exposure for each year divided by the total number of person-years

Adjusted RR (95% CI), relative to unexposed miners.WLM16.6 WLM 1.10 (0.65 – 2.08)105.3 WLM 2.80 (1.82 – 6.08)159.5 WLM 4.76 (3.06 – 10.01)271.6 WLM 4.27 (2.68 – 9.69)* NB WLM is in this study is based on 166.67 hours at work, not 170 hours.

Kreuzer et al. 2003East GermanyCase control study

A total of 1192 cases and 1640 controlsMales = 1046 cases, 1414 controlsFemales = 146 cases, 226 controlsGeneral population controls matched on basis of gender and age.Age range from <50 – 75 yrs.

Data collected via combination of methods: self-report questionnaire, interview and comprehensive radon exposure assessment.Alpha detectors in each residence used to calculate mean exposure estimate for a 12 month period.

Residential exposure5 – 34 yrs.


Conditional logistic regression.Risk was adjusted for gender, age, region, smoking status and occupational asbestos exposure. Risk was not presented by gender or by smoking status.

Both genders combinedOdds ratio (95%CI),0 - 50 Bq/m3 reference exposure.50 - 80 Bq/m3 OR 0.95 (0.77 – 1.18)80 - 140 Bq/m3 OR 1.13 (0.86 – 1.50)>140 Bq/m3 OR 1.30 (0.88 – 1.93)Risk estimate by exposure duration5 – 15 years50 - 80 Bq/m3 OR 1.03 (0.81 – 1.31)80 - 140 Bq/m3 OR 1.03 (0.77 – 1.38)>140 Bq/m3 OR 1.37 (0.95 – 1.98)5 – 25 years50 - 80 Bq/m3 OR 1.14 (0.87 – 1.49)80 - 140 Bq/m3 OR 1.05 (0.75 – 1.45)>140 Bq/m3 OR 1.36 (0.89 – 2.08)5 – 35 years





50 - 80 Bq/m3 OR 0.88 (0.60 – 1.27)80 - 140 Bq/m3 OR 0.77 (0.50 – 1.19)>140 Bq/m3 OR 1.44 (0.83 – 2.52)

Krewski et al. 2005USAPooled analysis

A total of 3662 cases and 4966 controls.Approx 70% males in both cases and controls.Controls matched on basis of gender and age (+/- 5 yr)Age ranged from <60 – 75+ yrs.

Meta-analysisCombination of 7 previously published case control studies conducted in 6 states of the USA.

Residential exposure5 – 30 yrs.Estimates of radon (and radon progeny) exposure was detected using long term alpha track detectors for a 12 month period.


A conditional likelihood regression was used to estimate the excess risk of lung cancer.

General Exposure for both genders combinedOdds ratio (95%CI) relative to <25 Bq/m3

25 – 49 Bq/m3 OR 1.13 (0.95 – 1.35)50 – 74 Bq/m3 OR 1.09 (0.89 – 1.34)75 – 99 Bq/m3 OR 1.16 (0.91 – 1.48)100 – 149 Bq/m3OR 1.24 (0.96 – 1.60)150 - 199 Bq/m3OR 1.22 (0.87 – 1.71)>200 Bq/m3 OR 1.37 (0.98 – 1.92)Risk was not presented by gender, smoking status or exposure duration.

Lagarde et al. 2001Research synthesis/case controlSweden

Mean time in residence was approx. 25 yrs (both cases and controls).Approx. 45% male, 55% female (cases and control).Ages ranged from 28 – 94yrs.Cases were selected from a national register. Controls were matched to

Data combined from 5 previously published and 1 new case control studies conducted in Sweden.

Residential exposureExposure for 32 yrs, except for 11 subjects younger than 35 yrs of age at the end of follow-up.

Primary lung cancer (ICD-7, code 162.1)

Conditional logistic regression model represented study, age group (5-yr intervals), sex, and matched area of current residence, and to adjust further the effect of radon exposure,Other confounders considered for ETS exposure were; urbanisation, occupational lung cancer risk, and socioeconomic status.

Residential exposure and smokingGeneral Exposure for both genders combined – Odds ratio (95%CI). Risk estimate based on 5 Swedish case control studies, exposure compared with <50 Bq/m3 for at least 3 years.Never smokers50 - 80 Bq/m3 OR 1.18 (0.75 – 1.88)80 - 140 Bq/m3 OR 1.24 (0.80 – 1.92)>140 Bq/m3 OR 1.44 (0.87 – 2.35)Current smokers50 - 80 Bq/m3 OR 1.08 (0.79 – 1.47)80 - 140 Bq/m3 OR 1.18 (0.86 – 1.61)>140 Bq/m3 OR 1.44 (1.00 – 2.06)





cases on birth year (+/- 3-years), gender and study.

Environmental smoking in the homeNot present50 - 80 Bq/m3 OR 0.93 (0.63 – 1.38)80 - 140 Bq/m3 OR 0.88 (0.58 – 1.34)>140 Bq/m3 OR 1.13 (0.70 – 1.82)Present50 - 80 Bq/m3 OR 1.43 (0.86 – 2.36)80 - 140 Bq/m3 OR 1.76 (1.08 – 2.86)>140 Bq/m3 OR 2.10 (1.21 – 3.65)

Leurand et al. 2011Research synthesisCzech republic, France and GermanyAlpha-Risk project.

Three case-control studies nested within cohorts of uranium minersCzech cohort:2 cohorts.1) 4353 miners employed for at least 4 yrs between 1948–1959.2) 5626 miners employed for at least 1 yr between 1968–1974. Both cohorts followed until the end of 1999.French cohort:5098 miners employed for at least 1 yr

Occupational history and exposure data were available from the cohorts.Smoking information was provided by self-administered questionnaires and occupational medical archives.

Occupational exposureExposure was measured in ambient air where the miners worked. Method not specified.

Not specified. Conditional logistic regression (lagged by 5 years).Confounders: birth period and cohort from which miners were issued. A log-linear model was fitted to estimate the odds ratio (OR), which in turn estimated the RR.A linear model for theexcess relative risk (ERR) of lung cancer was developed – both with and without adjustment for smoking

Overall RR adj for level of radon exposure (95%CI)Never smokers - 1.00Ex-smokers - 1.94 (1.35 – 2.80)Current smokers - 6.41 (4.68 – 8.80)WML adj RR (95% CI), relative to never smokers exposed to <50 Bqm3

50 - 100Never smokers – 2.08 (0.83 – 5.24)Ex-smokers - 3.94 (1.59 – 9.76)Current smokers – 12.03 (5.74 – 25.23)100 - 200Never smokers – 2.01 (0.81 – 4.97)Ex-smokers - 4.97 (2.14 – 11.58)Current smokers – 18.61 (8.96 - 38.64)200 - 400Never smokers – 4.93 (1.95 – 12.49)Ex-smokers – 6.28 (2.59 – 15.23)Current smokers – 20.98 (9.97 – 44.15)





between 1946–1990 and followed from 1946 to 1994.German cohort: 59,000 miners employed for at least 180 days by the Wismut Co. First employment between 1946 and 1989. Follow-up was between 1946 and 1998.

> 400Never smokers – 7.06 (2.42 – 20.57)Ex-smokers – 16.79 (6.78 – 41.59)Current smokers – 36.69 (16.92 – 70.59)

Lubin et al. 2003Pooled analysis of case control studiesUSA/China

USA:4081 cases (2766 females and 1315 males)5281 controls (3779 females and 1502 males)China (Shenyang)301 Cases,355 Controls – females onlyChina (Gansu)768 Cases(205 female, 563 males)1795 controls

All studies used long-term alpha-track detectors as the principal measurement device.

Residential exposureExposure was measured in ambient in residences and estimated over for 5 – 30 yrs.China – levels recorded for 1 yr at current residence in places where they have lived for at least 5 yrs

All types A linear excess odds ratio (EOR) model was used.USA data adj. for study, sex, age, duration of smoking, number of cigarettes smoked per day, number of residences and years of exposure covered with alpha-track measurements.Chinese studies were adj. for age, smoking risk, number of residences and coverage, and for the Gansu study, town, sex and socioeconomic factors.

Overall Adjusted OR (95% CI) - both gender combinedUSA (6 studies) 1.106 (1.00 - 1.28)China (2 studies) 1.139 (1.01 - 1.37)Risk estimate not presented by gender or by smoking status.





(427 female, 1232 males)No age details provided.

Lubin et al. 2004Research synthesisChina

A total of 1069 cases and 2014 controls.Males = 563 cases, 1232 controlsFemales = 506 cases, 782 controlsGeneral population controls matched on basis of gender and age.Age range from <45 – 70+ yrs.

Meta-analysisCombination of 2 previously published case control studies conducted in 2 provinces of China.1 of the studies used only females.High proportion of smoking males in one study (91%)

Residential exposureOverall residential exposure was between 5 – 30 years.Estimates of radon (and radon progeny) exposure was detected using long term alpha track detectors for a 12 month period.


A linear excess odds ratio (EOR) model used.Risk was adjusted for gender, age, smoking status, air pollution index, prefecture of residence and socioeconomic status.

General exposure for both genders combinedOR(95%CI) relative to <100 Bq/m3

100 - 149 Bq/m3 1.12 OR (0.80 – 1.50)150 – 199 Bq/m3 1.42 OR (1.00 – 2.00)200 – 249 Bq/m3 1.13 OR (0.80 – 1.60)250 – 299 Bq/m3 1.27 OR (0.80 – 1.90)>/= 300 Bq/m3 1.52 OR (1.10 – 2.20)Risk by smoking status at 100 Bq/m3

– Odds ratio (95%CI)Never smoker OR 1.00Ever smoker OR 2.28 (1.8 – 3.0)Current smokerLight OR 1.77 (1.3 – 2.3)Moderate OR 2.93 (2.2 – 4.0)Heavy OR 4.47 (2.8 – 7.1)Risk not presented by gender or exposure duration.

Pavia et al. 2003Meta-analysisCountries not detailed

A total of 9127 cases and 16,449 controlsControls matched for at least: sex, smoking status, age.

Meta-analysisCombination of 17 previously published case control studies.

Residential exposureEstimates of radon (and radon progeny) exposure was detected using both air and surface monitors for a 12 month period for the majority of the


Weighted log–linear regression analysis calculated.Coefficients and 95% confidence intervals were calculated from the model according to several levels of radon concentration.

General Exposure for both genders combined – Odds ratio (95%CI)50 Bq/m3 1.07 OR (1.04 – 1.11)100 Bq/m3 1.15 OR (1.07 – 1.24)150 Bq/m3 1.24 OR (1.11 – 1.38)200 Bq/m3 1.33 OR (1.15– 1.54)250 Bq/m3 1.43 OR (1.19 – 1.72)





Age range from 30 – 84 yrs.

included studies (82%).

The DerSimonian & Laird random effect model used for meta-analysis.

Risk was adjusted for gender, age and smoking status.Women only(based on 6 case control studies)Lung cancer risk to women exposure to 150 Bq/m3 compared with unexposed150 Bq/m3 1.29 OR (1.04 – 1.60)Risk was not presented by smoking status or exposure duration.

Pisa et al. 2003Case controlItaly

138 cases and 291 controls. Cases were all deceased and were identified via death certificates.Males = 122 cases, 253 controlsFemales = 16 cases, 38 controlsGeneral population controls matched on basis of gender and year of birth.Age range from <55 – 65+ yrs.

Data collected using a combination of methods: self-report questionnaire, face to face interview and a comprehensive radon exposure assessment.

Residential exposureEstimates of radon exposure were measured using both air monitors for a 12 month period.


Multiple unconditional logistic regression used.

Overall OR (95%CI).<40 Bq/m3 used as reference categoryBoth genders combined40 - 76 Bq/m3 OR 2.00 (1.00 – 3.90)77 - 139 Bq/m3 OR 1.80 (0.90 – 3.70)140- 199 Bq/m3 OR 2.40 (0.90 – 6.2)>200 Bq/m3 OR 1.0 (0.30 – 3.10)Males40 - 76 Bq/m3 OR 2.10 (1.00 – 4.40)77 - 139 Bq/m3 OR 2.00 (0.90 – 4.40)140- 199 Bq/m3 OR 2.70 (0.90 – 7.90)>200 Bq/m3 OR 1.40 (0.40 – 4.70)Females40 - 76 Bq/m3 OR 1.20 (0.20 – 7.40)77 - 139 Bq/m3 OR 0.80 (0.10 – 7.30)140- 199 Bq/m3 OR 0.30 (0.00 – 4.00)Risk was adjusted for gender, age, dietary variables and smoking status.Risk was not presented by either smoking status or exposure duration.





Schnelzer et al. 2010Nested case control studyGermany

Cases: 704 miners who died of lung cancer Controls: 1,398 matched individually for birth year and attained age.

Smoking status attained from questionnaires and company records.Data on radonexposure were taken from a job-exposure matrix

Occupational exposureUranium miners in Germany, employed for at least 180 days.

All types, determined from death records

Conditional logistic regression used.Temporal factors considered were: attained age at the reference case’s death,age at first exposure, duration of exposure, average radon exposure per year in WLM, time since last exposure and time since first exposure.Confounders considered:Smoking, type of employment.

Overall exposure (WLM)Risk RR (95% CI)>0 - <50 0.86 (0.45 – 1.65)>50 - <100 1.34 (0.65 – 2.73)>100 - <500 2.14 (1.12 – 4.09)>500 - <1000 3.63 (1.86 – 7.08)>1000 - <1500 4.59 (2.25 – 9.37)>1500 3.61 (1.70 – 7.68)Occupational radon exposure, smoking and lung cancer riskSmokers compared with non-smokersRR 7.6 (4.4 – 13.1)Excess relative risk due to smokingERR = 0.23% (0.11 – 0.46%)

Tomasek et al. 2008Cohort studyFrance and Czech Republic

10,000 male uranium miners aged approx. 54 yrs at follow up.

Mortality data from company/public records.Smoking information by questionnaire.

Occupational exposureUranium miners in France and Czech RepublicMean exposure of 10.9 yrs.French miners exposed for at least 1 yr exposure, Czech miners, at least 4 yrs exposure.

All types WLMMultiple unconditional logistic regression used.

Overall risk (SMR) of lung cancer resulting from occupational exposureFranceMean Exposure WLM 36.5 (range 1- 37)Risk SMR 1.55 (1.33, 1.79)Czech republicMean Exposure WLM 57.3 (range 0.3 – 387)Risk SMR 3.77 (2.48, 4.08)CombinedMean exposure WLM 46.8 (0.1 – 960)Risk SMR 2.87 (2.68, 3.08)


6.2 Results6.2.1 Occupational radon exposure and risk of lung cancer

Two prospective studies reporting on occupational exposure to radon in uranium miners in Europe were located. The results presented in Table 6.2 indicate that such exposure identifies radon as a risk factor for the development of lung cancer. Tomasek et al.67 reports from two European cohorts individually.

Table 6.2 Occupational radon exposure and risk of lung cancer in Europe (cohort studies)

Study Country Exposure WLM (range)

RR (95% CI)

Grosche et al. 2006 Germany 241 (0-3224.5) 2.08 (1.08 – 2.79)

Tomasek et al. 2008 Czech Republic 57.3(0.3 – 387) 3.77 (2.94 – 4.84)

Tomasek et al. 2008 France 36.5(0.7 – 960) 1.55 (1.34 – 1.79)

In a nested case control on a sub-population of the same cohort of German uranium miners as shown in Grosche et al.,68 the study by Schnelzer et al.69 similarly indicates that as the occupational exposure to radon increases, so does the risk of lung cancer, and that risk increases in a concentration dependent manner (Table 6.3).

Table 6.3 Level of occupational radon exposure and risk of lung cancer in German uranium miners, (Schnelzer et al. 2010)69

Cumulative exposure (sum of annual exposure) (WLM)

Risk RR (95% CI)

>0 - <50 0.86 (0.45 – 1.65)

>50 - <100 1.34 (0.65 – 2.73)

>100 - <500 2.14 (1.12 – 4.09)

>500 - <1000 3.63 (1.86 – 7.08)

>1000 - <1500 4.59 (2.25 – 9.37)

>1500 3.61 (1.70 – 7.68)

The IARC monograph55 presented data indicative of risk of lung cancer also resulting from radon exposure in miners not actively mining uranium. Standardised mortality ratio (SMR) data indicates that iron ore miners exposed to radon at lower concentrations than those reported in uranium mines (UK study, radon levels in early periods were in the range of 0.35–3.2 WL, and decreased to 0.1–0.8 WL) are at increased risk of lung cancer relative to the general population (Table 6.4). No details were presented in the monograph of exposure duration. None of the three studies stated they had adjusted for smoking. The authors note in the Chinese study that increasing radon concentration was correlated with increasing dust concentration and that dust may be a confounding factor.


Table 6.4 Occupational radon exposure and risk of lung cancer in haematite/iron miners, IARC monograph55

Country Type of mine Risk (SMR relative to general population

USA (Minnesota) haematite (ferric oxide) 1.00

UK (Cumbria) iron ore(type not specified) 1.53 (1948 -67)1.13 (1967+)

China haematite (ferric oxide) 3.7Exposure duration or intensity not reported in the monograph. Smoking status not reported.

Similarly, the study by Jonsson et al.70 presents findings on the risk of lung cancer resulting from radon exposure in a cohort of Swedish iron ore miners where the radon levels are low compared with radon levels recorded in uranium mines. The risk estimates may be indicative of those experienced by miners of other materials. The findings are based on a cohort of 5486 males with a mean exposure of 14.9 years. The mean cumulative exposure level of radon was 65 WLM or (32 KBq year/m3). The risk estimates in Table 6.4 summarise the lung cancer risk in this cohort for exposures of between 16.6 and 271.6 WLM, relative to unexposed mine workers at the same mine for comparison. The results show that exposures of 105.3 WLM or greater are associated with increased lung cancer risk in this cohort of miners (Table 6.5). The authors note that occupational quartz particles may be a confounder in this particular mine, potentially contributing to the lung cancer risk.

Table 6.5 Occupational radon exposure and risk of lung cancer in Swedish iron ore miners, (Jonsson et al. 2010)

Cumulative exposure (WML*) Adjusted RR (95% CI)

16.6 1.10 (0.65 – 2.08)

105.3 2.80 (1.82 – 6.08)

159.5 4.76 (3.06 – 10.01)

271.6 4.27 (2.68 – 9.69)* NB WLM is in this study is based on 166.67 hours at work, not 170 hours.

6.2.2 Occupational radon exposure and risk of lung cancer: Joint effects with smoking

The IARC monograph55 identified thirteen studies that consider the interaction between occupational exposure to radon and smoking. Of these, the majority (11 out of13) suggest an important interaction and that occupational radon and smoking combined lead to greater lung cancer risk than due to either radon exposure or smoking alone. However the monograph does not present an overall risk estimate as a result of the interaction between radon and smoking, and relative risk estimates are only presented for four of the 13 studies (Table 6.6).

Table 6.6 Occupational radon exposure, smoking and risk of lung cancer in miners, IARC monograph 55

Country Type of mine RR due to smoking

Czech Republic Uranium 4.1 – 6.6


Country Type of mine RR due to smoking

Czech Republic Shale clay 6.2

Beaverlodge 1 Uranium 2.5

France Uranium 3.4No confidence intervals or radon exposure levels were reported for any study. 1 not specified in the monograph,1 Beaverlodge uranium mine, Canada; country not specified in monograph

In addition to the monograph, one research synthesis71 and one nested case control study69 investigated the impact of the interaction between occupational radon exposure and smoking on the risk of lung cancer. When radon exposure is combined with smoking, the lung cancer risk is greatly increased almost eight fold due to smoking in this cohort of miners when compared to non-smoking colleagues, as highlighted in Table 6.7.69 In this study, smoking status information was either self-reported or derived from Wismut company health records. Current smokers or those who had quit less than 20 years were compared with non-smokers (never smokers or those who had quit more than 20 years).

Table 6.7 Occupational radon exposure and risk of lung cancer in German uranium miners: risk to smokers compared with non-smokers, (Schnelzer et al. 2010)69

Category Risk

Smokers vs non smokers (RR, 95% CI) 7.6 (4.4 – 13.1)

Excess relative risk due to smoking (ERR) 0.23% (0.11 – 0.46%)

Leuraud et al.71 examined smoking and occupational radon exposure in French, Czech and German uranium miner cohorts. The German cohort is derived from the Wismut cohort (n=59,001) and is the same as that used by Grosche et al.,68 and by Schnelzer et al.69 It is unclear whether there was an overlap in the study participants.

Estimates of lung cancer risk for non-smoking miners are consistent with previous reports (Table 6.2, Table 6.3, Table 6.5) of comparable WLM exposures (Potentially due to same participant data), and suggest that never smokers who have been exposed to >200 WLM are at significantly increased risk of lung cancer resulting from occupational radon exposure (Table 6.8). This risk increases markedly at each exposure level for both current smokers and ex-smokers who have stopped smoking for less than 10 years.

Table 6.8 Occupational radon exposure, smoking status and risk of lung cancer in German, French and Czech uranium miners, Leuraud et al. 201171

Cumulative exposure(WML)

RR (95% CI)Never smokers

RR (95% CI)Ex-smokers (>10years)

RR (95% CI)Current smokers and Ex-smokers (<10years)

<50 1.00 1.86 (0.80 – 4.30) 7.23 (3.59 – 14.58)

50 - 100 2.08 (0.83 – 5.24) 3.94 (1.59 – 9.76) 12.03 (5.74 – 25.23)

100 - 200 2.01 (0.81 – 4.97) 4.97 (2.14 – 11.58) 18.61 (8.96 – 38.64)

200 - 400 4.93 (1.95 – 12.49) 6.28 (2.59 – 15.23) 20.98 (9.97 – 44.15)

>400 7.06 (2.42 – 20.57) 16.79 (6.78 – 41.59) 36.69 (16.92 – 70.59)Reference group: never smoking uranium miners exposed to <50WML


6.2.3 Residential radon exposure and risk of lung cancer

In contrast to the studies examining occupational exposure to radon, studies examining residential radon exposure generally fail to normalise exposure with a standard metric – for example there is no equivalent to WLM to account for the varying proportion of time people spend within the home over time. Data from case control studies from several countries examining the potential risk of lung cancer resulting from residential exposure to radon were included in the IARC monograph.55 Combined analysis was conducted on case control studies divided on the basis of three broad geographical regions: North America, Europe and China. Risk estimates are presented in Table 6.9.

Table 6.9 Residential radon exposure and risk of lung cancer, IARC monograph55

Country ExposureBq/m3

Exposure duration(time at residence)

Risk (95% CI)

USA 100 5-30 years OR 1.11 (1.00 – 1.28)

Europe 100 5-30 years ERR 0.08 (0.03 – 0.16)

Europe 100 5-30 years ERR 0.16 (0.05 – 0.31)*

China 100 5-30 years OR 1.33 (1.01–1.37)

China 100 30 years+ OR 1.32 (1.07–1.91)Adjusted for gender, education level, smoking status, respondent (self or proxy). *estimates adjusted for random uncertainties in measuring radon concentration.ERR excess relative risk - difference between the proportion of subjects with lung cancer who were exposed to radon and the proportion of subjects with lung cancer who were not exposed

6.2.4 Residential radon exposure and risk of lung cancer in Europe

The European estimate reported in Table 6.9 above is based on data from a combined total of 7148 cases and 14,208 controls. The monograph reported a linear dose response relationship with no threshold and estimated the excess relative risk (ERR) to be 0.08 (95%CI 0.03 – 0.16) per 100 Bq/m3 increase in the concentration of radon.

A case control study conducted in East Germany, further examined the risk of lung cancer stratified by exposure duration.72 This study suggests that the risk of lung cancer resulting from residential radon exposure was low, and that exposure times of between five and thirty-five years to mean radon concentrations ranging from 50 - >140 Bq/m3 did not significantly alter the resulting risk of lung cancer (Table 6.10). A potential confounder is that a large proportion of the cases (98% males, 49% females) were smokers, which was not reflected in the control group (735 males, 23% females). Despite this, the results in Germany from this one study are consistent with those from the US reported by Krewski et al.66 in Table 6.11 below from combined studies.

Table 6.10 Duration of residential radon exposure in Germany, (Kreutzer et al. 2003) 72

Exposure 1 Risk estimate by exposure duration (years) OR (95% CI)5 – 15 years

Risk estimate by exposure duration (years) OR (95% CI)5 – 25 years

Risk estimate by exposure duration (years) OR (95% CI)5 – 35 years

50 - 80 Bq/ m3 1.03 (0.81 – 1.31) 1.14 (0.87 – 1.49) 0.88 (0.60 – 1.27)

80 - 140 Bq/m3 1.03 (0.77 – 1.38) 1.05 (0.75 – 1.45) 0.77 (0.50 – 1.19)

>140 Bq/m3 1.37 (0.95 – 1.98) 1.36 (0.89 – 2.08) 1.44 (0.83 – 2.52)


1mean exposure measured over 12 months

6.2.5 Residential radon exposure and risk of lung cancer in the US

Data from seven case control studies included in the IARC monograph risk estimate above were analysed and published in three separate research syntheses.64-66 Data is presented from the pooled analysis of studies in the Krewski et al.66 paper and suggests that exposures below the 100 Bq/m3 examined in the monograph, and as low as 25 Bq/m3, for five to 30 years may impart an increased risk of lung cancer ranging from 9%-37% (Table 6.11). However, this effect was not statistically significant.

Table 6.11 Residential radon exposure and risk of lung cancer in the US, ( Krewski et al. 2005)66

Exposure Bq/m3 Risk Adjusted OR (95%CI)

25 – 49 1.13 (0.95 – 1.35)

50 – 74 1.09 (0.89 – 1.34)

75 – 99 1.16 (0.91 – 1.48)

100 – 149 1.24 (0.96 – 1.60)

150 - 199 1.22 (0.87 – 1.71)

>200 1.37 (0.98 – 1.92)Relative to exposures of <25 Bq/m3

6.2.6 Residential radon exposure and risk of lung cancer in China

Lubin et al.73 report pooled data from two large case control studies conducted in China examining the potential association between residential exposure to radon and risk of lung cancer. Residential exposure to radon of 100 Bq/m3 for 30 years or more led to a 33% increase in risk (OR 1.33, 95%CI: 1.01–1.37) compared with non-exposed individuals. In a meta-analysis, Lubin et al.73 expanded the analysis of data from these two studies and examined radon exposures of up to >300 Bq/m3 in a dose dependent manner (Table 6.12).

Table 6.12 Residential radon exposure and lung cancer risk in China,(Lubin et al. 2004)73

Exposure (Bq/m3) Risk Adj OR (95% CI)

100 - 149 1.12 (0.80 – 1.50)

150 – 199 1.42 (1.00 – 2.00)

200 – 249 1.13 (0.80 – 1.60)

250 – 299 1.27 (0.80 – 1.90)

≥ 300 1.52 (1.10 – 2.20)

6.2.7 Level of residential radon exposure and risk of lung cancer

The search identified two syntheses of research that combined case control studies from Europe, USA and China in meta-analysis in order to generate a summary estimate of risk of residential exposure to radon.74, 75 There is a significant overlap in the studies included


in the two reviews; therefore, only data from the most recent meta-analysis is presented below.

Results of the meta-analysis by Pavia et al.,75 including data from 17 case control studies, suggests that exposures of 50 Bq/m-3 and above represents a small (7%) yet significant increase in the risk of lung cancer, whilst exposures of 100 - 250 Bq/m-3 represent a moderate (15 – 43%) risk (Table 6.13). The duration of exposure leading to these summary estimates of lung cancer risk were not specified, although exposure is likely to be five to 30 years, as is the timeframe reported by Darby et al.74,76

Table 6.13 Residential radon exposure and risk of lung cancer - a synthesis of data from different exposure levels, (Pavia et al. 2003)75

Exposure Bq/m-3 RR (95% CI)

50 1.07 (1.04–1.11)

100 1.15 (1.07–1.24)

200 1.33 (1.15–1.54)

250 1.43 (1.19–1.72)

Overall risk adjusted to 150 Bq/m-3 1.24 (1.11–1.38)* No estimate of exposure duration was reported

6.2.8 Residential radon exposure, smoking status and risk of lung cancer

Two research syntheses were identified that specifically addressed the potential interaction between residential exposure to radon and smoking.

Lagarde et al.77 examined the effect of both active smoking and environmental tobacco smoke (ETS) in the home in a Swedish population. The results suggest that smoking, active or passive, significantly increases the risk of lung cancer resulting from radon exposure only at exposures >140 Bq/m-3 (Table 6.14). The study did however find a significant interaction between ETS and radon exposure of >80 Bq/m-3. Risk estimates are based on five Swedish case control studies with exposure compared with a reference group exposed to <50 Bq/m3 for at least three years.

Table 6.14 Residential radon exposure, smoking status and risk of lung cancer in Sweden, (Lagarde et al. 2001)

Radon levelBq/m3

Never smokersRisk Adjusted OR (95% CI)

Current/ex-smokersRisk Adjusted OR (95% CI)

No ETS in homeRisk Adjusted OR (95% CI)

ETS present in homeRisk Adjusted OR (95% CI)

50 - 80 1.18 (0.75 – 1.88) 1.08 (0.79 – 1.47) 0.93 (0.63 – 1.38) 1.43 (0.86 – 2.36)

80 - 140 1.24 (0.80 – 1.92) 1.18 (0.86 – 1.61) 0.88 (0.58 – 1.34) 1.76 (1.08 – 2.86)

>140 1.44 (0.87 – 2.35) 1.44 (1.00 – 2.06) 1.13 (0.70 – 1.82) 2.10 (1.21 – 3.65)

The risk of lung cancer resulting from a potential interaction between smoking and residential exposure to a mean radon concentration of 100Bq/m3 for at least five years was examined by Lubin et al.73 in their synthesis of two case control studies from China. The results show that in this population, estimates of risk are considerably higher for each category of smoker exposed at equivalent radon levels (80 - 140 Bq/m3) than non-smoking counterparts (Table 6.15). Smokers who have smoked more than 20 cigarettes a


day for over 40 years are at 4.5 times the lung cancer risk of non-smokers of the same population.

Table 6.15 Residential radon exposure of 100 Bq/m3 for at least five years, smoking status and risk of lung cancer, (Lubin et al. 2004)

Smoking status Adjusted OR (95%CI)

Never smoker 1.00

Ever smoker 2.28 (1.8 – 3.0)

Current smoker Light(level not specified) 1.77 (1.3 – 2.3)

Moderate (30 years smoking 10 cigarettes equivalents per day) 2.93 (2.2 – 4.0)

Heavy (40 years smoking 20 cigarettes equivalents per day) 4.47 (2.8 – 7.1)

6.2.9 Residential radon exposure, gender and risk of lung cancer

As with occupational exposure, no studies were identified that examined risk of lung cancer resulting from residential radon exposure by gender. However, sub-group analysis of data from seventeen critically appraised case control studies by Pavia et al.75 reported an increased lung cancer risk in women exposed to a mean of 150 Bq/m3 (adjusted OR 1.29, 95%CI 1.04, 1.60). The duration of the exposure was not reported for this estimate.

A small case-control study conducted in an Alpine region of Italy with high natural radon radioactivity also presented data in separate genders.78 Some of the data presented by this case control study is included in the Pavia et al 2003 meta-analysis. The reference group for risk assessment was people exposed to 40 Bq/m-3 radon. The results, though not statistically significant, suggest men may be at greater risk. However, the variability in the data set, which appears twice as much in females, and variable exposure response data make this one study difficult to interpret (Table 6.16).

Table 6.16 Residential radon exposure, gender and risk of lung cancer in Italy (Pisa et al. 2001)

Exposure Risk estimate by gender OR (95% CI)Males

Risk estimate by gender OR (95% CI)Females

40 - 76 Bq/m3 2.10 (1.00 – 4.40) 1.20 (0.20 – 7.40)

77 - 139 Bq/m3 2.00 (0.90 – 4.40) 0.80 (0.10 – 7.30)

140- 199 Bq/m3 2.70 (0.90 – 7.90) —

140->200 Bq/m3 — 0.30 (0.00 – 4.00)

>200 Bq/m3 1.40 (0.40 – 4.70) —

6.3 SummaryData from individual prospective studies and syntheses of retrospective (case control) studies clearly indicates that exposure to radon incurred whilst mining uranium causes lung cancer. Risk in uranium miners increases in a dose-dependent manner with increased level of exposure. Workers engaged in mining of other ores and minerals are also at increased risk of lung cancer, though not to the same extent as uranium miners. The relationship is compounded significantly by past or current smoking.


Meta-analysis of case control studies from around the world75 suggests that residential exposure to radon also poses a significant risk for lung cancer, though to a lesser extent to miners exposed to the same level of radon. Various syntheses of case control studies, and individual studies, from different continents suggest that residential exposure of ≥250 Bqm3 may be necessary to realise an increased risk of approximately 40%. Whilst smoking may increase risk, there is little data to inform gender difference. Some data is also available regarding the population attributable risk (PAR) of residential radon exposure in the USA, particularly considering the greater levels of exposure in some parts of the USA due to geological emissions of radon. It is estimated that approximately 10,000 lung cancer cases per year in the USA are attributable to residential radon exposure (Samet, 1989). Steenland and colleagues21 attribute a further 2000 lung cancer cases to exposure to radon at work in buildings (excluding miners) equating to a PAR of 1.3% (based on a ratio of time spent at home and work of 5:1).

Relative to the Australian context, data from the 1990 ARPNSA survey61 would suggest on average, Australian homes would be exposed to radon levels of approximately 11 Bq/m3. Whilst homes surveyed had radon levels ranging from of one to 400 Bq/m3, only 0.1% of the 3300 Australian homes recorded exposure to radon of more than 200 Bq/m3, which would represent a risk of lung cancer.


Radon has been identified as a Group 1 carcinogen, with occupational and residential exposures being linked to lung cancer.55 The IARC monograph55 also identifies radon exposure as a risk for leukaemia (especially myeloid leukaemia) and childhood leukaemia, kidney cancer, prostate cancer, malignant melanoma, and some childhood cancers.


There is clear evidence to suggest that uranium miners are at particular risk of lung cancer resulting from occupational exposure to radon at levels of 100 WLM or greater. Uranium miners who smoke increase their lung cancer risk by approximately seven times. Miners involved in mining iron have also been shown to have increased risk of lung cancer resulting from occupational exposure to radon, even when working at lower exposures or less hours per month.

The evidence also suggests that residential exposure to radon could represent an increased risk of lung cancer, though not to the same extent seen in miners due to the lower exposure levels. Exposure to more than 250 Bq/m3 for between five and 30 years represents a significant risk factor for lung cancer.


6.5 Methodology quality of studiesScoring of each included study for individual critical appraisal items is shown below in Table 6.17

Table 6.17 Radon exposure: Methodological quality of included studies

Study Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Total (yes)

Include/Exclude

Darby et al. 2001 Research synthesis Y N N Y U U U Y Y Y 4 Include

Darby et al. 2004 Research synthesis Y N N U U U Y Y Y Y 5 Include

Grosche et al. 2006 Cohort study N Y U N Y Y Y Y Y - 6 Include

Jonsson et al. 2010 Cohort study N Y U Y Y Y U Y Y - 6 Include

Kreuzer et al. 2003 Case control Y U Y Y Y Y U Y Y - 7 Include

Krewski et al. 2005 Research synthesis N U Y Y Y Y U Y Y U 6 Include

Lagard et al. 2001 Research synthesis/Case control

Y Y U Y Y Y U Y Y U 7 Include

Leurand et al. 2011 Research synthesis Y U N U U Y Y Y Y Y 6 Include

Lubin et al. 2003 Research synthesis Y N U U U U Y Y Y Y 5 Include

Lubin et al. 2004 Research synthesis Y U Y Y U Y N Y Y U 6 Include

Pavia et al. 2003 Research synthesis Y Y U Y Y Y Y Y U Y 8 Include

Pisa et al. 2001 Case control N Y N Y Y Y Y Y Y - 7 Include

Schnelzer et al. 2010 Case Control N Y Y U Y Y U Y Y - 6 Include

Tomasek et al. 2008 Cohort study N Y Y U Y Y Y Y Y - 7 Include


Darby et al. 2001

This research synthesis combined data from fifteen (15) case control studies conducted in seven (7) different countries (USA, China, Sweden, Finland, Germany, England, Canada). To address the overall relative risk of residential exposure to radon at 100 Bq/m-3 for at least five (5) was reported, compared with an exposure to 0 Bq/m-3. No inclusion criteria or selection procedure were reported for this study. No demographic details are provided for included participants. The aim of the review was clearly stated.

Darby et al. 2004

This study combined data from the same case control studies as the IARC monograph, reported lung cancer risk by level of exposure from 13 previously published case control studies, spanning nine (9) European countries. The analysis was based on a total of 7148 cases and 14,208 controls of both genders. Overall exposure was between five (5) and 34 years and estimates of residential exposure was made using both air and surface monitors for a 12 month period. Risk was adjusted for gender, age, smoking status, region of residence and exposure time; however risk was not presented by gender, smoking status or exposure duration. Search strategy and inclusion criteria were not detailed, however methods to combine data were appropriate.

Grosche et al. 2006

This cohort study analysed data from a cohort of 59,001 male German uranium miners who worked for the Wismut company to model risk of lung cancer due to the occupational exposure of radon. Risk estimates are adjusted for age and calendar period. Mean duration of follow-up was 30.5 years with a total of 1 801 630 person-years. Loss to follow-up was low at 5.3%. Data was not presented by smoking status, although smoking was adjusted for in the analysis.

Jonsson et al. 2010

Jonsson et al.70 presents findings on the risk of lung cancer resulting from radon exposure in a cohort study of Swedish iron ore mine where radon levels are low compared with radon levels recorded in uranium mines. The risk estimates are based on a cohort of 5486 males with a mean exposure of 14.9 years. The authors note that occupational quartz particles may be a confounder in this particular mine, potentially contributing to the lung cancer risk. Death data was extracted from company and/or medical records.

Kreuzer et al. 2003

This case control study was conducted in East Germany and involved a total of 1,192 cases and 1,640 controls, to examine the risk of lung cancer resulting from residential radon exposure of between five (5) and thirty five years to mean radon concentrations ranging from 50≥140 Bq/m3. A point to note is that a large proportion of the cases (98% males, 49% females) were smokers, which was not reflected in the control group (735 males, 23% females).

Krewski et al. 2005

This research synthesis pooled data from seven case control studies conducted in the USA, for residential exposures to radon of between five (5) and 30 years. No details were reported on how the studies were chosen for inclusion in the synthesis and whether


critical appraisal was conducted. The same seven case control studies were reported in two other reviews (see excluded studies).

Legarde et al. 2001

This study combined data from five existing case control studies with new data from a case control study on a Swedish population. The study examined whether smoking or whether there was environmental tobacco smoke (ETS) in the home increased the risk of lung cancer in combination with radon exposure (>50Bq/ m3, at least three years). There was not report of how the studies were identified or whether they were critically appraised. Lung cancer was determined from medical records or death records.

Leurand et al. 2011

This paper analysed data derived from three (3) case control studies of European uranium miners to examine the potential relationship between smoking and occupational radon exposure. Data is derived from French, Czech and German uranium miner cohorts. The German cohort is the same as that used by Grosche et al. 68 and Schnelzer et al.69 Search strategy and inclusion criteria not reported, however methods to combine data were appropriate.

Lubin et al. 2003

The paper reports on pooled data from seven USA case controls studies (same cohorts used for the Krewski et al. 2005 paper) and new data from two individual case control studies conducted in China. The synthesis was an invited paper and no details of inclusion criteria, search strategy or critical appraisal are reported.

Lubin et al. 2004

This research synthesis analysed data from two (2) case control studies published between 1989 - 2002 to generate a summary estimate of the lung cancer risk resulting from residential exposure to radon ranging between <100 and >300 Bq/m3 in two (2) provinces of China. Exposure duration varied between 5 – 30 years. Data is derived from the same cohorts reported by Lubin et al.79 No details were reported on how the studies were chosen for inclusion in the synthesis or whether included studies were critically appraised. Risk was adjusted for gender, age, smoking status, air pollution index, prefecture of residence and socioeconomic status. Of note is the observation that 91% of males in one of the two included studies smoked, whereas 90% of females did not. In the other study (females only, 34% of participants smoked).

Pavia et al. 2003

A meta-analysis by Pavia et al.75 combined data from seventeen (17) case control studies, many of which were included in the Darby et al.74 meta-analysis. Details of inclusion and selection criteria were well reported. The duration of exposure leading to these summary estimates of lung cancer risk were not specified. Methods used for statistical analysis were well reported and appropriate.

Pisa et al. 2001

This case control study was conducted in an Alpine region of Italy with high natural radon radioactivity. Some of the data presented by this case control study is included in the Pavia et al.75 meta-analysis. The reference group for risk assessment was 40 Bq/m-3.


Heterogeneity (as shown by the large confidence interval) was high in risk estimates, which may be due to the small sample size (275 men and 54 women). Confounders considered were gender, age and exposure to known occupational carcinogens.

Schnelzer et al. 2010

Based on the same cohort of German uranium miners as Grosche et al.,68 this cohort study focuses on the potential relationship between smoking and occupational radon exposure in the risk of lung cancer. Smoking status information was either self-reported or derived from Wismut company health records. Death data was extracted from either company or district mortality records. Control selection was well detailed.

Tomasek et al. 2008

Data was analysed from Czech and French cohorts of uranium miners. The French miners were occupationally exposed for at least one year and the Czech miners for at least four years. Attempts were made to improve the sensitivity of risk estimates by using time integrated exposure estimates. This was done by expressing radon exposure by working level month (WLM). Mortality data was extracted from death certificates and used to calculate SMR’s. Outcomes were measured in a reliable way and although dropouts were not detailed, they were accounted for in the analysis.


7 Risk factor: Arsenic exposure7.1 IntroductionArsenic is one of the most common elements in the earth’s crust, and arsenic contamination of air, water or soil results from various natural (volcanic activity) or anthropogenic sources (mining, smelting and fuel combustion). Arsenic is referred to as metalloid because of its intermediate properties between a metal and non-metal. Arsenic compounds are commonly categorised into three groups: inorganic arsenic compounds, organic arsenic compounds and arsenic gas. Carcinogenic effects attributable to arsenic may be due to exposure to any of these compounds.80

Both ingestion (via contaminated food and water) and inhalation have been identified as common routes via which arsenic may enter the human body. Ingestion or inhalation of arsenic (mainly inorganic) gives rise to two metabolites in the body through methylation processes; methylarsonic acid and dimethylarsenic acid. The mechanism of arsenic carcinogenesis is not yet fully understood; however, the most plausible explanation is that high partial pressure of oxygen in the lungs causes oxidative stress, wherein dimethylarsine (a metabolite of dimethylarsenic acid) reacts with oxygen to produce free radical species, which then causes DNA damage.80-82

As in other countries, mining and metal manufacturing are the primary and largest sources of arsenic exposure in Australia.83 Arsenic compounds are also commonly encountered in the manufacture of various products including agricultural applications (insecticides, pesticides), dye-stuffs, pharmaceuticals, wood preservatives and applications in mining, metallurgical, glass-making and semi-conductor industries.80, 82 Occupational exposure to arsenic primarily results from inhalation of arsenic-containing particulates in industrial environs such as smelters, coal-burning power plants, battery assembly, glass manufacturing and electronics.80 Inhalation of arsenic amongst workers in these industries appears to result in greater risk of lung cancer than exposure simply characterised by proximity to these industrial sites where arsenic in the air has been measured at concentrations of 1 µg/m3 and up to 10 µg/m3 80, 84. The Australian Health Guidelines suggest that the eight-hour time weighted average exposure limit should be 0.05 milligrams (mg) of arsenic and soluble compounds per cubic metre (m3) of air.83

Exposure to inorganic arsenic in ground water used for drinking has been identified as a major public health concern. Exposure via ingested water has been identified as increasing the risk of lung cancer in several countries around the world, and particularly in areas with artesian wells (high levels of arsenic >500 µg/L). However, the reported risk of lung cancer resulting from low levels (<100 µg/L) of exposure to arsenic is inconsistent and uncertain.80, 81 Countries with high concentrations of arsenic found in drinking water include large areas of Bangladesh, China, India (West Bengal) and smaller areas of Argentina, Australia, Chile, Mexico, Taiwan, the USA and Vietnam. In countries like Australia, Brazil, Japan, Mexico, Thailand and the USA, mining, smelting and other industrial activities contribute to high concentrations of arsenic in local water sources in some areas.85 Inorganic arsenic is also found in food sources such as rice, grains and fish, albeit in small quantities.80

In the initial search of the literature undertaken for this report, 111 studies were identified that potentially informed the association between arsenic exposure and risk of lung cancer. The second search identified three additional studies. In total, there were 114 studies and the IARC monograph.80 Following more detailed title and abstract examination, 54 studies were excluded and 21 of the studies located by the search were included in the IARC monograph.80 On full-text examination of the remaining 39 studies,


10 studies were included for critical appraisal, with the remainder excluded as they did not match the eligibility criteria for the review. Following critical appraisal nine studies plus the IARC monograph80 were included in the final report.

The studies informing the association between arsenic and lung cancer included 21 relevant studies covered by the IARC monograph,80 one pooled analysis,84 three cohort studies,86-88 four case-control studies89-92 and one nested case-control study.93 Three studies investigated arsenic exposure via ingestion.86, 88, 89 and the remaining six studies investigated arsenic exposure via inhalation. Of the 21 studies included from the monograph, 17 studies related to inhalational exposure and four studies related to ingestion of arsenic with drinking water. The studies included in the 2012 monograph were conducted across different countries, mostly developed countries, except for studies that focussed on arsenic concentration in drinking/well water, which mainly originated from developing countries.

The studies that evaluate the carcinogenic effects of arsenic included in this report vary considerably in terms of study design, exposure indices utilised (measures of average airborne concentration of exposure, cumulative exposure across work experience, and duration of exposure), units of measurement, comparison populations and adjustments for potential confounding factors. The follow-up period also varied considerably across the cohort studies, ranging between four and 51 years; the average follow-up being approximately 35 years. The studies included from the search adjusted for smoking but it is unclear whether studies included in the 2012 IARC monograph similarly adjusted for smoking. Table 7.1 summarises the characteristics of studies relevant to an association between arsenic and lung cancer risk.


Table 7.1 Study characteristics relevant to the association between arsenic exposure and lung cancer

Citation Sample demographics Study method Exposure Type of Lung Cancer


Baastrup et al. 2008Cohort studyDenmarkProspective Danish cohort Diet, Cancer & Health study.

Danish cohort of 57,053 persons, including 27,178 men & 29,875 women.6-10 years follow-up.

Data collection from medical registers, Danish Cancer Registry & lifestyle questionnaires from participants.

Two exposures for arsenic in drinking water calculated for each participant. First one included time-weighted average exposure & second included cumulated arsenic exposure.

Cancers identified from Danish Cancer Registry.

Cox proportional hazard models for calculation of two types of exposure.Data adjusted for various confounding factors.

Adj IRR (95%CI)(median exposure 0.7-1.2 µg/L)0.99 (0.92-1.07)Cumulated exposure (5mg)1.0 (0.98-1.02)

Ferreccio et al. 1998Case ControlChile

151 lung cancer cases & 419 controls enrolled in three regions of Northern Chile

2 controls selected for each lung cancer admitted to hospital within 1 mth of index case. Data collected by nurse through structured questionnaire & physical examination.

Data collected on arsenic levels in drinking water from utility companies from 1950 to 1996

Type of lung cancer not reported.

Unconditional regression analysis with univariate & multivariate models

Adj OR (95%CI)0-0.01: ref0.01-0.029 mg/L1.7 (0.5-5.1)0.03-0.049 mg/L3.9 (1.2-13.4)0.05-0.199 mg/L5.5 (2.2-13.5)0.20-0.40 mg/L9.0 (3.6-22.0)

Hughes et al. 1988Pooled analysis of 12 studies mostly from USA

Large population-based cohorts in communities residing around copper smelters.

Analysis based on 12 cohort studies

Exposure due to residing in a community surrounding arsenic-producing industries.No reported. exposure duration/intensity of

Description unclear

Regression modelNot clear if potential confounding factors adjusted

Overall riskPooled OR (95%CI):1.08 (0.66 -1.43)Mortality:1.14 (0.69-1.88)Incidence: 1.02 (0.46-2.28)




IARC Monograph – Volume 100C 80

Cohort & case control studiesGlobal

1 case-control study, 5 nested case-control studies, 13 cohort studies investigate occupational exposure via inhalation. 3 cohort studies & one case-control study investigate arsenic in drinking water. Rest of the studies included from the monograph, study design description unclear.

Studies summarised by working group of experts.Other aspects include study design, analysis, & adjustment for confounding factors.Inclusion criteria not reported.

Arsenic exposure categorised as inhalation or ingestion. Arsenic exposure included non-occupational general population and occupational.Majority of the studies investigating ingestion (mostly drinking water) were ecological studies which were not included.

In most of the studies lung cancer type is not stated.

Individual risk estimates from both cohort and case-control studies are presented.

Risk estimates extracted by the IARC working group are presented in a tabular form.The majority of the studies show a significant positive association.

Lundstrom et al. 2006Nested case controlSweden

Men - 46 cases and 141 age-matched controls. Mortality followed from 1955 to 1987 & incidence followed from 1958 to 1987.Primary smelter workers

Each case matched with three controls for age. Data collected from detailed work histories & medical records.

Cumulative airborne arsenic exposure estimated (mg As/m3 X 10 m3/d X 250 days/yr X number of exposed years) as a cumulative air arsenic exposure index (CAAEI).Exposure duration:Cases: 35 (8-48yrs)Controls: 30 (2-50)yrs

Type of lung cancer not specified.

Multiple linear logistic regression. adj. for potential confounding factors including smoking & lead exposure.

Overall Adj OR (95% CI)1.01 (1.00-1.03)Smokers:1.07 (1.02-1.11)

Pershagen et al. 1985Case controlSweden

Men - 212 cases & 424 controls. Cases constituted men who died between 1961 & 1979.Men living near arsenic-emitting copper smelter

Identified cases & two controls randomly chosen from same region. Data collected by questionnaire & interview.

Arsenic community exposure but further details unclear. Residential exposure, exposed area compared to reference area.

Type of lung cancer not specified.Diagnosis based on histology, cytology or radiography.

Multivariate regression, Mantel & Haenszel method.

RR (95% CI):Non-smokers: 2.3 (0.7-7.6)Smokers: RR 17.5 (8.9-34.4)




Qiao et al. 1997Cohort studyChina

8346 members (7,867 men & 479 women). Four year follow-up with 241 lung cancer cases diagnosed.Tin miners

Participants enrolled as part of an annual screening program at least once 1992-1995.Data collected from standardised questionnaire & re-interview with some members for validation.

Cumulative individual worker’s exposure to arsenic estimated using an index for arsenic exposure – (Index of Arsenic Exposure Months, IAEM), calculated as a time-weighted average of arsenic concentration X time exposure months.

Diagnosis by pathologists, cytologists & radiologists.Histological confirmation according to WHO diagnostic criteria.

Proportional hazard model for relative risk & SMR computed using Poisson distribution.Age-adjusted SMR, relative to local population. RR compared to lowest quartile

IAEM. RR (95%CI)Q1 (0.062-1.731)1.00 (ref)Q2 (1.733-7.287)3.15 (1.23-8.05)Q3 (7.288-16.090)5.55 (1.95-12.54)Q4 (16.093+)4.94 (1.95-12.54)

‘t Mannetje et al. 2011Multi-centre case controlCentral/Eastern Europe and UK

2852 cases (men -2,197 & women – 655) and 3104 controls (men -2,295 & women – 809).Workers employed in smelters, foundries, metal plating & manufacturing & processing of metals and metal containing products.Inorganic arsenic dust & fumes are emission by-products from arsenic-containing ores, heated at smelters to process copper, lead and other metals.

Newly diagnosed cases and controls frequency matched based on gender & age.Data collected by face-to-face interviews using specialised questionnaires.

Indices to assess exposure included expert’s confidence in the presence of exposure, frequency of exposure and the intensity of exposure.Three cut-points used for exposure intensity determined by industry experts.

Histological diagnosis

Unconditional logistic regression.Adjusted for age, gender, tobacco consumption & other potential confounding factors.

Adj OR (95%CI)Overall risk, unadj. other metals:1.79 (1.16-2.77)Overall risk, adj. other metals:1.65 (1.05-2.58)Duration in years.Arsenic dustNot exposed: 1.00 (ref)1-6yrs: 2.12 (0.84-5.34)6-17 yrs:1.71 (0.66-4.45)17+ yrs: 1.02 (0.43-2.40)Linear trend p - 0.33Arsenic fumes/mistNot exposed: 1.00 (ref)1-5 yrs : 2.18 (0.66-7.18)5-10 yrs: 1.45 (0.45-4.68)10+ yrs: 1.20 (0.45-3.19)Linear trend p - 0.31




Taylor et al. 1989Case controlChina

Men – 107 cases & 107 controls between 35-80 years & who were alive in 1985.Tin miners

All cases & controls matched by year of birth and from same region.Data collected by interview with questionnaire.

Individual worker’s exposure to arsenic estimated using an index for arsenic exposure – (Index of Arsenic Exposure Months, IAEM).

Diagnosis confirmed by a panel of pathologists, clinicians & cytologists, diagnostic criteria for lung carcinoma.

Univariate & multivariate regression analyses.Adj. age, radon & smoking

Compared to lowest quartile IAEM. RR (95%CI)Q1 – 0 = 1.0 (ref)Q2 – 0.003-24.36.8 (2.0-23.9)Q3 – 24.4 – 66.523.9 (5.5-104.0)Q4 – 66.6 – 255.622.6 (4.8-106.4)

Tsuda et al. 1989Retrospective cohortJapan

281 people, 126 men and 155 women from 49 families. Follow-up from 1959 to 1987.

Details collected from death certificates, medical records and autopsy records. Smoking history and occupational history obtained from residents themselves or near relatives.

residential exposure categorised based on arsenic concentration of well water:Low:<0.05ppm (1mg/L)Medium:0.05ppm–0.5ppmHigh:≥0.5 ppmExp. estimated to be 5yrs.

Details unclear.Cause of death classified according to ICD-9.

Description unclear

SMR (95%CI)relative to local areaLow: 0 (0-10.06)Medium: 2.84 (1.5-16.37)High:16.41 (7.15-36.34)Arsenic exposure by smoking status:Low:Non-smokers: 0 (0-29.88)Smokers: 0 (0-15.18)Medium:Non-smokers: 0 (0-45.60)Smokers:3.72 (1.90-21.40)High:Non-smokers: 10.14 (5.20-58.38)Smokers: 18.73 (7.38-44.19)


7.2 ResultsThe results are presented based on the two common modes of exposure; inhalation and ingestion and derived from data extracted from 21 studies in the IARC monograph80 and nine other located studies.

7.2.1 Inhalational arsenic exposure and risk of lung cancer

All occupations and workers

The multi-centred case control study conducted by ‘t Mannetje et al.92 reported a statistically significant increase in the overall lung cancer risk of 79%, resulting from occupational exposure to arsenic (Table 7.2). Risk of lung cancer in the exposed subjects was similarly increased whether arsenic dust or fumes were considered (Table 7.2). Overall risk from arsenic and its compounds, irrespective of physical exposure as dust or mist, was attenuated to 65% once chromium, nickel and cadmium exposures were considered. A similar attenuation in risk was reported between whether arsenic was in dust or fumes/mist form upon adjustment for these other metals as shown in Table 7.2.

Table 7.2 Risk estimates for ever exposed versus non-exposed, before and after adjustment for metals and other occupational exposures (‘t Mannetje et al. 2011)

Study Risk/Association (OR & 95% CI)Adjusted for other occupational exposures excluding metals

Risk/Association (OR & 95% CI)Adjusted for other occupational exposures including metals

Arsenic and compounds 1.79 (1.16-2.77) 1.65 (1.05-2.58)

Arsenic dust 1.65 (0.98-2.77) 1.52 (0.89-2.57)

Arsenic fumes and mist 1.75 (0.93-3.28) 1.51 (0.79-2.89)

In addition, ‘t Mannetje et al.92 examined the effect of exposure duration on the risk of lung cancer. Occupational exposure to arsenic dust and fumes/mist of between one and more than17 years led to non-significant increases in the risk of lung cancer (Table 7.3). The increase in linear trend was non-significant for any of the dose-response categories, but rather showed an inverse relationship with a tendency to decrease with greater duration of exposure (Table 7.3).

Table 7.3 Risk estimates for lung cancer according to exposure-response analyses for arsenic dust and arsenic fumes/mist in terms of duration (years) (‘t Mannetje et al. 2011)

Study Risk/Association (OR & 95% CI)*

Risk/Association (OR & 95% CI)*

Arsenic dust Not exposed 1.00

Arsenic dust 1-6yrs 2.12 (0.84-5.34)

Arsenic dust 6-17yrs 1.71 (0.66-4.45)

Arsenic dust 17+ yrs 1.02 (0.43-2.40)

Arsenic dust Linear trend p 0.33


Study Risk/Association (OR & 95% CI)*

Risk/Association (OR & 95% CI)*

Arsenic fumes/mist Not exposed 1.00

Arsenic fumes/mist 1-5 yrs 2.18 (0.66-7.18)

Arsenic fumes/mist 5-10 yrs 1.45 (0.45-4.68)

Arsenic fumes/mist 10+ yrs 1.20 (0.45-3.19)

Arsenic fumes/mist Linear trend p 0.31*Adjusted for age, gender, tobacco consumption and cumulative exposure to asbestos, silica dust, welding fumes, nickel, cadmium and chromium

7.2.2 Smelter workers and living near smelters

Seven studies (one pooled analysis, five cohort studies and one nested case-control) investigated occupational exposure to arsenic in smelting workers or those residing near a smelter. The majority of the studies reported a positive association between arsenic exposure and lung cancer (Table 7.4).

A pooled analysis of 12 cohort studies84 examined the health of communities surrounding arsenic producing copper smelters and found no significant overall association between exposure to arsenic and lung cancer (OR 1.08, 0.66-1.43). The paper reported heterogeneity between studies, with studies having low statistical power to detect even small increases in risk attributable to low levels of inorganic arsenic exposure.84 Insufficient details were reported for further exploration of the data.

Beyond the included pooled analysis, individual cohort studies identified also provide information regarding the risk imposed by smelters and living in their vicinity. Ades and Kazantis 1988 cited in IARC 201280 reported a 22% increase in the risk of lung cancer due to cumulative exposure to arsenic; however, it was unclear whether the increased risk was solely due to arsenic or in combination with other metals. There was a high correlation between arsenic and lead cumulative exposures, and when each of these risk factors were adjusted for in the model, neither showed a significant increase in RR. Increased duration of employment was associated with increased risk of lung cancer in the cohort exposed to arsenic for 20-29 years only. The RR increased two-fold with 10 years of employment in the high exposure category; however, this risk estimate was based on only two cases (Ades & Kazantis 1988 cited in IARC 2012).80

Lung cancer mortality increased by 45% (SMR 1.45, 1.11-1.86) in a cohort of employees at a UK tin smelter, compared to the local UK population (Binks et al. 2005 cited in 80 The identified risk was significant for exposure durations of 15-20 years and 20-35 years. However, the risk decreased with increasing duration (25-plus years) of employment, suggesting a non-linear relationship is likely due to the decreased data available at longer duration of exposure (Binks et al. 2005 cited in IARC 2012).80 Other included studies by Ades & Kazantis 1988; Jarup et al. 1989; Lubin et al. 2000 cited in IARC 201280 that investigate subjects with similar or greater duration of exposure report similar increased risk estimates with similar imprecision about the estimates (Table 7.4). Lubin et al. 2000 cited in IARC 2012 280, investigating intensity of arsenic exposure in detail, reported that risk of lung cancer increased with increasing duration in each category (light, medium or heavy) of arsenic exposure. Risk estimates were statistically significant for 25 years or greater exposure to light airborne arsenic concentrations and for 1-4 years exposure and greater than 10 years exposure to medium airborne arsenic concentrations. Exposure to heavy airborne arsenic concentrations was only significant for the greater than 10 years exposure category.


Enterline et al. 1987 cited in IARC 201280 report a clear increase in RR (from 0.58 to 1.60) with increased exposure to arsenic amongst workers employed at eight US copper smelters. Mean exposure levels ranged from 7.5-68.6 µg/m3 and mean time-weighted exposure ranged from 114.5-957.7 µg/m3/year. No overall mean exposure was reported. Estimates of SMR relative to the local population ranged from 0.0-2.10 (no confidence intervals reported). The highest SMR correlated with the smelter producing the highest concentration of arsenic. Lung cancer risk was significantly increased for arsenic exposed workers >250µg/m3yr (RR 1.21, no confidence intervals reported). Similarly, the risk of lung cancer increased with increasing cumulative exposure to arsenic and was significantly higher (RR 8.7, 1.6-90.4) when exposure was in excess of 100 mg/m3 years Jarup & Pershagen 1991 cited in IARC 2012.80 Despite the imprecision in risk estimates, the high upper confidence limits would tend to indicate that the real effect is significant (Table 7.4).

Table 7.4 Risk estimates of lung cancer due to occupational arsenic exposure – Smelter studies; IARC monograph80 unless otherwise stated

Study Exposure and cohort characteristics

Risk estimate (95% CI where provided) – Intensity of exposure

Risk estimate (95% CI where provided) – Duration

Ades & Kazantis 1988Cohort studyLondon, UK1970-1982

4393 male workers who worked for at least one year at a zinc-lead-cadmium smelter. Follow-up for 10 years.Exposure level reported as three categories. RR associated with 10 years employment at each exposure level.Background category included all jobs where arsenic exposure not considered as above the plant’s background levels.

RRRR due to cumulative exposure (mg/m3 years) to arsenic: 1.22

RR10 years of employment:0 (Background): 1.251 (Low): 1.362 (High): 2.05By duration of employment (yrs):1-4yrs: 15-9 yrs:0.96 (0.54-1.71)10-19yrs:0.94 (0.56-1.58)20-29yrs2.08 (1.25-3.44)30-39yrs:1.82 (0.85-3.92)≥40yrs:6.89 (1.74-27.3)

Binks et al. 2005Cohort studyNorth Humberside, UK

1462 male workers working in a tin smelter employed between 1967 & 1995 followed through to 2001.No reported details on exposure assessments.SMR relative to local UK population.

SMR & 95% CIOverall risk:1.45 (1.11-1.86)

SMR & 95% CIDuration of employment (years):<15:1.11 (0.53-2.04)15 - <20:2.60 (1.46-4.29)20 - <25:2.00 (1.09-3.36)25+ :1.37 (0.87-2.06)





Enterline et al. 1987Cohort studyUSA, 1949-1980

6078 male white workers in 8 US copper smelters who worked for at least 3 years.Arsenic time-weighted exposure in µg/m3 year (lagged 5 yrs).Time-weighted exposure = air arsenic levels in each job and period (µg/m3) X amount of time workers spent in job(s) in years. Data adjusted for age, calendar year and latency period. Follow-up 1949-1980.

RRTime weighted exp.<100 µg/m3: 0.58100-249 µg/m3: 0.85250-999 µg/m3: 1.21>1000+ µg/m3:1 .6

—

Jarup et al. 1989Cohort studyStockholm, Sweden1928-1967 to 1981

3916 male workers employed (Industry not reported) for at a copper smelter for least 3 months 1928-1967, followed to 1981.Arsenic exposure measured in two categories – duration of exposure (yrs) & dose category (mg years/m3).

SMROverall:3.72 (3.04-4.50)Dose category (mg years/m3):<0.25: 2.71 (1.48-4.54)0.25 - <1: 3.60 (1.92-6.15)1 - <5: 2.38 (1.39-3.82)5 - <15: 3.38 (1.89-5.58)15 - <50: 4.61 (3.09- 6.62)50 - <100: 7.28 (2.67–15.85)100+: 11.37 (5.88-19.86)

SMRDuration of exposure:<10 yrs: 3.7110-29 yrs: 3.57>30 yrs: 2.16

Jarup & Pershagen 1991Nested case-controlStockholm, Sweden

Cumulative arsenic exposure in copper smelter workers (mg/m3 x years). Data adjusted for age, smoking status & other occupational exposures.107 dying cases and 214 deceased controls identified from a cohort of 3916 male workers employed for a least 3months 1928-1967.

RR & 95% CI<0.25: 1.00.25-<1: 0.7 (0.2-2.2)1-<5: 1.0 (0.3-2.9)5-<15: 1.3 (0.4-4.6)15-<50: 1.5 (0.5-4.2)50-<100: 2.0 (0.4-9.4)>100: 8.7 (1.6-90.4)

—





Lubin et al. 2000Cohort studyMontana, USA1938-1989

8014 males employed ≥ 12 months before 1957 at a copper smelter.Exposure reported in three categories by exposure: light (&unknown), medium and heavy airborne arsenic-exposed work areas.Time-weighted average airborne arsenic concentrations:light (0.29 mg/m3), medium (0.58 mg/m3) and heavy (11.3 mg/m3).Data adjusted for age, calendar year, work status and duration of exposure. Follow-up from 1938 through to 1989 with a maximum of 52 years follow-up.

RR & 95% CILight & unknown, mean exp. 13.8yrs:1-4yrs: 1.00 (ref)5-14 yrs: 0.95 (0.6-1.4)15-24 yrs: 1.22 (0.8-1.9)25-34 yrs: 1.86 (1.2-2.9)≥35 yrs: 1.98 (1.3-3.1)Medium, mean exp. 5.7yrs:0 yrs: 1.00 (ref)1-4 yrs: 1.39 (1-1.9)5-9 yrs: 1.3 (0.7-2.4)≥10 yrs: 3.01 (2.0-4.6)Heavy, mean exp.yrs:0 yrs: 1.00(ref)1-4 yrs: 1.11 (0.8-1.6)5-9 yrs: 1.40 (0.5-3.8)≥10 yrs: 3.68 (2.1-6.4)

RR & 95% CILight & unknown, mean exp. 13.8yrs:1-4yrs: 1.00 (ref)5-14 yrs: 0.95 (0.6-1.4)15-24 yrs: 1.22 (0.8-1.9)25-34 yrs: 1.86 (1.2-2.9)≥35 yrs: 1.98 (1.3-3.1)Medium, mean exp. 5.7yrs:0 yrs: 1.00 (ref)1-4 yrs: 1.39 (1-1.9)5-9 yrs: 1.3 (0.7-2.4)≥10 yrs: 3.01 (2.0-4.6)Heavy, mean exp.yrs:0 yrs: 1.00(ref)1-4 yrs: 1.11 (0.8-1.6)5-9 yrs: 1.40 (0.5-3.8)≥10 yrs: 3.68 (2.1-6.4)

Other studies (not in the IARC monograph 80




Hughes et al. 1988Pooled analysis

Large population-based cohorts in communities residing around copper smelters (locations not detailed in monograph). Analysis based on 12 cohort studies.Arsenic exposure in communities surrounding arsenic-producing industries

OR & 95% CIOverall:1.08 (0.66 -1.43)Mortality:1.14 (0.69-1.88)Incidence:1.02 (0.46-2.28)

OR & 95% CIOverall:1.08 (0.66 -1.43)Mortality:1.14 (0.69-1.88)Incidence:1.02 (0.46-2.28)

7.2.3 Miners

Tin and tungsten miners

Both cohort and nested-case control studies, specifically those conducted in China, found that workers in tin mines exposed to arsenic showed an increased risk of lung cancer compared to those not exposed (Table 7.5). There was a significant increase in trend in the risk of lung cancer with increasing intensity of exposure to arsenic. The risk for workers at tin mines in Chinese cohorts ranged from 1.86 to 22.6 in the high exposure categories compared to those not exposed (Table 7.5 Chen & Chen 2002, Chen et al. 2007, Qiao et al. 1997, Taylor et al. 1989; Xuan et al. 1993).80

Increased risk of lung cancer in workers employed in Chinese tungsten mines attributable to exposure to arsenic was inconclusive, relative to pottery workers (Table 7.5;


McLaughlin et al. 1992 cited in IARC 2012)80 Data from miners employed in iron-copper mines showed no association between arsenic exposure and lung cancer. Workers employed in tin mines showed a significant positive trend for risk of lung cancer with increasing cumulative exposures to arsenic (Table 7.5; McLaughlin et al. 1992 cited in IARC 2012).80

Gold miners

Kusiak et al. 1991 cited in IARC 201280 examined the effect of arsenic exposure in workers employed in a gold mine before and after 1945. The results from this study showed that there was a significant (p = 0.0001) linear increase in mortality until 1945; however, the increase was not significant (p = 0.6) after 1946 (Table 7.5). A historical cohort study that examined the lung cancer mortality in both miners and workers from a refinery plant in France found that the risk of lung cancer mortality was two-fold in both gold miners and refinery workers when compared to the general population, the risk being similar for both types of workers (Table 7.5; Simonato et al. 1994 cited in IARC 2012).80

Table 7.5 Risk estimates of lung cancer due to occupational arsenic exposure – Mining studies, IARC monograph80 unless otherwise stated

Study Exposure and cohort characteristics Risk estimate (95% CI where provided)

Kusiak et al 1991Cohort studyOntario, Canada1977-86

Mean index of exposure (%As-y) in two categories – exposure to arsenic before 1946, lagged by 20 yrs & exposure to arsenic after 1945, lagged by 20 yrs.54,128 men who worked in Ontario gold mines 1955-1986.

SMRBy exposure (%As-y) to arsenic before 1946:0.00: 0.980.05: 0.990.20: 1.460.59: 1.701.56: 1.635.76: 2.52By exposure (%As-y ) to arsenic after 1945:0.00: 1.250.05: 1.260.19: 1.160.60: 1.523.00: 1.17

Simonato et al 1994Cohort studySalsigne, France

Historical cohort study of 1330 workers from gold mines and a refinery plant followed up from 1972 through to 1987. Outcome – mortality.Exposures estimated based on identifying periods at different exposures and investigating their relationship with risk.

SMR & 95% CIOverall: 2.13 (1.48-2.96)Observed cases = 35Gold miners: 2.17 (1.31-3.39)Refinery workers: 2.29 (1.44-3.47)

Xuan et al 1993Cohort studyYunnan, China

Workers from tin mines.No further details on exposure and cohort in the monograph.Full-text could not be retrieved.

SMROverall: 3.1Observed cases = 983


Study Exposure and cohort characteristics Risk estimate (95% CI where provided)

Chen & Chen 2002Nested case-control studySouthern China

Total arsenic exposure (µg/m3 –year) and cumulative exposure (µg/m3 –year) further into three categories.Data adjusted for age and smoking.130 cases and 627 controls – male tin miners

RR & 95% CICumulative exposure:Low<100: 2.1 (1.0-4.4)100-499.9: 2.0 (1.0-4.1)Medium<100: 1.7 (0.7-4.1)100-499.9: 1.9 (0.9-4.0)500-999.9: 1.5 (0.6-3.5)High<100: 2.2 (0.9-5.0)100-499.9: 3.4 (0.9-12.6)500-999.9: 2.3 (1.0-4.9)≥1000: 3.5 (1.8-7.0)Total exposure:<100: 2.0 (1.1-3.7)100-499.9: 2.0 (1.0-3.7)500-999.9: 1.9 (1.0-3.7)≥1000: 3.5 (1.8-7.0)

Chen et al 2007Nested case-control studyChina

Arsenic exposure measured as per mg/m3 increase per year. Data adjusted for smoking.518 cases from a cohort of males in tin mining and pottery industries. 1884 matched controls.

RR & 95% CIOverall: 1.86 (1.14-3.04)

McLaughlin et al 1992Nested case-control studyChina

Cumulative arsenic exposure (µg/m3/y) for different occupations using a detailed quantitative exposure matrix. Data adjusted for age and cigarette smoking.316 cases and 1352 controls – men from a cohort in 29 tungsten, tin and iron-copper mines and potteries.

RRPotteries: (ref, data not provided)Tungsten mines:Low (0.1-5.52): 1.3Medium (5.53-28.5): 0.5Iron-Copper mines:Low (0.1-5.52): 0.6Tin mines:Low (0.1-5.52): 1.4Medium (5.53-28.5): 1.5High (≥28.6): 2.8


Other studies (not in the monograph 80)Study Exposure and cohort characteristics Risk estimate (95% CI where

provided)

Qiao et al 1997Cohort studyChina

8346 members (7,867 men and 479 women). Four year follow-up with 241 lung cancer cases diagnosed. Tin miners.Cumulative individual worker’s exposure to arsenic estimated using an index for arsenic exposure – Index of Arsenic Exposure Months, IAEM), calculated as a time-weighted average of arsenic concentration X time exposure months.

RR & 95% CIQ1 (0.062-1.731): 1.00Q2 (1.733-7.287): 3.15 (1.23-8.05)Q3 (7.288-16.090): 5.55 (1.95-12.54)Q4 (16.093-): 4.94 (1.95-12.54)P = 0.0002

Taylor et al 1989Case-controlChina

Men – 107 cases and 107 controls between 35-80 years & who were alive in 1985. Tin miners.Individual worker’s exposure to arsenic estimated using an index for arsenic exposure – Index of Arsenic Exposure Months, IAEM.

RR & 95% CIQuartiles of exposure:Q1 – 0: 1.0Q2 – 0.003-24.3: 6.8 (2.0-23.9)Q3 – 24.4 – 66.5: 23.9 (5.5-104.0)Q4 – 66.6 – 255.6: 22.6 (4.8-106.4)Intensity of exposure (IAEM/yrs):0: 1.00.001-2.07: 8.7 (2.5-30.5)2.08 – 6.69: 3.9 (1.0-15.3)Duration of exposure in years:0: 1.01-23: 6.8 (2.0-23.7)24-55: 19.8 (4.4-88.6)

7.2.4 Smelter workers and miners

Taylor et al.91 showed that male workers in China with exposure to both smelting and tin mining had the highest risk of developing lung cancer compared to those with no occupational exposure and to those who were exposed to either smelting or mining (Table 7.6). The results showed that the risks were comparable for both smelter workers and miners. It has to be noted that the analysis includes only six cases and controls exposed to smelting, 142 to mining only and 26 to both smelting and mining, which may account for the lack of precision in effect estimates indicated by the wide confidence intervals.

Men living near an arsenic producing industry (copper smelter) showed a two-fold increase in the risk of developing lung cancer compared to those living in unexposed areas (Table 7.6).90 The RRs for both miners and smelter workers were significantly greater than for those unexposed; however, risk estimates were smaller and more precise when compared to those in the Taylor et al.91 study (Table 7.6). Variation in the different working conditions, sources of exposure information and exposure indices between the countries (China and Sweden) where the studies were conducted may be contributing factors to differences observed in the reported data.


Table 7.6 Risk of lung cancer, by occupation in smelters or mines

Study Risk/Association (OR & 95% CI)None

Risk/Association (OR & 95% CI)Smelter only

Risk/Association (OR & 95% CI)Mining only

Risk/Association (OR & 95% CI)Smelter + mining

Taylor et al. 1989Case controlChina

1.0 12.3 (1.7-91.9) 8.8 (2.4-32.2) 22.0 (4.9-98.2)

Study Risk/Association (RR & 95% CI)Residence in exposed areas

Risk/Association (RR & 95% CI)Miners

Risk/Association (RR & 95% CI)Smelter workers

Pershagen 1985Case controlSweden

2.0 (1.2-3.4) 4.1 (1.7-9.7) 3.0 (2.0-4.7)

7.2.5 Fertiliser manufacturing plant, stoking, pesticide and refinery workers

Two studies that included manufacturing and production workers found a significant increase in lung cancer mortality, particularly in males, associated with occupation (Table 7.7). There was a significant increase (almost three-fold) in risk of lung cancer in male production workers, with an overall cumulative exposure ranging from 20-34 unit-years; however, there was no significant increase in the trend and it was unclear whether the data was adjusted for smoking (Bulbulyan et al. 1996 cited in IARC 2012 2).80 The study by Mabuchi et al. 1980 cited in IARC 201280 showed a significant six-fold increase in mortality in workers employed for more than 25 years in areas of work with high exposures to arsenic. The type of work that predominantly involved arsenic exposure alone also showed a significant increase in lung cancer mortality (Mabuchi et al. 1980 cited in IARC 2012).80

Hansen 1992 cited in 80 examined lung cancer risk in a cohort of stokers in Denmark (with intensive exposures to heat radiation and coal dust) and found that there was a 45% increase in lung cancer mortality relative to persons not employed as stokers. Studies by Tollestrup et al. 199580 and Grimsrud et al. 200580 in US apple orchard workers and nickel refinery workers respectively showed that there was no significant increase in lung cancer risk, even with increasing exposures to arsenic as in the case of Grimsrud et al. 2005 cited in IARC 201280 (Table 7.7). It is worth noting that the number of workers in both studies was small and levels of arsenic exposure, though unreported, were expected to be low due to the types of occupation.


Table 7.7 Risk estimates of lung cancer due to occupational arsenic exposure – Fertilisation plant, stoking, pesticides and refinery studies, IARC monograph80 unless otherwise stated




Bulbulyan et al* 1996Voskresensk, Russia1945/1985-1990

Overall cumulative exposure level (unit-years) & lung cancer mortality by gender in both production workers & other workers.2039 men & 2957 women employed at a fertilisation plant between 1945-1985. Cohort followed until 1990. Data adjusted for age, gender & calendar year.

RRUnexposed: 1.0≤19: 1.87 (0.77-4.54)20-34: 2.8 (1.21-6.46)35-49: 0.86 (0.2-3.64)≥50: 1.44 (0.5-4.15)

—

Hansen 1992Denmark

Historical cohort study with a 10 yr follow-up of 2777 male stokers (employed to tend a furnace & supply it with fuel).No clear details on exposure assessments

SMR & 95% CI1.45 (1.10-1.86)

—

Tollestrup et al 1995Wenatchee, WA, USA

Cohort of 1225 male & female workers who lived in study area during apple growing season. Workers prepared and applied lead arsenate spray during apple season.Three levels of exposure defined based on the use of lead arsenate pesticide; however, no details on these levels provided.

HR & 95% CIMales: 0.59 (0.19-1.85)Females: data not reported

—

Mabuchi et al 1980Baltimore, USA

1393 male & female workers employed in manufacturing & packaging of various pesticides in a plant. Follow-up period & loss to follow-up unclear. Exposure to arsenic graded as high, medium & low according to job type. Highest exposure was assumed among arsenic acid operators & production workers in insecticide division.

SMRWork exposure group:Arsenical: 0.38Predominantly arsenical: 3.36Predominantly non-arsenical: 0.00Unspecified production: 6.82Maintenance/shipping: 1.56Office: 0.00

SMRAccording to duration of employment:<4 months: 0.744-11 months: 1.751-4 years: 0.525-24 years: 1.8725+ years: 6.78

Grimsrud et al 2005Norway

Arsenic exposure measured in mg/m3 x years in three categories with unexposed as the reference category in workers employed at a Nickel refinery. Data adjusted for smoking & other occupational exposures.213 cases & 525 controls matched according to gender & year of birth.

RR & 95% CIUnexposed: 1.0Low (0-0.0009):1.3 (0.7-2.3)Medium (0.01-0.17):1.2 (0.7-2.3)High (0.18-5.9):1.2 (0.6-2.4)

—


*Individual exposures were given scores according to industrial hygiene survey, which were multiplied by duration of employment

7.2.6 Inhalational arsenic exposure and risk of lung cancer by smoking status

The risk of lung cancer increased in both smokers and non-smokers living in an area of Sweden where subjects were exposed to arsenic.90 However, the elevated risk was statistically significant and more pronounced only in smokers (Table 7.8). This finding was consistent with the fact that there were more cases than controls that smoked in both the reference and exposed areas. The risk of lung cancer increased for both miners and smelter workers among smokers and non-smokers, but more so in smokers as it did in miners (Table 7.8). The significant increase in risk of lung cancer among smokers residing in arsenic exposed areas suggests synergism indicative of a multiplicative effect.90

Table 7.8 Risk estimates for lung cancer due to arsenic exposure among men living near arsenic-emitting smelters, by smoking status (Pershagen et al. 1985)

Category Risk/Association (RR & 95% CI)Non smokers

Risk/Association (RR & 95% CI)Smokers

Reference area 1 8.3 (4.5-15.4)

Exposed area* 2.3 (0.7-7.6) 17.5 (8.9-34.4)

Miners 10.4 (2.7-40.2) 35.2 (12.2-102.0)

Smelter workers 8.4 (3.2-21.9) 26.2 (12.7-53.9)*Miners and smelter workers excluded

Analyses that included all male workers and workers who smoked showed that the risk of lung cancer was significant in cases compared to controls as shown in Table 7.9. The median duration of exposure for both cases and controls was 30 years. The arsenic levels measured ranged between 0.4 and 1.5 mg/m3 in the 1940s and between 0.1 to 0.5 mg/m3

in the 1950s.93

Table 7.9 Cumulative air arsenic exposure index* (CAAEI) in all male primary smelter workers and in primary smelter workers who were current smokers (Lundstrom et al. 2006)

Risk/Association (OR & 95% CI)All workers

Risk/Association (OR & 95% CI)Only smokers

1.01 (1.00-1.03) 1.07 (1.02-1.11)*CAAEI – mg/m3 x 10 m3/d x 250 d/year x number of exposed years. Actual cumulative exposure not provided.

Qiao et al.87 reported a 32% increased risk of lung cancer in Chinese tin miners who were former and current smokers compared to those who never smoked (Table 7.10). The risk of lung cancer increased and was statistically significant for miners who had smoked >41 years (Table 7.10). It has to be noted that there was a higher percentage (82%) of cases among current smokers, with cigarette smoking being the most common form of tobacco use.


Table 7.10 Age-adjusted relative risks for ever and current tobacco use in male tin miners at high risk for lung cancer (Qiao et al. 1997)

Category Risk/Association (RR & 95% CI)Never

Risk/Association (RR & 95% CI)Former

Risk/Association (RR & 95% CI)Current

Risk/Association (RR & 95% CI)P for trend

Any tobacco 1.00 1.33 (0.65-2.71) 1.59 (0.84-3.1) 0.09

Cigarettes 1.00 1.11 (0.73-1.70) 1.32 (0.94-1.85) 0.01

Years smoked

None Low (<28) Medium (28-41)

High (>41) P for trend

— 1.00 0.40 (0.15-1.05)

1.46 (0.74-2.87) 2.05 (1.06-3.94)

0.0001

7.2.7 Inhalational arsenic exposure and risk of lung cancer by gender

Two studies presented data on lung cancer mortality stratified by gender. In a cohort of Russian male and female workers employed in a fertiliser manufacturing plant, there was a significant increase in lung cancer mortality in male production workers after a latency period of 20 years or more (Table 7.11). The increase in mortality observed among female production workers was not statistically significant; however, this finding is based on only three reported lung cancer deaths Table 7.11; Bulbulyan et al. 1996 cited in IRAC 2012.80 The study by Mabuchi et al. 1980 cited in IARC 201280 showed a significant increase in lung cancer mortality in male production workers exposed to high levels of arsenic compared to their counterparts locally and nationally. Although there was an increase in mortality among female production workers compared to workers nationally, it was not statistically significant. Among 1393 employees included in this study, there were 1050 males and 343 females (Mabuchi et al. 1980 cited in IARC 2012).80

Table 7.11 Lung cancer mortality in male and female workers

Study Risk/Association (SMR & 95% CI)MalesProduction workers

Risk/Association (SMR & 95% CI)MalesOther workers

Risk/Association (SMR & 95% CI)FemalesProduction workers

Risk/Association (SMR & 95% CI)FemalesOther workers

Bulbulyan et al 1996 - Total group

1.24 (0.75- 1.94) 0.97 (0.59- 1.49) 2.09 (0.43- 6.10) 0.84 (0.27-1.97)

Bulbulyan et al 1996 - ≥20 yr latency

1.86 (1.08-2.97) 0.73 (0.27-1.59) 2.14 (0.26-7.73) 0.32 (1.0-1.78)

Study Risk/Association (SMR & 95% CI)MalesCompared to local workers

Risk/Association (SMR & 95% CI)MalesCompared to US workers

Risk/Association (SMR & 95% CI)FemalesCompared to local workers

Risk/Association (SMR & 95% CI)FemalesCompared to US workers

Mabuchi et al 1980

1.68* 2.65* 0.83 1.51


*P<0.05

7.2.8 Ingested arsenic exposure (drinking water) and risk of lung cancer

World Health Organisation94 guidelines on drinking water quality currently recommend 0.01 mg/L as the safe level of arsenic in drinking water. The majority of the studies included in the IARC monograph80 that addressed the risk of lung cancer associated with arsenic exposure via ingestion of drinking water were ecological studies. In addition, studies that considered Blackfoot Disease were excluded as they were endemic to only some geographical regions, such as areas of Taiwan. Only four studies from the IARC monograph80 and three other primary studies relating to arsenic exposure from drinking water were included in this report (Table 7.12).

Two cohort studies conducted in Japan (Tsuda et al. 1989; Tsuda et al. 1995 cited in IARC 2012)80 and two case control studies conducted in Chile89 found a significant positive association between arsenic in drinking water and risk of lung cancer in study subjects (Table 7.12). In contrast, a cohort study conducted in Denmark found no clear association between arsenic in drinking water and lung cancer (Table 7.12).86 The mean and median arsenic exposures, 1.2 and 0.7 µg/L respectively, were however lower than those recorded in either Japan or Chile, which may be a mitigating factor for the lack of effect reported in this study. Elevated risks of lung cancer mortality were observed with concentrations of arsenic in drinking water ranging between 0.5 and 1.0 ppm (0.5-1.0 mg/L) in two cohort studies (Tsuda et al. 1995 cited in IARC 2012)80 conducted in Japan (Table 7.12). However, there were no lung cancer deaths reported in the lowest exposure categories. It should be noted that both studies utilised small samples sizes reflected in the wide confidence intervals.

Case control studies conducted in Chile by Ferreccio et al. 1998; 2000 cited in IARC mongraph80 showed significant positive dose-response relationships between arsenic exposure and lung cancer risk. The study by Ferreccio et al. 2000 cited in IARC 201280 showed significant risk for lung cancer based on average arsenic concentrations in drinking water from 1930-1994. Similarly in the study by Ferreccio et al.89 the risk of lung cancer increased considerably and upwards above an arsenic concentration of more than 0.03 mg/L.

Table 7.12 Risk estimates of lung cancer due to arsenic exposure from drinking water, IARC monograph 80 unless otherwise stated

Study Exposure and study characteristics Risk estimate

Tsuda et al 1995Cohort studyNiigata Prefecture, Japan1959-1992

Arsenic exposure in three different levels in ppm categorised as lowest exposure, intermediate exposure & highest exposure groups.113 persons who drank from industrially contaminated wells in 1955-59. Historical cohort study followed for 33 years. Data adjusted for age & smoking. Outcome- mortality relative to local population.

SMR<0.05ppm: 0.0 (0-2.4)0.05-0.99ppm:2.33 (0.12-13.39)≥1.0 ppm: 15.69 (7.38-31.02)Total: 3.66 (1.81-7.03)



Ferreccio et al 2000Case controlNorthern Chile

Average arsenic concentration from public water supply records during 1930-94 in µg/L in five exposure categories. Data, age & gender adjusted.151 cases & 419 matched hospital controls.Outcome – incidenceEvidence of synergy between cigarette smoking & arsenic ingestion in drinking water.

OR & 95% CI0-10: 1.010-29: 1.6 (0.5-5.3)30-49: 3.9 (1.2-12.3)50-199: 5.2 (2.3-11.7)200-400: 8.9 (4.0-19.6)OR for lung cancer among smokers exposed to 200 µg/L compared with non-smokers exposed to less than 50 µg/L: 32.0 (7.2-198.0)

Other studies (not in the IARC monograph 80


Baastrup et al 2008Cohort studyDenmark

Danish cohort of 57,053 persons, including 27,178 men & 29,875 women. 6-10 years follow-up.Two exposures calculated for each participant. First one included time-weighted average exposure & second included cumulated arsenic exposure.

IRR & 95%CITime-weighted average exposure (median exposure 0.7-1.2 µg/L):0.99 (0.92-1.07)Cumulated exposure (mg):1.0 (0.98-1.02)

Ferreccio et al 1998Case ControlChile

151 lung cancer cases & 419 controls enrolled in three regions of Northern Chile.Data collected on arsenic levels in drinking water from utility companies from 1950 to 1996.

OR % 95% CIDose-response – Lifetime Mean arsenic concentrations (mg/L)0-0.02: 10.01-0.029: 1.7 (0.5-5.1)0.03-0.049: 3.9 (1.2-13.4)0.05-0.199: 5.5 (2.2-13.5)0.20-0.40: 9.0 (3.6-22.0)

Tsuda et al 1989Retrospective cohortJapan

281 people, 126 men & 155 women from 49 families. Follow-up from 1959 to 1987.Cohort divided into three groups according to arsenic concentration of well water:≥0.5 ppm – high0.05ppm – 0.5ppm – medium<0.05ppm - low

SMR & 95%CILow: 0 (0-10.06)Medium: 2.84 (0.15-16.37)High: 16.41 (7.15-36.34)

*1 ppm = 1 mg/L = 1000 µg/L

7.2.9 Ingested arsenic exposure (drinking water) and risk of lung cancer by smoking status

A significant increase in lung cancer mortality was observed in Japanese smokers exposed to high concentrations of arsenic in drinking water as shown in Table 7.13.88 There was a significant difference in lung cancer mortality between smokers and non-smokers in the high concentration group; however, the interpretation of findings as indicated by the wide confidence intervals may be limited by a small sample size.88


Table 7.13 Risk estimates for lung cancer mortality according to arsenic concentration of well water, by smoking status (Tsuda et al. 1989)

Category Risk/Association (SMR & 95% CI)High group (≥0.5ppm)

Risk/Association (SMR & 95% CI)Medium group (0.05-0.5 ppm)

Risk/Association (SMR & 95% CI)Low group (0.05 ppm)

Smokers & ex-smokers

18.73 (7.38-44.19) 3.72 (.19-21.40) 0 (0-15.18)

Non smokers 10.14 (.52-58.38) 0 (0-45.60) 0 (0-29.88)

Table 7.14 shows risk estimates for smokers and non-smokers from two case control studies conducted in Chile (Ferreccio et al. 1998; Ferreccio et al. 2000 cited in IARC 2012).80 The significant increase in risks in both non-smokers and smokers showed a positive trend with increasing concentrations of arsenic in drinking water. However, there was a significant difference in risks between smokers and non-smokers in the highest concentration group in the study by Ferreccio et al. 2000 cited in IARC 2012 2,80 similar to the study by Tsuda et al.88 The significant difference in risk observed in smokers compared to non-smokers in the study by Ferreccio et al. showed that the joint effects of smoking and arsenic were greater than their individual effects. The wider confidence intervals do limit the applicability of these findings.

Table 7.14 Risk of lung cancer and exposure to arsenic in drinking water by smoking status

Study Risk/AssociationLifetime average arsenic drinking water (mg/L)

Risk/AssociationNever smokedOR

Risk/AssociationEver smokedOR

Ferreccio et al 1998

<0.001 1 1


0.001-0.029 1.1 1.9


0.03-0.049 — 5.1


0.05-0.199 5.7 5.4


>0.200 8.3 9.2

Study Risk/AssociationAverage arsenic in drinking water (µg/L)

Risk/AssociationNever smokedOR & 95%CI

Risk/AssociationEver SmokedOR & 95%CI


≤49 1 6.1 (1.31-39.2)


50-199 5.9 (1.2-40.2) 18.6 (4.13-116.4)


≥200 8.0 (1.7-52.3) 32.0 (7.22-198.0)


7.2.10 Ingested arsenic exposure (drinking water) and risk of lung cancer by gender

Table 7.15 shows data from two studies with mixed results conducted in two different settings. Nakadaira et al. 2002 cited in IARC 201280 found a significant observed/expected ratio only in males although there was an excess in both Japanese males and females. The seven cases observed in males were all smokers. Of all the participants, 97% of males were smokers and only 9% of women were smokers, which could explain the difference in the mortality between the two genders. However, joint effects of smoking and arsenic cannot be adequately ascertained from this study due to the small sample size. In contrast, a study conducted in the USA by Lewis et al. 1999 cited in IARC 201280 found no clear association between arsenic concentration in drinking water and risk of lung cancer in both males and females. High levels of arsenic in drinking water in this study, and in general in the USA, were comparable to low levels of exposure as seen in studies conducted in other countries for example, Japan and Chile.

Table 7.15 Risk of lung cancer and exposure to arsenic in drinking water in males and females, IARC monograph80


Lewis et al 1999Millard County, UT, USA

Arsenic in well-water, 3.5-620 µg/L.Men & women included – numbers not provided.

SMRMales: 0.57 (0.38-0.82)Females: 0.44 (0.16-0.95)

Nakadaira et al 2002Niigata Prefecture, Japan

Industrially contaminated well-water with arsenic.86 patients with chronic arsenic poisoning. Follow-up for 34 years (1959 to 1992).

SMRMales: 11.01Females: 5.34

7.3 SummaryOccupational exposure to arsenic compounds in smelter workers, miners (particularly tin and gold miners) and in production workers causes lung cancer; with risk elevated two-to-three fold with greater levels of exposure and longer duration of exposure to arsenic (i.e. longer duration of employment). These findings assume importance in the Australian context considering the increase in mining activities and also the number of workers in the smelter industry. The evidence surrounding the risk of lung cancer from inhalation in communities residing near arsenic producing industries is inconclusive. The pooled analysis by Hughes et al.84 showed a small but non-significant increase in risk, and the study by Pershagen et al.90 showed a significant increase in risk only among smokers. There is clear evidence to suggest that ingestion of arsenic in drinking water with concentrations more than 0.05 ppm or 0.05 mg/L or 50 µg/L (in some cases more than several hundred) increases the risk of lung cancer mortality, especially in parts of countries like Japan, Taiwan and Chile.

Some of the strengths of the studies in this report include large sample sizes amongst the included cohort studies with extended follow-up, long duration of exposure and a wide range of exposure levels. The major limitations across the studies include the lack of sensitivity of exposure measurements (i.e. employment history), small sample sizes (particularly in stratified groups informing the greatest duration and latency of exposure at greater risk of attrition), different exposure measurements and exposure indices precluding meta-analysis. The lack of adequate information on smoking status, particularly from data derived from the IARC monograph must also be highlighted whilst considering the results presented here.


Studies on occupational exposure were primarily conducted in smelter workers and miners. Studies that examined dose-response relationship showed consistent positive associations between cumulative exposures and lung cancer mortality. The results indicate that there is an increased risk for lung cancer mortality from increased exposures (broad range of exposures) to arsenic, particularly high intensity exposures (>0.25 mg/m3) and exposures over longer durations (ranging between 10 and 40 years). The association between inhalational arsenic exposure and lung cancer in communities in close proximity to arsenic producing industries is inconclusive because of the small number of studies and mixed results amongst those that are available. Migration has been suggested as an important confounding factor that may lead to a decrease in the measured excess risk because of the latency period between initial exposure to arsenic and the onset of lung cancer.84

The risk is further elevated in workers who smoke indicating a multiplicative effect of smoking and arsenic. Liu and Chen 1996 cited in IARC 201280 used electron-probe microanalysis to examine the content of arsenic in the lungs and found that arsenic content was 17 times higher in patients diagnosed with lung cancer compared to those unexposed. However, only few studies examined the joint effects of smoking and arsenic on elevated lung cancer risks.

Globally, ingestion of arsenic through drinking water is the major source of exposure to the general population80 and epidemiological studies have shown that arsenic ingested from drinking water is strongly associated with an increased risk of lung cancer and other adverse health outcomes. This phenomenon has particularly been observed in parts of countries like Taiwan, Chile, China, Bangladesh and India, where concentrations of arsenic in drinking water far exceed safe levels as recommended by WHO.94 Comparison with data from developed countries including the USA, Finland and Denmark highlights differences. These countries had lower concentrations of arsenic in the drinking water (well below the prescribed limits of safety levels), which was reflected in the lack of significant association between arsenic in drinking water and risk of lung cancer reported from these areas.


The IARC monograph80 identified arsenic and inorganic arsenic compounds as Group 1 carcinogens in humans. Current epidemiological evidence shows that inhalational exposure to arsenic as a result of occupation can cause lung cancer. In addition, exposure to elevated concentrations of arsenic in drinking water can cause lung cancer.


The current evidence is sufficient to conclude that inhalational exposure to arsenic and arsenic compounds can cause lung cancer. There is also a clear dose-response linear relationship between increasing cumulative inhalational exposure to arsenic and lung cancer risk, particularly in smelter workers. The evidence is unclear regarding the effects of low levels of arsenic exposure, irrespective of route of exposure, and for the carcinogenic effects of arsenic in residents or communities residing in close proximity to arsenic producing industries.

Based on the data from studies conducted in some parts of Japan, Chile and Taiwan, there is enough evidence to conclude that lung cancer is caused by ingestion of arsenic from drinking water. However, these findings are not generalisable to developed


countries, including Australia, where concentrations of arsenic in drinking water are well below the WHO prescribed safety levels.83


Methodological quality of studiesIndividual critical appraisal checklist items for arsenic are shown below in Table 7.16

Table 7.16 Arsenic exposure: Methodological quality of included studies

Study Study/ Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Total (Y) Include/Exclude

Baastrup et al 2008 Cohort Y Y N/A Y U U U Y Y — 5 Include

Ferreccio et al 1998 Case-control Y Y Y Y Y N/A U Y Y — 7 Include

Frost et al 1987 Case-control Y Y Y N Y N/A Y U Y — 6 Exclude

Hughes et al 1988 Pooled analysis N U U Y N/A N/A N/A Y Y Y 4 Include

Lundstrom et al 2006 Case-control Y Y Y Y Y N/A Y Y Y — 8 Include

Pershagen 1985 Case-control Y Y Y Y Y N/A U Y Y — 7 Include

Qiao et al 1997 Cohort Y Y N/A U Y Y U Y Y — 6 Include

‘t Mannetje et al 2011 Case-control Y Y Y Y Y N/A U Y Y — 7 Include

Taylor et al 1989 Case-control Y Y Y Y N N/A U Y Y — 6 Include

Tsuda et al 1989 Retrospective cohort Y Y N/A Y N Y Y U U — 5 Include


Baastrup et al. 2008

The study scored 5 on the JBI critical appraisal test. It was not clear whether the outcomes were assessed using objective criteria and also if there was a sufficient follow-up of the cohort. Data was not presented by smoking status, although smoking status was adjusted for in the analysis. The sample size was large and representative of the population. Loss to follow-up was not reported.

Ferreccio et al. 1998

The study was of good quality, with the exception of no reporting on outcomes of people who withdrew from the study. There was some missing data even though arsenic exposure data were objectively measured and in a reliable way. Data were adjusted for various confounding factors.

Frost et al. 1987

The study was excluded because it did not address smoking as a confounding factor in the analysis. In addition there was a lack of clear details on exposure and measurements.

Hughes et al. 1988

This study was a pooled analysis, not a traditional meta-analysis; hence scored only four (4) on critical appraisal. The review question was not clear and was more of a statement. It was unclear whether the search strategy and the sources of studies were adequate. Reasons were stated for selection of studies. It was unclear whether some of the studies included adjusted for confounding factors including smoking. It was unclear whether studies were critically appraised. The recommendations were supported by reported data; and there were specific directives for future research.

Lundstrom et al. 2006

This nested case-control was of good quality and scored 8 on the critical appraisal check list. Various confounding factors were identified and adjusted for including smoking and there was one analysis restricted only to smokers. Cases and controls were selected in the ratio of 1:3 from a cohort of 3979 male workers.

Pershagen 1985

This was a good quality case control study with respect to matching of cases and controls. The measurement of outcomes was good compared to the other studies reviewed. There was insufficient addressing of confounding factors. The study found no interaction between mining and smoking beyond the additive effect on statistical testing.

Qiao et al. 1997

The subject sample was representative and the participants were at a similar point with regards to exposure. It was unclear whether potential confounding factors, except age were adjusted for in the analysis. The study did not provide a clear description of people lost to follow-up or people excluded from the analysis. Outcomes were assessed and measured based on histological, cytological and radiological reports. A proportional hazards model was used to estimate relative risk.


‘t Mannetje et al. 2011

There was a good matching of cases and controls in the study: cases and controls were frequency matched. Smoking was adjusted for as a confounding factor as was, age when cases died and exposure duration. This is a high quality case control study. A limitation of this study was the high correlation between different metals under study. Unconditional logistic regression was the statistical method.

Taylor et al. 1989

The methods and objectives were generally well described in this study. Cases and controls were representative of the target population and controls were matched to individual cases. Exposure and methods of interview/data collection were well described. Confounding factors were considered and adjusted appropriately. Statistical methods used were adequately described. It was unclear whether outcomes were measured objectively. The outcomes of people who were excluded were not described.

Tsuda et al. 1989

A retrospective cohort study of moderate quality scored 5 on the appraisal check list. The sample size was small and the exposure measurement was unclear. Potential confounding factors were identified and included in the analysis. Statistical methods were not described adequately.


8 Risk factor: Polycyclic aromatic hydrocarbons (PAHs)8.1 IntroductionPolycyclic aromatic hydrocarbons (PAHs), also known as polynuclear hydrocarbons, are a large group of aromatic, lipophilic chemical compounds characterised by the presence of two or more benzene rings in their chemical structure. Polycyclic aromatic hydrocarbons are by-products of incomplete combustion of organic material such as coal and crude oil processing, combustion of natural gas, combustion of refuse and also tobacco smoking.95,96 This group of chemicals includes hundreds of compounds; amongst these, Benzo-a-pyrene (BaP) is the most commonly measured as a marker of exposure to PAH.96-98 Sources of PAHs include tobacco smoke, industrial and urban air pollution and diet. Tobacco smoke is a major source of exposure to PAHs, particularly for active smokers.97,98

Exposure to PAHs arising from wood burning heaters and dietary sources such as toasted cereals and cooked meats may be of relevance for non-smokers who are not exposed to PAHs through their occupation. According to the National Pollutant Inventory 2010/2011,99

domestic solid fuel heating is a major source of PAH emission. Occupational exposure and identified inhalation of PAHs in various industries has been linked to lung cancer.97,98 Benzo-a-pyrene has been classified as a Group 1 carcinogen by IARC.97,98

Polycyclic aromatic hydrocarbons may enter the human body to elicit carcinogenesis through multiple routes including the airways, skin and digestive tract. Following metabolic activation of PAHs by enzymes, these bio-available PAHs, are slowly absorbed through most epithelia resulting in further elevation in enzyme activity (mixed function oxidases) and greater activation of PAH substrates at the site of cellular entry. This mechanism is considered to be a major contributing factor for the tendency of PAHs to act as carcinogens at the site of cellular entry. In these cells, the common mechanism of PAH-induced carcinogenesis is DNA damage through formation of DNA-reactive metabolites.97

Occupational exposures to PAHs have commonly been assessed by measurements taken from air samples at work sites; more recently these measures have focussed on direct measurement of BaP.100 Sampling methods used to establish amount and intensity of exposure ideally not only include measurement of PAH particulates but also the gaseous fractions of BaP or other PAH compounds. It is reported that occupational exposures to BaP in relevant industries can be as high as 100 µg/m3.97 There are currently no ambient air quality standards in Australia for PAHs as a group of compounds. Different states have different guidelines for monitoring and variations in concentrations of these large organic compounds within industries and across various industries is complex.

One-hundred and thirty potentially relevant studies were located by the review search. Two IARC monographs97, 98 were also identified from the second search. The 2012 IARC monograph98 was essentially an update of the 2010 monograph. Of the 130 studies identified, 39 studies were excluded on further title and abstract examination, whilst 38 studies were either included in the IARC monograph or a selected research synthesis paper.96 Full-text of the remaining 53 retrieved studies was assessed. Following full-text examination, 46 studies were excluded due to not matching the eligibility criteria for this review or where studies were more relevant to other relevant risk factors in this review (e.g. air pollution, iron and steel founding).

Seven individual studies were identified for critical appraisal and ultimately included in the final report; three cohort studies101-103; three case-control studies104-106 and one meta-


analysis/pooled analysis.96 The study by Armstrong and colleagues104 was a case-cohort design and the study by Bertrand et al.102 included both cohort and case-control analyses. The final report also included data extracted from 12 studies in the IARC monographs.97, 98

All other relevant studies were included in the synthesis paper.96

The most common method of data collection employed by the various included studies was self-administered questionnaires. Outcome assessment and data collection also relied upon cancer registries and medical records. Incidence of lung cancer and mortality due to lung cancer were the major outcomes reported and used to establish risk estimates. Most statistical models adjusted for likely confounders such as age, gender and smoking status. The majority of studies did not present risk estimates stratified by smoking status. Characteristics of the included studies relevant to the association between exposure to PAHs and lung cancer risk are shown in Table 8.1


Table 8.1 Study characteristics relevant to the association between PAH exposure and lung cancer




Armstrong et al. 1994Quebec, CanadaCase-cohort

Random sample (sub-cohort) of 1,138 from among 16,297 men employed for at least 1 yr between 1950 & 1979 in an aluminium production plant.338 lung cancer deaths recorded

Case-cohort study design, where exposure information is required from a random sample of entire cohort, rather than for matched controls.

Two indices of cumulative exposure (average concentration x time): benzene soluble matter (BSF) (mg/m3 – years) & benzo-a-pyrene (BaP) (µg/m3 – years). Job-exposure matrix used.

All types.Lung cancer ascertained from cancer & tumour registries and records of patients from a hospital.

Proportional hazard or rate ratio regression analysis to obtain cancer rate ratios for groups defined by exposure and smoking.Potential confounders adjusted: age, calendar period & smoking

Mortality: Rate ratios & 95% CI, by smoking status:Never reported smoking = 1.00Ever smoked = 3.00 (1.62-5.59)Ever smoked, by pack years<20 = 0.95 (0.45-2.02)20-39 = 3.00 (1.59-5.69)40-59 = 3.44 (1.79-6.62)≥60 = 6.20 (3.11-12.38)Never smoked more than 20 cigarettes per day = 3.05 (1.46-6.35)Unknown smoking habit = 2.33 (1.06-5.17)Mortality: Rate ratios & 95% CI, by cumulative exposure:BSF (mg/m3 – years):<1 = 1.001-9 = 1.15 (0.84-1.59)10-19 = 2.25 (1.50-3.38)20-29 = 1.90 (1.22-2.97)≥30 = 2.08 (1.30-3.33)BaP (µg/m3 – years):<10 = 1.0010-99 = 1.48 (1.09-2.00)100-199 = 2.23 (1.46-3.39)200-299 = 2.10 (1.40-3.15)≥300 = 1.87 (1.05-3..33)





Armstrong et al 2009Quebec, CanadaCohort

16431: 5977 men at 1 large & 2 small aluminium smelters, & 9726 men & 728 women who completed 1 yr employment before 1989. 677 lung cancer cases.

Large cohort study with follow-up from 1950 until the end of 1999.Exposure-response relationship

Job-exposure matrix using estimates of BaP for each job combined with work histories to give estimates of cumulative exposure in µg/m3 - years

All types, description unclear.

Poisson regression model. Multiplicative & additive models of combined effect of occupational BaP exposure & smoking.Potential confounders adjusted: age, calendar year & smoking

Overall lung cancer mortalitySMR & 95% CI1.32 (1.22-1.42)RR & 95% CI for lung cancer incidenceBy cumulative exposure to BaP (µg/m3 – years):0 = 1.000.0000001-= 1.75 (1.23-2.48)20- = 3.02 (2.01-4.52)40- = 1.94 (1.27-2.97)80- = 3.09 (2.12-4.51)160- = 2.86 (1.96-4.18)320- = 3.77 (2.23-6.38)By no. of cigarettes per day:0 = 1.001-= 1.49 (1.12-1.98)21-= 2.89 (2.18-3.84)41-=1.48 (0.83-2.66)61-= 1.99 (0.72-5.49)Unknown = 1.02 (0.73-1.41)SMR & 95% CI for lung cancer mortalityBy cumulative exposure to BaP (µg/m3 – years):0 = 0.62 (0.44-0.87)0.0000001-= 1.09 (0.96-1.23)20- = 1.88 (1.47-2.38)40- = 1.21 (0.91-1.59)80- = 1.93 (1.59-2.32)160- = 1.79 (1.48-2.15)





320- = 2.36 (1.49-3.54)By no: of cigarettes per day:0 = 0.80 (0.61-1.04)1-= 1.19 (1.04-1.36)21-= 2.32 (2.05-2.61)41-=1.19 (0.65-2.00)61-= 1.60 (0.44-4.09)Unknown = 0.82 (0.66-1.00)

Bertrand et al. 1987Lorraine, FranceCohort

Cohort of 534 male manual workers from two coke oven plants between 1963 & 1982.

Cohort design, follow-up from 1963 to 1982.Mortality ascertained from medical records

Exposure assessment: Comparison between two plants . No further details on exposure


Wilkinson’s signed rank test & Armitage’s statistical test of homogeneity of proportions for duration of exposure.

Lung cancer mortality between two coke oven plantsPlant A – 3.05 (p<1%)Plant B – 1.75 (NS)Cohort mortality in comparison with French male mortalityO/E = 2.51 (p<1%)

Bosetti et al. 2007MultinationalMeta-analysis & pooled analysis

Workers from all relevant industries with high exposures to PAH: coal gasification, coke production, aluminium production, carbon black, coal tar related & carbon electrode

57 cohort studies published between 1997 & 2005.

Occupational exposure to PAHPAH exposure intensity & duration not reported

Description unclear Pooled RRs & 95% CI computed as weighted average of SMR/SIR using inverse variance of the logarithm of SMR/SIR as weight (fixed-effect model)Potential confounders adjusted for: smoking, age, sex, calendar period

Overall SMR & pooled RR (95%CI) for various industries Aluminium productionSMR = 1.01RR = 1.03 (0.95-1.11)Coal gasificationSMR = 2.14RR = 2.29 (1.98-2.64)Coke productionSMR = 1.49RR = 1.58 (1.47-1.69)Tar distillationSMR = 1.19RR = 1.21 (0.95-1.55)





CreosoteSMR = 1.11RR = 1.14 (0.85-1.51)Carbon blackSMR = 1.21RR = 1.30 (1.06-1.59)Carbon electrodeSMR = 0.96RR = 1.00 (0.82-1.23)

Olsson et al. 2010Seven European countriesMulticentre European case-control study

2197 men & 655 women from six Central & Eastern European (CEE) countries and UK aged between 40 & 74 years in various industries classified as exposed to PAH

2861 newly diagnosed lung cancer cases & 2936 population or hospital controls.Nine cases & 13 controls excluded from final analysisData collection from interviews and questionnaires

Two exposure indices: duration of exposure across all job periods in yrs; cumulative exposure calculated as product of frequency (mid-interval values of average work time: 3%, 17.5%, 65%), intensity of airborne BaP (mid-interval values: 0.075, 0.55, 3 µg/m3) & duration of exposure in years summed all over work periods in the person’s job history

All types of lung cancer including squamous cell carcinoma, small cell carcinoma & adenocarcinoma

Unconditional logistic regressionPotential confounding factors adjusted for: age groups, gender, tobacco pack-years & other occupational exposures.

OR & 95% CIOccupational PAH exposureNeverCEE = 1.00UK = 1.00EverCEE = 0.93 (0.77-1.14)UK = 1.97 (1.16-3.35)Maximum intensity to PAH (µg/m3)0.05-0.1CEE = 0.82 (0.65-1.04)UK = 2.12 (1.12-4.00)0.1-1CEE = 1.17 (0.84-1.64)UK = 1.42 (0.57-3.52)1-5CEE = 1.11 (0.60-2.05)UK = 2.68 (0.74-9.77)Cumulative exposure





<0.04CEE = 0.73 (0.50-1.06)UK = 1.79 (0.82-3.90)<0.15CEE = 0.99 (0.69-1.44)UK = 1.68 (0.67-4.20)<0.77CEE = 0.89 (0.62-1.29)UK = 2.14 (0.75-6.110≥0.77CEE = 1.13 (0.80-1.58)UK = 2.77 (0.94-8.11)Years exposed to PAH<5CEE = 0.90 (0.64-1.26)UK = 1.30 (0.60-2.82)6-10CEE = 1.12 (0.75-1.68)UK = 1.40 (0.55-3.58)11-20CEE = 0.76 (0.51-1.13)UK = 15.11 (2.05-74.89)21-30CEE = 0.94 (0.60-1.47)UK = 1.18 (0.32-4.23)30+CEE = 1.02 (0.66-1.57)UK = 3.60 (0.73-17.80)





Pastorino et al. 1984Northern ItalyPopulation-based case-control study

Study area in Northern Italy region characterised by high density of small and medium-sized industries

211 cases & 351 age matched controls. One control chosen for each case for first two years of study & two controls for each case the following two years.

Description unclear

Description unclear Analysis by stratification according to potential cofounders. Adjusted risk ratios between incidence of lung cancer among exposed and unexposed

RR for PAH exposure by no: of cigarettes per day0-9 = 1.310-19 = 7.020+ = 9.9

Veglia et al. 200710 Western European countriesCohort

Cohort of 217,055 subjects included both genders, between the age range of 35 & 74 years. 103,162 men & 113,893 women

Large cohort study with a follow-up period of 6 years.Data collected with questionnaires

CAREX=based job exposure matrix for exposures to lung carcinogens

Description unclear Cox proportional hazard regression modelPotential confounding factors adjusted: gender, smoking history, education, BMI, fruit & vegetable consumption & leisure time physical activity

HR & 95% CIOverall = 1.42 (1.1-1.8)Men = 1.43 (1.2-1.8)Women = 1.24 (0.6-2.4)


8.2 Results8.2.1 Occupational exposure to PAH and risk of lung cancer

A meta-analysis establishing overall SMR and pooled analysis for overall RR showed an increased risk of lung cancer in occupations and industries with high exposure to PAH (Table 8.2).96 The majority of studies included in the review by Bosetti et al.96 did not adjust for smoking in their analyses. The statistically significant risk estimates reported from individual studies ranged from 1.30 (in carbon black production workers) to 2.29 (in coal gasification workers) compared to those workers not exposed to PAHs within those industries (Table 8.2). The relatively modest increases in risk experienced by workers employed in or around processes of aluminium production, tar distillation, creosote and carbon electrode manufacture were not statistically significant. This variation seen across different industries can be explained by the limited data available on exposures, variability in the nature of the data and its measurement, and the relatively small number of studies available investigating specific industries, except aluminium production where the analysis combined data from some 15 studies.

Table 8.2 Overall SMR and pooled RR with 95% CI for exposure to PAH in various industries and occupations96

Industry/occupation SMR RR & 95% CI

Aluminium production 1.01 1.03 (0.95-1.11)

Coal gasification 2.14 2.29 (1.98-2.64)

Coke production 1.49 1.58 (1.47-1.69)

Tar distillation 1.19 1.21 (0.95-1.55)

Creosote 1.11 1.14 (0.85-1.51)

Carbon black production 1.21 1.30 (1.06-1.59)

Carbon electrode manufacture 0.96 1.00 (0.82-1.23)*RR calculated as weighted average of the SMRs, using the inverse of the variance as weight

A further two studies105 investigated occupational exposure to PAH and reported relative risk estimates (Table 8.3). Both studies showed increased risk for lung cancer in workers who were exposed to high levels of PAHs compared to those who were not exposed; however, there was no increase in risk in the cohorts from the Central and East European (CEE) countries investigated by Olsson et al.105 Workers in PAH-related industries in CEE countries were exposed to lower levels of PAHs compared to their counterparts in the UK. Furthermore, the cohort of workers in the UK were also reportedly exposed to high levels of asbestos, and a separate analysis conducted by these authors revealed a joint effect of exposure to PAHs and asbestos.105 In addition, compared to CEE countries, there were fewer cases of lung cancer recorded in the UK cohort, reflected in the wider confidence intervals regarding reported risk estimates (Table 8.3). The study by Gustavsson et al. (2000)107 showed that the risk of lung cancer amongst workers with the highest intensity of exposure (>5 µg/m3 BaP) to PAHs (combustion products), for at least one year, was almost twice the risk compared to those not exposed (Table 8.3).

The increase (60%) in the risk of lung cancer was significant in workers in the highest quartiles of cumulative exposures to combustion products (Table 8.3; Gustavsson et al. 2000).107 In contrast, the study by Olsson et al (2010) showed a relatively modest, but non-significant increase (1.13, 0.80-1.58) in risk in cohorts from CEE countries with high


cumulative exposure (Table 8.3). The cohort of workers from the UK with the highest quartile of cumulative exposure were 2.8 times more likely to develop lung cancer than those not exposed to PAHs.105

Table 8.3 Risk estimates for lung cancer from occupational exposure to PAHs

Study/country/follow-up

Exposure and cohort characteristics

OR (95% CI where provided)

Gustavsson et al 2000Sweden

1042 male cases, matched by 5-yr age group and year of inclusion (1985-90) with 2364 male population controls.Exposure assessment in terms of unexposed vs exposed & cumulative exposure. Industry not specified.Data adjusted for age, year of inclusion, tobacco smoking, residential radon level, environmental exposure to nitrogen dioxide, diesel exhaust & asbestos

Unexposed vs exposed (µg/m3 BaP):Unexposed = 10.05-0.4 (>1 year) = 1.07 (0.72-1.60)0.5-4.9 (>1 yr) = 1.33 (0.89-2.00)≥5 (>1yr) = 2.10 (1.25-3.53)Cumulative exposure (µg/m3 x yrs of BaP):>0-2.9 = 1.20 (0.80-1.80)3.0-6.6 = 1.05 (0.71-1.57)6.7-23.8 = 1.05 (0.69-1.59)≥23.9 = 1.60 (1.09-2.34)

Other studies (not in the 2010/2012h Monographs)Study/country/follow-up

Exposure and cohort characteristics

OR (95% CI where provided)

Olsson et al 2010Six Central & Eastern European (CEE) countries and UK

2197 men & 655 women aged between 40 & 74 years in various industries classified as exposed to PAHCumulative exposure calculated as product of frequency (mid-interval values of average work time: 3%, 17.5%, and 65%).

Ever vs never exposedNeverCEE = 1.00UK = 1.00EverCEE = 0.93 (0.77-1.14)UK = 1.97 (1.16-3.35)Cumulative exposure<0.04CEE = 0.73 (0.50-1.06)UK = 1.79 (0.82-3.90)<0.15CEE = 0.99 (0.69-1.44)UK = 1.68 (0.67-4.20)<0.77CEE = 0.89 (0.62-1.29)UK = 2.14 (0.75-6.110≥0.77CEE = 1.13 (0.80-1.58)UK = 2.77 (0.94-8.11)

Although there was a linear trend for increase in risk with increasing duration of exposure to PAHs for all the three cohorts (see characteristics Table 8.1), the increase in risk was non-significant. Figure 8.1 shows the pooled risk estimate for lung cancer from occupational exposure to PAHs by longest duration of exposure, i.e. equal to or more than 30 years of exposure. The analysis suggests that such levels of exposure lead to a 26%


increase in risk compared to those not exposed; however, this increase is not statistically significant (Figure 8.1). Heterogeneity between the three cohorts was low as indicated by the chi square statistic and low value for the I2 index. Despite the imprecision in the UK cohort, the weight attributed to this cohort in the analysis is small.

Figure 8.1 Occupational exposure to PAHs and risk of lung cancer, by longest duration of exposure (≥30 years)

The main exposure in all the three cohorts - BaPCEE = Central and East European countriesUK = United Kingdom

8.2.2 Occupational PAH exposure and risk of lung cancer in coal gasification workers

Coal gasification workers exposed to PAHs showed a significant increase in risk of lung cancer in both of the relevant cohort studies identified, but not the single case-control study. This is illustrated in the analysis presented in Figure 8.2, with pooled risk estimates from three studies that were similar enough to warrant statistical combination; however, there was significant heterogeneity present between the individual cohort studies analysed (Kennaway & Kennaway, 1947; Wu et al. 1988 cited in IARC monograph108). Consistent with other studies conducted in China, the increase in risk of lung cancer in the study by Wu et al. 1988 cited in IARC monograph,108 in coal gasification workers was 3.5 times compared to those workers not exposed to PAHs. This increase in risk was quite significant in workers in the period from 1971 through 1981 when compared to those employed in 1971 (1.29, 1.16-1.44), suggesting this significant increase observed may be related to the latency of effect. The details on exposure and exposure measurements were not described. An early study by Kennaway and Kennaway conducted in 1947 (cited in IARC monograph108) also showed an increased risk of lung cancer of 30% in coal gasification workers exposed to PAHs relative to unexposed people in the general population. Retrospective analysis by Bovenzi et al. 1993 cited in IARC monograph108 showed no significant increase in risk of lung cancer; however, the imprecise results with a high upper confidence limit suggest a more precise estimate is more likely to indicate that a risk of lung cancer due to exposure does exist (Figure 8.2).


Figure 8.2 Occupational exposure to PAHs and risk of lung cancer in coal gasification workers

Kennaway & Kennaway 1947 (UK) – exposure assessment based on occupational title. No further details on exposure assessments. Data not available on smoking. Gas workers. Follow-up from 1921-1938. SMR.Wu 1988 (China) – 3107 workers at six coal plants. No details on exposure assessment. Short report. SRR. Follow-up from 1971-1982.Bovenzi et al 1993 (Trieste, Italy) – 756 cases matched with 756 population-based controls. Gas workers. Data adjusted for smoking. OR

Table 8.4 shows data from studies included in the IARC monographs97, 98 also derived from workers employed in coal gasification but where data was not suitable for meta-analysis with those in Figure 8.2. The results similarly indicate a relationship between exposure to PAHs in this industry and risk of lung cancer, particularly in highest quartiles of cumulative exposure. The association with lung cancer appears independent of duration of employment, although the imprecision in the estimate favours the likelihood of an underlying effect similar to the case-control study by Bovenzi et al. 1993 cited in IARC monograph,108 shown in Figure 8.2.

Table 8.4 Occupational exposure to PAHs and risk of lung cancer in coal gasification workers


Exposure and cohort characteristics Risk estimate (95% CI where provided)

Kawai et al. 1967Cohort studyJapan, 1953-1965

503 workers at a gas generator plant.Exposure assessment based on occupational titles. Further details not available

SMR33.3 (12.2-72.6)




Martin et al. 2000Nested case-control studyFrance, 1978-1989

Male workers employed for more than one year at a company producing gas & electricity.310 lung cancer cases matched with 1225 controlsJob-exposure matrix with index of cumulative exposure & also by duration of employment. Residual confounding from tobacco smoking

SMRCumulative exposure:Unexposed = 1.0Q1 = 1.02 (0.21-4.94)Q2 = 1.59 (0.39-6.49)Q3 = 0.55 (0.07-4.57)Q4 = 3.87 (1.15-12.9)Duration of employment in years:1-10 = 1.0011-20 = 1.36 (0.48-3.87)21-30 = 1.05 (0.36-3.05)>30 = 1.36 (0.45-4.15)

8.2.3 Occupational exposure to PAHs and risk of lung cancer in coke production workers

Excluding the meta-analysis presented previously (see Table 8.2)96 three studies reported an increased risk in lung cancer in coke-production workers compared to the general population, as shown in Table 8.5. The risk was particularly significant in gas stokers within the coke production plants and with longer duration of exposure to PAHs. The increase in risk varied between 2 and 3 times in the three studies here; however, the meta-analysis96 showed an increase in risk of 1.5 times (see Table 8.2 above) on statistical pooling of relevant studies.

Table 8.5 Occupational PAH exposure and risk of lung cancer in coke production workers



Kennaway & Kennaway 1947UK, 1921-1938

National mortality analysis of all deaths in England & Wales.Exposure assessment based on occupational titles, which included gas stokers & coke-oven chargers

SMRGas stokers = 2.84 (2.27-3.52)Coke-oven chargers = 2.13 (1.50-2.93)

Case-control studiesStudy/country/follow-up


Wu-Williams et al. 1993People’s Republic of China

965 female incidence cases identified from local cancer registries between 1985-87, age-matched with 959 randomly selected female population-based controlsExposure assessment in terms of years of exposure to coke-oven emissions. Data adjusted for tobacco smoking, study area, age & education

ORAny = 1.5 (0.9-2.5)Years of exposure:1-10 yrs = 1.211-20 yrs = 1.4≥21 yrs = 3.0


Other studies (not in the 2010/2012 Monographs)Study/country/follow-up


Bertrand et al. 1987Lorraine, France

Cohort of 534 male manual workers from two coke oven plants between 1963 & 1982.Exposure assessment according to individual exposures

SMRO/E = 2.51 (p<1%)

8.2.4 Occupational PAH exposure and risk of lung cancer in creosote workers

Creosote is a by-product from distillation of tar and is used to treat older electrical poles. The study conducted by Tornqvist et al. (cited in IARC)97 on a sample of power linesmen did not show an increased risk of lung cancer as seen in Table 8.6. This is similar to the result of the meta-analysis by Bosetti et al.96 which showed a relatively low, non-significant increase in risk.

Table 8.6 Occupational PAH exposure and risk of lung cancer in creosote workers. 97


Exposure and cohort characteristics SIR (95% CI)

Tornqvist et al 1986Sweden1961-1979

3358 power linesmen and 6703 power station operators identified in the Swedish 1960 Census through linkage to National Cancer RegistryExposure assessment based on job histories. Data not adjusted for smoking

Power linesmen = 0.7 (0.4-1.0)

8.2.5 Occupational PAH exposure and risk of lung cancer in aluminium production workers

Although a meta-analysis (see Table 8.2)96 and a study by Friesen et al. (2009, cited in IARC)109 (Table 8.7) showed a non-significant increase in lung cancer risk, meta-analysis of two large cohort studies101,104 conducted in Canada showed a significant doubling in the increase in relative risk of lung cancer (Figure 8.3). These same studies also suggest an increasing exposure-response trend (Table 8.7). The two studies included in the meta-analysis below did not show significant heterogeneity. The data in all three studies101, 104 were adjusted for smoking; however, the Australian cohort did not show any statistically significant increase in risk, even after adjustment (Table 8.7). The majority of the studies included in the meta-analysis96 did not adjust for smoking. The difference could also be due to varying levels of exposure in different countries.96 In addition, the differences could in part be explained by the different types of processes/anodes (Soderberg & Prebake anodes) used in aluminium production processes in different countries (IARC, 2012).109 Generally, workers employed in aluminium production plants that implement smelter technology are exposed to high levels of PAHs (Friesen et al. 2009).109


Figure 8.3 Occupational cumulative PAH exposure (BaP) and risk of lung cancer in aluminium production workers

Cumulative exposure in µg/m3

Table 8.7 Occupational PAH exposure and risk of lung cancer in aluminium production workers



Friesen et al. 2009Australia1983-2002

4316 male workers from two Australian prebake aluminium smelters employed for at least 90 days. Cohort linked to state & national cancer registriesTwo surrogates of PAH were measured (– BaP (Benzo-a-Pyrene), a specific carcinogenic PAH & Benzene Soluble Fraction (BSF), which includes all PAHs plus other benzene-soluble compounds.Time-weighted exposure: BaP - µg/m3-year, BSF – mg/m3-yearData adjusted for smoking, age & calendar year. Exposure categories in three groups

RRBaP:Low (>0-0.41) = 0.7 (0.3-1.9)Medium (0.41-10.9) = 1.5 (0.6-3.6)High (>10.9) = 2.0 (0.9-4.8)BSF:Low (>0-0.10) = 0.8 (0.3-2.0)Medium (0.10-0.86) = 1.7 (0.7-4.2)High (>0.86) = 1.6 (0.7-3.8)

Other studies (not in the 2010/2012 Monographs)Study/country/follow-up


Armstrong et al. 1994Quebec, Canada

338 lung cancer deaths & a random sample (sub-cohort) of 1,138 from among 16,297 men employed for at least one year between 1950 & 1979 in an aluminium production plant.Two indices of cumulative exposure (average concentration x time): benzene soluble matter (BSF) (mg/m3 – years) & benzo-a-pyrene (BaP) (µg/m3 – years). Job-exposure matrix used.Data adjusted for age, calendar period & smoking

Lung cancer mortality: Rate ratios & 95% CI, by cumulative exposure:BaP (µg/m3 – years):<10 = 1.0010-99 = 1.48 (1.09-2.00)100-199 = 2.23 (1.46-3.39)200-299 = 2.10 (1.40-3.15)≥300 = 1.87 (1.05-3..33)BSF (mg/m3 – years):<1 = 1.001-9 = 1.15 (0.84-1.59)10-19 = 2.25 (1.50-3.38)20-29 = 1.90 (1.22-2.97)≥30 = 2.08 (1.30-3.33)




Armstrong et al. 2009Quebec, Canada

16431: 5977 men at one very large & two small aluminium smelters, and 9726 men and 728 women who completed one year employment before 1989. 677 lung cancer cases.Job-exposure matrix using estimates of BaP for each job combined with work histories to give estimates of cumulative exposure in µg/m3 – years.Data adjusted for age, calendar year & smoking.

Overall lung cancer mortality1.32 (1.22-1.42)SMR & 95% CI for lung cancer mortalityBy cumulative exposure to BaP (µg/m3 – years):0 = 0.62 (0.44-0.87)0.0000001-= 1.09 (0.96-1.23)20- = 1.88 (1.47-2.38)40- = 1.21 (0.91-1.59)80- = 1.93 (1.59-2.32)160- = 1.79 (1.48-2.15)320- = 2.36 (1.49-3.54)

8.2.6 Occupational PAH exposure and risk of lung cancer in chimney sweeps and in workers exposed to soot

The analysis presented in Figure 8.4 shows the relatively small, non-significant increase in risk in chimney sweeps and in workers exposed to soot. The two cohort studies identified from the IARC monographs were conducted in Finland (Pukkala 1995)98 and Norway (Haldorsen et al. 2004).97 The two studies presented standardised incident ratios (SIR) and the exposure assessments were based on occupational titles. The cohorts in the two studies were identified from a census linked to cancer registries in the respective countries. The follow-up period was between 14 and 20 years respectively. The data in the study by Haldorsen et al. (2004) was adjusted for smoking.

Figure 8.4 Occupational PAH exposure and risk of lung cancer in chimney sweeps and in workers exposed to soot

8.2.7 Occupational PAH exposure, smoking status and risk of lung cancer

The three studies in Table 8.8 presented data stratified either by smoking habit or by the number of cigarettes smoked per day. The studies could not be combined for analysis because of the variation in the data presented. The studies by Pastorino et al.106 and Armstrong et al.104 showed significant increase in risk, with the authors suggesting a possible combined effect between occupational exposures to PAHs and smoking. The non-significant increase in risk in the study by Armstrong et al.101 may be due to limitations in data collection, where the data available was not considered adequate to construct full smoking histories for the complete cohort.


Table 8.8 Occupational PAH exposure, smoking status and risk estimates for lung cancer

RR for lung cancer from occupational PAH exposure Pastorino et al 19840-9 cigarettes per day 10-19 cigarettes per day 20+ cigarettes per day

1.3 7.0 9.9

SMR & 95% CI for lung cancer mortality, by no: of cigarettes per day Armstrong et al 20090 1- 21- 41- 61- Unknown

0.80 (0.61-1.04)

1.19 (1.04-1.36)

2.32 (2.05-2.61)

1.19 (0.65-2.00)

1.60 (0.44-4.09)

0.82 (0.66-1.00)

Lung cancer mortality by smoking habit, Rate Ratios & 95% CI Armstrong et al 1994Never reported smoking

Ever smoked

Ever smoked, by pack years <20

Ever smoked, by pack years 20-39

Ever smoked, by pack years 40-59

Ever smoked, by pack years ≥60

Never smoked more than 20 cigarettes per day

Unknown smoking habit

1.00 3.00 (1.62-5.59)

0.95 (0.45-2.02)

3.00 (1.59-5.69)

3.44 (1.79-6.62)

6.20 (3.11-12.38)

3.05 (1.46-6.35)

2.33 (1.06-5.17)

8.2.8 Occupational PAH exposure, gender and risk of lung cancer

Veglia et al.103 provided risk estimates indicative of an increased risk of lung cancer in both men and women exposed to PAHs. However, the increased risk estimate reported in women was not statistically significant and showed greater imprecision than that reported for men, most likely due to the smaller sample size available/number of women occupationally exposed to PAHs (Table 8.9).

Table 8.9 Occupational PAH exposure, gender and hazard ratio and 95% CI for lung cancer 103

Overall Men Women

1.42 (1.1-1.8) 1.43 (1.2-1.8) 1.24 (0.6-2.4)Adjusted for age, gender, social class, diet, physical activity and smoking habits

8.3 SummaryThe evidence suggests that occupational exposure to polycyclic aromatic hydrocarbons (PAHs) in various PAH-related industries, particularly coal gasification, coke production and potentially aluminum production, causes lung cancer. Increases in risk estimates relative to persons not exposed ranged from 1.2 to 2.3 times. It is worth noting that specific PAHs cannot be causally associated with lung cancer as most of the exposures investigated have involved mixtures of PAHs. The major limitations encountered amongst the included studies in this report, including in the research synthesis, were: non-adjustment for smoking; insufficient details on exposures and exposure assessments and heterogeneity apparent between these same measures due to the different worksites; duration of exposure; industrial processes and chemical compounds potentially present between the studies. A strong but inconsistent association was shown between smoking and exposure to PAHs across all smoking categories.



Polycyclic aromatic hydrocarbon compounds and mixtures are classified by IARC as Group 1 carcinogens (IARC 201097, 2012108). Benzo-a-pyrene is often considered as a marker of exposure to PAHs. Polycyclic aromatic hydrocarbon mixtures or compounds not only cause lung cancer but are also causally associated with bladder cancer and skin cancer.


Due to their exposure to PAHs, workers employed in coal gasification and coke production are twice as likely to develop lung cancer as workers not exposed to PAHs or the general population. There is some evidence to suggest that workers employed in aluminium production are at increased risk of developing lung cancer from exposures to PAHs, though the variation in results of reported studies is large. There is inconsistent evidence for a causal association between exposure to PAHs and lung cancer for workers employed in coal tar distillation, creosote production, carbon black production and carbon electrode manufacture. The risk of lung cancer associated with PAH exposure appears to increase significantly in smokers; however, the evidence is inconclusive.


8.5 Methodological quality of studiesIndividual critical appraisal checklist items for studies relevant to the risk of lung cancer resulting from PAH are shown below in Table 8.10.

Table 8.10 PAH exposure: Methodological quality of included studies

Study Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Total (Y) Include/Exclude

Armstrong et al. 1994 Case-cohort Y Y N Y Y N/A U Y Y — 6 Include

Armstrong et al. 2009 Cohort Y Y N/A Y U Y N Y Y — 6 Include

Bertrand et al.1987 Cohort & case-control Y Y Y Y Y U U N U — 5 Include

Bosetti et al. 2007

Review with Meta-analyses & Pooled analyses Y Y Y Y N/A N/A N/A Y Y N 6

Include

Olsson et al. 2010 Case-control Y Y Y Y Y N/A Y Y Y — 8 Include

Pastorino et al. 1984 Case-control Y Y Y Y N N/A Y U Y — 6 Include

Veglia et al. 2007 Cohort Y Y N/A Y N Y Y Y Y — 7 Include


Armstrong et al. 1994

The methods and objectives were generally well described in this study. Subjects were representative of target population. Cases and cohorts (random sample of cohorts) were not matched as this was a case-cohort study design. Confounding factors considered appropriately. Outcome measures and statistical methods used were adequately described. It was unclear whether outcomes were assessed using objective criteria. The outcomes of people who withdrew or were excluded were not described.

Armstrong et al. 2009

This was a well-designed study with the cohort representative of the target population. Confounding factors were identified and adjusted in the analysis. It was not clear whether outcomes were assessed using objective criteria. There was sufficient follow-up period; however, it was not clear whether people who withdrew were described and included in the analysis. Statistical methods were described in detail including a brief overview of additive and multiplicative models.

Bertrand et al. 1987

The study included both cohort and case-control analyses. Case-control analysis was performed in this cohort to determine the influence of tobacco as an extra occupational risk for all subjects who died. The methods and objectives were clearly stated in this study, with clear selection criteria for both cases and controls. Study subjects were from France and appear representative of target population. Controls were frequency matched to cases by year of birth, age at death and smoking habits. Outcomes and their measurement as well as procedures of the study were adequately described. However, it was not clear if they were measured in a reliable way. The outcomes of people who withdrew were not described or included in the analysis.

Bosetti et al. 2007

This study was a pooled analysis, not a traditional meta-analysis or a systematic review; hence scored low for about five of the criteria on the critical appraisal checklist as they were not applicable to this type of study design. The research question was not clear. All cohort studies published between 1997 and 2005 were included regardless of their methodological quality. The recommendations were supported by reported data; however, the authors did not state any specific directives for future research.

Olsson et al. 2010

A high quality multicentre study conducted in East European countries with clear description of details and methods. The subject sample was clearly described and the participants were at a similar point in the course of their condition. Case and control selection was well described. Several potential confounding factors were identified and adjusted for. People who withdrew or were excluded were described but not included in the analysis. Outcomes were assessed and measured in a reliable way. Statistical analysis was adequately described and appropriate statistical method was used to estimate OR & 95% CI.


Pastorino et al. 1984

Overall the study addressed its objectives. Cases and controls were representative of target population and controls were matched to cases by age. Methods of data collection well described that included description of trained interviewers. Potential confounding factors were identified and addressed. Lung cancer cases ascertained from cancer registry. Data was collected from the next of kin for cases and for 10% of controls the information was obtained other than the subjects. Reason for excluding patients from the analysis was mentioned. Statistical methods were adequately described.

Veglia et al. 2007

This was a large, well-conducted, multicentre study in 10 Western European countries. Overall the study addressed its objectives. The study sample was representative of the population as a whole. Several potential confounding factors were identified and addressed. Outcomes were assessed based on self-administered questionnaires and diagnosis ascertained from cancer registries. People who withdrew or excluded were described but not included in the analysis. A clear description of statistical methods including methods to minimise errors were adequately described.


9 Risk factor: Family history9.1 IntroductionIn 2009, lung cancer was the underlying cause of 7781 Australian deaths,110 leaving behind family members who may also be afflicted with the disease.

Lung cancer is frequently cited as an example of a disease that is almost exclusively attributable to some environmental or exogenous exposure. However, it has been suggested that individuals may differ in their susceptibility to environmental risk factors.111 This susceptibility to environmental factors may be informed by investigation of the individual’s family history, as such information captures shared environmental, behavioural and genetic risks within a family unit. The immediate family unit includes first degree relatives, such as parents or siblings. These relatives may provide important information about lung cancer risk as they share not only a common environment, but also a high degree of genetic material.

Research suggests that individuals with a family history of lung cancer may also be at increased risk of developing the disease. Currently, it is unclear whether any increase in risk is due to the shared environment or genetic factors. The only direct evidence for a genetic predisposition to lung cancer (to date) is provided by the increased incidence of cancer associated with a number of rare gene-linked cancer syndromes, such as carriers of constitutional TP53112 and retinoblastoma113 gene mutations, as cited in Matakidou et al.111 Since the 1960s, various case–control and cohort studies of the relationship between family history and risk of lung cancer have provided some evidence of familial aggregation of lung cancer outside the context of these rare Mendelian syndromes. For the purposes of this report, risk of lung cancer associated with a family history of the disease is limited to epidemiological studies investigating familial relationships. Beyond the scope of this report is a large volume of accumulated evidence investigating links to lung cancer attributable to some genetic profile or susceptibility; for example, where risk may be associated with as specific enzyme or other protein profile.

The search identified two relevant research synthesis papers;111, 114 however, there was a large overlap of included studies between the two publications (32 of 42 studies), and the summary estimates of risk were included from Matakidou et al.111 cited in Lissowska et al. 2010.110 Therefore, in concordance with the scope of this report, only the most recent publication is included. Characteristics of the research synthesis relevant to the association between family history and lung cancer are shown in Table 9.1.


Table 9.1 Study characteristics relevant to the association between family history and lung cancer




Lissowska et al. 2010Original Case control study combined with meta-analysis of 41 other studies.Case controls: 36Prospective Cohort: 6Multinational

Demographics only reported for the case control study, not for the meta-analysis.Ages ranged from 20 - 79 years2861 cases2205 – men656 – women3118 controls matched by age, gender and geographical area.2305 – men813 - women

Case control studyIn person structured interviews used to collect data on lung cancer prevalence of family members.Self-reports of cancer in relatives were not confirmed by checking medical records.Smoking history of relatives was not obtained.Meta-analysisSearch of PubMed (inception – 2009). Data pooled using random effects model

Self-reports of the prevalence of lung cancer in first degree relatives.Exposure determined as being first degree relatives, e.g. parents and siblings.Number of first degree relatives ranged from 2 – 26 (median= 6)Number of siblings ranged from 0-17 (median = 2)

Cytologically or histologically confirmed lung cancer (all types).

Multivariate analysisAdjusted estimates of risk were presented by individual study, where possible. Whenever estimates were not given, odds ratio and 95% confidence intervals were calculated from published frequency tables, if they were available, using Mantel–Haenszel common odds ratio estimate. Studies were pooled using random-effects model and the percentage variability of the pooled odds ratio attributable to heterogeneity between studies was quantified using the I2 statistic. Publication bias was examined with Egger regression asymmetry test.

General exposureFamily member with lung cancer RR/OR (95%)Cohort studiesRR= 1.95 (1.63 - 2.33)Case control studiesOR= 1.66 (1.50 - 1.85)Combined = 1.72 (1.56 – 1.88)Lung cancer risk by genderMales: RR = 1.50 (1.08 – 2.08)Female: RR = 1.73 (1.50 – 2.00)Case Control: General exposureFamily member with lung cancer OR (95%)Mother = 2.24 (1.26-4.00)Father = 1.45 (1.10-1.91)Siblings = 1.75 (1.23-2.48)Any family member = 1.63 (1.31-2.01)1 family member = 1.54 (1.24-1.92)2 + family members = 3.60 (1.56-8.31)Exposure by smoking status – never smokersFamily member with lung cancer OR (95%)Adjusted for smoking, gender and





Parents = 1.34 (0.55 – 3.21)Siblings = 2.24 (0.74 – 6.79)Any family member = 1.68 (0.83 – 3.37)Exposure by smoking status – ever smokersFamily member with lung cancer OR (95%)Adjusted for smoking, gender andParents = 1.53 (1.18 – 2.00)Siblings = 1.65 (1.13 – 2.39)Any family member = 1.55 (1.24 – 1.95)


9.2 Results9.2.1 Family history and risk of lung cancer

The included paper was a synthesis of six prospective cohort studies, 36 case-control studies, as well as novel data from a multicentre IARC case-control study involving 2861 cases and 3118 controls across seven European countries.

Meta-analysis of 40 of the included studies illustrated a significant increase in the overall lung cancer risk (OR 1.72, 1.56 – 1.88) if a first degree family member is/was affected by lung cancer. The relationship appeared consistent across study designs, as shown in Table 9.2.

Table 9.2 Pooled analysis of the overall risk of lung cancer associated with family history114

Study design Effect Size OR (95% CI)

Prospective cohort (6 studies) 1.95 (1.63 - 2.33)

Case control (34 studies) 1.66 (1.50 - 1.85)

Combined (40 studies) 1.72 (1.56 – 1.88)

9.2.2 Family history, smoking status and risk of lung cancer

The IARC case-control portion of Lissowska et al.114 found that cases were more likely to have smoked tobacco than controls (7.8% of non-smokers among cases compared to 33.3% among controls), and also had a higher cumulative tobacco consumption (18% cases and 6% controls reported over 50 pack-years of smoking). The results (Table 9.3) suggest that ever-smokers who have any family member with lung cancer, either parent or sibling, have a significantly increased risk of also developing lung cancer. However, when the analyses were stratified by age (<50 vs. 50-plus), gender, and smoking status (never vs. ever), there were no statistically significant differences in risk of lung cancer associated with a family history of lung cancer. This statistical non-significance may in part be due to heterogeneity within the never-smoker group, as shown by the wide confidence intervals in Table 9.3.

Table 9.3 Risk of lung cancer associated with family history, by smoking status – and affected family member (case-control)

Affected family member Adjusted OR (95% CI)Never smokers

Adjusted OR (95% CI)Ever smokers

Parents 1.34 (0.55 – 3.21) 1.53 (1.18 – 2.00)

Siblings 2.24 (0.74 – 6.79) 1.13 (1.13 – 2.39)

Any family member 1.68 (0.83 – 3.37) 1.55 (1.24 – 1.95)

9.2.3 Family history, gender and risk of lung cancer

A summary estimate of lung cancer risk was reported for both men and women (Table 9.4). Results suggest that women with a family member affected by lung cancer have a higher risk of lung cancer than men.


Table 9.4 Family history and the risk of lung cancer by gender114

Study Risk (OR) 95% Confidence Interval

Males (10 studies) 1.50 1.08 – 2.08

Females (25 studies) 1.73 1.50 – 2.00

9.2.4 Risk of lung cancer by family member affected

In cases and controls included in the study by Lissowska et al.,114 the number of first-degree relatives ranged from two to 26 with median of six. The number of siblings in the families ranged from 0 to 17, with median of two. Overall, 898 cases (31.4%) and 958 controls (30.7%) reported a history of any cancer in a first-degree relative. Of these, 289 cases (32.2%) and 187 controls (19.5%) reported a history of lung cancer.

A family history of lung cancer in a mother, father, or siblings significantly increased the risk of lung cancer. The results also suggest that where more than one family member is affected by lung cancer, the lung cancer risk increased to almost four -fold of those without a family history of lung cancer (p trend < 0.001), as highlighted in Table 9.5.

Table 9.5 Risk of lung cancer associated with family history, by family member type, from the Lissowska et al. (2010) 114 case-control study

Family member Risk (OR) 95% CI

Mother 2.24 1.26-4.00

Father 1.45 1.10-1.91

Siblings 1.75 1.23-2.48

Any family member 1.63 1.31-2.01

1 family member 1.54 1.24-1.92

2 or more family members 3.60 1.56-8.31

9.3 SummaryThere is evidence to suggest that people with a family member with lung cancer have approximately twice the risk lung cancer of those without an affected family member.

The complexity of research that examines family history makes it challenging to draw to firm conclusions as these studies capture and encompass shared environmental, behavioural and genetic risks within a family unit. The results would suggest that having a mother diagnosed with lung cancer represents the highest risk, followed by siblings. Lung cancer risk was compounded further where two or more family members were diagnosed with the disease. Smokers who had a family member with lung cancer were at increased risk, relative to those who did not smoke.

The included synthesis did not include detailed descriptions of the participants, therefore, potentially important similarities (and differences) to the Australian population are difficult to establish. It is worth noting also that research into non-modifiable risk factors, such as family history, is now moving towards studies of genomics, where genetic variations that predispose a person to lung cancer are being identified, described and quantified, in an effort to associate these variations with the magnitude of risk. Such research investigating the genomic factors that predispose a person to disease is likely to


provide a clearer picture in the future of the association between such familial factors and lung cancer.


IARC identifies that a first-degree family history of lung cancer is a well-established risk factor for lung cancer, increasing risk by approximately two-fold.115


The evidence suggests individuals with a family member with lung cancer are at increased risk of developing lung cancer themselves. Analysis of epidemiological evidence indicates that as the number of family members afflicted with lung cancer increases, so too does the risk of lung cancer.

The role of modifiable (such as shared environment) and non-modifiable factors (such as genes) in the association between family history and increased lung cancer risk is unclear and difficult to establish from analysis of epidemiological evidence reported on in this review.


9.5 Methodological quality of studiesIndividual critical appraisal checklist items are shown below in Table 9.6

Table 9.6 Family history: Methodological quality of included studies


Include/Exclude

Lissowska et al. 2010 Meta-analysis + case control

Y Y N N N N Y Y Y U 5 Include


Lissowska et al. 2010

This research synthesis combined primary data from large multi-centred European case control study conducted during 1998–2002 and data from 41 (35 case control and 6 cohort) other studies identified through a search of PubMed up to June 2009. A total of 35,092 cases and 27,357 controls were included across the 42 included studies. As for Matakidou et al.111 review, the aims were defined and the search strategy was appropriate. However, only the PubMed database was searched for English language studies, raising the possibility that relevant studies were not identified.

Only primary data or data which superseded earlier work were included. Adjusted estimates of risk were presented by individual study, where possible. Whenever estimates were not given, odds ratio and 95% confidence intervals were calculated from published frequency tables, if they were available, using Mantel–Haenszel common odds ratio estimate. Studies were pooled using random-effects model and the percentage variability of the pooled odds ratio attributable to heterogeneity between studies was quantified using the I2 statistic. Publication bias was examined with Egger regression asymmetry test.

No details were reported as to the basis of inclusion of studies in the review. There was a significant overlap (30/42) in the number of studies between this and the Matakidou review.


10 Risk factor: Iron and steel founding10.1 IntroductionThe Australian iron and steel industry is a fundamental building block for many activities in the Australian economy. It provides key materials for construction, infrastructure, resource developments and other manufacturing, including the automotive industry. The industry also plays a major role in recycling steel. The iron and steel industry’s manufacturing facilities are predominantly based in regional Australia, including the Illawarra, Mornington Peninsula, Newcastle, Whyalla, and in the western suburbs of Sydney and Melbourne 116. The number of people employed as iron and steel foundry workers in Australia is difficult to ascertain; however, the numbers are likely to be significant as the broader Australian steel industry has a reported turnover of $29 billion and provides employment to over 91,000 people.117

Foundry is a term used to describe the process and technology of casting metals into shapes by melting them into a liquid, pouring the metal in a mould, and removing the mould material or casting after the metal has cooled and solidified. The process of iron and steel founding has been listed as a Group 1 carcinogen by IARC since 1987. Foundries produce shaped castings from re-melted metal ingots and scrap metal which are used as parts for machinery, motor vehicles, railway engines, stove parts and wheels. The industrial processes are often integrated and difficult to separate from one another.

Foundry workers are exposed to hot working conditions and a wide variety of compounds capable of causing cancer as identified by IARC118 and cited in IARC monograph 2012.108 Foundry workers are potentially exposed to a number of inhaled Groups 1 carcinogens, such as: crystalline silica; asbestos; polycyclic aromatic hydrocarbons (PAHs); benzene; formaldehyde; sulphuric acid mist and toxic metals (such as chromium, nickel and cadmium).119 Several of the carcinogens have been considered separately within this report; however, exposure to combinations of such risk factors may present a unique risk of lung cancer for iron and steel foundry workers.

The search identified 124 titles relevant to this report, including a recently updated IARC monograph108 that considered publications until 2006 and included 17 cohort studies and four case-control studies. Twenty-one studies were retrieved for detailed examination and three studies were included in addition to the monograph. A research synthesis (11 cohort studies) with pooled and meta-analyses was identified by the search for literature.96 There was, however, considerable overlap of studies with the monograph (nine of the 11 studies were included in both), so care has been take not to present data twice. Cohort studies conducted in Korea119 and France120 were also included. The smoking status of subjects, and subsequent adjustments, was generally poorly reported. Therefore, caution is required when interpreting the findings. The important characteristics of the included studies are detailed in Table 10.1.


Table 10.1 Study characteristics relevant to the association between iron and steel founding and lung cancer


Study method Exposure Type of lung cancer


Ahn et al. 2010Cohort studyKorea

17,098 workers, 14,611 men & 2,487 women from 208 small-sized iron & steel foundries who worked anytime between 1992-2000

Cohort identified by contacting employers of 388 iron foundries, out of which 208 companies provided details.Follow-up from 1 January 1992 to 31 December 2005Cancer morbidity ascertained from Cancer Registries

Exposure assessment done to classify job categories: production & office workNo exposure assessment of individual carcinogens.

Not specified Poisson regression analysis for cancer morbidity using a Person Year& Mortality Computation Program (PAMCOMP)Standardised incidence ratios (SIRs) relative to general Korean population.Standardised incidence rate ratios (SRRs) of production workers relative to office workers on same site.Adj for; gender, age & calendar year.Unclear whether data was adjusted for smoking.

Risk by job classification.SIR (95% CI)Both genders:Overall: 1.33 (1.03-1.69)Production: 1.45 (1.11-1.87)Office: 0.71 (0.26-1.54)Men:Overall: 1.28 (0.98-1.64)Production: 1.38 (1.04-1.80)Office: 0.75 (0.27-1.63)Women:Overall: 2.29 (0.83-4.98)Production: 2.79 (1.02-6.07)Office: no employeesRisk by duration of employmentSIR (95% CI)Both genders:≤ 10yrs: 1.12 (0.66-1.77)≤ 10yrs: 1.66 (1.20-2.24)Men:>10yrs: 1.12 (0.65-1.79)≤ 10: 1.55 (1.09-2.12)Women:>10yrs: 1.15 (0.02-6.40)≤ 10: 3.90 (1.26-9.09)Risk from working in production





in an iron foundry (rel. to office) SRR (95% CI), both genders:2.91 (1.25-6.80

Bosetti et al. 2007Research synthesis with pooled analyses & meta-analysesUSA, Canada, Finland, Denmark, UK & France

Workers from iron and steel foundries with high exposures to Polycyclic Aromatic Hydrocarbons (PAH)

Review included cohort studies identified through Medline, published between 1997 & 2005.11 cohort studies relevant to risk of lung cancer. 9 of which also included in IARC (2012)

Occupational exposure to PAH resulting from being a foundry worker.PAH exposure intensity &duration not reported

Not specified Pooled RRs & 95% CI computed as weighted average of SMR/SIR using inverse variance of the logarithm of SMR/SIR as weight (fixed-effect model)Potential confounders adj. for: smoking, age, sex, calendar period

Risk from working in production in an iron foundry. Overall SMR & pooled RR (95%CI) for exposure to PAHSMR: 1.39Pooled RR (9 studies) :1.40 (1.32-1.49)Individually, 7 of 11 studies reported an increased lung cancer risk resulting from occupational exposure to PAH as an iron/steel foundry worker.

Bourgkard et al. 2008Cohort studyFrance

16 742 males & 959 females ever employed for at least 1 year between 1959 & 1997 were followed up for mortality from January 1968 to December 1998

Historical cohort study of all workers ever employed in a French carbon steel-producing factory for at least 1 year between 1 January 1959 and 30 June 1997.Data collected from administrative records, medical records & occupational physicians

Occupationalexposures assessed by a factory-specific job exposurematrix (JEM) validated with atmosphericmeasurements.

Not specified Two series of internal statistical analyses : 1) a Poisson regression in which age & time period effects were taken into account by including expected numbers of cases as offsets.2)Cox regression with age as the main time variable & time-varying exposure variables.Data adjusted for smoking and other occupational exposures

Risk from working in production in an iron foundry. RR & 95% CI for iron oxide exposures among menDuration of exposure (yrs) (intensity level >2)Non-exposed: 1.001–10yrs: 0.87 (0.58 to 1.29)>11yrs: 0.64 (0.35 to 1.15)Frequency weighted cumulative index(intensity level.freq.years)Non-exposed: 1.00≤0.02: 1.30 (0.86 to 1.95)0.02–0.41: .35 (0.90 to 2.03)0.41–3.81: 0.99 (0.63 to 1.56)>3.81 = 1.03 (0.63 to 1.70)





Smoking habitNever = 1.00Former = 6.82 (1.58 to 29.4)Current = 26.22 (6.50 to 105.8)

IARC 2012 108

MonographGlobal

Workers from iron & steel foundries. Risk by Individual carcinogens not detailed.No demographic details.

Cohort & case control studies published up to 2006. Studies incl. based on consensus of expert opinion.17 cohort & 4 case control studies relevant to risk of lung cancer. 9 of which also included in IARC (2012) monograph

Employment in an iron or steel foundry given as exposure. No summary details of exposure duration & intensity reported.


No overall summary estimate reported. SMRs or OR reported for individual studies.

Of the 17 included cohort studies, smoking status data was unavailable for 10 studies and only detailed in 3 other studies.Of the 4 case control studies, smoking status data was unavailable for 1 study.


10.2 Results10.2.1 Overall risk of lung cancer in iron and steel foundry workers

A research synthesis (both pooled analysis and meta-analysis) showed an increased risk of lung cancer in workers in iron and steel foundries; this finding was consistent when the risk was calculated relative to the general population or relative to unexposed workers (Table 10.2;96). Iron and steel foundry workers are not only exposed to high levels of polycyclic aromatic hydrocarbons (PAHs), but also other potential carcinogens such as crystalline silica, asbestos and other heavy metals.96 It was unclear whether studies included in the review by Bosetti et al.96 were adjusted for smoking in their analyses.

Table 10.2 Iron and steel foundry workers and overall risk of lung cancer



Bosetti et al. 2007MultinationalResearch synthesis

Cohort studies published between 1997-2005.Occupational exposure to PAH resulting from working as an iron or steel founder.*

Overall SMR & pooled RR (95%CI) (9 studies)SMR: 1.391

Pooled RR 1.40 (1.32-1.49)2

* exposure duration or intensity not reported.1 relative to general population. 2 relative to those not employed in foundries.

Meta-analysis of seven studies, including six from the IARC monograph108 and a cohort study by Ahn et al.119 shows a similar statistically significant increase in the risk of lung cancer in iron and steel foundry workers of 33% (RR: 1.33 1.05-1.70) when compared with non-exposed workers or the general population (Figure 10.1). Moderate to high heterogeneity should be considered when interpreting the value presented here for occupational exposure to iron and steel founding (Figure 10.1). Some of the inconsistency observed in the result is likely due to the different measurement methods used to establish exposure, varying duration and intensity of exposure, and differences in the industrial processes used at the varying sites across the different countries where the cohorts of participants were employed. Noticeable imprecision in the study by Blot et al.121 is likely due to the small sample involved in foundry work in this study. In addition, the workers in this study were employed for a longer duration than those in other studies, which may be the basis for the elevated risk estimates recorded. The retrospective study by Rodriguez et al.122 was limited to steel founding workers only where the processes used, according to these authors, impart lesser risk than founding of iron. A recent large cohort study by Ahn et al.119 showed increase in risk with exposure to the work environment in iron and steel foundries. In contrast, a study by Hoshuyama et al.123 reported no increase in risk for lung cancer in workers employed for than six months when compared with the general population. However, there was a significant increase in the risk of lung cancer for workers exposed specifically to high levels of PAHs and particulate matter in the air (e.g. iron dust) compared to other non-exposed blue collar workers.


Figure 10.1 Iron and steel foundry workers and overall risk of lung cancer

Cc is case control, ncc is nested case control, remainder are cohort studiesAhn et al 2010 (Korea) -14,611 men & 2,487 women from 208 small-sized iron and steel foundries who worked anytime between 1992-2000. SIR relative to general populationBlot et al. 1983 (USA) – Population based case-control study. 335 cases & 332 controls. Data adjusted for smoking & age. Exposure assessment from next-of-kin interview, occupational history & residential historyHoshuyama et al 2006 (China) - 121 846 male iron & steel production workers employed > 6 month. Follow-up from 1980-1993. Lung cancer mortality relative to general populationMoulin et al 1993 (France) – 4427 workers. Follow-up from 1968-1986Rodriguez et al 2000 (Spain) – Nested case-control study. Steel founding. Data adjusted for smokingTola et al. 1979 (Finland) - 3425 male foundry workers at 13 iron foundries. Follow-up 1918/72 – 1976. No data on smokingXu et al. 1996 (China) – 8887 deaths. Exposure assessment based on occupational titles. No smoking data.

10.2.2 Risk of lung cancer for workers in iron and steel foundries, by exposure to specific agents

In a study of automotive iron foundry workers that examined exposures to specific toxic agents, a significant increase in risk of lung cancer was reported for workers exposed to upper quartiles (Q3 and Q4) of silica, as seen in Table 10.3. Actual details on exposure levels to silica were unclear. In the same cohort, exposures to formaldehyde were not associated with an increased risk of lung cancer.124

Table 10.3 Risk estimates of lung cancer in iron and steel foundry workers, by specific exposure to silica and formaldehyde124



Andjelkovich et al. 1995USAAutomotive iron foundry

A cohort of 3929 men potentially exposed to formaldehyde between 1960-1989. 2032 unexposed men selected from the same cohort for comparison. Cohort followed for mortality 1960–1989. Information on smoking obtained from survey: response rate 65% in exposed and 55% in unexposed group.Exposure to formaldehyde & silica classified by Occupational hygienist; cumulative exposure calculated.Exposure categorised in to quartiles.

Silica:Q2 vs Q1: 2.34 (0.68-10.7)Q3 vs Q1: 3.41 (1.16-14.5)Q4 vs Q1: 3.98 (1.41-16.6)Formaldehyde:exposed vs unexposed: 0.71 (0.43-1.21)


10.2.3 Risk of lung cancer in iron and steel foundry workers, by job category

Two studies presented data on workers at risk of lung cancer in particular job categories in the iron and steel industry as seen in Table 10.4. As expected by the nature of the exposure, those workers at the industrial site engaged in production were at increased risk of developing lung cancer when compared to the general population, whilst office workers at the industrial site were not.119 Exploring particular roles with industry would indicate that blast furnace operators are at significant risk of developing lung cancer.122 This may be due to the vicinity of these operators to the combustion processes in this occupation, and greater direct contact of higher concentrations of the gaseous and particulate matters in the air released from furnaces and liquid metals. Irrespective of the statistical significance of the risk apparent with blast furnace operation, all roles in the steel founding operation had upper confidence limits that, if representative of the true value of risk, would be of significant health concern (Table 10.4). Further research on these individual studies would be required to align risk of lung cancer with specific roles in the industry with any certainty.

Table 10.4 Risk estimates of lung cancer in iron and steel foundry workers, by job category

Study details Exposure and cohort characteristics Risk estimate (95% CI where provided)

Rodriguez et al. 2000Nested case-control studySpain

All male workers employed at an iron & steel producing plant at least 13 months 1952-1995. Approx. 24490 subjects. 144 lung cancer cases from 1973 and onwards identified. 558 controls free from lung cancer & alive at time of sampling selected based on incidence density sampling. Nested case-control analysisWork histories obtained from company medical records & payrolls, & smoking histories from company medical recordsData adj. for smoking

OREver employed at:Coke batteries: 1.06 (0.46-2.44)Blast furnace:2.55 (1.25-5.21)Steel mill: 1.30 (0.63-2.66)Lamination: 1.00 (0.60-1.66)Steel foundry: 1.64 (0.69-3.91)Maintenance furnace:0.82 (0.23-2.89)Coke-byproducts: 0.55 (0.10-2.99)Others jobs: 1.00

Other studies not in the IARC monograph108

Study details Exposure and cohort characteristics Risk estimate (95% CI where provided)

Ahn et al. 2010(Nested case-control study)Korea

17,098 workers, 14,611 men & 2,487 women from 208 small-sized iron & steel foundries who worked anytime between 1992-2000Exposure assessment done to classify job categories: production & office work.Adj. for gender, age & calendar year. Not clear if the data was adj. for smoking.

SIROverall: .1.33 (1.03-1.69)Office: 0.71 (0.26-1.54)Production: 1.45 (1.11-1.87)

10.2.4 Risk of lung cancer in iron and steel foundry workers, by duration of employment

Characteristics of six studies assessing the association between duration of employment and the risk of developing or dying from lung cancer are presented in Table 10.5. Three of


these studies that reported exposure of comparably similar duration greater than 30 years were statistically combined in meta-analysis; the summary estimate illustrating that long-term employment (>30 years) as a foundry worker imparts an 86% increase in the risk of lung cancer relative to people not employed in the industry (RR: 1.86, 1.13-3.04; Figure 10.2). Moderate inconsistency in this analysis attributable to heterogeneity, or differences between the studies, may be due to the differences in industrial processes in which workers were employed, for example, steel125 versus iron founding.126 Also worth considering is the variability likely in an analysis of an open category of duration where it is impossible to determine the range of exposures. For example, 30-plus years may attract subjects who have worked a maximum of 35 years in one study and more than 50 years in another.

Figure 10.2 Risk of lung cancer in iron and steel foundry workers employed for more than 30 years

Becher et al. (1989) - case-control study, Adzersen et al. (2003) & Moulin et al. (1993) - cohort studies.

Figure 10.3 shows the meta-analysis of four studies of iron and steel foundry workers employed for less than 10 years. Unlike in workers employed for more than 30 years, workers employed for shorter durations did not show a statistically significant increase in risk of lung cancer. There was moderate heterogeneity between the studies. Only one study126 showed a significant increase in risk in mortality with shorter duration and further to that there was a decreasing trend with increasing duration of employment (Figure 10.3; Table 10.5). The authors in this study note that a high proportion of unskilled workers are usually found at ‘dirty’ workplaces (or places where there is high exposure to carcinogenic agents), and hence, change jobs more frequently.126 As a result, these short-term employees are at a higher risk of developing lung cancer compared to long-term employees.126 The data from Finkelstein et al.127 also showed no significant increase in lung cancer risk where workers were employed for five years or more.

Figure 10.3 Risk of lung cancer in iron and steel foundry workers employed for less than 10 years

Individual study details available in table 10.5


Table 10.5 Risk of lung cancer in iron and steel foundry workers, by duration of employment, IARC monograph108



Moulin et al. 1993Cohort studyFrance, 1968-1986

Stainless steel producing company. 4227 workers employed for >3 years between 1968 and 1984.Exposure assessment based on Work area & duration of employment. No quantitative exposure levels assessed as no measurements from the plants were available.

SMREmployment duration (yrs):<10yrs: 2.11 (0.69-4.92)10-19yrs: 2.53 (0.52-7.40)20-29yrs: 1.53 (0.04-8.50)>30yrs: 3.33 (0.40-12.04)

Adzersen et al. 2003Cohort studyGermany

A cohort of 17708 workers from 37 iron foundries, employed >1 year 1950-1985. The cohort was followed for mortality 1951-1993.Exposure assessment based on duration of employmentSmoking data not available for cohort so was extrapolated .

SMROverall: 1.64 (1.24- 2.22)Duration of employment:1-10yrs: 1.72 (1.11-2.73)10-19yrs: 1.58 (0.93-2.93)20-29yrs: 1.55 (0.98-2.86)30+ yrs: 1.48 (0.93-4.06)

Becher et al. 1989Case ControlPoland

901 deaths from lung cancer in 1980-1985 among males. 875 controls selected among men dying from causes other than respiratory cancer or chronic respiratory disease, frequency matched to the cases with regard to age.Exposure assessment - Next of-kin interviewed to obtain a residential, occupational and smoking history. Data adjusted for age, smoking, other occupational exposures

ORDuration of employment in foundry (yrs)1-20yrs or unknown:1.28 (0.75-2.20)20-30yrs: 1.58 (0.94-2.66)>30 yrs: 2.66 (1.31-5.42)

Finkelstein et al. 1994Case ControlCanada

967 men aged 45-76yrs who died from lung cancer in Hamilton & Sault Ste-Marie, Ontario, 1979-1988. Control: 2827 men who died from other causesExposure assessment based on job and industry recorded from death certificates. Job histories were sought from the employers. No smoking adjustment.

ORFoundry worker for >5 yrs: 1.94 (0.7-5.2)

Other studies not in the IARC monograph 108



Ahn et al. 2010Korea

17,098 workers, 14,611 men & 2,487 women from 208 small-sized iron & steel foundriesNo individual exposure assessment.Job duration calculated with a 5 year lag.SIR calculated relative to the general population.

Morbidity in production workers by job duration (yrs).SIR (95% CI)Overall<10yrs: 1.12 (0.66-1.77)>10yrs: 1.66 (1.20-2.24)




Bourgkard et al. 2008France

16 742 males & 959 females. Occupational exposures were assessed by a factory-specific job exposurematrix (JEM) validated with atmosphericmeasurements.

Iron oxide exposures among male foundry workersRR (95%CI)Exposure duration (yrs)Non-exposed: 1.001–10yrs: 0.87 (0.58 to 1.29)>11yrs: 0.64 (0.35 to 1.15)

10.2.5 Risk of lung cancer in iron and steel foundry workers by smoking status

Four studies presented data for the risk of lung cancer in iron and steel founding workers by their smoking status (Table 10.6). The findings show that there is a strong and significant association between iron and steel foundry workers who smoke and risk of lung cancer (Table 10.6). This correlated with high prevalence of cigarette smoking in workers in these studies, particularly in the studies by Rodriguez et al.122 and Bourgkard et al. (2008).120 The percentage of workers who smoked more than 20 cigarettes per day was 36.8% among cases compared to only 9.1% in the controls.122 In the study by Bourgkard et al. (2008),120 the percentage of current and former smokers among men was 77% and 31% among women. The increase in risk associated with smoking varied quite considerably across the studies. Differences in the categorisation of the presented data precluded meta-analysis.

Table 10.6 Risk of lung cancer in iron and steel foundry workers, by smoking status

Study Risk for non-smokers Risk for smokers

Becher et al. 1989 Ref category Smoking (pack-years)*1-20: 1.38 (0.85-2.24)20-40: 4.22 (2.90-6.14)> 40: 6.40 (4.45-9.25)

Blot et al. 1983 1.0 Light or former smoker: 3.0 (1.2-7.6)Moderate: 1.2 (0.6-2.2)Heavy: 2.8 (1.1-7.1)

Rodriguez et al. 2000 Ref category Smokers: 32.5 (9.06-116.7)1-20 cigs: 22.1 (3.0-160.7)>20 cigs: 118.1 (15.9-880.8)

Other studies not in the IARC 2012 monographStudy Risk for non-smokers Risk for smokers

Bourgkard et al. 2008 1.00 Former: 6.82 (1.58 to 29.4)Current: 26.22 (6.50 to 105.8)

*One pack year = smoking of 20 cigarettes daily for one year


10.2.6 Risk of lung cancer in iron and steel foundry workers by gender

Ahn et al.119 presented risks for lung cancer stratified by gender and also by blue collar or white collar roles in the iron and steel founding industry (Table 10.7). The increase in the risk of lung cancer in both male and female production workers was 1.5 to almost 3 times compared to that of the Korean general population. This risk due to the direct engagement of workers in the heavily industrialised processes of iron and steel founding is clearly highlighted by the lack of risk observable in male and female office workers within the same industry.119 These authors also report no increase in lung cancer risk either overall or when males and females were considered separately for employment durations of less than 10 years as production workers (males: 1.12 (0.65-1.79); females: 1.15 (0.02-6.40)). However, working as a foundry worker for 10 years or more represented a significant risk for males (SIR: 1.55, 1.09-2.12) and females (SIR: 3.90, 1.26-9.09) (Ahn et al.).119

Table 10.7 Risk of lung cancer in iron and steel foundry workers; by gender and job, (Ahn et al. 2010)

Category Men Women Total

Office workers 0.75 (0.27-1.63) not given 0.71 (0.26-1.54)

Production workers 1.38 (1.04-1.80) 2.79 (1.02-6.07) 1.45 (1.11-1.87)

Overall 1.28 (0.98-1.64) 2.29 (0.83-4.98) 1.33 (1.03-1.69)

10.3 SummaryData from analyses and research literature presented here indicate that exposure to the industrial processes necessary for iron and steel founding causes lung cancer. The evidence suggests this occupational exposure represents a 30 – 40% increase in risk of lung cancer compared with those not employed in this industrial process. Risk appears to increase with increased duration of exposure and evidence indicates that approximately 10 years of exposure is necessary for any of the above mentioned risk to be realised; with a clear increase in risk amongst workers in the industry for more than 30 years. An IARC monograph108 containing 21 studies, a research synthesis containing 11 studies, and two cohort studies were included in this report to inform the association between employment as an iron or steel foundry worker and the risk of lung cancer. There was some variability in the study findings presented.

Data from four included studies consistently indicated that the risk of lung cancer is increased in iron and steel foundry workers who smoke. An individual study indicated that the risk is significant for both male and female workers; however, the variability in the data and small number of female workers in comparison to male workers in the study makes it difficult to make any definitive statement regarding any potential difference between genders.

It is worth reiterating that the risk of lung cancer attributable to occupational exposure as an iron or steel foundry worker results from contact with a variety of potential carcinogens including PAHs, silica and various metallic pollutants addressed in this report. Consideration of this occupation as a risk factor in its own right allows some illustration of the impact a combination of factors may have in lung cancer risk.



IARC identified occupational exposure during iron and steel founding as carcinogenic to humans, and has classified this occupation as a Group 1 carcinogen.108 The actual carcinogens associated with elevated lung cancer risk are unclear as foundry workers are exposed to several agents that may lead to lung cancer either alone or in combination.


Occupational exposure to the industrial processes necessary for iron and steel founding represents a modest, though significant risk of lung cancer in individuals of some 30-40%. Risk increases as duration of employment in such occupations increases beyond 10 years. Risk is increased amongst smokers occupied in this industry.


10.5 Methodological quality of included studiesIndividual critical appraisal checklist items for studies relevant to the risk of lung cancer resulting from Iron and steel founding are shown below in Table 10.8

Table 10.8 Iron and steel founding: Methodological quality of included studies

Study Study Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Total (yes)

Include/Exclude

Ahn et al. 2010 Cohort study y y u u y y u y y n/a 6 Include

Bosetti et al. 2007 Research synthesis with pooled analysis & meta-analysis

y u y y n u y y y y 7 Include

Bourgkard et al. 2009

Cohort study y u u y y y y y y n/a 8 Include


Ahn et al. 2010

The research aims of the study were clear and the sample appeared to be representative of the Korean population of foundry workers, as subjects of both genders were included. Lung cancer risk was calculated relative to both the general population and to unexposed workers (office workers) at the same plants. The outcomes were assessed using objective criteria and statistical analyses were appropriate. It is unclear whether smoking was adjusted for in the analyses as the confounders were not detailed.

Bourgkard et al. 2009

This paper examined the risk of lung cancer to steel foundry workers as was conducted in France. Participants employed for at least one (1) year were considered. The research aims of the study were clear and smoking was adjusted for in the statistical model. Although females were included in the cohort, the data is only presented for males only. Risk is estimated based on a job exposure matrix, derived from job-specific descriptions of carcinogens.

Bosetti et al. 2007

This review considered studies published until 2005, identified through a search of the Medline database. Eleven (11) cohort studies were included. The basis on which studies were included/excluded was not detailed and no critical appraisal was reported. Data is well presented and the analyses are appropriate. Potential confounders were identified and included in the statistical model.


11 Risk factor: Silica exposure11.1 IntroductionThe term silica constitutes a group of minerals containing silicon and oxygen, which are the two most abundant elements found in the earth’s crust. Silica is found in many natural resources and is abundantly found in nature as sand. There are two forms of silica: crystalline and amorphous. Little epidemiological research exists on amorphous silica, which is generally considered to be less toxic than crystalline silica. The IARC Monograph128 highlights silica as a potential human carcinogen. Exposure to crystalline silica dust has been linked to various occupational diseases, particularly a condition known as silicosis that causes scarring of lung tissues. Silicosis develops from repeated and prolonged exposure to crystalline silica dust. Research suggests causal associations between occupational silica exposure and lung cancer, and between silicosis and lung cancer.

The risk of developing lung cancer from exposure to respirable crystalline silica is particularly relevant to Australia in the context of the mining industry. Exposure to silica is also considered a hazard for many occupations, including those associated with foundries, pottery, sandblasting, construction, clay and glass products, and quarrying. The Australian national exposure standard for all three forms (quartz, cristobalite and tridymite) of crystalline silica is estimated to be 0.1 mg/m3.129

Air sampling and assessment of airborne crystalline silica is usually based on particle count procedures, and various assessment methods include filter collection methods coupled with X-ray diffraction or infrared spectrophotometry.128 The detection limits in respirable dust samples for quartz and cristobalite are 5µg and 10 µg respectively, and these equate to an atmospheric level of 0.01-0.02 mg/m3 for a 0.5 m3 air sample.128

Forty-three studies were located by the initial search and a further eight papers were located from the additional search. Of these, 12 were excluded after title and abstract examination. The remaining studies were four meta-analyses130-133, two pooled analyses134, 135 and one systematic review (Pelucchi et al 2006).136 On full-text examination of 23 papers, five further papers were excluded, seven located studies were contained within the IARC Monograph128, and one full-text was not available. The IARC Monograph128 included a total of 68 studies. Forty out of 68 were included in the seven research syntheses and the combined search, and eight studies were not considered for inclusion. Two of the seven meta-analyses131, 132 and both cohort studies137, 138 were considered to be of good methodological quality following critical appraisal, with the remaining syntheses found to be of moderate quality. The most common method of data collection in the cohort studies was self-administered questionnaires. Outcome assessment and data collection methods included cancer registries and death certificates. Lung cancer incidence and lung cancer mortality were the major reported outcomes. Most statistical models adjusted for potentially confounding factors such as: age; smoking status; diet; socioeconomic status and body mass index (BMI). The majority of studies did not clearly present risk estimates separately by smoking status. Characteristics of the included studies, relevant to the association between exposure to silica and lung cancer risk, are shown in Table 11.1.


Table 11.1 Study characteristics relevant to the association between silica exposure and lung cancer




Erren et al. 201110 countriesMeta-analysis

An update of an earlier meta-analysis based on studies of lung cancer in both silicotics and non-silicoticsMost included studies focussed on occupational exposureNo demographic information provided

38 cohort and case control studies based on silicotics and 11 studies based on non-silicotics were included.The numbers of each study design unclearSearch covers 1979 - 2006

SilicaNo details of exposure duration or intensity were reported.

Lung cancer confirmed in individual studies by radiology, autopsy examinations, cancer registries and compensation lists

Both fixed and random effects methods used for analyses.Meta-regressionConfounding variables adjusted for: smoking.Other factors explored in the analysis were: record source, geographical location, periods of investigation.

Pooled estimate of overall lung cancer risk associated with silicosis RR (95%CI)Silicotics (with silicosis, 38 studies)Fixed effect modelRR 2.2 (2.0 - 2.3)Random effects modelRR 2.0 (1.8 - 2.3)Non-silicotics (no silicosis, 11 studies)Fixed effects modelRR 1.2 (1.1-1.3)Random effects modelRR 1.2 (1.0-1.4)No estimates of risk presented by smoking status or by gender

Lacasse et al. 200511 CountriesMeta-analysis

Cohort study23,305 silicosis patients across 27 cohort studiesCase controlCases: 593Controls: 1082No demographic information provided

27 cohort studies and 4 case-control studies.Search covers 1966 - 2004

Occupational exposure to silica that led to silicosisEstimates of exposure ranged from 5 – 35 years

Description unclear

Lung cancer incidence and mortality. SMRs and SIRs pooled togetherSMR values were weighted by the inverse of their variance and combined according to a random-effects model.Potential confounding factors adjusted for: smoking, mining sectors & cumulative radon exposure

Pooled estimate of overall lung cancer risk associated with silicosis SMR (95%CI)(27 Cohort studies)SMR 2.45 (1.63-3.66)Pooled estimate of overall lung cancer risk associated with silicosis OR (95%CI) (4 Case-control studies)OR 1.70 (1.15-2.53).No estimates of risk presented by smoking status or by gender

Lacasse et al. 2009

Workers from diatomaceous earth, ceramic,

4 prospective cohort studies and 6 case-

Occupational exposure to

Description unclear

Pooled data from all studies into a joint analysis in order to

Pooled estimate of overall lung cancer risk associated with silica exposure (10





6 CountriesMeta-analysis

industrial sand, mining, stone, quarrying and aluminium industriesNo demographic information provided

control studies.Cohorts:8635 of which 267 had confirmed lung cancerCase control:Cases: 2161Controls: 5057Search covers 1966 - 2007

respirable silica and lung cancer

generate a dose-response curveRegression analysis conductedPotential confounding factors not addressed

studies) RR (95%CI)Two levels of silica exposure(no exposure reference)1.0 mg/m3/yrRR 1.22 (1.01 - 1.47)6 mg/m3/yrRR 1.84 (1.48–2.28No estimates of risk presented by smoking status or by gender

Pelucchi et al. 2005MultinationalSystematic Review

Workers in various industries and settings, such as mines, stone quarries and graniteproduction, ceramic and pottery industries, steel production,and many othersNo demographic information provided

28 cohort, 15 case–control and two proportionate mortality ratio (PMR) studiesSearch covers 1996 - 2005

Occupational exposure to silicaSilica exposure intensity and duration not reported


Both fixed and random effects methods used for analyses.Potential confounders adjusted for: smoking, age, sex, calendar period

Pooled estimate of overall lung cancer risk associated with silica exposure, RR (95%CI)Overall(random effects, 27 cohort studies):RR 1.34 (1.25 – 1.45)(fixed effects, 27 cohort studies):RR 1.19 (1.16 – 1.21)Pooled estimate of overall lung cancer risk associated with silica exposure and silicosis RR (95%CI)Non-silicoticsRR 1.19 (0.87 – 1.57) (1 cohort study)RR 0.97 (0.68 – 1.38) (1 case control study)Known silicotics:RR 1.69 (1.32 – 2.16)( 7 cohort studies)RR 3.27 (1.32 – 8.20)(1 case control study)Undefined silicotics:





RR 1.25 (1.18 – 1.33) (20 cohort studies)RR 1.41 (1.18 – 1.70)(13 case control studies)No summary estimates of risk by either smoking status or gender were presented

Preller et al. 2010NetherlandsProspective cohort study

Men aged 55-69 years (n=58 279)

Netherlands CohortStudy, which included self-reported, lifetime job histories.

Silica exposure intensity and duration. Cumulative exposure in mg/m3.year ranging from <3 to ≥3 . Duration of exposure ranging from 10 to 51 years

Lung cancer ascertainment from cancer registry

Cox proportional hazard modelPotential confounding factors adjusted for: Age, family history of lung cancer, smoking status, alcohol consumption, fruit and vegetable consumption and asbestos exposure.

Overall lung cancer risk associated with silica exposure RR (95%)RR 1.65 (1.14 - to 2.41)Overall lung cancer risk associated with silica exposure by duration (years), RR (95%)1 -10 RR 0.67 (0.43 – 1.04)11 – 25 RR 0.88 (0.60 – 1.29)26 – 51 RR 1.65 (1.14 – 2.41)Overall lung cancer risk associated with silica exposure by silica concentration (mg/m3), RR (95%)>0 - <0.075 RR 0.97 (0.70 – 1.33)0.075 – 0.2 RR 1.21 (0.82 – 1.78)0.2 – 0.6 RR 1.14 (0.63 – 2.06)Cumulative exposure for ≥3 vs <3 mg/m3.year).RR 1.47 (0.93 - 2.33)No estimates of risk by smoking status were presented.Data was derived from male participants only.

Smith et al. 1995

SilicoticsNo demographic details

14 cohort studies and 4 case-control studies

Silica exposure intensity and duration not

Description unclear

Methods used to pool data no reported

Pooled estimate of overall lung cancer risk associated with silica exposure in silicotics, RR (95%CI)





MultinationalMeta-analysis

reported Adjustment factors reported: smoking

Overall: 2.2 (2.1-2.4)(23 studies)No summary estimates of risk were presented by either smoking status or gender.

Steenland et al. 20015 CountriesPooled analyses

Pooled cohort of 65,980 workers (44,160 miners and 21,820 nominees)No demographics reported

10 cohort studies with quantitative exposure data

Pooled-exposure response analyses in silica-exposed workers.Median cumulative exposure ranged from 0.13 – 11.37 (mg/m3 -years)

Description unclear

Conditional logistic regression analysisLog of cumulative exposure.Confounders included in the model not described

Pooled risk of lung cancer associated with a cumulative exposure to silica, OR (95%)Q1 – 1.0 (reference)Q2 - 3.1 (2.5 - 4.0)Q3 - 4.6 (3.6 - 5.9)Q4 - 4.5 (3.5 - 5.8)Q5 - 4.8 (3.7 - 6.2)No summary estimates of risk presented by either smoking status or gender.

Vida et al. 2010CanadaPooled analyses

Study 1- men between 35 to 70 years; 857 cases, 533 population controls, 1,349 cancer controlsStudy 2 – men and women between 35-75 years; 738 casesand 899 controls

A pooled analysis of 2 population-based case-control studies.

Occupational exposure to crystalline silica including levels of exposure

Histologically confirmed lung cancers

Unconditional logistic regression for ORs. Potential confounding factors adjusted: age, ancestry, smoking history

Pooled risk of lung cancer associated with exposure to silica, OR (95%CI)UnexposedOR 1.00 (reference)Any exposureOR 1.31 (1.08 – 1.59)Non-substantial level of exposure1.20 (0.97 – 1.49Substantial level of exposureOR 1.67 (1.21 - 2.31)Pooled risk of lung cancer associated with exposure to silica, by smoking status, OR (95%CI)Unexposed0 cigarette yrs





OR 1 0(reference)>0-<400 cigarette yrsOR 2.19 (1.28-3.76)≥400-<1000 cigarette yrsOR 6.91 (4.40-10.85)≥1000 cigarette yrsOR 16.90 (10.87-26.28)Any exposure0 cigarette yrsOR 1.28 (0.52-3.17)>0-<400 cigarette yrsOR 3.20 (1.51-6.77)≥400-<1000 cigarette yrsOR 6.76 (4.01-11.40)≥1000 cigarette yrsOR 23.20 (14.41-37.36)Non substantial exposure0 cigarette yrsOR 0.98 (0.32-3.00)>0-<400 cigarette yrsOR 3.09 (1.36-7.00)≥400-<1000 cigarette yrsOR 5.98 (3.44-10.40)≥1000 cigarette yrsOR 22.00 (13.46-35.96)Substantial exposure0 cigarette yrsOR 2.25 (0.59-8.56)





>0-<400 cigarette yrs3.67 (0.95-14.14)≥400-<1000 cigarette yrs9.49 (4.68-19.24)≥1000 cigarette yrs26.93 (15.16-47.84)Categories of exposure were not well defined

Yu et al. 2007Hong KongProspective cohort study

2,789 silicotic workers in Hong Kong diagnosed during the period 1981–1998

Cohort comprised of all newly diagnosed male cases (incident cases) of silicosis seen at the Pneumoconiosis Clinic of the Tuberculosis and Chest Service of the Department of Health

Retrospective exposure assessment - cumulative dust exposure (CDE) or mean dust concentration (MDC)

Cancer case ascertainment from death registry and ICD classification

Cox proportional regression analysisAxelson’s indirect method was used to adjust for smoking.Adjustment factors: Age, smoking status, calendar year of first exposure to silica

Overall lung cancer risk in silicotics by smoking status, HR (95%)Never smoker HR 1.0 (reference)Ex-smoker HR 3.43 (0.81 – 14.53)Current smoker HR 5.89 (1.44 – 24.14)Overall SMR - 1.69 (1.35–2.09)No estimates of risk presented by gender.


11.2 Results11.2.1 Occupational silica exposure and risk of lung cancer

Pooled risk estimates from two published meta-analyses of prospective and retrospective studies suggest an increase of some 20 – 30% in the overall risk of lung cancer associated with exposure to silica, relative to those not exposed (Table 11.2).

Table 11.2 Overall risk of lung cancer associated with exposure to silica

Study Occupation No. Studies

Relative Risk (95%CI)

Erren et al 2011 Not specified 11 1.2 (1.0 – 1.4)

Pelucchi et al 2006 Mine, quarry, granite, ceramic, steel + 27 1.34 (1.25 – 1.45)Random effects model

Data derived from cohorts exposed to silica at work was also extracted from eighteen relevant studies in the 1997 IARC monograph.128 The participants investigated in these studies included workers mining gold, lead and zinc ores (five cohort and two case-control studies); workers in quarries and granite production (two cohort studies); workers in ceramics, pottery, refractory brick and diatomaceous earth production (seven cohort and one case-control studies), and foundry workers (one cohort study).

Meta-analysis of appropriate studies in workers exposed to silica in the ore mining industry shows elevated overall risk of lung cancer due to occupational exposure (Figure 11.1) similar to that reported by the published meta-analyses above (Table 11.2). Significant heterogeneity is present in the analysis, and likely reflects different data collection processes, different levels of exposure between the various studies conducted at different sites over different periods, and the influence of other confounding factors such as air pollution and exhaust fumes to which miners are commonly exposed. It is not clear if the studies have been adjusted for smoking as the details have not been explicitly stated in the monograph. All the cohort studies provided details on follow-up, which was variable and ranged from 19 to 32 years.

Figure 11.1 Overall risk of lung cancer due to occupational silica exposure in workers in ore mining industry

No exposure details provided for the studies. M indicates males where specified.Cocco – Italy. 4740. Lead & zinc mines. Follow-up 28 years.Kusiak – Canada. 13,603 non-uranium gold miners. Follow-up 31 years.Reid & Sluis-Cremer – South Africa. 4925 gold miners. Follow-up 19 years.Ahlman – Finland. 597 copper and zinc ore miners. Follow-up from 1954/1973-1986Hessel – Case-control study. 231 cases and 318 controls.


Two further studies including cohorts working in ore mining show increasing risk for lung cancer in the highest categories of silica exposure in terms of exposure intensity-response and duration of underground employment (Table 11.3). However, risk appears to increase more markedly and significantly with increasing intensity of exposure (Hnizdo & Sluis-Cremer, 1991 cited in IARC monograph128), whereas the difference with increasing duration of exposure (level not provided) was not significant.

Table 11.3 Risk estimates of lung cancer due to occupational silica exposure – Ore mining; cohort & case-control studies, IARC Monograph (1997)128

Reference and cohort population

Exposure Risk estimate & 95% CI

Hnizdo & Sluis-Cremer 1991South AfricaCohort study2209 male gold miners. Follow-up 1968-1986.

Cumulative dust exposure per 1000 respirable surface area-years.Exposure-response (per 1000 respirable surface area-years)≤1516-3031-40≥41

RR1.02 (1.01-1.04)1.01.5 (0.6-4.3)2.07 (0.7-6.0)2.92 (1.02-8.4)

de Klerk et al 1995 Australiacase control98 cases and 744 controls. Australian gold miners.

Lung cancer by duration of underground employmentNone0-4 years5-9 years10-19 years20-29 years30-39 years≥ 40 years

1.00.9 (0.4-2.1)0.9 (0.4-2.3)1.1 (0.6-2.3)0.9 (0.4-1.7)1.1 (0.6-2.3)2.3 (0.8-6.5)

Meta-analysis of comparable studies of industry workers exposed to silica suggests that the risk of lung cancer is increased significantly. A significant increase is clear in workers employed in ceramics, compared to those not exposed. However, this was not the case for workers in the pottery industry (Figure 11.2). The single study informing the diatomaceous earth industry suggests risk is also increased (Figure 11.2).


Figure 11.2 Risk estimates of lung cancer due to occupational silica exposure in workers in Ceramics, Pottery and Diatomaceous earth industries

*No exposure details provided. M, W indicates males and females respectively where details providedMeijers (case-control) Netherlands. 381 male cases and controls.Thomas 1982 – USA. 3870 lung cancer deaths. Follow-up 22 years.Thomas & Stewart 1987 & Thomas 1990 - USA. 2055 subjects. Follow-up 1939/66 through 1980Cherry – UK. 5115 pottery workers. Follow-up 7 years.McDonald – UK. 1016 pottery workers born in 1916-45.Checkoway – USA. 2570 subjects. Follow-up 1942-87

Further studies providing details of exposure in the same occupational groups also showed that the risk of lung cancer increased with average exposures greater than 200 µg/m3 and cumulative exposure greater than ≥1.50 mg/m3 (Table 11.4).

Table 11.4 Risk estimates of lung cancer due to occupational silica exposure – Ceramics, pottery, refractory brick and diatomaceous earth; cohort & case-control studies, IARC Monograph (1997)128


Exposure Risk estimate(95% CI )

Burgess et al 1997; Cherry et al 1997; McDonald 1997Cohort studiesUK, No details on sample demographics.

Lung cancer by average exposure≥200 µg/m3

≥400 µg/m3

1.88 (1.06-3.34)2.16 (1.11-4.18)

Winter et al 1990Case controlUK3669 male workers, below 60 years in the pottery industry. Follow-up 1970-85.

Cumulative exposure to respirable quartz (mg/m3 x yrs)0-0.140.15-0.490.50-1.49≥1.50

SMR1.08 (0.35-2.54)0.99 (0.43-1.95)1.62 (1.05-2.39)1.51 (0.93-2.31)


Three studies relevant to quarries and granite production and foundry workers are presented in Table 11.5. Costello et al. (1995 cited in IARC monograph)128 showed that there was a three-fold increased risk of lung cancer in granite production workers employed and exposed for more than 10 years and following 20 years latency. The study by Guenel et al. 1989, cited in IARC monograph,128 showed that there was no difference between skilled and unskilled stone workers in terms of developing lung cancer when exposed to silica. The exposure details are not clearly provided in the study by Andjelkovich et al. 1994, cited in IARC monograph,128 reporting no significant increase in risk amongst participants as a result of exposure.

Table 11.5 Risk estimates of lung cancer due to occupational silica exposure – Quarries and granite production and foundry workers; IARC Monograph (1997)128



Costello et al 1995USA3246 male granite workers. Follow-up from between 1940 and 1971 through 1989.

Granite (≥20 yrs latency and ≥10 years tenure)Limestone (≥20 yrs latency)Traprock (≥20 yrs latency)

SMR3.54 (1.42-7.29)1.50 (0.95-2.25)0.63 (0.13-1.84)

Guenel et al 1989 Denmark2071 stone workers. Follow-up 1943-84.

Exposure details not provided.Skilled workersUnskilled workers

SIR2.00 (1.49-2.69)1.81 (1.16-2.70)

Andjelkovich et al 1994 USA220 cases and 2200 controls. Gender not stated.

Lung cancer by exposure to silica in quartiles compared to quartile 1 (ref)Quartile 1 (referent)Quartile 2Quartile 3Quartile 4

OR1.01.27 (0.74-2.18)1.14 (0.65-2.01)0.90 (0.50-1.64)

11.2.2 Duration of silica exposure and risk of lung cancer

The findings of a prospective cohort study conducted in the Netherlands suggests that exposure to silica for 26 – 51 years is associated with a moderate increase in lung cancer risk in men, as shown in Table 11.6. This reinforces the results reported in gold miners above by de Klerk et al. 1995, cited in IARC monograph128 (Table 11.3), where there was a sizeable but non-significant increase in risk reported up to 40 years of exposure.

Table 11.6 Duration of silica exposure and risk of lung cancer

Study Duration (years) Relative Risk (95%CI)

Preller et al 2010(men only)

1 – 1011 – 2526 – 51

0.67 (0.43 – 1.04)0.88 (0.60 – 1.29)1.65 (1.14 – 2.41)

11.2.3 Intensity of silica exposure and risk of lung cancer

In a meta-analysis conducted by Lacasse et al.132 on the dose-response association between silica and lung cancer, an increased risk of lung cancer was correlated with


increasing cumulative exposure to silica (Table 11.7). In addition, the authors report that any exposure level greater than 1.84 mg/m3 per year was associated with a significant lung cancer risk; however, the increase in risk of lung cancer plateaus at an exposure level of 6 mg/m3.

Table 11.7 Cumulative silica exposure and risk of lung cancer

Cumulative exposure to silica mg/m3/year Risk/association

1.0 1.22 (1.01 – 1.14)

6.0 1.84 (1.48 – 2.28)

Two further studies presented data on the association between intensity of silica exposure and lung cancer risk. The study by Preller et al.137 did not show a significant association between cumulative exposure to silica and risk of lung cancer. Vida et al.135 categorised participants by exposure intensity; however, the methods used to do this were not clearly reported. This study showed an increased risk of lung cancer associated with a substantial level of exposure to silica. The results of these two studies are shown in Table 11.8.

Table 11.8 Intensity of silica exposure and risk of lung cancer

Study Intensity Risk/Association

Preller et al 2010 Cumulative exposure (mg/m3),>0 to <3≥3

RR (95%CI)0.95 (0.73-1.25)1.47 (0.93-2.33)

Vida et al 2010 No exposureAny exposureNon-substantial levelSubstantial level of exposure

OR (95%CI)1.0 (reference)1.31 (1.08 – 1.59)1.20 (0.97 – 1.491.67 (1.21 - 2.31)

11.2.4 Silica exposure and risk of lung cancer in people with silicosis

Five research syntheses examined the risk of lung cancer associated with silica exposure in participants with silicosis. All of the measures reported showed an approximate two-fold increase in the risk of lung cancer for this group, compared with non-silicotic participants, except for Steenland et al.134 where the risk increase was approximately four-fold (Table 11.9). The increased risk reported has been attributed to inaccuracies in the analysis and the majority of included studies being from the US, where silicosis appears as a frequent contributing cause of lung cancer.134 The data extracted from two additional studies in the IARC monograph (1997 showed similar findings in terms of exposure (Rubino et al. 1985) to silica in years and in different industries (Westerholm 1980,Table 11.10).128


Table 11.9 Lung cancer risk associated with silica exposure in silicotic patients

Study No: of Studies SilicoticsRisk/Association (95%CI)

Erren et al 2011 38 RR 2.2 (2.0 - 2.3) Fixed effect modelRR 2.0 (1.8 - 2.3) Random effects model

Lacasse et al 2005 27 cohort studies4 case control studies

SMR 2.45 (1.63-3.66)OR 1.70 (1.15 – 2.53)

Pelucchi et al 2006 7 cohort studies1 case control study20 cohort studies13 case control studies

Known silicotics:RR 1.69 (1.32 – 2.16)RR 3.27 (1.32 – 8.20)Undefined silicotics:RR 1.25 (1.18 – 1.33)RR 1.41 (1.18 – 1.70)

Smith et al 1995 23 RR 2.2 (2.1-2.4)

Steenland et al 2001 10 cohort studies Silicosis by quintiles of cumulative exposure (mg/m3-years)Q1 – 1.0 (reference)Q2 - 3.1 (2.5 - 4.0)Q3 - 4.6 (3.6 - 5.9)Q4 - 4.5 (3.5 - 5.8)Q5 - 4.8 (3.7 - 6.2)

Table 11.10 Risk estimates of lung cancer due to occupational silica exposure in silicotics, case-control studies, IARC Monograph (1997)128



Rubino et al 1985Italy,764 male deaths in silicotics.

Data collected from compensation register on deceased from 1970-83Lung cancer by duration of exposure in years1-1011-20≥ 20.

1.21 (0.4-2.6)1.73 (1.17 (2.29)1.59 (1.13-2.05)

Westerholm 1980Sweden3610 male and female silicotics. Follow-up 1931-69.

Data collected from national register. No exposure details.Mining/quarrying/tunnellingSilicosis (1931-48)Silicosis (1949-69)Steel/ironSilicosis (1949-69)

SMR5.9 (2.8-10.8)3.8 (2.3-5.8)2.2 (1.0-4.0)

11.2.5 Silica exposure, smoking status and risk of lung cancer

A pooled analysis of two population-based case-control studies presented lung cancer risk associated with silica exposure by smoking status to examine joint effects with smoking. Although there appears to be substantial heterogeneity in the results (as indicated by the large confidence intervals), all of the categories of smoker are associated with significant risk of lung cancer. However, as previously mentioned, the category definitions of this


study are poorly reported, so extrapolations based on these categories are difficult. The results are shown below in Table 11.11.

Table 11.11 Silica exposure, smoking status and risk of lung cancer135

Exposure 0 pack/yrs >0-<20 pack/yrs

≥20-<50 pack/yrs ≥50 pack/yrs

Unexposed 1 (reference) 2.19 (1.28-3.76) 6.91 (4.40-10.85) 16.90 (10.87-26.28)

Any level of exposure

1.28 (0.52-3.17) 3.20 (1.51-6.77) 6.76 (4.01-11.40) 23.20 (14.41-37.36)

Non-substantial exposure

0.98 (0.32-3.00) 3.09 (1.36-7.00) 5.98 (3.44-10.40) 22.00 (13.46-35.96)

Substantial exposure

2.25 (0.59-8.56) 3.67 (0.95-14.14) 9.49 (4.68-19.24) 26.93 (15.16-47.84)

11.3 SummaryThe evidence suggests exposure to silica represents a 20 – 30% increase in risk of lung cancer over those not exposed. Risk attributable to silica exposure increases concomitant with increased intensity and appears to require extended duration of 25-plus years. Relative risk of lung cancer appears consistent across the different occupational categories investigated. There appears to be a strong association between silicosis and an increased risk of lung cancer associated with exposure to silica.

A strong association was also shown between smoking and exposure to silica, with all categories of smoker being associated with significant risk of lung cancer. However, these results should be treated with caution, as the results exhibited substantial heterogeneity (as indicated by the large confidence intervals) and were based on the analysis of two Canadian population-based case-control studies.


Silica in its crystalline form (quartz and cristobalite) is classified as a Group 1 human carcinogen.128 The available epidemiological evidence shows that occupational exposure to crystalline silica causes lung cancer in humans; however, the IARC concluded that “carcinogenicity may be dependent on inherent characteristics of the crystalline silica or on external factors affecting its biological activity or distribution of its polymorphs”.128


Occupational exposure to silica represents a modest, though significant, increase in risk of lung cancer for individuals of some 20-30%. As duration or level (concentration) of silica exposure increases, so too does the risk of developing the disease. People with silicosis who are exposed to silica are approximately twice as likely to develop lung cancer as people who are exposed to silica but do not have silicosis. Smoking also increases the risk of lung cancer from exposure to silica, and this risk increases the more a person smokes.


11.5 Methodological quality of studiesTable 11.12 Silica exposure: Methodological quality of included studies

Study Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Total (Y Include/Exclude

Erren et al. 2011 Meta-analysis Y U U Y U U U Y Y Y 5 Include

Lacasse et al. 2009 Meta-analysis Y U Y Y Y Y Y Y Y Y 9 Include

Lacasse et al. 2005 Meta-analysis Y U Y Y Y Y Y Y Y Y 9 Include

Pelucchi et al. 2006 Systematic Review Y U Y N U U N Y Y Y 5 Include

Preller et al. 2010 Cohort Y Y NA Y Y Y Y Y Y 8 Include

Smith et al. 1995 Meta-analysis Y U U Y U Y U Y Y U 5 Include

Steenland et al. 2001 Pooled analysis Y U U Y U U Y Y Y U 5 Include

Vida et al.2010 Pooled analysis Y U Y Y N N Y U Y U 5 Include

Yu et al. 2007 Cohort Y Y NA Y U Y Y Y Y — 7 Include


Erren et al. 2011

The objectives and the aim of the meta-analyses were well described. The search strategy and sources of studies were not stated. The criteria for including studies were adequate. It was unclear whether two independent reviewers critically appraised the included papers and the methods to minimise errors in data extraction were also not described. Appropriate methods were used to combine the studies and described in detail. The recommendations provided were supported by the data reported along with some specific directives for new research.

Lacasse et al. 2009

The objective of this meta-analysis was clearly stated and described. The search strategy was not appropriate; however, the sources of studies were adequate. The criteria for including studies were adequate. Two independent reviewers assessed the eligibility of each article for inclusion in meta-analysis and there were methods to minimise errors in data extraction. Appropriate methods were used to combine the studies. The recommendations provided were congruent with the data reported and there were some appropriate directives for further research.

Lacasse et al. 2005

The objective of this meta-analysis was clearly stated and described. The search strategy was not appropriate; however, the sources of studies were adequate. The criteria for including studies were adequate and the studies were appraised by independent investigators for inclusion in the meta-analysis. There were methods to minimise errors in data extraction. Appropriate methods were used to combine the studies. The recommendations provided were congruent with the data reported and there were some appropriate directives for further research.

Pelucchi et al. 2005

The systematic review was of moderate quality. There was no clear description of methods including selection, appraisal of studies and data extraction. The objective of this review was described. Search was conducted in Medline database. Appropriate methods were used to combine the studies. The recommendations and research directives were well described.

Preller et al. 2005

The subject sample was clearly described and the participants were at a similar point in the course of their condition. The details of cohort selection were clearly described. Potential confounding factors were identified and adjusted for. The follow-up period was adequate with 11.3 years of follow-up and people lost to follow-up or excluded were described. Outcomes were assessed and measured in a reliable way. Statistical analysis was adequately described and appropriate statistical method was used to estimate RR.

Smith et al.1995

The objective of the paper was clearly stated and described. It was unclear whether the search strategy and the sources of studies were adequate. The criteria for appraising studies were not clearly described and the methods used to minimise errors in data extraction were not clear as well. General principles of meta-analysis were followed;


however, the study did not provide sufficient details. The authors did not mention any specific directives for future research.

Steenland et al. 2001

This study was not a pooled analysis, not a traditional meta-analysis; hence scored low on critical appraisal. The objective was clearly stated. It was unclear whether the search strategy and the sources of studies were adequate. Reasons were stated for selection of studies. It was unclear whether studies were critically appraised. The recommendations were supported by reported data; however, the authors did not state any specific directives for future research.

Vida et al. 2010

This study was a pooled analysis of two large population-based case-control studies. Therefore the search strategy and critical appraisal of studies were not applicable or unclear. In addition, the method to use to combine these two studies was not clearly described. The study did not provide any specific directives for research.

Yu et al. 2007

The subject sample was clearly described and the participants were at a similar point in the course of their condition. Potential confounding factors were identified and adjusted for. It was unclear whether outcomes were assessed using objective criteria. The follow-up period was adequate and people lost to follow-up or excluded were described. Outcomes were measured in a reliable way. Statistical analysis was adequately described.


12 Risk factor: Nickel exposure12.1 IntroductionNickel (Ni) and its compounds are naturally present in the Earth’s crust and are emitted into the atmosphere via natural sources (such as windblown dust, volcanic eruptions, vegetation forest fires and meteorite dust), as well as via human activities (such as mining, smelting, refining, manufacture of stainless steel and other nickel containing alloys, fossil fuel combustion and waste incineration).139

Pure nickel is combined with other metals into alloys (including steel). It is used as an alloy to impart hardness, strength, corrosion resistance and other electrical, heat, and magnetic properties.140 Nickel alloys are used for electroplating (Ni acetate, Ni ammonium sulphate), coinage (Ni copper alloys), jet engines (Ni chromium), catalysts (Ni sulphide, sinter Ni oxide), battery plates (Ni Cadmium, Ni-metal-hydride) and welding components (Ni copper). Ferronickel (FeNi) is used to produce stainless steel, which has a large range of applications including: uses in construction and engineering; hospital equipment; domestic uses; engine components, and food processing.139

The major world demand for nickel is to produce stainless steel for consumer goods, chemical processing plants, and construction. Western Australia produces more than 180,000 tonnes of nickel per year, which represents 99%of Australia's nickel and about 13% of the world’s production after Russia and Canada.141 Production of nickel has declined in Canada and the US due to competitive low-cost producers, notably in Western Australia, Indonesia, and Colombia.142

Several million workers worldwide are occupationally exposed to nickel through airborne fumes, dust, and mist containing nickel and its compounds (such as Ni oxide and Ni sulphide). The principal routes of entry into the body are via inhalation, ingestion or contact of insoluble nickel compounds with skin. 139, 143139, 143139, 143137,141,139,143 Nickel has been shown to accumulate in exposed lung tissue where it can have several effects which could contribute to the development of lung cancer, including inhibition of natural killer cells that are responsible for immunological integrity. Nickel also binds to DNA, leading to chromosomal damage, DNA-repair inhibition, alteration of DNA methylation and histone modification.139 Historically, metallic nickel exposure is more prevalent in nickel-producing industries through inhalation with mean levels of 0.01-6.0mg/m3. Workers in nickel-using industries such as alloy and stainless steel manufacture, electroplating, electrowinning (electroextraction), welding, grinding, and cutting, are mainly exposed to soluble nickel. 139, 143

Non-occupational exposure to nickel is considered to be low; the main sources of exposure in the general, non-smoking population are through ambient air and diet (including food and drinking water). However, diet is considered to contribute to an exposure of less than 0.2mg/day. The variability of nickel content in different types of foods makes it difficult to determine an average dietary intake.139 The World Health Organisation, reports that nickel concentrations are higher in urban and rural areas than remote areas, and have been estimated to range from 1-3ng/m3 in remote areas to between 5-35ng/m3 in rural and urban areas (WHO cited in IARC mongoraph).139

The search for literature identified an IARC monograph originally published in 1990 and updated in 2012. The 2012 monograph139 included one pooled analysis, three cohort and one nested case-control studies relevant to this report.139 As the monograph search only went up to 2006, an additional search to date was undertaken. Additional searching identified a further pooled analysis and a cohort study. Following critical appraisal of


these additional studies, the cohort study143 was excluded. Care was taken to avoid reporting duplicated data. Of the six included studies, five were conducted in Europe144-147

and one in Canada.148

All of the included studies investigated occupational exposure of male workers to various forms of nickel. A job exposure matrix based on personal measurement was utilised to estimate exposure in studies conducted in Norway144, 146, 149, 150 while studies in other countries based their exposure estimation on self-respondent questionnaires or interviews that were interpreted by expert groups. 145, 147, 148, 151 All of the included studies were of good or moderate quality. The 2012 IARC monograph139 did not report an overall summary risk estimate; therefore, the important characteristics of each relevant study were extracted and presented with those of Beveridge et al.142 in Table 12.1.


Table 12.1 Study characteristics relevant to the association between nickel exposure and lung cancer




Anderson et al 1996NorwayCohort study

Male employees working at the Falconbridge nickel refinery. 379 workers with 1st employment 1916-40 & 3 years of employment & 4385 workers with one year of employment 1946-83, and alive at 1/1/1953.

Data collected from 82 different working areas. Follow-up started after 3 (1916-40) or 1 (1946-83) years of total employment.Cancer incidence coded from The Cancer Registry of Norway since 1953.

Occupational exposure:Concentrations of airborne and different forms of nickel were estimated by an expert group for 82 different work areas derived from previous job exposure matrix. Work history from plant records; nickel exposures from 5 900 measurements for total nickel 1973–1994 and estimates of specific nickel compounds leading to job exposure matrix.Exposure duration not reported.

Lung cancer incidence identified according to The NorwayCancer RegistryCancer type not specified

Age specific incidences were calculated, relative to the 1953 to 1993 Norwegian male population, RR relative to unexposed workers.Multivariate Poisson regression analysis used to calculate RRs, adj. for age, smoking status (available in 95% of entire cohort), and birth cohort.

Overall SIR (95%CI) resulting from occupational exp. to Ni(rel. Norwegian male population.)3.0 (2.6-3.4)Cumulative exp. to Nickel (mg/m3), rel. to unexposed workers). RR (95%CI)Soluble nickel<1 : 1.0 (ref)1-4 : 1.2 (0.8–1.9)5-14 : 1.6 (1.0–2.8)≥ 15 : 3.1 (2.1-4.8)Nickel oxide (mg/m3)<1 : 1.0 (ref)1-4 : 1.0 (0.6–1.5)5-14 : 1.6 (1.0–2.5)≥ 15 : 1.5 (1.0-2.2)RR (95%CI)Unexposed: never-smoker: 1 (ref)ever smoker:2.9 (0.6-2.3)Exposed:never-smoker:1.1 (0.2-5.1)ever smoker:5.1 (1.3-20.5)

Antilla et al 1998FinlandCohort study

1 388 workers employed at a nickel refinery & copper/nickel smelter 3 month+ 1945–1985, follow-

Data collected from company employment records and follow-up of cancer from 1953 according to Finnish

Occupational exposure. Air measurements available beginning in 1966

Type not detailed, ICD 7, 162

Adj. for age, gender, and calendar period.

Overall SIR (95%CI)1.22 (0.65-2.08)Refinery workers (n=418, inc 49 women)





up 31/12/19951,339 men(34,320 person-yrs)49 women (1,081,person-yrs)Mean follow-up 25.5 years.

Cancer Registry Overall: 2.61 (0.96-5.67)5yrs+ exposed: 1.99 (0.41-5.80)20+yrs latency: 3.38 (1.24-7.36)Smelter workers (n=566 males)Overall: 1.39 (0.78-2.28)5yrs+ exposed: 1.01 (0.43-1.98)20+ys latency: 2.00 (1.07-3.42)

Beveridge et al 2010CanadaPooled analysis

1598 cases & 1965 controls, male residents of Montreal.15 categories of occupations including; sheet metal workers, mechanics, printers, construction & painters.Cases matched on age & residential area. One study had 2 sets of controls: gen population & other non-lung cancer.

Pooled analysis of 2 population based case control studies. Population controls randomly selected from electoral listsInterviews & questionnaires (self-reported or surrogate)Data collected for socio-demographic, lifestyle characters, and detailed job history

Lifetime occupational exposure according to detailed job history determined by an expert group blind to subjects’ disease status.Unexposed (<5yrs occ exp to Ni)Substantial (med-high lvls of Ni for >5% of work week, > 5yrs)No definition provide for non-substantial exp.Basis for categories not reported

Histologically confirmed lung cancer, type not specified.

Unconditional logistic regression adjusted for smoking, age, respondent status, years of education, occupations & study.

Adj. OR (95%CI), rel. to unexposed in all categories.OverallAny exposure: 1.3 (1.1-1.7)Non-substantial:1.3 (0.9–1.6)Substantial1.5 (0.7–3.1)By duration (any exposure)<5yrs:0.9 (0.5-1.6)5-20yrs :1.2 (0.8-2.0)>20yrs :1.6 (1.1-2.3)Smoking status (any exposure)Non-smokers:2.5(1.3-4.7)Smokers: 1.1 (0.9-1.4)

Grimsrud et al 2002NorwayNested case-control study

5389 male workers employed at a Kristiansand nickel refinery ≥ 12 months between 1910–1994 & alive at 1/12/1952

Nested case-control study of 213 lung cancer cases identified in Cancer Registry between 1952–1995 & 525 controls from workforce matched

Occupational nickel exposures from 5 900 measurements for total nickel between 1973–1994.Relative concentrations of

Lung cancer incidence identified according to NorwayCancer Registry

Conditional logistic regression adjusted for smoking status & work duration.Alloy data unadjusted for exposure to water soluble Ni.

Adj. OR (95%CI) (rel to unexposed, all categories)Water soluble NickelLow: 1.3 (0.5-3.5)Low-medium:1.8 ( 0.7-4.5) Medium:1.9 (0.8-4.6)





Nested within the cohort utilised by Grimsrud et al. 2003.

by age, sex and year of birth (94% of all originally identified cases & controls)

four forms of nickel were estimated on the basis of speciationanalyses of refinery dusts & aerosols conducted during1990s.Risk estimates due to specific nickel compounds categorised on basis of cumulative exp based on a job exposure matrix.

Medium-high: 2.5 (1.0-6.0)High:3.8 (1.6-9.0)p-trend: 0.002Ni oxideLow:1.7 (0.7-4.2)Low-medium:2.3 ( 0.9-5.8) Medium: 2.7 (1.1-6.6)Medium-high: 2.3 (1.0-5.7)High: 2.2 (0.9-5.4)p-trend: 0.201Ni sulphideLow: 1.6 (0.6-4.2)Low-medium: 2.8 (1.1-6.9)Medium: 2.5 (1.0-6.3)Medium-high: 2.3 (0.9-5.5)High: 2.8 (1.1-6.7)p-trend: 0.119Metallic nickelLow: 1.4 (0.6-3.3)Low-medium:1.3 ( 0.6-3.0) Medium: 1.3 (0.6-3.0)Medium-high: 1.7 (0.8-3.8)High: 2.4 (1.1-5.3)p-trend: 0.126Nickel exp. (<0.75mg/m3/yr) and smoking statusNon & ex(>5yrs) smokers:1 (ref)Smokers (1-20g/day):12.3 (3.6-42.3)





Smokers (>20g/day):37.6 (9.3-151)Nickel exp. (>0.75mg/m3/yr) and smoking statusNon & ex(>5yrs) smokers:5.0 (1.4-17.3)Smokers (1-20g/day):22.1 (6.7-72.8)Smokers (>20g/day):34.4 (9.3-121)

Grimsrud et al 2003NorwayCohort study

Cohort of 5 297 male workers employed at a Kristiansand nickel refinery ≥ 12 months between 1910–1989 and alive at 1/1/1953

Work history from plant records; lung cancer incidence followed up until 12/31/2000 from The Cancer Registry of Norway. Age specific incidences from 1953 to 1993 for entire Norwegian male population was used to calculate SIRs

Nickel exposures from 5 900 measurements for total nickel between 1973–1994 and estimates of specific nickel compounds leading to job exposure matrix

Lung cancer incidence identified according to The NorwayCancer Registry

Multivariate Poisson regression analysis adjusted for age and smoking status (available in 89% of entire cohort)

SIR (relative to Norwegian male population)Overall (any exp to Ni): 2.6 (2.3-2.9)Roasting:3.4 (2.3-4.8)Smelting:2.7 (2.1-3.6)Ni electrolysis:4.0 (3.3-4.8)Cumulative exposure to Ni (mg/m3X yr)(relative to unexposed in all categories)Adj. RR (95%CI)Total Nickel:0.01-0.41:1.2 (0.6-2.3)0.42-1.99: 2.1 (1.1-3.9)≥2.0: 2.4 (1.3-4.5)Water soluble nickel0.01-0.34: 1.3 (0.7–2.4)0.35-1.99: 1.8 (1.0–3.2)≥2.0: 3.1 (1.7-5.5)Nickel oxide:





0.01-0.12: 1.7 (1.0–3.1)0.13-1.99: 2.5 (1.4–4.4)≥2.0: 2.1 (1.2-3.8)Nickel exp. and smoking <1.0mg/m3/yr Nickel:Never: (ref)Ever smokers: 5.6 (2.0-15.0)>1.0mg/m3/yr Nickel:Never: 1.8 (0.5-6.2)Ever smokers: 9.1 (3.4-25.0)

Grimsrud & Peto 2006Wales (UK)Pooled analysis

Two cohorts of male workers with 5+ yrs of employment hired 1902–1969 or between 1953–1992 and followed through 1985 and 2000, respectively.No demographics reported,

Not detailed Minimum of 15 yrs exposure (exp. type not detailed)


Pooled standardised mortality ratios compared (SMRs), based on national mortality rates.Confounders not detailed.

Pooled SMR (95%CI)Any Ni exposure1.33 (1.03-1.72)


12.2 Results12.2.1 Occupational nickel exposure and risk of lung cancer

Two pooled analyses147, 148 and two cohort studies144-147, 151 reported a significant overall risk resulting from any occupational exposure to nickel (Table 12.2). The pooled analyses indicate risk increases by some 30% relative to those not exposed, whilst the cohort studies from Norway suggest this significant increase may be much greater in the order of 2.5 to 3 times the risk (Table 12.2); however, results should be interpreted with caution as neither pooled analysis reported demographics, exposure details or confounders adjusted. Grimsrud et al.150 examined lung cancer risk resulting from different nickel-exposed occupations within a Norwegian nickel refinery. Exposure of >1 year was associated with significantly increased risk for all three occupations, ranging from a 2.7-fold increase in smelter workers, to a four-fold increase in nickel electrolysis workers, relative to the general male Norwegian population (Table 12.2). In contrast, a Finnish cohort study145 found the lung cancer risk to nickel/copper smelter workers to be non-significant, relative to the local Finnish population.

Table 12.2 Occupational exposure to nickel and overall lung cancer risk; all studies included in the IARC monograph139 except for where denoted.

Study Type, duration & intensity of exposure

Risk estimate (95%CI)(rel. to unexposed)

*Beveridge et al. 2010Pooled analysis of 2 case control studies,Canada

Ni 1->20yrs15 categories of occupation. Exposure categories1 based on interviews

Any level: Pooled OR 1.3 (1.1-1.7)Non-substantial: OR 1.3 (0.9–1.6)Substantial: OR 1.5 (0.7–3.1)

Grimsrud & Peto 2006Pooled analysis of 2 cohort studies,Wales

Not reported SMR (relative to local population.)1.33 (1.03-1.72)

Anderson et al. 1996Cohort studyNorway

Ni refinery, >1yr exp SIR (relative to Norwegian male population.)3.0 (2.6-3.4)

Antilla et al. 1998Cohort studyFinland

Ni refinery & Ni/Cu smelter>3mo exp

SIR (95%CI) (relative to local population.)1.22 (0.65-2.08)Refinery workers (n=418, inc 49 women)Overall: 2.61 (0.96-5.67)Smelter workers (n=566 males)Overall: 1.39 (0.78-2.28)

Grimsrud et al. 2003Cohort studyNorway

Ni refinery, >1yr exp SIR (relative to Norwegian male population)Overall: 2.6 (2.3-2.9)Roasting: 3.4 (2.3-4.8)Smelting: 2.7 (2.1-3.6)Ni electrolysis: 4.0 (3.3-4.8)

* denotes study not included in IARC 2012, 1 categorisation process not defined


12.2.2 Duration of nickel exposure and risk of lung cancer

Two included studies informed on risk of occupational nickel exposure by duration and suggest that a significant increase in lung cancer risk becomes evident after extended duration of exposure of approximately 20 years (Table 12.3). Occupational exposure to nickel of less than five years does not appear to increase risk of lung cancer (Table 12.3).

Table 12.3 Duration of nickel exposure and risk of lung cancer

Study Risk estimate (95%CI)*<5 years

Risk estimate (95%CI)*5-20yrs

Risk estimate (95%CI)*>20yrs

Antilla et al. 1998 — 1.99 (0.41-5.80)2

1.01 (0.43-1.98)3

—

Beveridge et al. 2010 0.9 (0.5-1.6)1 1.2 (0.8-2.0) 1.6 (1.1-2.3)1any exposure 2refinery workers 3smelter workers *relative to unexposed

12.2.3 Cumulative exposure to nickel

Two studies conducted in Norwegian nickel refineries (possibly overlapping cohorts), reveal a dose response effect of occupational exposure to both water soluble nickel and nickel oxide (Table 12.4). Although the absolute cumulative exposures are substantially higher (approximately 10-fold) in the cohort study146, the trend observed in risk estimates is the same for both studies. Despite the differences in exposure, both studies show a marked jump in risk to the highest exposure category when considering water soluble nickel, a profile that is not evident in either study considering Ni oxide alone (Table 12.4) Grimsrud et al.144 report water soluble nickel to be a significant risk at cumulative exposures of >0.35mg/m3 and nickel oxide greater than 0.01 mg/m3, whereas Anderson et al.146 report exposures of >5mg/m3 to either water soluble nickel or nickel oxide as being a significant risk factor for lung cancer (Table 12.4).

Table 12.4 Cumulative exposure to water soluble nickel and Ni oxide and risk of lung cancer; IARC 2012.139

Study Cumulative exp. (mg/m3 X yrs)

RR (95%CI)*water soluble Nickel

RR (95%CI)*Ni oxide

Anderson et al. 1996 Cohort study,Norway

1-45-14≥15

1.2 (0.8–1.9)1.6 (1.0–2.8)3.1 (2.1-4.8)

1.0 (0.6–1.5)1.6 (1.0–2.5)1.5 (1.0-2.2)

Grimsrud et al. 2002 Nested case control, Norway

0.01-0.34:0.35-1.99:≥2.0:

1.3 (0.7–2.4)1.8 (1.0–3.2)3.1 (1.7-5.5)

1.7 (1.0–3.1)2.5 (1.4–4.4)2.1 (1.2-3.8)

*relative to unexposed

12.2.4 Occupational nickel exposure, smoking status and risk of lung cancer

All of the included studies collected smoking history data; however, only four studies presented risk estimates stratified by smoking status (Table 12.5). The pooled analysis148 reported a higher RR in non-smokers relative to smokers exposed; however, this study utilised a different definition of “non-smoker” compared with the other studies (so may have residual smoking exposure). The analysis also included a wide range of occupations


exposed to nickel, whereas the other included studies focused on nickel refinery workers. All of the other studies reported significantly higher lung cancer risk estimates in smokers occupationally exposed to nickel, compared with exposed non/never smokers. However, variance was high as indicated by the confidence intervals (Table 12.5). A multiplicative effect between smoking and nickel exposure on lung cancer risk has been suggested in one study,146 as seen in Table 12.5. The risk of lung cancer almost doubled when compared to smokers who had not been exposed to nickel; comparison of upper confidence limits suggests this difference may be greater still (Table 12.5). Similarly, risk increased five-fold in workers who were exposed to nickel and who smoked, compared to those who were exposed but never smoked (Table 12.5).

Table 12.5 Risk resulting from exposure to nickel and smoking status

Study Exposure Risk estimate (95% CI)

Andersen et al. 1996Norway nickel refineryCohort study

Unexposed:Exposed:

Never-smoker: 1 (ref)Ever smoker: 2.9 (0.6-2.3)Never smoker: 1.1 (0.2-5.1)Ever smoker: 5.1 (1.3-20.5)

Beveridge et al. 2010Canada, various occupationsPooled analysis

Any exposure Non-smokers1: 2.5(1.3-4.7)Smokers: 1.1 (0.9-1.4)

Grimsrud et al. 2002Norway nickel refineryNested case control study

<0.75mg/m3/yr:>0.75mg/m3/yr:

Non & ex(>5yrs) smokers: 1 (ref)Smokers (1-20g/day):12.3 (3.6-42.3)Smokers (>20g/day):37.6 (9.3-151)Non & ex(>5yrs) smokers:5.0 (1.4-17.3)Smokers (1-20g/day):22.1 (6.7-72.8)Smokers (>20g/day):34.4 (9.3-121)

Grimsrud et al. 2003Norway nickel refineryCohort study

<1.0g/m3/yr:>1.0g/m3/yr:

Never smoker: (ref)Ever smokers: 5.6 (2.0-15.0)Never smoker: 1.8 (0.5-6.2)Ever smokers: 9.1 (3.4-25.0)

1 a non-smoker is defined as being a subject who had smoked less than 100 cigarettes in their lifetime or had quit smoking >20 yrs before recruitment.

12.2.5 Occupational nickel exposure, type of nickel compound and risk of lung cancer

Grimsrud and co-workers144 examined the potential relationship between the type of nickel compound and lung cancer risk in Norwegian male nickel refinery workers (Table 12.6). Cumulative median exposures to various types of nickel compounds were reported and the risks were categorised into five exposure categories based on a job exposure matrix and 5900 measurements of airborne nickel taken over an approximate 20-year period. Exposures to any of the nickel compounds lead to significant increases in lung cancer risk; however, nickel sulphide became a significant risk at lower exposures than nickel oxide and water soluble nickel, with metallic nickel becoming a significant risk at the highest exposure level (Table 12.6).


Table 12.6 Type of nickel compound and lung cancer risk, (Grimsrud et al. 2002)

Nickel compound Exposure category (Cumulative median exposure – mg/m3 x years)

Adj. OR (95% CI)

Water soluble nickel Low: 0.05Low-medium: 0.28Medium: 0.63Medium-high: 1.60High: 4.93

1.3 (0.5-3.5)1.8 (0.7-4.5)1.9 (0.8-4.6)2.5 (1.0-6.0)3.8 (1.6-9.0)

Nickel oxide Low: 0.02Low-medium: 0.10Medium: 0.36Medium-high: 1.67High: 12.6

1.7 (0.7-4.2)2.3 ( 0.9-5.8)2.7 (1.1-6.6)2.3 (1.0-5.7)2.2 (0.9-5.4)

Nickel sulphide (sulphide) Low: 0.02Low-medium: 0.06Medium: 0.16Medium-high: 0.41High: 1.43

1.6 (0.6-4.2)2.8 ( 1.1-6.9)2.5 (1.0-6.3)2.3 (0.9-5.5)2.8 (1.1-6.7)

Metallic nickel Low: 0.01Low-medium: 0.03Medium: 0.13Medium-high: 0.35High: 2.32

1.4 (0.6-3.3)1.3 ( 0.6-3.0)1.3 (0.6-3.0)1.7 (0.8-3.8)2.4 (1.1-5.3)

Data adjusted for smoking

12.3 SummaryThe evidence suggests that occupational exposure to nickel represents a significant risk of lung cancer compared to those not exposed. The variability in studies located and analysed makes it difficult to provide a definitive quantifiable risk; however, the consistency in the risk presented, despite the variability, is considerable. The majority of the research informing this report was conducted in Europe, with no included studies conducted in Australia. Cumulative nickel exposure showed a dose dependant increase in lung cancer risk; however, the threshold for significance was quite different in each of the two studies. Evidence from a pooled analysis of two studies conducted in a Canadian nickel refinery found that the risk of lung cancer was only statistically significant after exposure of 20 years. A Norwegian cohort study found that all classifications of nickel workers examined were at significantly increased risk of lung cancer, with nickel electroplaters being at greatest risk.

No studies reported risk by gender and all but one included study focused exclusively on male workers. No evidence was identified to inform on the risk resulting from non-occupational exposure to nickel.



Nickel has been identified as a Group 1 carcinogen, with occupational exposure probably being linked to lung cancer.139 IARC also identifies nickel as a risk for cancer of the nose and nasal sinus.


Occupational exposure to nickel represents a significant, though modest, increase in risk of lung cancer. This association with lung cancer risk is most apparent for male workers occupationally exposed to nickel for extended duration in the order of 20 years. Risk of lung cancer is apparent whether route of entry to the body is via inhalation or ingestion.


12.5 Methodological quality of studiesIndividual critical appraisal checklist items for nickel are shown in Table 12.7.

Table 12.7 Nickel exposure: Methodological quality of included studies

Study Study/ Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Total (Y) Include/Exclude

Beveridge et al 2010 Case-control Y U Y Y Y N/A Y Y Y 7 Include

Lightfoot et al 2010 cohort Y U N/A N Y Y N Y N 4 exclude


Beveridge et al. 2010

The methods and objectives were generally well presented in this study. Cancer incidence was identified by hospital records across all major Montreal area. Confounding factors were carefully accounted for. Outcome measures and statistical methods used were adequately described. Exposure was estimated by an expert group based on interviews.

Lightfoot et al. 2010

Although this is a large cohort study which consisted of 10,523 male workers in a Sudbury nickel plant, the failure to control for smoking habits render the conclusion merely speculative. Exposure was based on duration of employment in the plant. Cancer incidence was determined according to the linkage to Ontario Cancer Registry. Standardised mortality ratio and standardised incidence ratio was calculated with reference to general population in Ontario.


13 Risk factor: Painting as an occupation13.1 IntroductionSince 1989, employment as a painter has been classified by IARC as an occupation associated with a high risk of lung cancer, cancer of the bladder and urinary tract, as well as mesothelioma. 152, 1532 In Australia, a painting trade worker is a worker who applies paint, varnish, wallpaper and other finishes to protect, maintain and decorate surfaces of buildings and structures.154 A recent estimate of the number of people employed as painting trades workers in Australia, based on the 2006 Census, with upward adjustment for population growth, is 41,220.155 A high proportion of workers are employed full-time (85%) and approximately 95% of painting workers are male (Australian Bureau of Statistics, 2012b).155 No estimate is available on the number of cancers or lung cancers associated with painting as an occupation in Australia.

Paint is a suspension of finely divided pigment particles in liquid, composed of a binder (resin causing it to adhere to the surface/substrate), a volatile solvent or water, and additives that impart special characteristics such as hardness and lustre.156 Paints are distinct from varnishes, which are light-bodied quick drying products that form a glossy or matt finish on application. Paints are also distinct from stains, which are varnishes that contain enough pigment or dye to alter the appearance of a wood surface. Paint, as well as varnish and stain products, contain thousands of chemical components that are used as pigments, extenders, binders, solvents and additives. Paint is most often used as a coating for metal, wood, gypsum or plaster to confer protective properties and/or to alter the appearance of the surface.157 The basic components of paints vary widely in terms of chemical composition, depending on the colour, the durability, and other required properties of the paint.156 Paint is generally applied in a liquid form, with volatile components evaporating to leave a dry film of paint after application.

One challenge in interpreting the existing evidence on painting and risk of lung cancer is the variety of paint products available and the changes in chemistry/composition of paint that have occurred over time.157 Another, is that exposure to potential carcinogens among painters occurs not only though inhalation of paint, but also inhalation of confirmed or suspected carcinogens such as asbestos, talc containing asbestos, chromium VI compounds, and cadmium compounds also common in the painter’s work environment.153,156 With regard to the inhalation of paint, spray painting is thought to be a more hazardous practice as it includes exposure to carcinogens predominantly in the form of aerosol or fine particles, which can be readily absorbed deep into the lungs158 In its description of health hazards related to different occupations, Comcare has identified lung cancer as a long-term health effect that can result from spray painting.159

Multiple genetic and cytogenetic effects have been reported among workers employed as painters.156 Existing information about safety and carcinogenicity of the range of individual chemicals present in paint also provides strong evidence to support genotoxicity as a mechanism underlying the observed association with cancer risk as a result of exposure. In Australia, the composition of paint is monitored and the painting environment regulated; however, there is little data available on how such measures minimise negative health effects. Some, though not all epidemiological studies investigating the association between lung cancer risk and painting as an occupation have found a slightly elevated risk. 152, 153 Critically, the evidence that painters have a slightly higher lung cancer risk than non-painters comes primarily from studies that have used job title/occupational classification as the measure of exposure.157


In the initial search of the literature, 44 studies plus an IARC monograph156 were identified as potentially relevant to understanding and quantifying the risk of lung cancer attributable to painting as an occupation. After review, two recent meta-analyses, Guha et al.153 and Bachand et al.,152 both of which were included in the IARC monograph,156 were appraised and classified as high quality studies. Despite considerable overlap between the studies included by the two meta-analyses, they do not use identical data sets. They also use different approaches to adjust for smoking in their analysis of lung cancer risk and conduct different sub-group analyses. As a result, they offer unique contributions towards understanding the association between lung cancer risk and painting work and were both included in this report. All except two of the remaining 42 studies identified in the initial literature search were included in one or both of the meta-analysis or were duplicate studies. The remaining two primary studies, Ramanakumar et al.157 and Tse et al.158 were included after critical appraisal. The evidence presented here for an association between painting as an occupation and lung cancer risk is therefore based on four studies: two meta-analyses;152,153 one pooled analysis157 and a case-control study.158 The two meta-analyses used data on lung cancer in subjects (primarily males) who worked as painters in many countries. The pooled analysis drew data from painters, also primarily male, in Montreal, Canada.157 The case-control158 was undertaken in Hong Kong, China and estimated lung cancer RR based on data from non-smoking Chinese males. No included publications studied participants who worked as painters in Australia. Table 13.1 summarises the characteristics of the included studies.


Table 13.1 Study characteristics relevant to the association between painting as an occupation and lung cancer




Bachand et al. 2010Meta-analysisGlobal, incl: Russia, New Zealand, Switzerland, USA, Germany, Uruguay, Canada, Norway, China, Argentina, Italy, Brazil, Sweden, Scotland, UK.

38 studies (15 cohort & 23 case control). Only 1 cohort & 20 case controls reported RR adjusted for smoking.(External technique used to adjust for smoking and all studies used in meta-analysis to report a smoking adjusted RR for painting and occupation, stratified by study design.)

All studies in IARC Monograph 47 (1989) as well as in meta-analyses by Chen & Seaton (1998) &Bosetti et al (2005) considered for inclusion. PubMed, LexisNexis Environmental database & ISI Web of Science searched for studies.Inclusion criteria reported. Critical appraisal by 3.Various meta-analyses using different study combinations. Range of RR estimated. Separate analysis for case control and cohort studies and within cohorts for morbidity and mortality studies.RR for cohort studies adjusted for smoking using external Bayesian approach.

Any years of work/level of exposure. Following types of workers: painting machine operators, construction painters, artistic painters, paint manufacturers, as well as mixed occupational groups that had painters.No quantification of exposure to particular suspected carcinogens in paints or the paint workers’ environment.

Various lung cancer types.

Fixed and random effects regression used to calculate summary risk estimates. Random effects regression reported.Main adjustments for socio-economic status, birth and other occupational exposures.Assumptions about smoking in cohorts based on smoking data from the country for each study undertaken during data collection period

RR any level/yrs exposure (smoking adj), 15 cohort studiesMorbidity: 1.00 (0.70-1.42)Mortality: 1.19 (0.98-1.44)RR (smoking adj), any level/yrs exposure, 23 case controls:1.29 (1.10-1.51)

Guha et al. 2010Meta-analysisGlobal, incl: China, Finland, Norway, Denmark, UK, USA, Uruguay,

47 studies (18 cohort; 29 case control), only 27 studies (4 cohort studies & 23 case controls) adjusted for smoking and were used to derive

All studies in 1989 IARC monograph considered for inclusion. In addition, PubMed and reference lists of pertinent publications searched. Exclusion criteria stated and studies critically appraised by 3

Any level of exposure/yrs of work. Some studies included work in other occupations exposed to paint such as

Various types

Random and fixed effect models used to calculate summary risk estimate.Overall relative risk (meta-RR, random effects) based on all included studies

RR (smoking adj.) any years of employment/level of exposure.All study designs (27 studies):1.35 (1.21-1.51)Cohort studies (4 studies):1.22 (0.97-1.52)





Switzerland, Argentina, Brazil, Canada, Sweden, India, Italy.

smoking adj.RR.All studies included >11 000 incident cases or deaths from lung cancer in painters.7/47 studies presented risks for female painters.

authors independently.Various analyses undertaken to develop summary lung cancer RR overall and for different sub-groups including study design and gender.

plasterers, glaziers, wallpaper hangers, artists, and decorators.No quantification of exposure to specific suspected carcinogens in paints or the paint workers’ environment.

(smoking adjusted and not smoking adjusted) reported as well as the RR based on smoking adjusted studies. Sub-group analysis under-taken to explore differences in risk estimates by study design, smoking status, gender and region.

Case controls (23 studies): 1.41(1.23-1.61)RR (smoking adj. plus other occupational exposures) (5 studies):1.57 (1.21-2.04)RR for never smoking painters, non-painters the ref (3 studies):2.00 (1.09-3.67)Lung cancer RR in never smokers & non-smokers, never painters the ref: (3 studies):1.96 (1.15-3.35)Lung cancer RR for female painters, any level/duration, non-painters the ref, (7 studies):2.04 (1.59-2.62)Lung cancer RR for male painters, any level/duration, (study number not stated):1.37 (1.29-1.44)Analysis of RR by duration of exposure (5 studies) found higher RR for longer duration.

Ramanakumar et al. 2011Pooled analysis of 2 population based case controlsCanada

Case control 1: 857 male lung cancer cases, 533 population based controls.Case control 2: 765 male & female lung cancer cases and 899 controls.

Population controls selected using random sampling. Age and sex matched. Case control 1interviews from 1979-1986; Case control 2 1996-2001. Interview undertaken with subject or next of kin/proxy.

Two kinds of exposures: (i) Painting as an occupation (lifetime work history based/any duration/level of exposure) and (ii) Exposure to wood and gypsum

Small cell, squamous cell & adenocarcinoma.

Unconditional logistic regression. Analysis limited to males Confounders adjusted for: smoking, age; ethnicity (French, Anglo, other); years of school attendance; medium family income; asbestos; silica; &

OR (95% CI)Painter (any duration): 1.6 (1.0-2.4)Painter ≤10 years: 2.0 (0.9-4.1)Painter >10 years: 1.2 (0.5-1.8)Exposure to wood and gypsum paints, Overall risk:Any exposure: 1.4 (0.9-1.9)





Cases and controls restricted to Canadian citizens resident in Montreal.Due to low number of females the analysis restricted to males.

Interview for lifetime histories incl. information on smoking other lifestyle factors and socio-economic status. And level and duration of occupational exposure to 3 diff. Agents. Latter also based on expert opinion.

paints classified as substantial, non-substantial and any level, based on a job description matrix and expert opinion.

cadmium compounds. Any exposure ≤15 yrs: 1.2 (0.8-2.4)Any exposure ≥15 yrs: 1.1 (0.7-1.5)Non substantial exposure:1.1 (0.8-1.9)Substantial exposure:1.4 (0.8-2.7)RR by date of first exposure to painting as occupation:First exposed ≤1965 1.5 (0.8-2.4)First exposed >1965 1.2 (0.9-1.6)

Tse et al. 2011Case controlKong Kong/China

Cases 132 Chinese non-smoking males (aged 35-79yrs) newly diagnosed with lung cancer.Controls 536 non-smoking male community referents

Cases from oncology centre in Hong Kong (Feb2004 - 30 Sept 2006).Controls randomly selected from same districts with no history of diagnosed cancer, frequency matched in 5-yr age groups to a lung cancer case.Interviews for data on lifestyle, occupational history & other exposures which included asbestos, arsenic, nickel, chromium, tars, asphalts, silica, spray painting, non-spray painting, pesticides, diesel engine exhaust, cooking fumes, welding fumes.

Stratification for spray painting and general painting work excl. spray painting.Exposure defined as at least once a week for at least 6 months.

Histologically confirmed primary lung cancer (all types). Separate analysis for adenocarcinoma.

Unconditional multiple logistic regression.Adj. for age, place of birth, education level, residential radon exposure, past history of lung diseases, any cancer in first degree relatives and intake of meat. Confounding factors selected based on testing sensitivity of results to a range of potential confounder variables.

OR for occupational exposure to general painting work for male non-smoking painters who did not do spray painting:2.79 (1.20-6.48)OR for occupational exposure to spray painting work for male non-smoking painters:3.29 (1.31-8.23)Lung cancer RR increased with increasing yrs of spray painting work but not yrs of general painting excluding spray painting.


13.2 Results13.2.1 Overall lung cancer risk associated with any duration of work as a painter/various levels of exposure

Recent meta-analyses of available studies152, 153 and pooled analysis157 indicate that employment as a painter increases risk of lung cancer by some 30% relative to people not employed as painters (Table 13.2). Risk estimates reported in the meta-analyses appear dependent on study design, with higher risk estimates reported from the included case-control studies than cohort studies (Table 13.2). The two meta-analyses do not provide information on whether the studies drew data from painters involved in general including spray painting, spray painting only, or general painting excluding spray painting. It is reasonable to expect summary risk estimates are based on data from all three categories. The individual case-control study included158 indicates risk increases some 2.5 to 3 times as a result of being employed as a painter. However, the wide range of the confidence intervals reported by this study reflect imprecise risk estimation, and considered in light of the other studies, it is likely that the true value or RR is closer to the lower confidence limit of approximately 1.3, irrespective of the reference group employed (Table 13.2).

Table 13.2 Overall lung cancer risk for painting as an occupation, any duration

Reference Risk estimate, smoking adj. (95% CI)

Bachand et al. 2010Meta-analysis

RR(95%CI)Case control studies (23 studies) 1.29 (1.10-1.51)Cohort studies (15) mortality data based: 1.00 (0.70-1.42)morbidity data based: 1.19 (0.98-1.44)

Guha et al. 2010Meta-analysis

RR(95%CI)All studies (27 studies) 1.35 (1.21-1.51)Studies which adjusted for other occupational exposures* (5 studies)1.57 (1.21-2.04) I2=0% p =0.68Cohort studies (4 studies)1.22 (0.97-1.52)Case controls (23 studies) 1.41(1.23-1.61)

Ramanakumar et al. 2011Pooled analysis

OR(95%CI)1.6 (1.0-2.4) with population controls as ref

Tse et al. 2011Case control study

General painting work (no spray) all non-smoking subjects OR(95%CI)2.36 (1.04-5.37) ref no exposure to general painting2.79 (1.20-6.48) ref no exposures to general painting or a range of other exposures* Spray painting, all non-smoking subjects3.29 (1.31-8.23) ref no exposure to spray painting or a range of other exposures*

*The other exposures included asbestos, arsenic, nickel, chromium, tars, asphalts, silica, spray painting, non-spray painting, pesticides, diesel engine exhaust, cooking fumes, welding fumes.

Despite the similar RR estimates presented by the included meta-analyses that included many of the same studies (Table 13.2),152 reported risk estimates based on included cohort studies (stratified by mortality and morbidity) indicate no difference in risk of lung cancer as a result of the exposure. The primary difference between the Guha et al.153 and Bachand et al.152 meta-analysis is that whilst the former developed its summary smoking


adjusted risk (RR) by excluding studies that had not adjusted for smoking, the latter used an external adjustment technique.

Ramanakumar et al.157 also examined the difference in lung cancer risk between painters employed in the construction industry and all industries combined. These authors found that whereas painters in the construction industry were at 60% greater risk of lung cancer than non-painters (OR 1.6 95% CI 1.0-3.1), those working in all other industries combined were no more likely to develop lung cancer than non-painters (OR 1.1 95% CI 0.5-2.4). The authors suggest that in the construction industry, painters may have been exposed to known lung carcinogens, including asbestos and silica. However, even if exposure to these carcinogens is the reason for the elevated risk, this does not detract from the observation of excess lung cancer risk for this profession.157

The high risk estimates reported in the Tse et al.158 case-control study suggest spray painting presents a higher risk of lung cancer than general paint work. The imprecise risk estimates are substantially larger than those reported by the included research syntheses. Despite this imprecision, the large upper confidence interval suggests that a real association between painting and lung cancer, and spray painting and lung cancer, does exist.

All reported results are adjusted for age and smoking, whilst the meta-analyses included data from some studies that adjusted for smoking and other confounding factors such as family cancer history, education and other occupational exposures like asbestos. The overall risk results reported from the two meta-analyses are based primarily on data gathered from male painters. Ramanakumar et al.157 adjusted for family income, ethnicity, respondent status, years of schooling, smoking, and exposure to at least one of the following carcinogenic agents: asbestos, silica or cadmium compounds. Tse et al.158 adjusted for place of birth, education level, residential radon exposure, past history of lung diseases, any cancer in first-degree relatives and intake of meat.

13.2.2 Wood and gypsum paints and overall risk of lung cancer

The pooled analysis of two case-control studies by Ramanakumar et al.157 conducted in Montreal, Canada presented lung cancer risk estimates for painting as an occupation (see Table 13.2), as well as wood and gypsum paints (Table 13.3). The study found that people exposed to any level of the wood and gypsum paints showed an increase in risk of lung cancer of approximately 40% compared to people not exposed to wood and gypsum paints; however, these values were not statistically significant. The classification of exposure as ‘non-substantial’ and ‘substantial’ was based on individual job histories and the expert opinion of chemists. Quantified definitions of `non-substantial and `substantial exposure’ were not provided.

Table 13.3 Lung cancer risk for exposure to wood and gypsum paints, (Ramanakumar et al. 2011)157

Exposure OR (95% CI)

Any exposure 1.4 (0.9-1.9)

Non-substantial 1.1 (0.8-1.9)

Substantial 1.4 (0.8-2.7)Adjusted for age, family income, ethnicity, respondent status, years of schooling, smoking, and exposure to at least one of the following carcinogenic agents, asbestos, silica cadmium compounds.


13.2.3 Dose response for painting as an occupation and lung cancer risk

Three of the included studies153, 157, 158 report results for duration of employment as a painter and risk of lung cancer. The results reported were mixed, with the results of the Guha et al.153 meta-analysis, presented in Table 13.4. Although no clear duration response appears in this data, they are suggestive of an increased risk with exposures greater than 10 years.

Table 13.4 RR of lung cancer and occupational exposure to paint by duration of employment, (Guha et al. 2010)153

< 10 years ≥10 years <20 years ≥20 years

1.13 (0.77-1.65) 1.95 (1.26-3.02) 1.37 (0.89-2.13) 2.00 (1.01-3.92)Based on 5 studies and adjusted for smoking.

The results of the Tse et al.158 study, which distinguished between risks in painters only involved in spray painting and those involved in general painting excluding spray painting, are shown in Table 13.5. For general painting work, the study showed no increase in risk with longer duration of employment. Conversely, considering spray painting work, the reported risk estimates suggest a significantly increased risk of lung cancer with increasing years of employment.

Table 13.5 Lung cancer risk for general painting work (not spraying) and spray painting in Chinese non-smoking men by duration of employment (Tse et al. 2011)

Exposure OR (95% CI)1-19 years

OR (95% CI)≥ 19 years

General painting work not incl. sprayingReference group aReference group b

2.37 (0.68-8.24)2.80 (0.80-9.86)

2.36 (0.83-6.72)2.79 (0.96-8.08)

Spray painting workReference group aReference group b

1.59 (0.32-7.96)1.86 (0.37-9.34)

3.66 (1.26-10.59)4.28 (1.46-12.57)

Reference group “a” consists of never exposed to the work. Reference group “b” is never exposed to the specified work plus any on a list of confirmed or suspected human carcinogens including asbestos, arsenic, nickel, chromium, tars, asphalts, silica, spray painting, non-spray painting, pesticides, diesel engine exhaust, cooking fumes, welding fumes and man-made mineral fibres.Adjusted for age, place of birth, education level, residential radon exposure, past history of lung diseases, any cancer in first-degree relatives and intake of meat.

Ramanakumar et al.157 report no increase in RR with increased duration of exposure to two exposure categories - painting as an occupation and exposure to wood and gypsum paints (Table 13.6). Rather, the lung cancer risks were reported to be higher in those employed for less than or equal to 10 years than those employed for longer than 10 years. No reason for this result was suggested aside from the sample size being relatively small, particularly where follow-up was for the greater time period.


Table 13.6 Lung cancer risk for painting as an occupation and exposure to wood and gypsum paints by duration of employment157

Exposure OR (95% CI)Population controls only

OR (95% CI)Population controls only

Painting as an occupation ≤ 10 years2.0 (0.9-4.1)

> 10 years1.2 (0.5-1.8)

Wood and gypsum paints ≤15 years1.2 (0.8-2.4)

>15 years1.1 (0.7-1.5)

Adjusted for age, family income, ethnicity, respondent status, years of schooling, smoking, and exposure to at least one of the following carcinogenic agents, asbestos, silica cadmium compounds.

13.2.4 Risk of lung cancer from occupational exposure to paint by gender

The meta-analysis by Guha et al.153 reported greater relative risk of lung cancer associated with painting as an occupation in females. Risk estimates for females are presented from seven included studies in this analysis (Table 13.7). The data reported suggest that risk of lung cancer may be slightly elevated in females.

Table 13.7 Lung cancer risk for painting as an occupation by gender153

Meta RR females(95% CI)

Meta RR males(95% CI)

Females 2.04 (1.59-2.62) Males 1.37 (1.29-1.44)

13.3 SummaryThe research identified and synthesised in this review suggests that occupational exposure to paint represents a modest risk factor for lung cancer. The results from the included research syntheses suggest an overall risk estimate indicating an approximately 30% higher risk of lung cancer amongst painters when compared to individuals not employed as painters. Considering the variation in results reported, the overall lung cancer risk estimates of the included studies based on subjects of any smoking status, for any duration of painting employment, ranged from painters being at no greater risk (cohort studies only) 152, 153 to painters being 60% more likely to develop lung cancer than those who have not been exposed to painting as an occupation. Both of the included meta-analyses that derived data from the same studies and that reported significant overall risk estimates for exposure to painting as an occupation, also revealed a difference in risk estimates dependent on the design of the original studies. 152, 153

Retrospective case-control studies reported greater and statistically significant risk estimates, whereas restriction of meta-analysis to cohort studies alone did not reinforce the conclusion that exposure to painting imparts a significant risk of lung cancer.

The risk estimate of the single case-control study undertaken in China, based on data from non-smoking men, was notably greater than that reported from the remainder of included studies.158 It distinguished risks associated with general painting and spray painting individually and found the risk estimate of lung cancer to be greater for spray painters. This study suggests that spray painters who are non-smokers in China may be 3.3 times more likely to develop lung cancer, and those engaged in general painting excluding spray painting 2.8 times more likely to develop lung cancer, than those who have not been exposed to painting as an occupation.158 Pooled analysis of two case-control studies undertaken in Canada presented lung cancer risks for exposure to wood


and gypsum paints.157 Individuals exposed to wood and gypsum paint have a 30% to 50% higher lung cancer risk than those who have not been exposed to wood and gypsum paints. The included studies presented mixed results on the relationship between lung cancer risk and duration of employment as a painter.157

In Australia and elsewhere, males dominate the workforce engaged in painting as an occupation. The meta-analysis by Guha et al.153 reported a higher risk of lung cancer among females exposed to paint, relative to those who were not. No studies offered risk estimates stratified by smoking status. Two studies however, presented risk estimates derived from only non-smoking painters, and showed these workers are between 2 and 2.5 times more likely to develop lung cancer than non-smoking individuals not exposed to painting as an occupation. Two studies reported results on differences in risk by date of first exposure to painting as an occupation, with mixed findings.

A limitation of the review is that no clarity emerged from the included studies regarding the impact of the duration of employment as a painter or spray painter that is associated with an elevated risk of lung cancer.


IARC classifies occupational paint exposure as carcinogenic to humans (Group 1) and states that occupational exposure as a painter causes cancer of the lung, bladder and urinary tract as well as mesothelioma.156


This review suggests that painters may have a higher risk of lung cancer than individuals who have never engaged in painting as an occupation. Those at increased risk include workers engaged in general painting and also those who perform spray painting work. None of the studies included in this review presented data relating specifically to occupational exposure to paint in Australia. The results of one included study suggest spray painters may be at slightly elevated risk compared with workers involved in general painting. No definitive statement can be made regarding the impact of different levels of exposure or duration of employment as a painter on lung cancer risk

Despite the identification of employment as a painter as a risk factor for lung cancer, the available evidence does not provide further insight as to which constituents of paint are more harmful than others.


13.5 Methodological quality of studiesIndividual critical appraisal checklist items for occupational exposure to paint are shown below in Table 13.8.

Table 13.8 Painting as an occupation: Methodological quality of included studies


Include

Guha et al. 2010 Meta-analysis Y Y Y U Y Y Y Y Y Y 9 Include

Bachand et al. 2010 Meta-analysis Y Y Y U Y Y Y Y Y Y 9 Include

Ramanakumar et al. 2011 pooled analysis U U Y Y Y NA U Y Y NA 5 Include

Tse et al. 2011 Case control N U Y Y Y NA U Y Y NA 5 Include


Guha et al. 2010

This meta-analysis used forty seven studies, 18 cohort and 29 case controls reporting lung cancer risks (not all adjusted for smoking) associated with painting as an occupation. The studies either had lung cancer incidence or mortality from lung cancer as the outcome of interest. An overall meta-risk estimate is reported using all included studies risks (smoking adjusted and not adjusted for smoking). Risk estimates are reported for females as well males, different regions, non-smokers and non-smokers plus never smokers as well as different study designs. The objectives addressed in the study are well stated, the search strategy is appropriate, a detailed search was undertaken and sources used are adequate. Critical appraisal was undertaken for the study by two or more reviewers independently, the criteria used to appraise studies were appropriate and detailed, methods were used to minimise error in data extraction. Methods used to combine studies were appropriate, the recommendations were supported by the data and specific directives for new research were appropriate. A drawback was that studies that reported risk estimates not adjusted for smoking were included. However, whilst non-smoking adjusted studies were included, the authors did attend to the issue of smoking via a meta-analysis based only the smoking adjusted studies.

Bachand et al. 2010

The objectives of the meta-analysis were well stated. The search strategy undertaken to identify studies to be used in the meta-analysis was clearly stated and appropriate. The sources used were adequate, critical appraisal for the study was undertaken by three reviewers, the criteria used to appraise studies were appropriate, the recommendations and conclusions of the study were supported by the data and analysis, the methods used to combine studies were appropriate and the specific directives for research were appropriate. The primary difference between the Guha et al.153 and Bachand et al.152 meta-analysis is that whilst the former developed its summary smoking adjusted risk (RR) by excluding studies that had not adjusted for smoking, the latter used an external adjustment technique to adjust for smoking in studies that did not adjust their lung cancer RR estimates for smoking.

Ramanakumar et al. 2011

This study included two case controls both undertaken in Montreal Canada. Lung cancer risk estimates (ORs), adjusted for smoking and a range of additional confounders, were developed for both paint as an occupation (any level of exposure to any kind of carcinogen related to painting work) and three categories of exposure to paints, varnishes and stains. It is unclear whether the sample in the two case studies is representative of patients with lung cancer in Canada. It is also unclear whether the patients were at a similar point in their lung cancer disease when they were interviewed to gather data used for the two case control studies or whether the results were adjusted for attrition on the studies. Bias was minimized in the selection of cases and controls, strategies were used to address confounding factors including smoking and a number of other confounders including age, ethnicity (French, Anglo, other), years of school attendance, medium family income, asbestos, silica, cadmium compounds. Outcomes were assessed using objective criteria, outcomes were measured in a reliable way and appropriate statistical analysis was used in the study.

Tse et al. 2011

The sample used in this case control study, undertaken in China, may be representative of the patient population for non-smoking men in China. It is unclear whether all the


patients were at a similar point in the course of their condition/illness. Bias was minimised in selection of cases and controls. Strategies to address confounding by other factors were implemented and smoking as well as a range of other lung cancer risk factors was adjusted for the estimation of the lung risk associated with painting as an occupation. Outcomes were assessed using objective criteria. Follow up was carried out over a sufficient time period. It was unclear how the outcomes of people who withdrew from the study were used in the analysis. Outcomes were measured in a reliable way and appropriate statistical analysis was used.


14 Risk factor: Cadmium exposure14.1 IntroductionCadmium is a metal with specific properties that make it useful for a wide variety of industrial applications. These properties include excellent corrosion resistance, low melting temperature, high ductility, and high thermal and electrical conductivity. The principle use of cadmium, in the form of cadmium hydroxide, is in production of nickel-cadmium (Ni-Cd) batteries. Other uses for cadmium and cadmium compounds include pigments, coatings and plating, stabilisers for plastics, alloys, semiconductors and solar panels. Cadmium is also present as an impurity in non-ferrous metals, iron, steel, fossil fuels, cement and phosphate fertilisers. Cadmium occurs naturally in the earth’s crust, mainly in the form of oxide, sulphide and carbonate ores, and is also found in sea water. Elemental cadmium is a soft, silver-white metal and is generally recovered as a by-product of zinc refining. In addition, cadmium can be recovered from recycled materials, such as Ni-Cd batteries and manufacturing scrap, and some residues or intermediate products.160

Particulate cadmium (elemental cadmium and as oxide, sulphide, or chloride) is emitted to the atmosphere from both natural sources and from human activities. Erosion of cadmium-containing rocks is the primary natural source of cadmium in the air. Other natural sources include volcanoes, sea spray and bush fires. The major industrial sources of cadmium emission to the environment include the mining and smelting of zinc, the combustion of fossil fuels, waste incineration and cement production. Cadmium does not break down in the environment, and atmospheric cadmium can be transported from emission sources and deposited in surrounding locations. There is uncertainty about the relative magnitude of natural cadmium emissions versus emissions from human activity; however, global cadmium emissions from human activity have decreased steadily since 1980.161 Mean cadmium concentrations in air vary according to proximity to industrial source and to population density. Measurement data from northern Europe for the period 1980-88 reported levels around 0.1ng/m3 in remote areas, 1-10ng/m3 in urban areas, 1-20ng/m3 in industrial areas, and levels of up to 100ng/m3 observed near emission sources.162

Industries with the highest potential for occupational cadmium exposure include cadmium production and refining, Ni-Cd battery manufacture, cadmium pigment manufacture, cadmium alloy production, mechanical plating, zinc smelting, cadmium-silver alloy soldering, and polyvinylchloride (PVC) compounding. Occupational exposures to cadmium have generally decreased since the 1970s.163 In recent years, the use of cadmium for traditionally common applications including pigments, stabilisers, and coatings has declined largely due to concerns over its toxicity and the introduction of regulations restricting its use, particularly in the European Union. Signatory members of the Australian PVC industry phased out the use of cadmium stabilisers in vinyl products in 2004.164 The National Occupational Health and Safety Commission (NOHSC) in Australia has set guidelines to limit cadmium exposure in the workplace; an eight-hour time weighted average exposure of 0.01 mg/m3.165

For the general population, exposure to cadmium occurs primarily from dietary sources and also via inhalation of ambient air or contaminated dust. In Australia, the main source of exposure to cadmium is dietary but studies show mean cadmium intake for all age groups is well below tolerable levels.166 Australia has adopted a strategy to maintain safe levels of cadmium in agricultural soil and produce.167 Exposure from ambient air is not thought to be significant in Australia, and if it occurred it would be highly localised around an industrial source. For smokers, cigarettes are a significant source of cadmium


exposure due to the large amount of cadmium in tobacco leaves.168 Cadmium accumulates in the body over time (especially in the kidneys) and urinary cadmium measurements reflect lifetime exposure.169 In a general population survey in Germany, mean urinary cadmium levels were 0.23 µg/L. For smokers, this level was 0.29 µg/L, former smokers 0.25 µg/L, and never-smokers 0.18 µg/L (Becker, 2003).170 Results of a study conducted in Australia also indicate that cadmium accumulation and urinary excretion is higher in smokers.171 Women typically have higher kidney and urinary cadmium concentrations than men, which may result from a higher rate of absorption in females.171

Cadmium and cadmium compounds have been classified by IARC160 as carcinogenic to humans (Group 1). The Australian NOHSC classifies cadmium and compounds as probable human carcinogens (Category 2).165 Several mechanisms have been identified that potentially contribute to cadmium-induced carcinogenesis. These mechanisms include disturbances to DNA repair and tumour-suppressor protein functions, resulting in chromosomal damage and genomic instability.172 Further reported effects include changes in DNA-methylation patterns as well as interactions with signal-transduction, which may contribute to the deregulation of cell growth.173

A search of the literature identified an IARC monograph which was initially published in 1972 and most recently updated in 2012. The IARC 2012 monograph160 primarily considered studies investigating five major historical cohorts with occupational exposure to cadmium and cadmium compounds. The cohorts included workers from copper-cadmium alloy plants in the UK, cadmium processing plants in the UK, Ni-Cd battery factories in the UK and Sweden, and cadmium recovery plants in the USA. A systematic review was also identified, which included studies of the same historical cohorts detailed in the IARC monograph.174 In addition to the monograph and review, occupational cadmium exposure was investigated in a pooled analysis from Canada148 and a case-control study from Europe.92 Two cohort studies investigating residential cadmium exposure in the US175 and Belgium176 were also included.

The majority of the included occupational cohort studies estimate lung cancer risk based on data from male workers, with exposure assessments derived from interviews and/or standardised job descriptions. Risks relating to exposure duration and/or intensity are detailed for some of the included studies. The two residential cohort studies used urinary cadmium excretion as the primary measure of exposure, and one reported gender-specific risks.175 A number of the studies present risk by smoking status. The important characteristics of the included studies are detailed in Table 14.1.


Table 14.1 Study characteristics relevant to the association between cadmium exposure and lung cancer




Adams et al. 2011Cohort studyUSAThird National Health and Nutrition Examination survey (NHANES III) cohort

Population study of stratified sample representative of non-institutionalised US populationAged ≥17yrs7455 men and 8218 women (after exclusions)

Cd concentration of spot urine samples was measured (uCd)Mean uCd 0.252µg/g for men & 0.352µg/g for womenFollow-up for mortality averaged 13.4yrs (men), 13.8yrs (women)

Lifetime residential cadmium exposure determined by urine analysisNo details given on potential occupational exposure but results were not materially changed after adj for occupation or industry

Lung cancer type not stated

Weighted Cox proportional hazards regression.Never-smokers considered as those who had smoked <100 cigarettes totalAdj for age, BMI smoking history, education & race

Adj. HR (95%CI) of mortality per twofold increase in uCdEntire populationMen: 1.81 (1.49-2.21)Women: 1.21 (0.79-1.84)Never-smokersMen: 2.16 (1.39-3.36)Women: 0.57 (0.33-0.97)

Beveridge et al. 2010Pooled analysis (data from 2 studies)Canada

1598 male cases and 1965 male age & residential area matched controls residing in MontrealCategories of high-risk occupations for exposureOne study had 2 sets of controls: gen population & other non-lung cancer

InterviewsPooled data from 2 population based case control studiesExposure assessment based on worker’s occupation, industry, job title & individual characteristics of the workplace & tasks as reported by the participants

Lifetime occupational exposure to cadmium determined from interviews

Lung cancer type not stated, however diagnosis histologically confirmed

Unconditional logistic regressionAdj for age, yrs education, occupation, smoking and study for pooled results

Adj OR (95%CI), rel to unexposed in all categoriesOverallAny level: 1.5 (0.9-2.7)Non-substantial: 1.1 (0.6-1.9)Substantial: 2.9 (0.7-11)By duration(any level of exposure)<5yrs: 1.0 (0.4-2.1)5-20yrs: 0.8 (0.4-1.7)>20yrs: 1.4 (0.7-2.8)By smoking status(any cadmium exposure)Non-smokers: 4.7 (1.5-14.3)Smokers: 1.4 (0.8-2.4)

IARC Monograph 2012

15 cohort studies with occupational exposure including

MonographDerived from expert panel discussion,

Most studies included participants with >1yr occupational exposure


No overall summary estimateTabular data

See Table 14.3 for relative risk determined for each included study





Research synthesisGlobal

Ni-Cd battery manufacture (UK),Ni-Cd battery factory (Sweden),Cu-Cd alloy plants (UK), Cd recovery (USA), Cd processing plants (UK)

search terms and inclusion criteria not detailedTabular data presented for 15 cohort studies of occupational exposure

Some studies provide details on intensity of exposure

presenting RR for each cohort studyAdj not clearly stated in monograph, some studies did not adj for smoking or exposure to other occupational agents

The IARC view is that there is sufficient evidence in humans for the carcinogenicity of Cd and Cd compounds and state that Cd and Cd compounds cause cancer of the lung

Navarro Silvera et al. 2007767676

Systematic reviewIncludes cohort studies from UK, Sweden and USA

Includes studies of same cohorts as in IARC Monograph with occupational exposure to Cd or Cd compounds

Medline search (1966-present)Men & women includedExcluded studies not published in English or not peer-reviewedData taken from seven occupational cohort studies

Occupational exposureExposure levels determined by job history for most studies


Most studies present standardised mortality ratio (SMR)Data not synthesisedAdj not clearly stated in review

Six of the seven cohort studies reported statistically significant increased risks of lung cancer associated with relatively high Cd exposure

Nawrot et al. 2006Cohort studyBelgium

Population sample (n=994) living in north-east Belgium, comparison of residents living near zinc smelters to reference area away from smeltersRandom sample stratified by gender & age from high-exposure (>3 mg cadmium/kg soil) and low-exposure (<1 mg cadmium/kg soil) areas on basis of a preliminary soil

Cadmium conc. of soil from participants gardens measuredAt baseline and follow up:Validated questionnaireUrinary excretion of cadmium (uCd) over 24h used as a biomarker of lifetime exposureBlood sampleParticipants recruited between 1985-89 and incidence of cancer followed until 2004, median follow up

Lifetime residential exposureCd in soil ranged from 0.8 mg/kg to 17 mg/kgMean uCd was 12.3nm/day in high-exposure area, 7.7nm/day in low-exposure area42 participants with history of occupational exposure (& significantly raised Cd excretion compared to case-controls), 39 of these lived in high-exposure area


Cox regression analysis used to calculate hazard ratios for cancer in relation to urinary & soil concs. of CdAdj for gender, age & smoking statusAdditional explanatory variables: number of pack yrs, time since ceased smoking, baseline serum creatinine, and 24h urinary arsenic excretion

HR (95%CI):Per twofold increase in uCd (unadj for arsenic):Total cohort: 1.70 (1.13-2.57)Resid. exp: 1.73 (1.09-2.72)Per twofold increase in uCd (adj for arsenic):Total cohort: 1.57 (1.01-1.35)Resid. exp: 1.57 (0.96-2.56)Per twofold increase in soil Cd:Total cohort: 1.57 (1.11-2.24)Resid. exp: 1.49 (1.04-2.14)High exposure vs low exposure area:





screenHigh-exposure area:Total pop. 9840Study pop. 521Low exposure area:Total pop. 9390Study pop. 473

17.2yrs (range 0.6-18.8)

Results presented for total cohort & excluding participants with occupational exposure (i.e. residential exposure only)

Total cohort: 4.17 (1.21-14.4)Resid. exp: 3.58 (1.00-12.7)Occupational vs resid. exp:3.23 (1.00-10.8)Smokers vs non-smokers:3.69 (1.31-10.3)Ex-smokers (pack yrs):1.76 (1.17-2.63)Ceased smoking <10yrs vs ≥10yrs: 1.68 (1.12-2.52)

t’ Mannetje et al. 2011Multicentre case-control study17 centres, 7 countries (Romania, Hungary, Poland, Russia, Slovakia, Czech Republic, and UK)

2853 cases and 3104 controls. Both males & femalesCases (age <75yrs), controls frequency matched based on gender & age (±3yrs)

A job-specific matrix was constructed using interview, questionnaire and an expert panel to establish exposure to cadmium

Occupations held for at least 1yrIndustries included: steel industry, coke manufacture, foundry, glass industry, mechanic, wood worker, painter, welder, chemical industry, tannery, toolmaker and machine tool operator, miner or quarryman, insulation worker, printing, meat workers, farmer, rubber industry, & asbestos compound production


Unconditional logistic regressionAdj for smoking, age, centre, gender, and exposure to other occupational agents

Adj OR (95% CI), relative to unexposed (all categories)Overall1.18 (0.83-1.67)Cadmium dust1.13 (0.74-1.73)Cadmium fumes/mist1.19 (0.77-1.82)Duration of exposure:Dust1-8yrs: 1.67 (0.88-3.15)8-19yrs: 0.71 (0.32-1.56)19+yrs: 0.95 (0.45-2.02)p for trend = 0.9530Fumes/mist1-9yrs: 1.11 (0.56-2.19)9-25yrs: 1.32 (0.67-2.57)25+yrs: 1.13 (0.54-2.35)





p for trend = 0.4606Cumulative exposure (mg/m3-h):Dust0.001-28: 1.86 (0.94-3.68)28-97: 0.96 (0.49-1.91)97+: 0.67 (0.30-1.51)p for trend = 0.7569Fumes/mist0.001-28: 1.15 (0.56-2.35)28-65: 0.52 (0.24-1.14)65+: 2.04 (1.07-3.90)p for trend = 0.2087


14.2 Results14.2.1 Occupational exposure to cadmium and risk of lung cancer

The pooled analysis of Beveridge et al.148 includes data from two case-control studies addressing occupational exposure to cadmium in Canada. The risk estimate for lung cancer with any level of cadmium exposure appeared elevated though was not statistically significant (Table 14.2). Subjects classified in the substantial exposure group had been exposed to medium or high cadmium concentrations for more than 5% of their work week and for five years or more. For individuals in this group, risk of lung cancer was higher than for those with non-substantial exposure (Table 14.2). Definitive interpretation of these results is difficult as the number of substantially exposed workers was relatively small, resulting in imprecise risk estimates.

Table 14.2 Risk estimates of lung cancer due to occupational cadmium exposure; research synthesis148

Author Type and duration of exposure

Exposure intensity/assessment

Risk (95%CI) (rel. to unexposed)

Beveridge et al. 2010Pooled analysis2 studies, Canada

Cd exposure mainly among metal machinists, sheet metal workers, metal product fabricators, & graphic artistsDuration from 1 to >20yrs

Exposure assessed by interviewsParticipants categorised as unexposed, non-substantial exposure or substantial exposure#

Any level: 1.5 (0.9-2.7)Non-substantial: 1.1 (0.6-1.9)Substantial: 2.9 (0.7-11)

#Exposed to medium or high Cd levels for >5% of work week for >5yrs

A multicentre case control study conducted across 17 centres in Europe also investigated occupational cadmium exposure and lung cancer.92 Subjects in this study worked in a range of occupations and included both male and female employees. Risk estimates were adjusted for concomitant exposure to known or suspected carcinogens. The overall risk for cadmium exposure (ever vs never exposed) is presented, along with risks for exposure to cadmium dust or cadmium fumes (Table 14.4). The risk estimates suggest no significant increase in lung cancer in these populations in association with cadmium exposure.

Table 14.3 Risk estimates of lung cancer due to occupational exposure to cadmium, case-control study (t Mannetje et al. 2011)92

Author Type and duration of exposure


Risk OR (95%CI)#

t Mannetje et al. 201117 centres,7 countries

Exposure to Cd dust or fumes/mist for 18 occupations at riskDuration from 1 to >25yrs

Exposure assessed by interviews, questionnaires and an expert panelIntensity categorised as low, medium or high

Dust: 1.13 (0.74-1.73)Fumes/mist: 1.19 (0.77-1.82)Combined: 1.18 (0.83-1.67)

#Risk estimates based on males and females

The IARC 2012 monograph160 presented data from 13 cohort studies investigating five separate historical cohorts with occupational cadmium exposure. The studies used interviews, questionnaires and job-specific records to estimate cadmium exposure in these cohorts. Eleven of the studies present overall risk of lung cancer resulting from


cadmium exposure (Table 14.3). The study by Holden et al. cited in IARC monograph160 and the follow-up by Sorahan et al. cited in monograph160 investigated workers from two Cu-Cd alloy plants in the UK. The rate of mortality from lung cancer was elevated in one factory (Factory B) but significantly decreased in the other (Factory A) (Table 14.3). This discrepancy may be explained by higher estimated levels of exposure for alloy workers in Factory B compared to Factory A. However, risk in vicinity workers from Factory B also appeared elevated in comparison, despite their estimated low level of exposure. When alloy workers from Factory A and B were combined, there was no difference in lung cancer risk compared to the general population.177 All other studies presented in Table 14.3 indicate slightly elevated risk estimates for cadmium exposure; however, it is difficult to draw conclusions regarding a causal effect. The assessment of risks is constrained by the small number of long-term and highly exposed workers, the lack of historical exposure data, and the inability to define and examine cumulative exposure across studies. None of these studies adjusted for smoking or co-exposure to other carcinogens, e.g. arsenic, so confounding is a likely issue.

Table 14.4 Risk estimates of lung cancer due to occupational cadmium exposure, cohort studies – IARC monograph160

Author Country Type and duration of exposure


SMR (95%CI)(rel. to local rates)

Elinder et al. 1985

Sweden Ni-Cd battery production >1yr

Estimated levels 0.02-0.3mg/m3

1.33 (0.57-2.62)

Holden 1980 UK Cu-Cd alloy plants >1yr

Estimated levels:Factory A: <0.15mg/m3

Factory B: 1mg/m3

Vicinity workers (Factory B): <0.05mg/m3

Factory A:0.26 (0.03-0.92)Factory B:1.78 (0.77-3.50)Vicinity workers (Factory B):1.38 (0.97-1.91)

Jarup et al. 1998

Sweden Ni-Cd battery production >1yr

Not reported 1.76 (1.01-2.87)

Kazantzis et al. 1992

UK Cd processing plants >1yr

Categorised exposure assessment but details not reported

1.12 (1.00-1.24)

Kipling & Waterhouse 1967

UK Ni-Cd battery production >1yr

Estimated levels 0.6-2.8mg/m3

1.14 (0.37-2.65)

Kjellstrom et al. 1979

Sweden Ni-Cd battery production >5yrs

Estimated levels 1mg/m3

1.48 (0.17-5.35)

Lemen et al. 1976

USA Cd recovery plant >2yrs

Not reported 2.35 (1.21-4.10)

Sorahan 1987 UK Ni-Cd battery production >1month

Estimated levels <0.5mg/m3

1.30 (1.07-1.57)

Sorahan et al. 1995

UK Cu-Cd alloy plants:Alloy workers >1yrVicinity workers >1yr

Estimated exposure0.04-0.6mg/m3

Alloy workers(Factory A & B combined):1.01 (0.60-1.59)Vicinity workers(Factory B):1.60 (1.21-2.09)




SMR (95%CI)(rel. to local rates)

Sorahan & Esmen 2004

UK Ni-Cd battery production >1yr

Not reported 1.11 (0.81-1.48)

Stayner et al. 1992

USA Cd recovery plants >6months

Categorised by exposure level

1.49 (0.95-2.21)

The systematic review of Navarro Silvera et al.174 included seven cohort studies that investigated the risk of lung cancer with occupational cadmium exposure. All of these studies (or follow-up studies) were included in the IARC 2012 monograph. The authors state that the majority of occupational cohort studies show statistically significant increased risks of lung cancer associated with relatively high cadmium exposure. They conclude that there is strong evidence of a positive association between occupational cadmium exposure and lung cancer risk.

14.2.2 Duration and intensity of occupational cadmium exposure and risk of lung cancer

The duration of occupational exposure to cadmium was addressed in four studies, as detailed in Table 14.5. Elinder et al.182 determined the risk of lung cancer was significantly increased for workers with more than five years exposure and 20 years latency, but data was not presented separately for workers with less than five years exposure. None of the included studies show a clear trend between duration of cadmium exposure and risk of lung cancer (Table 14.5).

Table 14.5 Duration of occupational cadmium exposure and risk of lung cancer

Study Risk <5yrs 5-10yrs 10-20yrs 20+yrs

Beveridge et al. 2010Pooled analysis

OR 1.0 (0.4-2.1) 0.8 (0.4-1.7) 0.8 (0.4-1.7) 1.4 (0.7-2.8)

Elinder et al. 1985Cohort study, 2012 monograph

SMR NA 1.75 (0.7-3.61)# 1.75 (0.7-3.61)# 1.75 (0.7-3.61)#

Sorahan 1987Cohort study, 2012 monograph

SMR 1.4 (0.73-1.83)<2yrs

1.3 (0.44-2.4)5yrs 1.5 (0.42-2.26)>15yrs

1.5 (0.42-2.26)>15yrs

t Mannetje et al. 2011Case control study

OR d: 1.67 (0.88-3.15)1-8yrs

f: 1.11 (0.56-2.19)1-9yrs

d: 0.71 (0.32-1.56)8-19yrs

f: 1.32 (0.67-2.57)9-25yrs

d: 0.71 (0.32-1.56)8-19yrs

f: 1.32 (0.67-2.57)9-25yrs

d: 0.95 (0.45-2.02)19+yrs

f: 1.13 (0.54-2.35)25+yrs

# >5yrs exposure and >20yrs latency; d=dust, f=fumes/mist

t Mannetje et al.92 analysed data further and investigated the risk associated with cadmium exposure by weighted duration (actual hours worked) and cumulative exposure. Risks are presented for cadmium dust and cadmium fumes/mist (Table 14.6). For cadmium fumes/mist, increased risks were observed in the highest categories for both weighted duration and cumulative exposure, which was not the case for cadmium dust. This difference may be due to absorption disparities; cadmium oxide fumes are easily


absorbed through the lungs, whereas absorption of cadmium dust is particle-size dependent.183 None of the tests for trend were statistically significant.

Table 14.6 Risk of lung cancer resulting from occupational cadmium exposure by weighted duration or cumulative exposure (t Mannetje et al. 2011)92

Exposure measure

Cadmium dust Exposure

Cadmium dust OR (95%CI)

Cadmium fumes/mist Exposure

Cadmium fumes/mist OR (95%CI)

Weighted duration(hrs worked)

1-800800-23002300+

1.20 (0.59-2.44)1.15 (0.58-2.31)1.03 (0.50-2.13)p for trend = 0.6930

1-10001000-21002100+

1.19 (0.56-2.51)0.53 (0.25-1.12)2.05 (1.09-3.88)p for trend = 0.2113

Cumulative exposure(mg/m3-h)

0.001-2828-9797+

1.86 (0.94-3.68)0.96 (0.49-1.91)0.67 (0.30-1.51)p for trend = 0.7569

0.001-2828-6565+

1.15 (0.56-2.35)0.52 (0.24-1.14)2.04 (1.07-3.90)p for trend = 0.2087

Three cohort studies included in the IARC monograph160 monograph investigated specific risks for lung cancer associated with different exposure intensities. All these studies reported increased risks for the highest categories of exposure (Table 14.7). The test for trend in the study from Stayner et al.184 was statistically significant. The results of a follow-up nested case-control analysis on a sub-group of the cohort hired after 1940 (Stayner, 1993 cited in IARC monograph160) were consistent with the full cohort analysis. For the studies of Kazantzis & Blanks188 and Sorahan and Lancashire, 185187 a positive association between exposure intensity and risk was also apparent (Table 14.7). The data presented from Sorahan and Lancashire187 are for workers with minimal or no exposure to arsenic, so potential confounding is likely to be reduced.

Table 14.7 Risk of lung cancer from occupational cadmium exposure, by exposure intensity160

Study Exposure category SMR (95%CI)

Kazantzis & Blanks 1992Cohort study, 2012 IARC monograph

Low exposureMedium exposureHigh exposure

1.08 (0.96-1.22)1.21 (0.91-1.57)1.62 (0.89-2.73)

Sorahan & Lancashire 1997Cohort study, 2012 monograph

200-499 mg/m3-days500-999 mg/m3-days1000+ mg/m3-days

1.68 (0.48-5.90)1.30 (0.26-6.59)2.68 (0.54-13.36)

Stayner et al. 1992Cohort study, 2012 IARC monograph

<584 mg/m3-days585-1460 mg/m3-days1461-2920 mg/m3-days>2920 mg/m3-days

0.34 (0.03-1)1.63 (0.65-3.07)2.17 (0.79-4.28)2.72 (1.24-4.8)p for trend <0.05

14.2.3 Residential exposure to cadmium and risk of lung cancer

Two cohort studies investigated the risks of lung cancer associated with residential exposure to cadmium.175, 176 For the study by Adams et al.175 in the general US population, participants were stratified by gender, and lung cancer mortality was compared to


concentration of urinary cadmium. Risks were expressed per two-fold increase in urinary cadmium and also presented for subjects with urinary cadmium levels in the top quartile (Table 14.8). Risk of lung cancer per two-fold increase in urinary cadmium was elevated for both men and women, but was higher for men. For individuals with urinary cadmium levels in the top quartile, lung cancer risk was significantly increased and men were at greater risk than women.

Nawrot et al.176 undertook a prospective population-based study on participants living in north-east Belgium. A random population living in an area near three zinc smelters with high soil cadmium levels (high-exposure) was compared to a reference population living away from the smelters (low-exposure). Cadmium concentrations were measured in participants’ urine and in soil from their gardens. The risk of lung cancer was significantly increased for individuals living in the high-exposure versus the low-exposure area (Table 14.8). In addition, risks were increased per two-fold increase in urinary cadmium and per two-fold increase in soil cadmium. The authors postulate that exposure to cadmium may occur through inhalation of house dust, and in areas with historically contaminated soils, house dust is a potential persistent source of exposure. Risk estimates presented here exclude data from 42 study participants (all male) with a history of occupational exposure to cadmium. On adjustment for age and smoking status, these cadmium-exposed workers had significantly increased risk of lung cancer (3.23 95% CI 1.00-10.8) compared to residentially exposed men.176

Table 14.8 Residential cadmium exposure and risk of lung cancer

Study HR (95%CI) per twofold increase in urinary Cd

HR (95%CI) for individuals with uCd in top quartile#

HR (95%CI) per twofold increase in soil Cd

HR (95%CI) for high-exposure vs low-exposure area

Adams et al. 2011Cohort study

Men: 1.81 (1.49-2.21)Women: 1.21 (0.79-1.84)

Men: 3.22 (1.26-8.25)Women: 1.82 (0.99-3.33)

NA NA

Nawrot et al. 2006Cohort study

1.57 (0.96-2.56) NA 1.49 (1.04-2.14) 3.58 (1.00-12.7)

#uCd >0.580µg/g for men and >0.819µg/g for women

14.2.4 Cadmium exposure, smoking status and risk of lung cancer

Smoking status data were collected for all of the included studies and adjusted for in risk estimate calculations, with the exception of the historical cohort studies presented in the IARC monograph.160 Three of the included studies reported risks of cadmium exposure by smoking status, as detailed in Table 14.9. When the study population in Adams et al.175 was restricted to participants defined as never-smokers (smoked <100 cigarettes in lifetime), the impact on reported risk for men and women was pronounced, with risk for men increasing and risk for women decreasing (Table 14.9). The analysis of Beveridge et al.148 suggests that occupational exposure to cadmium is significantly more hazardous to non-smokers than smokers. The results of Nawrot et al.176 indicate the risk for smokers (former and current) is higher than for non-smokers.


Table 14.9 Risk of lung cancer resulting from any level of cadmium exposure in non-smokers vs smokers

Study Risk for non-smokers# Risk for smokers

Adams et al. 2011Cohort study

Men: 2.16 (1.39-3.36)Women: 0.57 (0.33-0.97)

NA

Beveridge et al. 2010Pooled analysis

4.7 (1.5-14.3) 1.4 (0.8-2.4)

Nawrot et al. 2006Cohort study

NA Smoking vs non-smoking: 3.69 (1.31-10.3)Current smoking: 1.59 (1.08-2.34)Pack-years: 1.76 (1.17-2.63)Quit <10yrs vs >10yrs: 1.68 (1.12-2.52)

#Non-smokers defined as having smoked <100 cigarettes in lifetime or quit >20yrs

14.3 SummaryOverall, the evidence suggests there is an increased risk of lung cancer associated with cadmium exposure, though the overall risk is difficult to quantify due to variability in the data presented. The majority of studies of occupational exposure report a modest risk, but with substantial exposure (exposure to medium or high cadmium concentrations for more than 5% of the work week, and for five years or more) the risk is high, relative to people not exposed (OR 2.9).148 Substantial exposure to cadmium fumes is associated with a high lung cancer risk (OR >2), but substantial cadmium dust exposure does not appear to increase risk.92 This difference may be due to cadmium fumes being easily absorbed through the lungs, while absorption of cadmium dust is particle-size dependent.183 A small sub-population of male workers described in Nawrot et al. (2006),176

with histories of occupational cadmium exposure, had a lung cancer risk more than three times that of men without occupational exposure.

In general, the studies of historical occupational cohorts presented in the IARC monograph160 and the Navarro Silvera et al.174 review present modest to moderate risks. However, these studies should be interpreted with caution, as accurate exposure assessment was difficult and data is not adjusted for smoking status or other potential confounders. Three of these studies investigated risk by exposure intensity, with Stayner et al.184 reporting a high risk (SMR 2.72) for the top exposure category, and a statistically significant test for trend over the four exposure categories. A positive association between exposure intensity and lung cancer risk was also apparent in the other two studies.185, 186 There appears to be no clear association between duration of cadmium exposure and lung cancer risk.

Residential exposure to cadmium is associated with significantly increased lung cancer risk. Per two-fold increase in urinary cadmium (a measure of lifetime exposure) or soil cadmium of residents’ gardens, the relative risk is approximately 1.5.176 For residents living in a high-exposure area, the risk is more than 3.5 times higher than a low-exposure area.176 Urinary cadmium is significantly associated with increased risk of lung cancer for both men and women.175 Men appear to be at greater risk than women, despite the tendency for women to accumulate higher cadmium levels.175 These studies which used urinary cadmium measurements to assess exposure are likely to have high sensitivity due to the specific measure of absorbed cadmium dose.

In Australia, the risk of harmful cadmium exposure for non-smokers is low. There are guidelines in place to limit industrial emissions of cadmium and to limit cadmium exposure in the workplace. The use of cadmium for many traditional applications, such as


stabilisers and coatings, is being phased out. However, cadmium does not break down in the environment and may accumulate in certain areas. In particular, areas subject to historical contamination may pose a risk. Soil contamination in areas surrounding zinc smelters, for example, may present a hazard especially if bordering on residential areas. In areas with high soil cadmium levels, inhalation of contaminated dust may be a potential source of persistent exposure.


Cadmium and cadmium compounds have been classified by IARC as carcinogenic to humans (Group 1) and stated to cause lung cancer. In addition, positive associations have been observed between cadmium exposure and cancer of the kidney and prostate.160


The evidence indicates that occupational and residential exposure to cadmium is associated with a modest to moderate increased risk of lung cancer. The risk appears to increase with intensity of exposure, but there is no clear association with exposure duration. Exposure to cadmium fumes presents a significantly greater risk than exposure to cadmium dust, as cadmium fumes are more easily absorbed.


14.5 Methodological quality of studiesIndividual critical appraisal checklist items for studies relevant to the risk of lung cancer resulting from exposure to cadmium are shown below in Table 14.10.

Table 14.10 Cadmium exposure: Methodological quality of included studies


Include/Exclude

Adams et al. 2011 Cohort study Y U n/a Y Y Y U Y Y n/a 6 Include


Pooled analysis of 2 case controls

Y Y Y Y Y U U Y Y n/a 7 Include


Systematic review

Y Y Y Y U U U n/a Y Y 6 Include

Nawrot et al. 2006 Cohort study N U n/a Y Y Y U Y Y n/a 5 Include

t Mannetje et al. 2011

Case control Y Y U Y Y Y U Y Y n/a 7 Include


Adams et al. 2011

This population-based study investigated cadmium exposure and cancer mortality in the general US population. Strengths of this study included its relatively large sample size and use of urinary cadmium measurements to assess exposure. This was the only study to present gender-specific risks. Limitations of this study are that only data on cancer mortality were analysed, not cancer incidence. This study also had limited ability to control for potential confounding due to occupational exposures.


Strengths of this pooled analysis include the relatively large number of lung cancer cases, collection of detailed job histories, and collection of data on potential confounders including exposure to other occupational agents. Although exposure assessments were performed by experts in the field, they relied largely on interviews and questionnaires which may not have accurately reflected actual exposure levels.


This systematic review aimed to present evidence on cancer risk associated with a number of trace elements. Data are presented covering many of the same cohorts with occupational cadmium exposure as detailed in the IARC monograph160. A limitation of this review is that there is no synthesis of data between studies.

Nawrot et al. 2006

This is the only study to investigate cancer risk in a population residing in a cadmium-contaminated area located near three zinc smelters in north-east Belgium. These residents were compared to a reference population living away from the smelters in an area with lower soil cadmium. Strengths of this study include thorough exposure assessment by measurement of urinary cadmium and soil cadmium levels in participants’ gardens. Validated questionnaires were used to collect data on potential confounders, such as history of occupational exposure and detailed smoking status. Limitations of this study include the fairly small overall number of lung cancer cases, particularly for non-smokers. The observational data do not prove causality and increased cancer risk may be due to pollutants other than cadmium. Arsenic exposure was adjusted for but there may be some residual confounding.

t’Mannetje et al. 2011

This multi-centre case control study was the only study to include data from female workers in risk estimates for lung cancer associated with occupational cadmium exposure. This was also the only study to present data for different methods of exposure (dust or fumes/mist) and included occupational exposure to other metals in its regression. The major limitation of this study was assessment of exposure. This was performed thoroughly but relied on interviews and questionnaires which are subject to inaccuracies such as recall bias.


15 Risk factor: Air pollution15.1 IntroductionConsiderable public concern arises from exposure to air pollution due to the predominantly involuntary nature of the exposure. Although many occupational exposures are recognisably aligned with ‘polluted’ air, in many parts of the world the ubiquity of air pollution and its reach into communities and dwellings, means people have little opportunity to actively avoid it. There are reasonable grounds to suggest that air pollution may increase incidence of lung cancer, especially in combination with other known risk factors for the disease, such as active and passive smoking.187 Known constituents of air pollution include sulphur dioxide (SO4), nitrogen dioxide (NO2), nitrogen oxides (NOx) and a large variety of particulate matter (PM).

Particulate matter (PM) is the generic term for a complex mixture of airborne solid and liquid particles including sulphates, nitrates, other salts, soot, metals and biological materials187, which have a wide distribution of size and mass. Particles greater than 2.5µm in diameter are derived from a number of sources including windblown dust and grinding operations, whereas particles smaller than 2.5µm in diameter (PM2.5) are generated primarily as a result of human activity, associated in particular with the combustion of fossil fuels, especially those associated with vehicular traffic.188 For research purposes, PM is usually categorised as being inhalable (PM10), fine (PM2.5) or ultrafine (PM0.1). Mechanisms of how components of air pollution lead to respiratory disease are unclear and dependent on the various agents and compounds in question. Inhalation is the most obvious route of entry of pollutants into the respiratory tract.

Several national environmental agencies in the US and Europe monitor PM2.5 concentrations at numerous sites throughout their jurisdictions, but even these relatively dense networks have limited geographic coverage. Few long-term measurement sites exist elsewhere in the world.189 A recent study utilising satellites to estimate PM2.5 levels, estimated the global level of PM2.5 to be approximately 27µm/m3 (mean of six year measurements). Australia compares well with these limits with a six year mean of 12µm/m3.189 There were no estimates provided for individual cities.

The Australian Bureau of Statistics190 reports that Australian cities do not suffer from the acute pollution problems found in many other developed countries. The majority of air pollutants are more common in urban and industrial areas than in rural Australia. 190, 191 However, this may be due to the fact that there is little long-term information about air quality over much of Australia. Summarised data from Sydney, Melbourne, Adelaide, Perth and Brisbane showed a declining trend in air pollution between 1994 and 1999.190 Notably ,fine particle pollution levels (PM2.5) between 1996 and 1999 were consistently below the levels in the years 1990 to 1995.190

Many of the risk factors addressed in this report can be classified as pollutants of the air including, for example, polycyclic aromatic hydrocarbons derived from combustion of cigarettes and other organic materials, and fibres of asbestos made airborne due to industrial processes. In this chapter of the review, the studies for inclusion have been selected on the basis of clear investigation of ‘air pollution’ per se, rather than any specific constituents or pollutants in the air that may have been investigated as potential risk factors for lung cancer in their own right. As such, this report has focussed on PM and gaseous constituents of air pollution resulting from urban air pollution and arising from vehicle exhaust due to proximity to heavy traffic roads. The contribution of other sources of pollution to air, in particular gaseous industrial emissions such as diesel, coal dust and combustion fumes, is beyond the scope of this section of the Systematic Review. Indoor air pollution resulting from combustion of coal was excluded from this report on the basis


that this method of heating is used infrequently in Australia and as such, is unlikely to represent a significant exposure hazard in Australia.

The initial search identified 42 citations potentially relevant to this risk factor. Of these, 11 were selected for further review. A systematic review was identified which contained 32 studies published between 1950 and 2007.188 Ten of the studies identified by the search were included in the systematic review. In addition to the systematic review, a further three cohort studies192-194 and a nested case control study195 published since 2007 were also included. Individual studies conducted in urban China and other Asian countries were not considered for inclusion in this review due to the stark differences with air pollution levels within Australia and the subsequent lack of applicability to the Australian context. PM2.5 concentrations were estimated to be 60–90 μg/m3 over eastern China, with values > 100 μg/m3 for its major industrial regions. The Indo-Gangetic Plain, from New Delhi eastward, was found to contain the highest PM2.5 concentrations in India, with values of 80–100 μg/m3.189

The included studies considered lung cancer risk of people residing in urban areas and were conducted in the US,188, 192, 193 the Netherlands195 and Denmark;194 no included studies were conducted in Australia. Data was collected for both males and females. All studies except Raaschou-Nielsen et al.194 used PM2.5 concentration as a measure of air pollution. All of the studies considered the effects of long-term air pollution in urban residential areas and focused on air pollution associated with non-industrial human activities, specifically vehicular traffic. The key characteristics of the studies relevant to the association between air pollution and the risk of lung cancer are presented in Table 15.1.


Table 15.1 Study characteristics relevant to the association between air pollution and lung cancer




Beelen et al. 2008The NetherlandsNested case controlNetherlands Cohort Study on Diet & Cancer (NLCS).

114,378 participantsAged 55-69yrs at enrolment, living throughout the NetherlandsFollow-up from September 1986 to December 1997Mean 11.3 yr follow up.

Demographic data (inc. smoking) collected via questionnaire.Exposure assessed using data from monitoring stations in routine air quality monitoring networks.Distance & proximity to heavy traffic roads also determined

Air pollution measured as sum of background & local elements.Exposure to black smoke, nitrogen dioxide (NO2), sulphur dioxide (SO2), & particulate matter ≥2.5 µm (PM2.5)Local traffic contributions also measured as motor vehicles per hour (MVH).Duration of exposure: 90% of participants 10yrs+

Type not stated.Lung cancer incidence confirmed by Cancer registry.

Multivariate analysisCox proportional hazard modelPotential confounding factors adjusted: age, gender, smoking status, indicators of socioeconomic status.Education, fruit consumption also considered.

adj. RR (95% CI) (95th vs 5th percentile of distribution for each category):NO2 (30µm/m3):0.86 (0.70-1.07)PM2.5(10µm/m3):0.81 (0.63-1.04)SO2 (20µm/m3):0.90 (0.72-1.11)Overall risk associated with air pollution by traffic intensity:Traffic intensity (10,000 MVH/24h):1.05 0.94-1.16Traffic intensity in a 100m buffer(335,000 MVH/24h):1.05 (0.92-1.19)Living near a major road: 1.11 (0.91-1.34)living near heavy traffic roads – by smoking status adj. RR (95% CI)Never smokers: 1.11 (0.88 - 1.41)Ex smokers: 0.98(0.77 - 1.25)Current smokers: 1.04 (0.91 - 1.19)living near heavy traffic roads with a 100m buffer – by smoking status. Adj. RR (95% CI)Never smokers : 1.55 (0.98 - 2.43)Ex smokers: 1.24 (0.85 - 1.81)Current smokers : 0.95 (0.73 - 1.23)

Chen et al. 2008Several countries

Adults older than 18 years of age, both genders.Both genders,

Systematic review of 32 studies. 9 cohort & 1 case-control studies

Exposure to environmental air pollution on annual basis.

Lung cancer incidence and mortality was coded by ICD 9:

Multivariate analysisDer Simonian Laird random effects model

Pooled RR (95%CI) or pooled RR associated with a 10µg/m3 increase (RR10), by pollutant, rel. lowest category in each case:





Systematic Review

mean age: 42 yrs (range 25-59yrs)Median follow up: 17 yrs

had controlled for smoking & were relevant to the association between long term exposure to ambient pollution & lung cancer.Medline, Embase & Risk abstract databases searched for papers published 1950-2007.

Gaseous pollutants (SO, CO, O3, NO, NOx)Particulate pollutants (PM10 & PM2.5).Definitions of what constitutes “near to” a “busy” or “major” road were not reported.

162.Types of lung cancer not specified.

used for meta-analysis.Adj. for: age, gender, occupation, indoor smoking, interviewer, employment in risk occupation, population density.

NOx: (2 studies)1.08 (1.02-1.15) (incidence)1.11 (1.03-1.19) (mortality)NO2: (mortality, 4 studies)Pooled RR10associated with a 10µg/m3 increase: 1.01 (0.94 - 1.09)(Incidence, 3 cohort studies)Pooled RR10 = 1.11 (0.99-1.24)SO2: (5 studies)Pooled RR10: 1.07 (0.96-1.19) (mortality)Pooled RR10: 1.12 (0.98-1.29) (Incidence)Both genders (4 studies):1.12 (0.97-1.30)Men only (1 study):1.00 (0.92-1.08)USA (2 studies): 1.58 (0.66-3.76)Europe (3 studies):1.00 (0.96-1.19)Particulate matter PM2.5:(Incidence, 4 studies)Pooled RR10: 1.15 (1.06-1.24)Both genders (4 studies):1.20 (1.08-1.33)Men only (1 study): 1.39 (0.79-2.46)USA (3 studies):1.15 (1.07-1.25)Europe (2 studies):1.23 (0.98-1.54)Living near a “major road” – highest category vs lowest:RR 1.31 (0.82-2.09) (incidence, 1 study)RR 1.44 (0.94-2.21) (mortality, 1 study)Living near a “busy road” highest category vs lowest:





RR 1.07 (0.93-1.23)

Pope et al. 2011USACohortACS-CPS II study

794,784 male (49%) & female (61%) participants aged 30yrs+ at enrolment. Mean age 56yrs (+/-10.5yrs)Cohort includes 3194 lung cancer deaths.6yr follow up

Exposure estimates PM2.5 ranged from 5-µg/m3/day. Exposure detection method not reported.Demographics (inc. smoking data) collected by self-reported questionnaires.

Estimated daily exposure to PM2.5 measured at residences in the study areas.Detection method not reported.

Types of lung cancer not reported.ICD-9 162 classification used.Cardiovascular disease also examined.

Multivariate analysis. Cox proportional hazards survival models used.Adj. for: smoking, gender, education, marital status, BMI, alcohol consumption, as well as various dietary factors and several occupational dust/fumes.

Overall risk with ambient exposure to 10µg/m3 PM2.5, Adj RR (95%CI):1.14 (1.04-1.23)Risk with ambient exposure to 10µg/m3 PM2.5 by smoking status Adj RR (95%CI), relative to never smokers.≤3 cigs/day:10.44 (7.30-14.94)8-12 cigs/day:11.63 (9.51-14.24)28-32 cigs/day:26.82 (22.54-31.91)≥43 cigs/day: 39.16 (31.13-49.26)

Raaschou-Nielsen et al. 2011DenmarkCohortDanish Diet Cancer & Health cohort

52,970 residents of Copenhagen & Aahus areas of Denmark. Men & women aged 50-64yrs at enrolment,20yr follow up

Demographics (inc. smoking data) collected by self-reported questionnaires.National records used to determine cause of death & loss to migration from the area.

Time weighted average levels of NOx and NO2 estimated for each residence based on actual & calculated measurements from the Danish AirGIS modelling system.Traffic load within 200m & whether a major road was within 50m also noted.

Types of lung cancer not stated

Multivariate analysis. Cox proportional hazards survival models used.Adj. smoking, ETS, education, fruit intake, employment, age.

Overall risk with NOx concentration (µg/m3)Adj. IRR (95%CI)<17.2: 1.0017.2-21.8: 1.09 (0.84-1.40)21.8-29.7: 0.93 (0.73-1.13)>29-7: 1.30 (0.79-1.51)Risk with NOx concentration (µg/m3), by smoking status. Relative to <17.2µg/m3 for each category. Adj. IRR (95%CI)Non-smokers:17.2-21.8 µg/m3:1.07 (0.59-1.94)21.8-29.7µg/m3:0.83 (0.46-1.51)>29-7 µg/m3: 1.91 (1.10-3.30)Current Smoker:17.2-21.8 µg/m3:1.09 (0.82-1.45)21.8-29.7µg/m3: 0.95 (0.73-1.23)>29-7 µg/m3: 1.21 (0.95-1.45)Males:





17.2-21.8 µg/m3: 1.14 (0.80-1.62)21.8-29.7µg/m3: 0.97 (0.70-1.34)>29-7 µg/m3: 1.16 (0.85-1.57)Females:17.2-21.8 µg/m3:0.95 (0.65-1.37)21.8-29.7µg/m3: 0.85 (0.60-1.20)>29-7 µg/m3: 1.45 (1.06-1.99)Overall risk associated with a major road within 50m or residence Adj. IRR (95%CI):No:1.00Yes:1.21 (0.95-1.55)Overall risk associated with traffic load within 200m (103 vehicle km/day) Adj. IRR (95%CI)<0.88:1.000.88-2.61:0.98(0.76-1.27)2.61-6.73:1.05 (0.83-1.34)>6.73:1.17 (0.92-1.47)

Turner et al. 2011USACohort study

188,699 lifelong never smokers.Data from the American Cancer Society Cancer Prevention Study II (CPS-II)26yr follow up.

Population-based cohort study Data collected via mailed questionnaire (inc. smoking status).

Chronic exposure to ambient fineparticulate matter (PM2.5) air pollution.Mean (1yr, measured 1999-2000) 17.6 µg/m3 (range; 14.3-21.1µg/m3).Data on exposure obtained from aerometric

Types of lung cancer not reported.

Cox proportional hazards regression modelAdj. for: smoking, age, race, education, marital status, BMI, passive smoking, veg/fruit/fibre & fat intake, as well as various occupational factors (asbestos: chemicals/acids/solvents, coal or stone dusts, coal tar/pitch/asphalt, formaldehyde, diesel engine exhaust), mean

Overall risk with chronic exposure PM2.5. Adj. HR (95%CI).1 yr exposure:1.27 (1.03 – 1.56)11 yr exposure: 1.25 (1.01-1.55)21yr exposure: 1.27 (1.02-1.56)Chronic exposure to ambient PM2.5 - by gender. HR( 95%CI)Male: 1.19 (0.83 - 1.73)Female: 1.30 (1.01 - 1.68)Chronic exposure to ambient PM2.5 & industrial exposure.





information retrieval system.

county-level residential radon concentrations, prevalent chronic lung disease (CLD) (asthma, chronic bronchitis, or emphysema) or hay fever at enrolment.

Exposed:1.17 (0.66-2.09)Non-exposed: 1.29 (1.03-1.61)Chronic exposure to ambient PM2.5 & passive smoking.None: 1.39 (1.03-1.87)Any: 1.17 (0.88-1.57)


15.2 ResultsThe synthesised data is reported by air pollution constituent.

15.2.1 Risk of lung cancer associated with exposure to fine particulate matter (PM2.5)

A systematic review and meta-analysis of the risk of lung cancer due to exposure to PM2.5 air pollution suggests risk is increased by 20% relative to persons not exposed to such levels of PM in the air (Table 15.2). Levels of PM2.5 that subjects were exposed to were similar across the included studies. All studies reported adjustment for individual smoking status. Risk estimates derived from studies conducted in the US suggest that exposures to mean PM2.5 concentrations of 10-17µg/m3 for 1-21 years represent an increased risk of lung cancer of between 15-27%188, 193; a similar risk estimate was reported from studies conducted in European countries, although this was not statistically significant due to the greater imprecision from a smaller sample size (Table 15.2). Investigating a cohort from the US, Turner and colleagues193 recently reported on the risk of lung cancer attributable to air pollution at 10-year intervals. Adjusted risk estimates were remarkably similar irrespective of the duration of exposure and were consistent with the results reported by the other included studies (Table 15.2).

Table 15.2 Risk of lung cancer associated with exposure to fine particulate matter (PM2.5)

Study Exposure Adjusted risk estimate, RR (95%CI)

Chen et al. 2008Systematic review, global

1yr, an increase of 10µg/m3

Overall (5 studies) 1.21 (1.10-1.32)USA (3, studies): 1.15 (1.07-1.25)Europe (2 studies): 1.23 (0.98-1.54)

Pope et al. 2011Cohort studyUSA

6yrs, 10µg/m3 1.14 (1.04-1.23)

Turner et al. 2011Cohort studyUSA

17µg/m3

1yr11yrs21yrs

1.27 (1.03-1.56)1.25 (1.01-1.55)1.27 (1.02-1.56)

Beelen et al. 2008The Netherlands, Nested case control

11.3yrs, 10µg/m3 0.81 (0.63-1.04)

Adjusted for smoking, age, gender, education, socioeconomic status.

15.2.2 Risk of lung cancer associated with exposure to fine particulate matter (PM2.5) and gender

Data presented by Chen et al.188 for both genders combined are indicative of an overall increased risk of lung cancer with an exposure increase of 10µg/m3 PM2.5 (based on four studies). The review by Chen et al.188 included a single study reporting an increase in the risk of lung cancer for males only; although the increase reported was not significant (Table 15.3).


Table 15.3 Risk of lung cancer associated with exposure to fine particulate matter (PM2.5) and gender, (Chen et al.)188

Exposure Pooled adj. RR (95%CI)


Both genders combined (4 studies):1.20 (1.08-1.33)Males only (1 study): 1.39 (0.79-2.46)

15.2.3 Risk of lung cancer associated with exposure to sulphur dioxide (SO2)

Two studies examined the association between SO2 exposure and lung cancer risk and indicate no significant increase in risk of lung cancer as a result of exposures that range from 10 – 20µg/m3 for one to 11 years (Table 15.4). This lack of association was consistent, examining incidence or mortality data and irrespective of geographical location (Table 15.4).

Table 15.4 Sulphur dioxide (SO2) exposure and risk of lung cancer




(5 studies)RR10: 1.07 (0.96-1.19) (mortality)RR10: 1.12 (0.98-1.29) (incidence)USA (2 studies): 1.58 (0.66-3.76)Europe (3 studies):1.00 (0.96-1.19)

Beelen et al. 2008The Netherlands Nested case control study

11.3yrs, 20µg/m3 RR 0.90 (0.72-1.11)

Adjusted for smoking, age, gender, education, socioeconomic status.

15.2.4 Risk of lung cancer associated with exposure to sulphur dioxide (SO2) and gender

As with PM2.5, Chen et al.188 reported risk estimates as a result of exposure to SO2 by gender (Table 15.5). The data suggests no increased risk of lung cancer for an increase of 10µg/m3 SO2 when data from both genders are combined (based on four studies), or when males are considered separately (one study).

Table 15.5 Risk of lung cancer associated with exposure to sulphur dioxide (SO2) and gender, (Chen et al. 2008)

Exposure Pooled adj. RR (95%CI)


Both genders combined (4 studies):1.12 (0.97-1.30)Males only (1 study): 1.00 (0.92-1.08)


15.2.5 Risk of lung cancer associated with exposure to nitrogen dioxide (NO2)

Neither an increase in mean NO2 concentration by 10µg/m3, nor concentrations of 30µg/m3, were associated with increased incidence188, 195 or mortality188 of lung cancer, irrespective of duration up to 11.3 years (Table 15.6).

Table 15.6 Risk of lung cancer associated with exposure to nitrogen dioxide (NO2)




Pooled risk estimates (RR)RR10: 1.01 (0.94 - 1.09) (mortality, 4 studies)RR10 = 1.11 (0.99-1.24) (incidence, 3 studies)

Beelen et al. 2008The Netherlands, Nested case control study

11.3yrs, 30µg/m3 0.86 (0.70-1.07)

15.2.6 Risk of lung cancer associated with exposure to nitrogen oxides (NOx)

Combining the data from two cohort studies, Chen et al.188 report small (8-11%) yet statistically significant increases in risk of lung cancer incidence and mortality associated with exposure to NOx (Table 15.7). In contrast, the study conducted by Raaschou-Nielsen et al.194 in a Danish cohort suggests that exposure to levels of NOx in ambient air (<17.2 to >29 - 710µg/m3) were not associated with increased incidence of lung cancer (Table 15.7).

Table 15.7 Risk of lung cancer associated with exposure to nitrogen oxides (NOx)

Study Exposure Adjusted risk estimate (95%CI)



Pooled risk estimates (2 studies)RR10 1.08 (1.02-1.15) (incidence)RR10 1.11 (1.03-1.19) (mortality)

Raaschou-Nielsen et al. 2011Cohort studyDenmark

20yr<17.2: 1.0021.8-29.7>29-7:

IRR 1.09 (0.84-1.40)IRR 0.93 (0.73-1.13)IRR 1.30 (0.79-1.51)

15.2.7 Risk of lung cancer associated with exposure to nitrogen oxides (NOx) and smoking status.

Raaschou-Nielsen et al.194 reported data on the association between NOx and lung cancer, stratified by smoking status. These authors found that neither current smokers nor non-smokers were at increased risk of lung cancer resulting from exposure to >17.2µg/m3 NOx (Table 15.8).194 There was also no difference in the risk estimated for males or females until exposures exceeded 29.7µg/m3 NOx, which represented a significant increase for women but not for men (Table 15.9).


Table 15.8 Risk of lung cancer associated with a 20yr exposure to nitrogen oxides (NOx) and smoking status, (Raaschou-Nielsen et al.)194

Study Exposure Adjusted IRR (95%CI)Non smokers

Adjusted IRR (95%CI)Current smokers

Raaschou-Nielsen et al. 2011DenmarkCohort study

<17.2: 1.0021.8-29.7>29-7:

1.07 (0.59-1.94)0.83 (0.46-1.51)1.91 (1.10-3.30)

1.09 (0.82-1.45)0.95 (0.73-1.23)1.21 (0.95-1.45)

Table 15.9 Risk of lung cancer associated with a 20 yr exposure to nitrogen oxides (NOx) and gender, (Raaschou-Nielsen et al.)194

Study Exposure Adjusted IRR (95%CI)Males

Adjusted IRR (95%CI)Females

Raaschou-Nielsen et al. 2011DenmarkCohort study

20yr<17.2: 1.0021.8-29.7>29-7:

1.14 (0.80-1.62)0.97 (0.70-1.34)1.16 (0.85-1.57)

0.95 (0.65-1.37)0.85 (0.60-1.20)1.45 (1.06-1.99)

15.2.8 Risk of lung cancer associated with exposure to vehicular traffic

Three included studies examined whether being exposed to increased levels of vehicular traffic represents a risk of lung cancer. None of the included studies reported significant increases in lung cancer risk, though point estimates of effect were elevated, particularly alongside ‘major’ roads (Table 15.10). Unfortunately some of the exposure categories, such as living near “busy” or “major” roads, were not clearly defined.188

Table 15.10 Risk of lung cancer associated with exposure to vehicular traffic

Study Exposure & Adjusted risk estimate, RR (95%CI)


(2 studies)Living near a “busy road” * highest category vs lowest:1.07 (0.93-1.23)Living near a “major road”* – highest category vs lowest:1.31 (0.82-2.09) (incidence, 1 study)1.44 (0.94-2.21) (mortality, 1 study)

Raaschou-Nielsen et al. 2011Denmark,Cohort study

Overall risk associated with a major road within 50m or residence Adj. IRR (95%CI):No:1.00Yes:1.21 (0.95-1.55)Overall risk associated with traffic load within 200m (103 vehicle km/day) Adj. IRR (95%CI)<0.88: 1.000.88-2.61: 0.98(0.76-1.27)2.61-6.73: 1.05 (0.83-1.34)>6.73: 1.17 (0.92-1.47)


Study Exposure & Adjusted risk estimate, RR (95%CI)

Beelen et al. 2008The Netherlands, Nested case control study

Overall risk of lung cancer associated air pollution by traffic intensity:Traffic intensity (10,000 MVH/24h): 1.05 0.94-1.16Traffic intensity in a 100m buffer(335,000 MVH/24h):1.05 (0.92-1.19)Living near a major road: 1.11 (0.91-1.34)

* Definition of near of what constituted busy or major roads not provided, neither was exposure duration. MVH = motor vehicles per hour.

15.2.9 Risk of lung cancer associated with exposure to vehicular traffic and smoking status

The nested case control by Beelen et al.195 was the only included study that examined the risk of lung cancer associated with exposure to air pollution due to high levels of vehicular traffic and smoking status. The study reported no increase in risk as a result of exposure amongst the groups with differing smoking status (Table 15.11).

Table 15.11 Risk of lung cancer associated with exposure to vehicular traffic and smoking status195

Study Exposure & Adjusted risk estimate (95%CI)

Beelen et al. 2008The NetherlandsNested case control study

Living near heavy traffic roads:Never smokers: 1.11 (0.88 - 1.41)Ex smokers: 0.98(0.77 - 1.25)Current smokers: 1.04 (0.91 - 1.19)Living near heavy traffic roads with a 100m buffer:Never smokers : 1.55 (0.98 - 2.43)Ex smokers: 1.24 (0.85 - 1.81)Current smokers : 0.95 (0.73 - 1.23)

15.3 SummaryResearch identified and synthesised in this review suggests that exposure to air pollution in the form of fine particulate manner significantly increases the risk of lung cancer by approximately 20-25% compared to persons who are not exposed to PM2.5. This evidence for an increased risk of lung cancer does not appear to extend to gaseous components of air pollution, including sulphur and nitrogen dioxide. However, there is mixed evidence as to whether other nitrogen oxides increase RR by some 10%.

The level of PM2.5 was similar across the included studies (10-17µg/m3) and comparable to the levels estimated for Australia (12µg/m3). Risk estimates derived from studies conducted in the US suggest that exposures to mean PM2.5 concentrations of 10-17µg/m3

for 1-21 years represent an increased risk of between 15-27%; whereas non-significant increases in risk were reported from studies conducted in European countries. No studies reported on potential interactions with smoking. Only one study reported risk by gender and suggested no increased risk for a cohort of men. Turner et al.193 investigated the risk of lung cancer attributable to air pollution at 10-year intervals and found that risk estimates were remarkably similar irrespective of the duration of exposure.

No association was reported for ambient exposure to either SO2 (10 – 20µg/m3) or NO2 (10µg/m3) for exposures ranging up to 11 years. This finding was consistent between studies examining incidence or mortality data and irrespective of geographical location.


As with PM2.5, Chen et al.188 reported no increased lung cancer risk for an increase of 10µg/m3 SO2 when data from both genders are combined (based on four studies), or when males are considered In contrast to a study on a Danish cohort194, these authors reported a small (8-11%) yet statistically significant increase in risk of lung cancer incidence and mortality associated with exposure to NOx.

Three included studies examined whether living near busy or major roads represents a risk of lung cancer. None of the included studies reported an increase in lung cancer risk; however, some of the exposure categorises, such as living near “busy” or “major” roads, were not clearly defined. Living within 50m of a major road or within 200m of a road with a traffic load of >6.73x103 vehicle km/day or a traffic intensity of 10,000 MVH/24h, were not associated with a significant increase in lung cancer risk.


According to Cancer Research UK,196 outdoor air pollution with exposures particularly to traffic fumes has been shown to increase the risk of lung cancer. Traffic fumes are considered to be the main source of outdoor air pollution. No current IARC classification for air pollution is available as the relevant publication is in preparation.

According to IARC,39 indoor air pollution from household combustion of coal for heating and cooking is classified as a Group 1 carcinogen for lung cancer mainly in China and in some other developing countries. However, indoor emissions from household solid fuel use constitute complex mixtures that contain thousands of chemicals at varying concentrations, and this variation must be considered when interpreting lung cancer risk from indoor air pollution.39


Air pollution in the form of fine particulate matter (PM2.5) increases the risk of lung cancer by some 20% relative to those people not exposed to such pollution. Gaseous air pollution such as sulphur dioxide and nitrogen dioxide does not appear to increase the risk of lung cancer. The levels of pollutants investigated in the studies located and reported on here are comparable to those likely to be encountered in the urban environment in Australia. Any risk as a result of air pollution is likely to be greater for those living in urban rather than rural areas.


15.5 Methodological quality of studiesTable 15.12 Air pollution: Methodological quality of included studies

Study Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Total (yes)

Include/exclude

Beelen et al. 2008 Nested case control

y y y y y n/a u y y n/a 7 Include

Chen et al. 2008 Systematic review

y y y y u y y y y y 9 Include

Pope et al. 2011 Cohort y y u u y y y y y n/a 7 Include

Raaschou-Nielsen et al. 2011

Cohort y u y y y y y y y n/a 8 Include

Turner et al. 2011 Cohort y u n/a y y y y u y n/a 7 Include


Beelen et al. 2008

Overall the study addressed its aims well. Cases were representative of target population. They all were never smokers. The methods and objectives were generally well stated. Exposure investigated was air pollution indicated by nitrogen dioxide (NO2), sulphur dioxide (SO2), and particulate matter PM2.5 and traffic intensity variables. Duration of exposure well stated (residents lived in the area for at least 10 years). However cut-off points for high exposure was not clearly reported. Follow up for 11.3 years. Confounding factors considered appropriately. Statistical methods were well described.

Chen et al. 2008

The objective of this systematic review was clearly stated. The search strategy was reported, and two major databases (Medline and Embase) from 1 January 1950 to 23 December 2007 were searched. There was no language restriction. Inclusion and exclusion criteria were described adequately; however, details were not reported on quality appraisal of studies. It is unclear whether the appraisal was conducted by two independent reviewers. The methods used to minimise errors in data extraction were not provided. Data analysis was adequately described with appropriate methods to combine studies and methods to investigate heterogeneity when detected. Recommendations were supported by the data presented and the authors provided specific directives for future research.

Pope et al. 2011

This paper examined the association between air pollution and cardiovascular disease (including lung cancer). The study was part of the American Cancer Society CPS II study. The sample was comprised of 75,000 American men and women and was representative of the population. Outcomes were assessed using objective criteria and statistical analysis was appropriate. It was unclear (apart from smoking), which confounders were considered and they were dealt with.

Raaschou-Nielsen et al. 2011

The research aims of this study were clear and the study sample representative of the population (Danish men and women). Outcomes were assessed objectively and potential confounders were identified and adjusted for in the statistical model.

Turner et al. 2011

Subjects were representative of target population; however they all are non-smokers. Exposure and methods of data collection well described. The methods and objectives were generally well stated in this study. Duration of exposure and follow up established over 26 years. Cut-off point for high exposure was determined at PM2.5 10ug/M3. Statistical methods were well described. Results were presented by gender difference. Confounding factors considered appropriately.


16 Risk factor: Chromium exposure16.1 IntroductionChromium (Cr) is a naturally occurring element found in the trivalent (Cr III) and hexavalent (Cr VI) states.197 Chromium III is the most environmentally stable valence state of chromium and is an essential micronutrient, with a recommended daily requirement ranging from 50 to 200 μg/day.197 CrIII displays extremely low or no toxicity via all routes of human exposure and does not pose a carcinogenic hazard.197 In contrast, the most highly oxidised form of Chromium, Cr VI, is considered to be a group 1 carcinogen in humans.198

Chromium (Cr VI) is produced primarily in industry and by human activities (e.g. combustion products). Cr VI is used to make bricks and linings for furnaces and is used in galvanising, printing, paints, degreasers and rust converters in.199 Chromium compounds are used for chrome plating (chromic acid), manufacture of dyes (soluble chromates such as: ammonium dichromate, potassium chromate, sodium chromate), wood treatment (chromium trioxide) and water treatment. Occupational exposure to Cr VI occurs in a variety of industries, including: the production, use and welding of chromium containing alloys and metals (e.g. stainless steels, high chromium steels); production and use of chromium containing pigments or paints (e.g. application in the aerospace industry and removal in the construction and maritime industries); electroplating; catalysts; chromic acid and pesticides.198

Chromium has been identified as a risk to Australian workers200; however, it is unclear how many Australians have been occupationally exposed to chromium as there are no comprehensive figures available of the number of workers involved in industries where exposure is likely. Problems with determining exposure and assessing carcinogenicity of Cr VI are also compounded by the fact that in industries where chromium exposure is likely, so is exposure to other known carcinogens.200, 201 In addition to occupational exposure to chromium, Cr VI is a constituent of tobacco smoke (0.004–0.069ug/cigarette)202, 203 and the potential confounding effect of exposure via cigarette smoke is unknown.

Residential exposure to Cr VI is unlikely to occur due to the conditions required to produce hexavalent chromium; although contamination of soil and groundwater has been reported by ecological studies204-206 in areas where Cr VI is manufactured and utilised, and could potentially represent a risk to the local population.

The absorption, retention and elimination of Cr compounds in the body depend on the solubility and particle size of the compound inhaled (or ingested). Inhaled Cr VI is readily absorbed from the respiratory tract and may be retained within the body for several hours to weeks. Absorbed Cr VI is distributed in nearly all tissues, with the highest concentrations found in the kidney, liver and bones.198 As a result of Cr VI oxidising potential and ability to be absorbed by biological tissues, exposure to relatively high airborne concentrations of Cr VI has been shown to cause respiratory and dermal irritation and ulceration, and ingestion of very high doses by both humans and laboratory animals results in gastritis, nephrotoxicity and hepatotoxicity (IARC, 1990).197 Once inside the cells of the body, Cr VI is reduced stepwise to the more stable Cr III, a process which gives rise to bio-reactive intermediaries. This process can lead to DNA damage - particularly to processes involving replication and transcription, leading to mutation, genomic instability, aneuploidy and cell transformation.


The search identified an IARC monograph published in 1990,197 revised and updated in 2012.198 The 2012 IARC monograph considered 37 cohort studies published until 2006 that examined occupational exposure to chromium and its compounds. There was however, a significant overlap of studies with the research synthesis of Cole et al.;207 therefore, data extracted from the 2012 monograph has been limited to those studies not included in this recent review. In addition to the 2012 IARC monograph and the review by Cole et al.,207 a further research synthesis, two cohort studies and one case-control study were included following critical appraisal.

The majority of studies investigated occupational exposure to Cr VI and estimated risk of lung cancer based on data from male workers, withexposure assessments derived from interviews and/or standardised job descriptions. The occupations where the participants were occupationally exposed to Cr VI included: sheet metal workers, printers, painters and those involved in chromate production. Studies were conducted in Canada, the US, Japan and several European countries; none were conducted in Australia. Only one study distinguished between different forms of Cr VI,92 which reported risk separately for Cr VI in dust and fume/mist form. None of the included studies reported lung cancer risk by gender and one study presented risk by smoking status. The important characteristics of included studies are detailed in Table 16.1.


Table 16.1 Study characteristics relevant to the association between chromium (VI) exposure and lung cancer




Beveridge et al. 2010CanadaPooled analysis

1598 cases & 1965 controls, males residing in Montreal.15 categories of occupations including; sheet metal workers, mechanics, printers, construction & painters.Cases matched on age & residential area. One study had 2 sets of controls: gen popln & other non-lung cancer.Non-smokers defined as having smoked <100 cigarettes in lifetime or quit >20yrs.

Pooled data from 2 population based case control studies.Interviews & questionnaire.Lifetime occupational exposure to chromium VI from 0 - >20 yrs as determined from interviews.

Lifetime occupational exposure according to detailed job history determined by an expert group blind to subjects’ disease status.Unexposed (<5yrs occ exp to Cr)Substantial (med-high lvls of Cr for >5% of work week, > 5yrs)No definition provide for non-substantial exp.Basis for categories not reported

Lung cancer type not stated, however diagnosis histologically confirmed.

Unconditional logistic regression.Adj for age, yrs education, occupation, smoking and study

Adj OR (95%CI), rel to unexposed in all categories.OverallAny exposure: 1.1 (0.9-1.5)Non-substantial:1.1 (0.8–1.5)Substantial1.1 (0.5–2.0)By duration(any exposure)<5yrs: 1.3 (0.7–2.2)5-20yrs: 1.1 (0.7–1.7)>20yrs: 1.1 (0.7–1.6)By smoking status (any exposure)Non-smokers: 2.4 (1.2–4.8)Smokers: 1.0 (0.7 – 1.3)

Birk et al. 2006GermanyCohort study

Exposure >1yr-30yrMale workers at one of two chromate production plants

Levels of urinary Cr (µg/L yr) were used a biomarker to estimate exposure.

Lifetime occupational exposure to Cr VI, reconstructed from medical records & job descriptions.


Logistic regression analysisSMR calculated relative to general German popn.high levels of exposure,relative to low & intermediateexposure, adjusting for the potential

SMR (95%CI) compared with German popln.Urinary Cr (g/L-yr).Overall: 1.48 (0.93–2.25)Duration of exposure1-4 yrs: 0.78 (0.16-2.29)5-9 yrs: 1.45 (0.53-3.16)10-19yrs: 1.19 (0.57-2.19)20+yrs: 1.79 (0.37-5.23)Urinary Cr - no lag0–39.9: 0.36 (0.01-2.00)





effects of age & smoking status(ever versus never).Lagged analysis of cumulative exposure (by 10 & 20yrs).

40–99.9: 0.95 (0.26–2.44)100–199.9: 0.94 (0.31–2.20)>200: 2.09 (1.08–3.65)Urinary Cr - 10yr lag0–39.9: 0.93 (0.34–2.01)40–99.9: 0.78 (0.16–2.28)100–199.9: 1.31 (0.43–3.07)>200: 2.05 (0.88–4.04)Urinary Cr - 20yr lag0–39.9: 1.10 (0.60–1.84)40–99.9: 1.01 (0.12–3.65)100–199.9: 1.10 (0.13–3.96)>200: 2.74 (0.75–7.03)

Boice et al. 1999USACohort study

77965 Aircraft manufacturing factory workers (inc. electroplaters, painters & process equipment operators), employed f>1yr as of Jan 1960.87% male, 13% female88% Caucasian8.4% routine exp & 8.0% intermittent exp.

Risk estimates based on standardised job descriptions and interviews.

Lifetime occupational exposure to Cr VI, reconstructed from company & medical records based on standardised job description.Mean exp. 24.2yrs, range 1-40yrs.Routine exposure. part of normal working day intermittent exp. was non-routine.

Cancer of the bronchus, trachea & lung (ICD 162)

SMR calculated relative to general population; of California for Whites and whole USA for Non-whites (due to small number of Non-whites). Adj. for date of birth, start and finish date of employment, gender and race.

SMR (95%CI) compared with general USA popln.Overall: 1.02 (0.82-1.26)By duration(any level of exposure, gender & race combined)<10yrs: 1.23 (1.11–1.36)10-19yrs: 1.08 (0.96–1.22)20-29yrs: (0.80-1.01)>30yrs: 0.70 (0.61–0.80)

Cole et al. 2005Setting not reportedSystematic review with meta-

Not reported. Included 49 studies, however only 26 adj. for smoking.

Medline & other (not detailed) databases searched for English language studies

Data extracted from 49 studies (84 papers) published. between 1950-2003.Overall risk resulting


Most studies were retrospective follow-up and used the standardised

Risk resulting from occupational exposure to Cr (All 47 included studies)Overall SMR (95%CI)





analyses published between 1950 – Jan 2005.Independent critical appraisal (2 reviewers), detailed inclusion criteria.

from occupational exposure to Cr VI – no details on length or intensity of Cr VI exposure or occupations.

mortality ratio (SMR). An overall SMR was calculated in the meta-analysis.Smoking was adjusted for, no details on other confounders.

1.41 (1.35 – 1.47)Adj. smoking (26 studies)SMR 1.18 (1.12 – 1.25)Smoking not adj.(21 studies)SMR 1.81 (1.71 – 1.92)

Hara et al. 2010JapanCohort study

1190 Males employed >6mo in a plating factory in Tokyo. Aged >35yrs in 1976.626 >6mo chromium exp, 564 were unexposed to chromium but were exp to other metals

Self reported questionnaires & company health records

Occupational exposure to Cr VI through working in Cr plating industry.Exposure duration 1 - >21yrs

Lung cancer type ICD C33-C34

SMR compared with national death rates. Adj for smoking and drinking for national statistics.

Overall SMR (95%CI)Cr exposed platers1.46 (0.98 – 2.04)Non-Cr exposed platers1.09 (0.67 – 1.60)Risk by exp. duration1-10yrs 1.50 (0.85–2.34)11-20yrs 1.50 (0.61–2.79)>21yrs 1.32 (0.49–2.56)

IARC monograph 2012GlobalResearch synthesis

No sample demographics detailed. Included: manufacturing (of textile dyes, paints, inks & plastics), metal finishing & chrome plating and welders.Tabular data presented for 37 cohort studies, (duration & exposure data incomplete for most). Significant overlap of studies with Cole et al 2005 SR.

Monograph derived from expert panel discussion. Search terms & inclusion criteria not detailed.Research syntheses, cohort and case control studies lifetime occupational exposure (duration not specified) were included.

Not detailed, however most studies focused on lifetime occupational exposure, as determined by questionnaire.Exposure duration estimates provided for only 3 studies & intensity levels for 6 studies.


Details mainly narrative, no statistical synthesis.

Overall SMR for 10 studies not included in Cole et al 2005 SR. None of the studies were conducted in Australia and only 2 studies provide some measure of exposure.3/10 studies report Cr VI represents an increased risk, however details are limited and CI’s wide, making the results difficult to interpret.





Luippold et al. 2005Cohort studyUSA

Total of 617 workers at one of two US chromate production plants.84% male, 16% female.74% Caucasian44% ever smokers, 44% never smokers, 12% unknown.Exp. determined for workers employed 1972-1998

Interviews, company records & medical records.

Occupation >1yr, mean 12.4yrs (plant 1) & 7.8yrs (plant 2). Risk estimates based on standardised job descriptions.Cr VI levels across both plants, mean annual Cr VI conc. <1.5µg/m3 range 0.36-4.36µg/m3

Cancer of the bronchus, trachea and lung (ICD 162)

SMR calculated relative to general USA population.Confounders considered: age, residential area, gender and smoking.

SMR (95%CI) compared with general USA popln.(any level of exposure or plant, gender & race combined)0.84 (0.17-2.44)

’t Mannetje et al. 2011Multicentre case–control study(17 centres, 7 countries (Romania, Hungary,Poland, Russia, Slovakia, Czech Republic, and UK).

2,852 cases & 3,104 controls. Both males & females.Cases (age <75yrs), controls frequency matched based on sex & age (±3 years).

A job-specific matrix was constructed using interview, questionnaire & an expert panel.

Occupations held for at least 1yrIndustries included:steel industry,coke manufacture, foundry, glass industry, mechanic, wood worker, painter, welder, chemical industry, tannery, toolmaker& machine tool operator, miner or quarryman,insulation worker, printing, meat workers, farmer, rubber industry, & asbestos compound production.


Unconditional logistic regressionModels adj. for age, centre, sex, tobacco consumption.Occupational exp. to asbestos, silica, wood dust, welding fumes, chromium, nickel, cadmium, & arsenic were also considered as confounders.

Adj OR (95%CI), relative to unexposed (all categories).Overall OR (95%CI):1.20 (0.93-1.55)Chromium dust (d):Overall: 1.25 (0.95-1.65)1-5yrs: 1.16 (0.75-1.79)5-17yrs: 1.04 (0.65-1.65)17+yrs: 1.53 (1.00-2.34)Chromium fumes/mist (f):Overall: 1.02 (0.75-1.39)1-9yrs: 1.10 (0.71-1.72)9-25yrs: 0.97 (0.62-1.53)25yrs+: 0.93 (0.58-1.49)Cumulative exposure mg/m3-hCr VI dust0.001-25: 1.19 (0.74-1.91)





25-175: 1.24 (0.80-1.92)175+: 1.32 (0.85-2.05) )P for trend: 0.1148Cumulative exposure mg/m3-hCr VI fumes/mist0.001-38: 0.97 (0.59-1.59)38-280: 0.80 (0.48 1.33)280+:1.31 (0.80-2.15)P for trend: 0.6356


16.2 Results16.2.1 Occupational exposure to chromium and risk of lung cancer

Cole et al.207 report an increased risk of lung cancer attributable to occupational exposure to Cr from synthesised data derived from 26 studies (49 papers) (Table 16.2). The overall risk estimate suggests an 18% increase in risk of lung cancer, relative to the unexposed local population (SMR 1.18, 1.12-1.25). No demographic details are reported, neither are details regarding study designs, exposure duration or intensity, limiting interpretation of the results. No details are reported of risk by gender or by smoking status.

Beveridge et al.148 pooled data from two case-control studies addressing occupational exposure to Cr VI in Canada. Though the effect estimates reported are not markedly different to those reported by Cole et al.,207 occupational exposure to Cr VI did not result in a statistically significant increase in lung cancer risk in this population (Table 16.2).

Table 16.2 Risk estimates of lung cancer due to occupational Cr VI exposure, research syntheses

Study Type and duration of exposure

Exposure Intensity/assessment

Pooled risk estimate (95%CI)(rel. to unexposed)

Cole et al. 2005Systematic review 26 studies, Global

Not reported Nor reported SMR 1.18 (1.12-1.25)

Beveridge et al. 2010Pooled analysis2 studies, Canada

Cr VI 1->20yrs Categories1 based on interviews

Any level: OR 1.1 (0.9-1.5)Non-substantial: OR1.1 (0.8–1.5)Substantial: OR 1.1 (0.5–2.0)

1 categorisation process not defined

A further 12 individual cohort studies and a multi centre case-control study provided varied results as to the overall risk of lung cancer due to occupational exposure to Cr VI (Table 16.3). The risk of lung cancer resulting from occupational exposure to Cr VI was statistically significant in three out of 13 studies (Table 16.3); however, the large confidence intervals, lack of exposure details and lack of population details make the results difficult to interpret. Demographic and occupational details of the cohorts were poorly reported, preventing combination of studies in meta-analysis in this review. Studies used interviews, questionnaires and job-specific records to estimate Cr VI exposure. The exception was Birk et al. (2006)98 who assessed chromium concentration in the urine of German electroplaters to establish exposure levels. An early study by Brinton et al.208 reported a 29-fold increase in lung cancer risk (SMR) in US male chromate plant workers (Table 16.3). This study was conducted prior to the industrial reforms in the US209

and therefore, exposure levels are most likely to be significantly higher than in subsequent studies.

The risk estimates presented by the remaining included studies suggest that there is no significant increase in risk of lung cancer resulting from occupational exposure to Cr VI. Despite the differences and limitations mentioned above, across these remaining studies, the consistently elevated upper confidence limit and trivial lower limit would suggest that the true risk estimate attributable to occupational exposure to Cr VI may very well support those studies that indicate a significant risk (Table 16.3). This trend was consistent even considering the different types of exposure investigated in the large


multi-centre case-control study conducted by t’Mannetje et al.92 (Table 16.3). Further detailed investigation will be required to confirm what is suggested by the available data here.

Table 16.3 Risk estimates of lung cancer due to occupational Cr VI exposure, cohort studies - IARC monograph (2012f) and Hara et al. (2010)


Exposure Intensity/assessment

Risk SMR (95%CI)(rel. local rates)

Bertazzi et al. 1981 Italy chromate paint & pigments, duration not reported

not reported, documented co-exp to asbestos

2.27(0.98-4.47)

Birk et al. 2006 Germany Chromate production, >1yr-30yrs

Derived from Cr levels in urine 0->200g/L-yr

1.48 (0.93-2.25)

Boice et al. 1999 USA aircraft manufacture,>1year

not reported 1.02 (0.82-1.26

Brinton et al. 1952 USA chromate production , duration not reported

not reported 28.9(18.87-42.35)

Halasova et al. 2005 Slovakia ferrochromium plant, duration not reported

not reported 4.04(3.08-5.21)

Hansen et al. 1996 Denmark welders, stainless steel grinders, & other metal workers, duration not reported

Mailed questionnaire 1.19(0.75-1.79)

Itoh et al. 1996 Japan chrome plater, duration not reported

not reported 1.81(0.99-3.04)

Lauritsen & Hansen1996

Denmark Not reported Mailed questionnaire 1.5 (0.8-2.6)

Luippold et al. 2005 USA Chromate production, duration not reported

not reported 0.84 (0.17-2.44)

Milatou-Smith,et al. 1997

Sweden stainless steel welders, >5years

Air measurement of Cr VI

1.64 (0.60-3.58)

Roberti et al. 2006 Italy Electroplaters, duration not reported

not reported, 3.13 (1.23-6.44)

Other studies (not included in the 2012 IARC monograph)Author Country Type and duration of

exposureExposure Intensity/assessment

Risk SMR (95%CI)(rel. local rates)

Hara et al. 2010Cohort study

Japan Electroplating, >1yr-21yrs

not reported 1.46 (0.98-2.04)

‘t Mannetje et al 2011,Multicentre case-control study

17 centres, 7 countries

Cr VI dust or fumes, <1yr->17yrs

20 occupations based on standardised job descriptions

Dust: 1.25 (0.95-1.65)Fumes/mist: 1.02 (0.75-1.39)Combined: 1.20 (0.93-1.55)

1risk estimates based on males and females


16.2.2 Duration of chromium exposure and risk of lung cancer

The duration of occupational exposure to Cr VI was addressed in five included studies, as detailed in Table 16.4. A statistically significant increased risk of lung cancer was reported in two studies.92, 210 Boice and colleagues210 report a 23% increase in lung cancer risk in US aircraft manufacturing workers, following occupational exposure to Cr VI for up to 10 years. The multicentre case-control study indicated a 53% increase in risk, resulting from more than 17 years of exposure to Cr VI dust, relative to unexposed workers.92

Table 16.4 Lung cancer risk resulting from occupational Cr VI exposure - by duration

Study Risk estimate

<5yrs 5-10yrs 10-20yrs 20yrs+

Beveridge et al 2010, Pooled analysis

OR 1.3 (0.7–2.2) 1.1 (0.7–1.7) 1.1 (0.7–1.7) 1.1 (0.7–1.6)

Boice et al 1999Cohort study

SMR 1.23 (1.11-1.36) 1.23 (1.11-1.36) 1.08 (0.96-1.22) 0.90 (0.80-1.01)1

0.70 (0.61-0.80)2

Birk et al 2006aCohort study

SMR 0.78 (0.16-2.29) 1.45 (0.53-3.16) 1.19 (0.57-2.19) 1.79 (0.37-5.23)

Hara et al 2010Cohort study

SMR 1.50 (0.85–2.34)3

1.50 (0.85–2.34)3

1.50 (0.61–2.79) 1.32 (0.49–2.56)

‘t Mannetje et al 2011,Case controlCr VI Dust

OR 1.16 (0.75-1.79) 1.04 (0.65-1.65)3

1.04 (0.65-1.65)3 1.53 (1.00-2.34)4

‘t Mannetje et al 2011,Case controlCr VI Fumes

OR 1.10 (0.71-1.72)5

1.10 (0.71-1.72)5

0.97 (0.62-1.53)6

0.93 (0.58-1.49)7

0.97 (0.62-1.53)6

0.93 (0.58-1.49)7

120-29yrs, 2>30yrs, 35-17yrs, 417+yrs,5 1-9yrs, 6 9-25yrs, 7 25yrs+

‘t Mannetje and co-workers92 analysed their data further based on actual hours worked and cumulative exposure to Cr VI and reported that even at weighted duration exposures of more than 2950 hours or at cumulative exposures of mor than 175mg/m3-hour, no statistically significant increase in risk of lung cancer was reported for either Cr VI dust or fumes (Table 16.5).

Table 16.5 Risk of lung cancer resulting from occupational Cr VI exposure by weighted duration or cumulative exposure, (‘t Mannetje et al 2011)

Exposure measure1 Cr VI dust Cr VI fumes

Weighted duration (hrs)2950+ work hours

1.40 (0.92-2.13)P for trend-0.0553

1.19 (0.75-1.87 )P for trend-0.6495

Cumulative exposure mg/m3-h175+

1.32 (0.85-2.05)P for trend- 0.1148

1.31 (0.80-2.15)P for trend-0.6356

1 the maximum categories are presented, relative to unexposed


Birk et al.211 used physiological measures to quantify occupational exposure to Cr VI. Risk was analysed with and without a time lag between exposure and mortality due to lung cancer (Table 16.6). The results of this study suggest that exposures to Cr VI that result in urinary concentrations of chromium of <200g/L-yr were not associated with an increased risk of lung cancer, even with a lag of 20 years since exposure. Occupational exposures to Cr VI which resulted in >200g/L-yr chromium led to a two-fold increase in risk in this population. This effect remained, though not statistically significant, irrespective of the time passed since exposure (Table 16.6).

Table 16.6 Risk of lung cancer resulting from occupational Cr VI exposure, 211

Cr in urine (g/L-yr) no lag 10yrs lag 20 yrs lag

0–39.9 0.36 (0.01-2.00) 0.93 (0.34–2.01) 1.10 (0.60–1.84)

40–99.9 0.95 (0.26–2.44) 0.78 (0.16–2.28) 1.01 (0.12–3.65)

100–199.9 0.94 (0.31–2.20) 1.31 (0.43–3.07) 1.10 (0.13–3.96)

>200 2.09 (1.08–3.65) 2.05 (0.88–4.04) 2.74 (0.75–7.03)

16.2.3 Chromium exposure, smoking status and risk of lung cancer

All studies reported that smoking data were collected and utilised in risk estimate calculation; however, only Beveridge et al.148 reported a risk of occupational exposure to Cr VI stratified by smoking status (Table 16.7). This pooled analysis suggests that occupational exposure to Cr VI is significantly more hazardous to non-smokers than smokers. These results should be treated with caution however, as the proportion of non-smokers was considerably smaller in the cases group (42.2%) than in the control group (72.2%), which may potentially confound the results.

Table 16.7 Overall risk of lung cancer resulting from occupational Cr VI exposure and smoking,148

Exposure Risk OR (95%CI) - Non-smokers Risk OR (95%CI) - Smokers

Any level 2.4 (1.2–4.8) 1.0 (0.7 – 1.3)1 Non-smokers defined as having smoked <100 cigarettes in lifetime or quit >20yrs.

16.3 SummaryThe evidence located and presented here informing the association between occupational exposure to Cr VI and increased risk of lung cancer suggests that Cr VI is a modest risk factor for the disease. The systematic review and meta-analysis of 26 studies reported a statistically significant increase of 18% relative to unexposed workers; however, no details regarding exposure type, intensity or duration were reported.207 Similarly, a pooled analysis reported that occupational exposures for more than 20 years increased risk of lung cancer by some 10% relative to the unexposed population; however, this risk was not significant, except for non-smokers who were at approximately two-fold increased risk.

The majority of individual studies included reported no overall significantly increased risk of lung cancer as a result of occupational exposure to Cr VI. However, almost all studies were characterised by imprecise yet large confidence limits about high risk estimates, making it difficult to draw firm conclusions in the absence of further detailed research.


Cohort studies conducted in Slovakia, Italy and the US198 reported significantly increased risks. The US cohort study was conducted using data from chromate production workers exposed to Cr VI prior to 1951, when working conditions were less tightly regulated, probably resulting in exposure to working levels of Cr VI substantially higher than more recent studies. Aircraft manufacturing workers occupationally exposed to Cr VI for 10 years at a US plant, were found to have a 25% increase in lung cancer risk, relative to unexposed co-workers. There was also evidence from a multi-centred case-control study92

to suggest that occupational exposures to Cr VI dust for more than 17 years may represent a significant lung cancer risk. This estimate is based on data for both male and female workers, whereas the remainder of the risk estimates were based on males only. The only study211 to utilise physiological methods to estimate the level of occupational risk reported that exposures which resulted in urinary chromium levels of >200g/L-yr had a two-fold greater risk of lung cancer than the general German population.

A limitation of the majority of included studies is the way in which exposure data was estimated from questionnaires instead of recorded measures of Cr VI. The actual impact of Cr VI as a risk factor for lung cancer is further complicated by the observation that for the most part, workers are occupationally exposed to other potential carcinogens concurrently.


Chromium VI has been identified as a Group 1 carcinogen, with occupational exposure probably being linked to lung cancer.198 IARC also identifies that chromium exposure may represent a risk for cancer of the nose and nasal sinus.


This report indicates that occupational exposure to Cr VI is a modest risk factor for lung cancer with an increased risk of approximately 15-20% relative to workers or the general population who have not been exposed. Greater risk is evident for workers exposed to Cr VI dust for more than 20 years, or male workers exposed to Cr VI resulting in urinary concentrations of >200g/L-yr. The risk that hexavalent chromium (Cr VI) presents to the Australian context is unclear due to the unknown number of Australians potentially exposed to this metal whilst at work, and the potential risk of exposure to additional carcinogens in these occupations. There is some evidence to suggest that Cr VI exposure increases the risk of lung cancer for those employed in chromate production, electroplating and aircraft manufacture.


16.5 Methodological quality of studiesIndividual critical appraisal checklist items for chromium are shown below in Table 16.8.

Table 16.8 Chromium exposure: Methodological quality of included studies


Include/Exclude

Beveridge et al 2010

Synthesis of 2 case controls

Y Y Y Y Y U U Y Y n/a 7 Include

Birk et al 2006 Retrospective Cohort

Y Y Y U Y Y Y Y Y n/a 8 Include

Cole et al 2005 Systematic review & meta analysis

Y Y U Y Y Y Y Y U Y 8 Include

Hara et al 2010 Prospective cohort U Y U Y Y Y Y Y Y n/a 7 Include

‘t Mannetje et al 2011

Case control Y Y U Y Y Y U Y Y n/a 7 Include



Limitations of this study included the way in which occupational exposure was determined – data collected through interviews and questionnaires, which may have led to over/under estimation of actual exposure. The type of chromium compound and its form (dust or fumes) were also unable to be determined. Strengths of this work include the relatively large number of lung cancer cases, the collection of detailed lifetime job histories, the labour-intensive expert assessment of exposure, and the collection of data on smoking and other potential confounders, including other occupational agents.

Birk et al. 2006

This paper utilised medical and company records to estimate occupational exposure for each worker included in the study. This was the only study to use physiological measures of Cr VI exposure in the form of urinary chromium concentrations. Concentrations are however reported as being chromium concentrations instead of Cr VI concentrations, suggesting that the laboratory method is unable to solely identify Cr VI. Consideration of other potential industrial/occupational carcinogenic confounders was not discussed.

Cole et al. 2005

This systematic review considered 114 studies and contained a meta-analysis using data from 49 of those studies. A limitation of this review was the lack of demographic data or exposure information on which the risk estimates are based on. This limits the applicability of the findings. The majority of the studies included in the IARC 2012f monograph (25/39) were also included in this review.

Hara et al. 2010

Smoking histories were not obtained when the cohort was established; however smoking status was recorded on subsequent health questionnaires and factored into calculations. The cohort was established in 1976, four years after legislation to reduce occupational exposure to hazardous chemicals (including Chromium). Workers would have been exposed to higher levels prior to this date but estimated levels from 1973 onwards were 0.025mg/m3.

‘t Mannetje et al. 2011

This multi-centred case control study was the only included study to state that it used data from female workers to calculate occupational exposure to CR VI risk of lung cancer. This was also the only included study to distinguish between the forms of Cr VI when calculating risk estimates and also to include occupational exposure to other metals in its regression.


17 Risk factor: Beryllium exposure17.1 IntroductionBeryllium (Be) is a naturally occurring metallic element which mostly occurs as beryllium aluminium silicate (beryl) in rocks, coal and oil, soil and volcanic dust.212 Other beryllium compounds include; beryllium oxide, beryllium halides, beryllium hydroxide, beryllium phosphate, beryllium nitrate and beryllium sulphate. Beryllium is also present in numerous household products, foodstuffs and drinking water.213

Worldwide, industrial grade beryl is used as the source of beryllium metal, alloys and oxide, all of which have many high-tech applications, particularly in the nuclear, electronic and ceramic industries.214 Beryllium is used as an essential material in numerous industries due to its unique combination of thermal, chemical, nuclear and mechanical properties; including very high melting and boiling points. Beryllium metal is used to make components in aircraft disc brakes, X-ray transmission windows, space vehicle optics and instruments, aircraft and satellite structures, missile parts, nuclear reactor neutron reflectors, nuclear weapons, fuel containers, precision instruments, rocket propellants, navigational systems, heat shields, mirrors, high-speed computers and audio components.212, 213 Beryllium chloride, beryllium fluoride and beryllium nitrate are all used in refining beryllium ores, manufacturing beryllium alloys, and as chemical reagents.

Beryllium enters the body through inhalation or ingestion. Swallowing beryllium is not linked to harmful effects in humans as very little beryllium is absorbed from the gastrointestinal tract into the bloodstream.214 Whilst exposure to airborne beryllium may be irritating to the eyes and skin, inhalation of high levels of beryllium dust or fumes may irritate the respiratory tract and cause chemical pneumonitis (inflammation of the lungs). Damage to the lung is alleviated and lung recovery is apparent where exposure is ceased. Some people who inhale beryllium however, develop a condition known as acute beryllium disease (ABD) which has symptoms similar to pneumonia and can be fatal. Both IARC215 and the National Pollutant Inventoryindicate that inhalation of beryllium and its compounds is considered to have cancer-causing potential in humans, most notably in the lungs.214, 215 However, not all forms of beryllium and its compounds are understood to be equally toxic, and the health effects of beryllium and its compounds are not currently well understood.214

Beryllium and its compounds are mainly used in Australia in very small quantities in electronic equipment.214 Beryllium is commonly used in high-tech devices where it is bound into electronic components. The risk of exposure to beryllium in the domestic environment is considered to be negligible.214 Occupational exposure to beryllium may occur in very specialised workplaces (such as mining or processing ores, alloy and chemical manufacturing with beryllium, machining or recycling metals containing beryllium, and nuclear industries) and near some industrial or hazardous waste sites. In the mid 1950s to mid 1970s, naval workers in Australia were exposed to beryllium through working with Jason pistols whilst paint-stripping ships. Some workers developed skin irritations, and symptoms of ABD were also reported which led to litigation in the mid 2000s,216 elevating interest in the potential health hazards associated with beryllium exposure. This method of paint stripping is no longer used. Today, beryllium exposure is carefully regulated and high occupational exposure through direct inhalation during work is unlikely. The eight-hour time weighted average (TWA) exposure limit for beryllium, identified through the National Pollutant Inventory, is 0.002 mg/m3.214 As a result, the relevance of beryllium and its compounds to Australia’s environment and public health stems not so much from its commercial use, but its presence in emissions from


combustion of fossil fuels in, for example, coal-fired power stations.214 Very rarely, tobacco smoke containing beryllium from leaves high in beryllium may be inhaled.214

In the initial search of the literature, 19 studies, including a recent IARC monograph215 were identified as potentially relevant to informing risk of lung cancer attributable to beryllium exposure. Following secondary searches, three more studies were identified, bringing the total to 22. Upon analysis of titles and abstracts, 10 studies were excluded due to duplication or not matching the eligibility criteria for this review. Eight of the remaining 12 studies were addressed in the IARC monograph215 and hence were considered for inclusion without further appraisal. Of the four213, 217-219 studies critically appraised, Levy et al (2009)211 was excluded for not adjusting for smoking.

In a systematic review by Hollins et al.,213 literature is identified that revisits existing data to assess whether recently published studies have improved upon methodological shortcomings of previously published studies. In its assessment it includes 17 studies published through 2007, including the eight in the IARC monograph.215 No meta- or pooled analysis is provided. In describing and assessing the 17 included studies, Hollins et al.213 consider whether and how smoking was adjusted for in the estimation of lung cancer risk and identified only six studies, namely Hinds et al.,220 Feingold et al. (1992)221 Ward et al.,222 Sanderson et al.,223 Levy et al.224 and Brown et al.225 that adjusted for smoking. Hinds et al.220 was inaccessible, and Feingold et al.221 offered quantitative estimates of cancer risk rather than lung cancer risk associated with beryllium exposure. Brown et al.225 did not establish nor quantify an association between beryllium exposure and lung cancer in their study in a cohort of plutonium workers in Colorado USA. This left five high quality studies218, 219, 222-224 for use in data extraction and analysis. Only two of the eight studies referred to in the IARC Monograph,215 Ward et al.222 and Sanderson et al.,223 are included, as the remaining six studies were identified as not having adjusted for smoking.

All five of the included studies report on data from a cohort of male workers employed for two or more days (1940-1970) in one or more of seven beryllium processing plants in the US. The oldest two plants, one located in Reading and the other in Lorain, are known to have had the highest beryllium exposure levels. Environmental air samples analysed to quantify beryllium exposure were only taken at three plants in Elmore, Reading and Hazleton. There were differences across the five studies in the methods used and/or the length of follow-up in the cohort studied. Ward et al.,222 Levy et al.224 and Schubauer-Berigan et al.218,219 included follow-up to 1988222, 224 and 2005 respectively.218, 219 Sanderson et al.223 is a nested case-control study undertaken in the Reading plant with follow-up to 2002. None of the studies identified provided any information regarding the relationship between non-occupational exposure to beryllium and lung cancer risk. Table 17.1 summarises the characteristics of the studies used to shed light on the association between occupational beryllium exposure and risk of lung cancer.


Table 17.1 Study characteristics relevant to the association between beryllium exposure and lung cancer



Analysis Association/Risk (95% CI and/or p provided where available)

Ward et al 1992Retrospective cohort studyUSA

9225 male workers (8905 white 320 non white) employed at 7 beryllium processing facilities for at least 2 days (Jan 1940 - Dec 31 1969). Follow up through December 1988.

Employment data from company records. Death certificates from state statistics office and other records. Incomplete data on smoking in cohort collected in a 1968 survey, (15% completed). Indirect method used to derive smoking in cohort/assumptions about smoking behaviour in cohort. Axelson & Steenland (1988) procedure to adjust for smoking with a conversion factor of 1.13.

Occupational exposure from working in one or more beryllium processing plants.No quantification. Risk estimates for any level of exposure.


Confidence Intervals (CIs) and p-values calculated using Fisher’s Exact method. Smoking adjusted SMRs for cohort (all 7 plants) and 2 plants.

SMR adjusted for smoking, ref US populationAll 7 processing facilities 1.12 (0.99-1.25)Lorain plant (oldest): 1.49Reading (2nd oldest): 1.09

Sanderson et al 2001Nested case control studyUSA

Cases (n=142) & controls (n=710) all male, identified within cohort of workers from a beryllium processing plant, Reading, USA. Follow up through 1992. 60% of cases & controls hired during 1941-1945. Almost two thirds of cases & over half controls employed for less than 1 year.

Cases & controls matched for age & race. Adjustment for smoking using indirect method. Also adjustment for other known carcinogens such as fluorides, copper, aluminium, cadmium, chromium, nickel, nitric acid aerosol, oxides of nitrogen. Incidence density sampling to select controls. Work history data for subjects entered blinded to case/ control status. Beryllium exposures quantified

Occupational exposure to beryllium dust or fumes. Any level of different kinds of exposure: beryl ore, beryllium fluoride (BeF), beryllium hydroxide (BeOH), beryllium oxide (BeO), beryllium-copper alloy (BeCu) & beryllium-aluminium alloy (BeAl). Also 3

Type of lung cancer not stated.

Conditional logistic regression by quartiles of beryllium exposure and continuous exposure response.

ORs for ever exposed to Be and Be types0 year lagBe Ore: 1.07Be OH: 1.12BeF: 1.14BeO: 1.52BeCu: 1.45BeAl: 0.71Be: 0.8820 year lagBe Ore: 1.50 (p<0.05)





based on personal & environmental samples taken in plant. Job exposure matrix developed. Exposures truncated at age of death, minus any lag. ORs estimated allowing for 0, 10 and 20 year lag.

quantified beryllium exposure categories expressed in ug/m3: (i) Cumulative exposure; (ii) Average exposure calculated by dividing cumulative exposure by total number of days employed; (iii) Maximum exposure estimated to be the highest time-weighted average (TWA) exposure of any job the worker held, regardless of duration.

Be OH: 1.48 (p<0.05)BeF: 1.59 (p<0.05)BeO: 1.93 (p<0.01)BeCu: 1.80 (p<0.01)BeAl: 0.91Be: 1.09ORs for quartiles of maximum beryllium exposure (ug/m3)0 year lag≤17.0: 1.0017.1-25.0: 1.82 (p<0.05)25.1-71.5: 1.08>71.5: 1.1420 year lag≤1.0: 1.001.1-23.0: 1.95 (p<0.05)23.1-56: 2.89 (p<0.01)>56.0: 1.67ORs for quartiles of cumulative beryllium exposure (ug/m3)0 year lag≤1 425: 1.001,426-5600: 0.735601-28 123: 0.85>28 123: 0.57 (p<0.05)20 year lag≤20:1.0021-2 195: 2.18 (p<0.01)





2 196-12 376: 1.89 (p<0.05)>12 376: 1.89 (p<0.05)ORs for average beryllium exposure(ug/m3)0 year lag≤11.2: 1.0011.3-24.9: 1.6125.0-34.0: 1.75 (p<0.05)20 year lag1.0: 1.001.1-19.3: 1.92 (p<0.05)19.4-25.5: 3.06 (p<0.01)Lagged analysis showed significant positive exposure-response trends.

Levy et al. 2002Retrospective cohort studyUSA

Re-analysis of the data used by Ward et al (1992). See Ward et al (1992) entry above for sample description.

As Ward et al (1992) described above including use of Axelson & Steenland (1988) method to adjust for smoking. However, a higher level of smoking is assumed in the cohort & hence a different size conversion factor was used to adjust for smoking.

Occupational exposure.Risk estimates for any level of beryllium exposure.


Modified life table analysis program (MLTAS) to estimate standard mortality ratios for cohort & each plant. Axelson & Steenland (1988) method used to adjust lung cancer mortality ratios for smoking.

SMR, US pop refAll 7 facilities: 1.04 (0.92-1.17)Lorain: 1.39 (1.05-1.79)Reading: 1.02 (0.84-1.22)Lucky: 0.67 (0.31-1.28)Cleveland: 0.89 (0.64-1.19)Elmore: 0.81 (0.45-1.34)Hazelton: 1.14 (0.61-1.95)Multiple plants: 1.37 (0.73-2.34)Unknown plants: 1.09 (0.50-2.07)

Schubauer-Berigan et al. 2011aRetrospective Cohort study

f9 199 workers employed (Jan 1940-Dec 1969) at 7 facilities in USA. Also studied by

Adjustment for birth cohort, smoking & race. Potential confounding by cigarette smoking accounted for using

Occupational exposure.For cohort no quantified


Cohort analysed using a modified person-years analysis programme,

SMR for any level of exposure, US pop refAll 7 facilities: 1.17 (1.08-1.28)Lorain plant: 1.45 (1.17-1.78)





USA Ward et al (1992), Levy et al (2002) and Sanderson et al (2001) but with longer follow up for mortality through to December 2005. Focus on a subset of workers in Reading, Hazleton and Elmore plants for whom quantification of beryllium exposure possible. This subset has 5 436 male workers.

indirect external & within-cohort adjustments. Quantitative beryllium exposure estimates based on general area & breathing zone samples taken in 3 beryllium processing facilities, data from company records on job categories & expert opinion about job exposure relationship. Daily weighted average exposure (DWA) for each task developed & a Job exposure matrix developed.

exposure. For sub-set in 3 plants risk estimates (SMRs) established for quartiles of annual maximum exposure and cumulative exposure.

LTAS.NET to calculate SMRs with US pop as reference.

Reading plant: 1.20 (1.04-1.37)Lucky: 0.92 (0.59-1.37)Cleveland: 1.09 (0.88-1.33)Elmore: 1.01 (0.74-1.36)Hazelton: 1.03 (0.70-1.47)Multiple plants: 1.64 (1.06-2.43)SMR for maximum exposure categories, US pop ref3 plants, Elmore, Reading, Hazleton:All workers (unlagged)<10 ug/m3: 0.83 (0.67-1.02)10 to <25 ug/m3: 1.45 (1.06-1.94)25 to <70 ug/m3: 1.49 (1.19-1.83)≥ 70 ug/m3: 1.27 (0.98-1.62)All ≥ 10 ug/m3: 1.40 (1.21-1.61)Excluding short term workers (unlagged)<10 ug/m3: 0.85 (0.66-1.07)10 to <25 ug/m3: 1.80 (1.13-2.73)25 to <70 ug/m3: 0.96 (0.60-1.47)≥ 70 ug/m3: 1.40 (0.97-1.97)All ≥10 ug/m3: 1.32 (1.04-1.65)SMR for cumulative exposure categories, US pop ref3 plants, Elmore, Reading Hazleton:All workers (lagged 10 yrs)0 to <550 ug/m3:1.08 (0.85-1.36)550 to <2500 ug/m3:1.12 (0.88-1.41)





2500 to 10300 ug/m3: 1.10 (0.86-1.38)≥10 300 ug/m3: 1.31 (1.03-1.65)Excluding short term workers (lagged 10 yrs)0 to <550 ug/m3: 0.63 (0.32-1.13)550 to <2500 ug/m3: 0.91 (0.60-1.32)2500 to 10300 ug/m3: 1.04 (0.75-1.39)≥10 300 ug/m3: 1.26 (0.97-1.61)Significant positive trend for cumulative exposure when short term workers (< 1 yr work) excluded.

Schubauer-Berigan et al 2011bRetrospective cohort studyUSA

Study based on the sample of 5 436 male workers from Reading Hazleton and Elmore beryllium processing plants USA used in Schubauer-Berigan et al 2011a.

Methods used to gather data, measure exposure and adjust for smoking same as Schubauer-Berigan et al (2011a). Main difference in method is a more comprehensive analysis of confounders. These include: race, plant, professional work & short-term work status, and exposure to acid mist, asbestos, cadmium, chromium, nickel & silica. Also, different statistical analysis used & different exposure metric.

Occupational exposure. See Schubauer-Berigan et al (2011a) entry above for details on exposure measurement & metrics.


Conditional logistic regression. Lung cancer hazard ratios estimated for mean DWA exposure categories. To evaluate statistical significance two-sided CIs calculated using Wald-type methods or profile likelihood methods.

HR for mean DWA exposure categoriesExcluding asbestos exposed and professionals (3 plants)<0.6 (ug/m3): 1.00.6- <2.0 (ug/m3): 1.30 (0.59-3.11)2.0 to <8.0 (ug/m3):2.41 (1.06-5.82)8.0 to <12 (ug/m3): 7.22 (2.62-21.4)12 to <50 (ug/m3): 6.68(2.81-18.0)≥50: (ug/m3): 4.80 (1.74-14.2)


17.2 Results17.2.1 Occupational beryllium exposure and overall risk of lung cancer

The overall risk estimates for lung cancer for any level of beryllium exposure are mixed, though suggestive of a modest risk of lung cancer attributable to beryllium exposure (Table 17.2). Ward et al.222 and Levy et al.224 used an identical data set and same indirect method to adjust for smoking in lung cancer risk estimation. However, Ward et al.222 assumed a slightly higher level of smoking in the cohort. Ward et al.222 found that workers exposed to any level of beryllium in the processing plants were marginally more at risk of lung cancer than the general US population, being just over 1.12 times (or 12% increase) more likely to develop lung cancer. The association was not statistically significant. Levy et al.224 reported a slightly lower, non-significant risk of lung cancer, as did the nested case-control study by Sanderson et al. (2001)223 in the analysis that allowed for a 20-year lag since first exposure to beryllium (Table 17.2). Schubauer-Berigan et al.212, who had an additional 20 years of mortality data in their dataset, found that workers were 1.17 times as likely as those in the general US population to develop lung cancer - a finding that was statistically significant. All three of these studies found substantial variation across plants in the lung cancer risks for any level of beryllium exposure (Table 17.2). All authors reported risk for sub-groups of workers based on the facility where they were exposed. Risk was highest at those plants with known highest exposure levels, namely the Lorrain and Reading facilities, where risk was approximately 1.4-1.5 times (Ward et al. 1992;222 Levy et al. 2002;224 Sanderson et al.;223 Schubauer-Berigan et al.212 greater than non exposed workers.

Sanderson et al.223 estimated lung cancer risk by type of beryllium exposure, noting substantial variations across the different types in the level of lung cancer risk in both their analyses that allowed for 0 years and 20 years lag since first exposure (Table 17.2). In the 20-year lagged analysis, a significant positive association was found between exposure and lung cancer risk for Be Ore, Be OH, BeF, BeO and BeCu, with the latter two exposure types having the highest lung cancer risk. In addition to smoking, Sanderson et al.223 adjusted for exposure to a range of industrial chemical agents known to be toxic to the lung, including: fluorides, copper, aluminium, cadmium, chromium, nickel, nitric acid aerosol, and oxides of nitrogen.

Table 17.2 Occupational beryllium exposure and overall risk of lung cancer

Reference Risk estimate(95% CI or/and p if reported)

Ward et al 1992Cohort study USA

SMR, US pop refAll plants 1.12 (0.99-1.25)

Levy et al 2002Cohort study USA

SMR, US pop refAll plants: 1.04 (0.92-1.17)

Schubauer-Berigan et al 2011a212

Cohort study USASMR, US pop refAll 7 plants: 1.17 (1.08-1.28)


Reference Risk estimate(95% CI or/and p if reported)

Sanderson et al 2001Nested case control USA

OR, control group reference0 year lagBe Ore: 1.07Be OH: 1.12BeF: 1.14BeO: 1.52BeCu: 1.45BeAl: 0.71Be: 0.8820 year lagBe Ore: 1.50 (p<0.05)Be OH: 1.48 (p<0.05)BeF: 1.59 (p<0.05)BeO: 1.93 (p<0.01)BeCu: 1.80 (p<0.01)BeAl: 0.91Be: 1.09

Ward et al.222 estimated lung cancer risks for the subset of workers in the beryllium exposed worker cohort in the US known to have suffered from ABD. These are not presented as they did not adjust for smoking. However, it is worth noting that the risks for those with ABD were higher.

Risk estimates from studies using objective and quantified measures of exposure (three plants), are presented in Table 17.3. Schubauer-Berigan et al. (2011a)212 found that workers who had a maximum exposure of ≥ 10 µg/m3 were 1.4 times more likely than those in the US population to develop lung cancer (Table 17.3). Short-term workers are often excluded in estimation of disease risks from carcinogenic exposures in epidemiological studies, as their special lifestyle characteristics may introduce additional confounding factors.213 When short-term workers were excluded, the exposure of 10µg/m3

was still associated with a slightly higher risk, but it was lower than when they were included. At an exposure of less than 10 µg/m3 for all workers and short-term worker excluded categories, the risks associated with beryllium exposure were less than in the US general population. Schubauer-Berigan et al.212 adjusted for smoking (using an indirect method) as well as race and birth cohort. Schubauer-Berigan et al.213 used the identical data as Schubauer-Berigan et al.,212 but conducted different statistical analysis, and adjusted for a wider range of confounding factors. Adjustment in Schubauer-Berigan et al.213 was for the following confounders: race, plant, professional work and short-term work status; and exposure to acid mist, asbestos, cadmium, chromium, nickel and silica. Lung cancer risk estimates are presented for all workers and for workers excluding those identified as being exposed to asbestos and/or being short-term workers. The results of the study by Schubauer-Berigan et al.213 are useful for shedding light on risk associated with high levels of occupational exposure.

Sanderson et al.223 reported markedly different levels of lung cancer risk attributable to measured occupational exposure to beryllium depending on whether they allowed for 0 or 20 years since time of first exposure (Table 17.3). When exposure was lagged by 20 years, a maximum exposure of between 1.1-23.0 µg/m3 resulted in workers being almost twice as likely to be diagnosed with lung cancer compared to the US norm. At a maximum exposure of between 23.1 and 56 µg/m3, exposed workers were just under three times as likely to develop lung cancer (Table 17.3). For an average exposure of 1.1 to 19.3 and


19.4-25.5 µg/m3, the workers were just under twice as likely (1.95, p<0.05) and three times as likely (2.89, p<0.01) respectively to develop lung cancer.

Table 17.3 Quantified levels of occupational beryllium exposure and overall risk of lung cancer

Reference Beryllium exposure Risk estimate(95% CI or/and p if reported)

Schubauer-Berigan et al 2011aCohort studyUSA

Maximum exposure (µg/m3)<10 µg/m3

10 to <25 µg/m3

25 to <70 µg/m3

≥ 70 µg/m3

All ≥ 10 µg/m3

SMR, US pop ref, unlaggedAll workers Excl. short term0.83 (0.67-1.02) 0.85 (0.66-1.07)1.45 (1.06-1.94) 1.80 (1.13-2.73)1.49 (1.19-1.83) 0.96 (0.60-1.47)1.27 (0.98-1.62) 1.40 (0.97-1.97)1.40 (1.21-1.61) 1.32 (1.04-1.65)

Schubauer-Berigan et al 2011bCohort studyUSA

Mean daily weighted average exposure (ug/m3)<0.6 (µg/m3)0.6- <2.0 (µg/m3)2.0 to <8.0 (µg/m3)8.0 to <12 (µg/m3)12 to <50 (µg/m3)≥50: (µg/m3)

HR, US pop refAll workers Excl. Asbestos & profs1.0 1.02.29 (1.29-4.30) 1.30 (0.59-3.11)2.84 (1.54-5.49) 2.41 (1.06-5.82)5.68 (2.66-12.4) 7.22 (2.62-21.4) 4.88(2.64-9.62) 6.68 (2.81-18.0)4.13 (2.14-8.41) 4.80 (1.74 – 14.2)

Sanderson et al 2001Nested case controlUSA

Quartiles of maximum beryllium exposure (µg/m3)0 year lag≤17.017.1-25.0: 1.8225.1-71.5: 1.08>71.5: 1.1420 year lag≤1.01.1-23.023.1-56>56.0Quartiles of average beryllium exposure (µg/m3)0 year lag≤11.211.3-24.925.0-34.0>34.020 year lag1.01.1-19.319.4-25.5>25.5

ORs0 year lag1.001.821.081.1420 year lag1.01.95 (p<0.05)2.89 (p<0.01)1.670 year lag1.001.611.75 (p<0.05)1.2720 year lag1.001.92(p<0.05)3.06 (p<0.01)1.70


17.2.2 Dose response for occupational beryllium exposure and risk of lung cancer

Ward et al.222 found that lung cancer SMRs increased with increasing latency from the time of exposure in the cohort of workers exposed to beryllium in processing plants in the US, but not with employment duration (Table 17.4).

Table 17.4 SMRs for lung cancer in US male beryllium workers employed 1940-1969 by latency and employment duration (Ward et al. 1992)

Latency (yrs) Duration of employment (yrs)<1

Duration of employment (yrs)1-5

Duration of employment (yrs)5-10

Duration of employment (yrs)>10

Total

<10 0.78 0.61 0.71 - 0.70

10-15 1.32 0.94 1.38 0.55 1.05

15-20 1.30 1.39 0.95 1.17 1.26

20-25 0.66 1.40 1.20 1.39 1.06

25-30 1.48 (p<0.05) 1.10 1.09 1.12 1.29

>30 1.52 (p<0.05) 1.29 1.77 1.30 1.46 (p<0.01)

Total 1.32 (p<0.01) 1.19 1.26 1.19 1.26 (p<0.01)

Sanderson et al.223 conducted a nested case-control study and reported a positive dose response trend, but only in the analysis with a 20-year lag (Table 17.5).

Table 17.5 Lung cancer risk estimates by cumulative occupational beryllium exposure, (Sanderson et al. 2001)

Quartiles of cumulative beryllium exposure(ug/m3)

Risk estimate, OR(95% CI or p if reported )

— 0 year lag

≤1425 1.00

1426-5600 0.73

5601-28123 0.85

>28123 0.57 (p<0.05)

— 20 year lag

≤20: 1.00 1.00

21-2195: 2.18 (p<0.01) 2.18 (p<0.01)

2196-12376: 1.89 (p<0.05) 1.89 (p<0.05)

>12376 1.89 (p<0.05)

Schubauer-Berigan et al.,212 found a positive dose response trend when short-term workers were excluded (p=0.001), but not for all workers (Table 17.6). At a cumulative beryllium exposure level of ≥10 300 ug/m3, the risk in the cohort of workers exposed to beryllium across the three facilities was approximately 30% higher than the lung cancer risk in the general US population (Table 17.6).


Table 17.6 Lung cancer risk estimates by cumulative occupational beryllium exposure (lagged 10 years), Schubauer-Berigan et al (2011a)

Quartiles of cumulative beryllium exposure (ug/m3)

Risk estimate, OR (95% CI or p if reported ) All workers

Risk estimate, OR (95% CI or p if reported ) Excluding short term workers

0 to <550 ug/m3 1.08 (0.85-1.36) 0.63 (0.32-1.13)

550 to <2500 ug/m3 1.12 (0.88-1.41) 0.91 (0.60-1.32)

2500 to 10300 ug/m3 1.10 (0.86-1.38) 1.04 (0.75-1.39)

≥10 300 ug/m3 1.31 (1.03-1.65) 1.26 (0.97-1.61)

17.2.3 Beryllium exposure, gender, smoking status and risk of lung cancer

None of the studies included in the review offered quantitative estimates of lung cancer risk due to beryllium exposure stratified by gender or smoking status.

17.3 SummaryThe research identified and synthesised in this review suggests that occupational exposure to beryllium represents a modest risk factor for lung cancer, and any risk is dependent on a relatively high level of exposure. Risk estimates for any level of exposure ranged from 1.04 to 1.49 times the risk in the US population as a whole. All risk estimates were based on data from a cohort of male workers exposed to beryllium in one or more of seven beryllium processing plants in the US (for at least two days between 1940 and 1970). The risks varied depending on assumptions made about smoking behaviour, adjustment for various confounding factors (for example, short versus long-term workers), latency of exposure, and which plant(s) the risks were developed for. Furthermore, the type of data analysis used also impacted on the risk estimates reported. It is unlikely that in Australia today, workers or people in their domestic environments are exposed to beryllium at the levels that the review suggests may present an elevated risk of lung cancer. Furthermore, the results of one study suggest that different exposures to different types of beryllium may present different levels of lung cancer risk. However, the evidence in this regard, being from one small study, is too scant to draw any firm conclusion on lung cancer risks by beryllium type.

The findings on dose response were mixed. In one study, a dose response trend was found in the relation between lung cancer risk and cumulative beryllium exposure, but only in the 20-year lagged analysis. In another, a statistically significant dose response trend was found, but only when short-term workers in the exposed cohort were excluded. None of the included studies presented lung cancer risk estimates by gender or by smoking status.

Any consideration of the risk of lung cancer represented by occupational exposure to beryllium must appreciate that all the studies used to inform the risk assessment were based on one cohort of workers exposed to beryllium in beryllium processing facilities between 1940 and 1970 in the US. This limits the generalisability of the findings. Furthermore, indirect methods had to be used to adjust for smoking in all studies, which implies a high likelihood of residual confounding by smoking.

Unfortunately, the review did not find any studies that quantified the association between non-occupational exposure to beryllium and lung cancer risk at the low levels expected in Australia today. The results from the US studies suggest that low exposure, even that


equivalent to an average exposure in industry, does not represent a significant risk of lung cancer. This is an important limitation in assessing the relevance of beryllium as a health hazard in Australia, as exposure stems primarily from non-occupational exposure via inhalation of beryllium from its presence in emissions from combustion of fossil fuels in, for example, coal-fired power stations.

The studies included in this review indicate that an elevated risk of lung cancer exists only with relatively high levels of occupational exposure to beryllium. Review of the available literature suggests that the evidence for beryllium’s carcinogenic potential in humans at exposure levels that exist in modern industrial and environmental settings is either inadequate or marginal.


IARC indicates that beryllium and beryllium compounds are Group 1 carcinogens in humans (IARC, 2012d).215 The 2012 IARC Monograph further states that beryllium and beryllium compounds can cause cancer of the lung.


The studies included in this review, all of which were based on data relating to occupational exposure in the US, indicate that high levels of occupational exposure to beryllium may present a modest risk of lung cancer. However, this risk assessment needs to be interpreted with consideration that the studies on which the evidence is based are weakened by the need to make assumptions about smoking for the majority (over 80%) of beryllium-exposed workers.


17.5 Methodological quality of studiesIndividual critical appraisal checklist items for beryllium are shown below in Table 17.7.

Table 17.7 Beryllium exposure: Methodological quality of included studies


Include

Hollins et al. 2009 Systematic review Y Y Y U Y U Y Y Y Y 8 Include

Levy et al. 2009 Cohort study N U NA N Y Y U Y Y NA 4 Exclude*

Schubauer-Berigan et al. 2011a Case control N Y NA Y Y Y U Y Y NA 6 Include

Schubauer-Berigan et al. 2011b Case control N Y NA Y Y Y U Y Y NA 6 Include* This study was excluded because smoking was not adjusted in the risk estimation.


Hollins et al. 2009

The objectives of this review are clearly stated. The search strategy and sources of the studies included in the review are adequate. The criteria used to appraise studies are thoroughly explained and informed by the approach used by the IARC working group in its evaluations of risk factors for lung cancer. It is unclear whether the critical appraisal of the seventeen studies included was undertaken by two or more reviewers but the authorship of the study suggests it was. Methods were taken to minimise error in data extraction. No meta-analysis is provided in the study. Instead risk estimates of the high quality studies are presented and compared. The recommendations made by the study and conclusions made are supported by the reported data and analysis. The study highlights weaknesses in the existing studies that have quantified the association between lung cancer and beryllium exposure most notably insufficient addressing of the smoking confounder, use of inappropriate reference populations and poor measurement of exposure. No risk estimates by sex or smoking status were provided in the review. It was used to identify three high quality studies from which data were drawn for use in the analysis and assisted in understanding the strengths and limitations of the studies used.

Levy et al. 2009

This study was excluded as it explicitly states that it did not adjust for smoking in its estimation of the lung cancer risk associated with beryllium exposure.

Schubauer-Berigan et al. 2011a212

This cohort study is based like the other included studies on data from subjects who worked for at least two days (1940-1970) in one or more of seven beryllium processing plants in the USA. The sample used in the study is not representative of patients in the population as a whole. The patients in the study were all at a similar point in the course of their condition/illness in the sense that they had died. However, it is unclear whether they were at a similar point in their lung cancer disease when they died. Two important confounders, smoking and birth cohort, are adjusted for in the analysis. However, due to the indirect method used to adjust for smoking, there is a concern that some confounding from smoking remains in the results. A strength of this study, like Sanderson et al. (2001)223 and Schubauer-Berigan et al. 2011b,213 is the careful attempt to measure beryllium exposure and presentation of lung cancer risk estimates for quantified exposure measures. Outcomes are assessed using objective criteria. Follow up is over a sufficient time period. It is unclear how attrition is dealt with in the analysis. Outcomes are measured in a reliable way and appropriate statistical analysis used. The study scored 6 on the JBI critical appraisal checklist.

Schubauer-Berigan et al. 2011b213

This cohort study used the identical data set as Schubauer-Berigan et al. (2011a).212 The population was not representative of patients in the population as a whole. The same point as made above applies to stage of lung cancer disease of subjects; the patients in the study were all at a similar point in the course of their condition/illness in the sense that they had died. However, it is unclear whether they were at a similar point in their lung cancer disease when they died. Follow up was over a sufficiently long period. This study made a very good attempt to address confounding factors in the estimation of risk, with additional confounders being adjusted for, including asbestos exposure. However, due to the need to adjust for smoking using an indirect method, a concern remains over smoking confounding the results. Statistical analysis was appropriate and outcomes were assessed in an objective way. The study scored 6 on the JBI critical appraisal checklist.


18 Risk factor: Red meat and processed meat consumption18.1 IntroductionEstimates of meat consumption by Australians have increased markedly from 71.6kg per person per year (or approximately 196g per day) in 1999226 to 87.4kg (or approximately 239g per day) per person per year in 2005.227 Such dramatic dietary changes have raised concern and have led to increased research into diet-related disease states, such as cancer. There is limited evidence from epidemiological studies to suggest that consumers of high levels of meat, particularly of red and highly salted or processed meat, may be at increased risk of lung cancer.228

Several mechanisms have been proposed for how meat consumption may constitute a risk for lung cancer. Red meat and processed meats are sources of saturated fats and salt (sodium chloride), as well as several mutagenic compounds, including nitrosamines (NOCs), heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons (PAH).229 PAHs are released during grilling or barbequing of meat (Conney et al. 1988 cited in Lam et al. 2009).175 This range of compounds, which may be present naturally in meat or be introduced during processing or cooking, could potentially contribute to a risk of lung cancer as a result of meat consumption. Processed meats contain high levels of sodium chloride which has also been linked with increased lung cancer risk.229, 230

No research syntheses examining the potential association between consumption of meat and lung cancer were identified in this review. The search identified five large prospective cohort studies and eight case-control studies that examined whether consuming either red or processed meat represented independent risk factors for lung cancer. Classification of red and processed meat varied between studies. Processed meat generally included small goods, cured meats and a variety of red meat sausage, and also pork products such as ham and bacon. One prospective cohort study178 and one case control231 were excluded as data specific to either red or processed meat consumption was unable to be extracted. Two case-control studies were excluded for either not focussing on lung cancer232 or where data relative to red meat was unable to be isolated (De Stefani, 2011).226

Of the included studies, two were conducted in Europe,233, 234 four were conducted in the US,228, 235 one study in Canada230 and three in Uruguay.236-238 A total of 789,083 individual participants were included across the four prospective cohort studies, and all included both male and female participants. Participants ranged in age from 25-74 years at base line and the follow-up period ranged from five to eight years. A total of 6512 cases and 7284 controls were included across the seven case-control studies. Two studies included males and females,229, 230 three studies focused on males236-238 and two focused on females.231, 239 Participants were similarly aged to those in the prospective cohort studies (20 - 89 years). Follow-up ranged from one181 to five years.180, 240 Important characteristics of each included study are detailed in Table 18.1.


Table 18.1 Study characteristics relevant to the association between red/processed meat consumption and lung cancer




Alavanja et al 2001USACase control study

Female Iowa residents aged between 40 – 84 years, newly diagnosed between 1993-1996.360 cases, 574 aged matched controlsMean age: 67 years for both groups

Data collected by food frequency questionnaire

Food frequency of red meat consumption as part of usual diet for the 2-3 years prior to study enrollment.

Primary invasive (not in situ) lung carcinoma.

OR & 95% CI were calculated using multiple logistic regressionModel adjusted for potentialconfounding factors included: age,pack–years of smoking, yellow–green vegetableintake, fruit and fruit juice intake, nutrient densitycalories, BMI and alcohol,non-malignant lung disease, years of education completed.

Highest (>9.8 serves per week) compared with lowest quintile of red meat intake (<3.5 times per week). Serve size not reportedOverallOR =3.3 (1.7-7.6)Former/never smoked: OR= 2.8 (1.4-5.4)Current smokers: OR= 4.9 (1.1-22.3)

Cross et al 2007USAProspective cohort

494,036 persons: Male (294,724)Female (199,312)Members of AARP aged between 50-71 at baseline, residing in 1 of 8 named regions of the US

Part of the National Institute of Health American Association for Retired Persons (NIH-AARP) Diet and Health Study. Mean follow up 6.8 yrs.Data collected by food frequency questionnaire

Frequency of meat and processed meat consumption.

All types. Incident cases of lung cancer identified as reported by the participants, cancer registries, state boards of health and the National Death Index.

Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression with time since entry (person years) as the underlying time metric.

Red MeatHighest quintile compared with lowest quintile of consumption. In Men median (mdn) = 67.0g/1000kca vs 12.2g/1000kcalIn women mdn = 54.7g/1000 kcal vs 8.0g/1000kcalHR=1.20; 95% CI=1.10–1.31 (both genders combined)Processed MeatHighest quintile compared with lowest quintile of consumption. Both genders combined mean =22.6g/1000kcal vs 1.6g/1000kcal





HR = 1.16; 95% CI = 1.06–1.26

De Stefani et al 1997UruguayCase control study

Male Montevideo residents aged between 30 – 89 years, newly diagnosed who had been residents of Montevideo for at 10 years.377 cases, 377 aged and residential area matched controls


Food frequency of meat, processed meat and egg consumption as part of usual diet for the year prior to study enrollment (controls) or becoming ill (cases).

All types Multivariate analysisPotential confounders included in the multivariateModels: age, residence, education, family history oflung cancer, body-mass index, total energy intake, cigarettesmoking (in pack-years), alpha-carotene and fat intake

Red MeatUpper quartile (388 or more serves per year) compared with lowest quartile (178 or less serves per year). Serve size not reportedOverall lung cancer (OR=1.25;0.78-1.89)By smoking status – Red meatNever/ex smokers (OR= 1.16; 0.55-2.47)Smokers (OR= 1.32; 0.71-2.46)Processed meatUpper quartile (282 or more serves per year) compared with lowest quartile(79 or less serves per year)Overall lung cancer (OR=1.19;0.75-1.89)


Male Montevideo residents aged between 30 – 89 years, newly diagnosed between 1994-1999.200 cases, 600 aged & residential area matched controls


Food frequency of red meat, processed meat and egg consumption for the 5 years prior to study commencement.

Adenocarcinoma Multiple unconditional logistic regressionPotential confounders included in the model: age, residence,Education, family historyof lung cancer, BMI, body mass indexsmoking status,total energy intake, total vegetables and fruits, reduced glutathione and nonmeat fatty foods

Upper tertile compared with lowest tertile for each factor, however frequency/portion size not reported.Red MeatAdenocarcinoma (OR=1.92: 1.27-2.90)Processed meatAdenocarcinoma (OR=0.83: 0.55-1.26)





intakes.


Male Montevideo residents aged between 30 – 89 years, newly diagnosed between 1996-2004.846 cases, 846 aged and residential area matched controls


Food frequency of red meat, and processed meat consumption as part of usual diet for the 5 years prior to study commencement

Adenocarcinoma Multiple unconditional logistic regressionPotential confounders included in the model: age, residence,Education, family history of lung cancer, BMI,smoking status,total energyintake, total vegetables andreduced glutathione and nonmeat fatty foods intakes.

Red MeatUpper quintile (>9.1 serves/week) compared with lowest quintile (5 or less serves/week). Serve size not reportedOverall - (OR=2.33; 1.63-3.32)Stratified by smoking status:Former smoker - (OR=3.53; 1.92-6.48)Smoker - (OR=2.33; 1.57-3.47)Processed meatUpper quintile (>4.6 serves/week) compared with lowest quintile (1.1 or less serves/week). Serve size not reportedOverall - (OR=1.79; 1.22-2.65)Stratified by smoking status:Former smoker - (OR=1.88; 1.13-3.12)Smoker - (OR=1.23; 0.86-1.74)

Hu et al 2011CanadaCase control study

Cases - 19,732 (men: 10725, women: 9007), newly diagnosed.Mean age: 60.1 +/- 13.4 yearsControls - 5039 (men: 2547, Women: 2492), sex stratified and aged

Population based Case ControlNational Enhanced Cancer Surveillance System (NECSS) study.Data collected by self-report

Food frequency of processed meat consumption as part of usual diet for the 2 years prior to study commencement

All types Unconditionallogistic regressionPotentialconfounding variables included: ageprovince, education, BMI, sex, total alcohol drinking, pack-years smoking, consumption

Processed meatUpper quartile (5.42 or more serves per week) compared with the lowest quartile (.94 or less serves per week). No serve size reported.OR=1.4; 1.1-1.7 (both genders combined)





stratified sampling. Mean age: 57.1 +/- 13.4 years.

questionnaire of total vegetables and fruit and total energy.

Lam et al 2009ItalyCase control study

1903 CasesMean age:upper tertile (65 +/- 8.9 years)lower tertile (67.8 +/- 7.6 years)2073 ControlsMean age:upper tertile (65 +/- 8.9 years)lower tertile (67.8 +/- 7.6 years)Information on gender not reported.

Population based Case ControlEnvironmental and Genetics in Lung cancer Etiology (EAGLE) studyData collected by self-report questionnaire

Food frequency of red meat, and processed meat consumption as part of usual diet. Exposure length not reported.

All types Unconditional logistic regression.Potentialconfounding variables included:age, gender, and area of residence, BMI, education, alcohol consumption, smoking status,dietary intakeof fruits and vegetables and differentmeat groups.Family history of lung cancer, previous lung diseases, and passive smoke exposure did not alter the results appreciatively and were not included in the final models.

Red MeatUpper tertile (>3.0 serves/week) compared with lowest tertile (0.7 or less serves/week)Overall - OR=1.8;1.5-2.2Stratified by smoking status:Never: OR=2.4;1.1-4.0Former smoker: OR=1.7;1.3-2.2Smoker: OR=1.7;1.3-2.2Processed meatUpper tertile (>8.6 serves/week) compared with lowest tertile (1.8 or less serves/week)Overall - OR=1.7; 1.4-2.1Stratified by smoking status:Never: OR=2.5;1.5-4.2Former smoker: OR=1.6;1.3-2.1Smoker: OR=1.77;1.32-2.4

Linseisen et al 2011Denmark,France, Germany, Greece, Italy, Netherlands,

478,427 persons (142,602 men and 335,825 women) who were aged between 25--70 at baseline, residing in 1 of 10 named

This data is derived from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. European

Frequency of meat and processed meat consumption. Portion size was estimated in grams(g)/day.

Lung cancer cases were classified using International Classification of Diseases-Oncology (ICD-O) criteria.Four major

Risk ratios (RRs) and 95% CIs were estimated using Cox proportional hazards regression with time since entry (person years) as the underlying time metric

Red MeatMen or women consuming >80 g red meat per day had a RR = 1.19 (95% CI 0.94–1.50) compared with those consuming less than 10 g/day.Processed meat





Norway, Spain, Sweden, and United Kingdom.Prospective cohort

European countries. men and women. Median follow-up of 8.7yrs.Data collected by self-report questionnaire

histological types: squamous cell carcinoma, small cell carcinoma, large cell carcinoma & adenocarcinoma.

Men or women consuming >80 g processed meat per day had a RR = 0.92, 95% CI 0.73–1.17, compared with those consuming less than 10 g/day.

Tasevska et al 2009USAProspective cohort

467,976 persons Male (278,380) and female (189,596) members of AARP aged between 50-71 at baseline, residing in 1 of 8 named regions of the US

Part of the National Institute of Health American Association for Retired Persons (NIH-AARP) Diet and Health Study. 8yr follow up.Data collected by food frequency questionnaire


All types. Incident cases of lung cancer identified as reported by the participants, cancer registries, state boards of health and the National Death Index

Sex-specific Cox proportional hazards regression models, with age as the underlying time metric, were used to estimate HRs and 95% CIs by gender.

Red MeatHighest quintile compared with lowest quintile of consumption.In Men median (mdn) = 67.0g/1000kca vs 12.2g/1000kcalHR= 1.22; 95% CI: 1.09 - 1.38In women mdn = 54.7g/1000 kcal vs 8.0g/1000kcalHR= 1.13; 95% CI: 0.97 - 1.32Processed MeatHighest quintile compared with lowest quintile of consumption.In Men median (mdn) = 24.8/1000kca vs 2.3g/1000kcalHR= 1.23; 95% CI: 1.10 - 1.37In women mdn = 18.3g/1000 kcal vs 1.2g/1000kcalHR = 1.00; 95% CI: 0.87 - 1.15


99579 persons, Male (48,229) andFemale (51,350) aged between 55-74 years aged at baseline, residing in one of 10 centres in

Data from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

Food frequency of meat and processed meat consumption.

All types Sex-specific Cox proportional hazards regression models, with age as the underlying time metric, were used to estimate risk HRs and 95% CI.

Highest quintile compared with lowest quintile of consumption.Red MeatMen median (mdn) = 67.1g/1000kca vs 14.5/1000kcal HR=1.11; 95%





the USA 5yr follow up. CI: 0.79 - 1.56Women mdn = 52.8g/1000kcal vs 9.4g/1000kcalHR=1.30; 95% CI: 0.87 - 1.95Processed MeatMen median (mdn) = 18.0/1000kca vs 5.6g/1000kcal HR=1.12; 95% CI: 0.83 - 1.53Women mdn = 12.6g/1000 kcal vs 3.8g/1000kcalHR=1.98; 95% CI: 0.68 - 1.41


18.2 Results18.2.1 Red meat consumption and overall risk of lung cancer

Figure 18.1 presents the meta-analysis of 11cohorts (nine studies) addressing the risk of lung cancer as a result of consumption of red meat. The results suggest high levels of red meat consumption increase the risk for the development of lung cancer relative to individuals who consume little or no red meat; with a calculated combined RR (95% CI) of 1.37 (1.18 – 1.60). Despite this apparent risk, consideration of the significant heterogeneity must be considered when interpreting this value. All included studies categorised red meat consumption based on responses to food frequency questionnaires. The analysis presents the RR comparing lowest exposure category (most studies no serves or <10g/day) to highest exposure category. However, the highest exposure category was variable ranging from more than nine serves per week in a US study (Alavanja et al. 2001)229 to greater than 80g per day in a recent study from Europe.241 Differences in study design used to establish the effect estimates have a clear impact, accounting for a significant portion of observed heterogeneity in the overall effect estimate. This is revealed by subgroup analysis and the consistency observed amongst studies of the same design. Analysis of prospective cohort studies reveals a reduced, though still statistically significant, overall effect estimate despite only one of the individual cohorts179 reporting a significant effect of red meat consumption. The included case-control studies reveal greater risk of lung cancer as a result of red meat consumption, but also provide less precision about the effect estimates due to the wider confidence limits.

Figure 18.1 Meta-analysis of risk of lung cancer with red meat consumption including all cohorts

(M) indicates men only, (W) indicates women only.


Furthermore, none of the studies included in the analysis addressed the possible role(s) of cooking methods of red meat and how that may influence the risk of lung cancer. Estimates of risk were adjusted for multiple factors, including: gender, smoking status, body mass index (BMI), energy intake, alcohol intake, consumption of fruits and vegetables, physical activity, level of education, gender and occupation.

18.2.2 Red meat consumption, smoking status and risk of lung cancer

All of the included studies collected smoking status data for participants; however, only two studies reported on lung cancer risk associated with red meat consumption by smoking status. Estimates of risk from these studies are shown in Table 18.2. Despite the study by Alavanja et al. 2001229 reporting high risk estimates in general for the included sample of US women, a clear increase in risk is illustrated in women who are current smokers and consume more than 9 serves of red meat per week. The large upper confidence limit makes it more difficult to determine any exact increase, but is indicative that one does in fact exist. The single study of male smokers who consumed meat was conducted in Uruguayan men who consumed similar quantities to the US women.180 Similarly, men who smoked, or were former smokers, and consumed large quantities of meat were at clear, increased risk of lung cancer.

Table 18.2 Red meat consumption, smoking status and risk of lung cancer

Smoking status Adjusted OR (95% CI)Alavanja et al 2001 (women only)

Adjusted OR (95% CI)De Stefani et al 2009 (men only)

Never/ex smokers 2.8 (1.4 – 5.4) 3.53 (1.92-6.48) (ex only)

Current smoker 4.9 (1.1-22.3) 2.33 (1.57-3.47)Highest risk category presented, relative to the lowest

18.2.3 Red meat consumption and risk of lung cancer by gender

Men

Overall risk of lung cancer attributable to high red meat consumption is summarised from five included studies in Figure 18.2. The overall risk estimate suggests that men are at increased risk, though the same factors as detailed across all cohorts (see above) should be taken into consideration in light of the heterogeneity present. Differences in study design used to determine the effect estimate are again apparent, with case-control studies, most derived from data in Uruguayan men, reporting more variable and larger effect estimates than included cohort studies (De Stefani et al. 1997; 2002; 2009).180 Differences between these studies on similar population groups included amount of meat consumed, which appears greatest in the 2009 study, and type of lung cancer.


Figure 18.2 Risk of lung cancer associated with red meat consumption for men

Highest risk category presented, relative to the lowest

Women

Analysis of three included studies indicates that red meat consumption does not significantly increase risk of lung cancer in women, though limited sample differences and clear differences between the included samples should be taken into account when considering this result (Figure 18.3). The significant heterogeneity present can be accounted for by the differences in study design; however, as only one case-control study is included, this heterogeneity could equally be as a result of differences in population, amount of meat consumed, or other participant characteristics between studies. Despite this, the larger, prospective studies performed by Tasevska et al.228, 235 are indicative of little or no difference in risk of lung cancer between those women who consume large amounts of red meat relative to those who do not.

Figure 18.3 Red meat consumption and risk of lung cancer in women



18.2.4 Processed meat consumption and risk of lung cancer

Figure 18.4 presents a meta-analysis of 11 cohorts (nine studies) combined, informing the risk of lung cancer as a result of consumption of processed meat. As with red meat, the results would suggest that processed meat consumption is similarly a risk factor for the development of lung cancer with a calculated combined RR (95% CI) of 1.24 (1.1 – 1.4). Significant heterogeneity also impacts on interpretation of this analysis; however, the clear differences that exist between study designs used to determine effect estimates observed with analysis of red meat, do not appear to impact on the overall effect measure reported to the same extent as for red meat, as revealed in Figure 18.1. The analysis for processed meat similarly presents the RR comparing the lowest exposure category (no serves or <10g/day) to the highest exposure category, which was variable, though the amounts consumed were less than reported red meat consumption. It is not unreasonable to expect some increased heterogeneity in results with processed meat. One consideration that did not impact on the analysis of red meat that has bearing on the interpretation of these results is the differences between studies in what was included as ‘processed’ meat. For example, in some studies white meat product, such as pork or chicken, was included, whereas in others, only processed red meat was investigated. A further variable introduced that may account for heterogeneity amongst these studies, again not necessary to consider for red meat, was the method of processing, for example whether a product was smoked or salted, and by what method, and whether it was subsequently cooked or not, and by what method.

Figure 18.4 Meta-analysis of risk of lung cancer with processed meat consumption in 11 included cohorts

(M) indicates men only, (W) indicates women only


18.2.5 Processed meat consumption, smoking status and risk of lung cancer

A study in male smokers and former smokers who consumed more than 4.6 serves of processed meat per week was conducted in Uruguayan men.180 Results from this single study suggest that smokers who consume increased quantities of processed meat are not at increased risk, whilst former smokers potentially are at increased risk (Table 18.3).

Table 18.3 Risk of lung cancer with processed meat consumption by smoking status (De Stefani et al. 2009)

Smoking status Adjusted OR (95% CI)De Stefani et al 2009 (men only)

Former smokers 1.88 (1.13-3.12)

Current smokers 1.23 ( 0.86-1.74)Highest risk category presented, relative to the lowest

18.2.6 Processed meat consumption and risk of lung cancer by gender

Men

Analysis of data derived from males alone suggests there is no risk of lung cancer as a result of high amounts of processed meat consumption (Figure 18.5). This overall effect estimate is not significantly impacted by heterogeneity and appears consistent between the two study designs and populations included.

Figure 18.5 Risk of lung cancer with processed meat consumption for men


Women

Two studies addressed the risk of lung cancer to women due to consumption of processed meat. The estimates of risk are summarised in Table 18.4. Neither of the studies reported


an increased risk of lung cancer attributable to high amounts of processed meat consumption.

Table 18.4 Risk of lung cancer with processed meat consumption for women

Study Study design Adjusted risk (95% CI)

Tasevska et al 2009 Prospective cohort HR = 1.00 (0.87 – 1.15)

Tasevska et al 2011 Prospective cohort HR = 1.98 (0.68 – 1.41)Highest risk category presented, relative to the lowest

18.3 SummaryAustralian Bureau of Statistics figures estimated that Australians consume approximately 87.4kg of meat per person per year, equating to approximately 239g per day per person.226 The evidence accumulated and analysed, particularly from prospective studies, suggests that consumption of large amounts of red meat may increase risk of lung cancer minimally, by approximately 10-20% relative to individuals who don’t consume large quantities. Portion size across studies was variable; however, this result is based on approximately five to 10 portions per week. Consumption of large amounts of processed meat also appeared to increase risk of lung cancer by a similar small amount; however, significant heterogeneity present makes it difficult to reach any definitive conclusion. Analysis of risk of lung cancer by gender separately indicated that high meat consumption by men may place them at a small increase in risk. This result was not seen in women; however, limitation in the number of included studies and the similar populations investigated across both genders makes any definitive conclusion difficult.


IARC does not list the consumption of red meat or processed meat as a recognised carcinogen in humans. Evidence from the National Institutes of Health (NIH)-AARP (formerly the American Association for Retired Persons) Diet and Health Study cohort suggests that meat consumption may be associated with statistically significant elevated risks (ranging from 20% to 60%) for oesophageal, colorectal (20%), liver, and lung cancer (16%), in individuals with the highest intake.178


There is evidence to suggest that consumption of high quantities of red meat leads to an increase in the risk of lung cancer of some 10 – 20%. The risk due to high consumption of processed meat appears similar; however, this conclusion should be interpreted with caution due to heterogeneity across included studies. The role(s) that different cooking methods may play in the risk of lung cancer was not addressed by any of the included studies.


18.5 Methodology quality of studiesIndividual critical appraisal checklist items for red meat and processed meat are shown in Table 18.5.

Table 18.5 Red and processed meat consumption: Methodological quality of included studies

Study Study Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Total (Y) Include/Exclude

Alavanja et al 2001 Case control study N Y U U Y Y Y Y Y 6 Include

Cross et al 2007 Prospective cohort Y Y Y Y U Y U Y Y 7 Include

De Stefani et al 1997 Case control study Y U Y Y U U Y Y Y 6 Include

De Stefani et al 2002 Case control study N Y Y U U Y U Y Y 5 Include

De Stefani et al 2009 Case control study N U U Y Y Y Y Y Y 6 Include

Hu et al 2011 Case control study Y Y Y Y Y U U Y Y 7 Include

Lam et al 2009 Case control study Y Y U Y Y U U Y Y 6 Include

Linseisen et al 2011 Prospective cohort Y U Y Y Y Y U Y Y 7 Include

Tasevska et al 2009 Prospective cohort Y Y Y Y U Y U Y Y 7 Include

Tasevska et al 2011 Prospective cohort Y U U Y Y Y Y Y Y 7 Include


Alavanja et al. 2001

The methods and objectives were clearly stated in this study, with clear selection criteria for both cases and controls. The study population were American women, residing in Iowa. Controls were aged matched to cases (by 5 year age groups) and were also from Iowa. Data was collected using a 60-item food frequency questionnaire. Confounding factors were considered appropriately. Outcomes measures and statistical methods were adequately described. Duration of exposure was 2-3 years.

Cross et al. 2006

The methods and objectives were clearly stated in this study, with clear eligibility criteria. The comparability with general population was described and the population participating in the study was representative of target population. Outcomes and their measurement as well as procedures of the study were adequately described. Data was collected using a mailed-out self-administered 124-item food frequency questionnaire that determined the frequency, not portion size of the foodstuffs. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression with time since entry (person years) as the underlying time metric. Risks were reported for both sexes combined.

De Stefani et al. 1997

Study quality was moderate and case and control selection was well described. The study population were Uruguayan men living in Montevideo. Controls were frequency matched to cases by age (10 year group), residence and urban/rural status and were admitted to the same hospitals as the cases (for non-neoplastic conditions). Data was collected using a 64-item food frequency questionnaire. Confounding factors were considered appropriately. Outcomes measures and statistical methods were adequately described. Duration of exposure was 1 year.


The description of the study design and setting and the eligibility criteria for subjects included in the study was clear. Subjects were Uruguayan men living in Montevideo. Controls were frequency matched to cases by age (10 year group), residence and urban/rural status and were admitted to the same hospitals as the cases (for non-neoplastic conditions). Outcomes and their measurement were adequately described. Statistical methods were described well. Data was collected using a 64 item food frequency questionnaire Confounding factors were considered appropriately. Outcomes measures and statistical methods were adequately described. Duration of exposure was 5 years.


The methods and objectives were clearly stated in this study, with clear selection criteria for both cases and controls. The study population were Uruguayan men living in Montevideo. Controls were frequency matched to cases by age (10 year group), by residence and were admitted to the same hospitals as the cases (for non-neoplastic conditions). Data was collected using a 64-item food frequency questionnaire. Confounding factors were considered appropriately. Outcomes measures and statistical methods were adequately described. Duration of exposure was 5 years. Study quality was moderate.


Hu et al. 2011

The methods and objectives were clearly stated in this study, with clear selection criteria for both cases and controls. Study subjects were from Canada and appear representative of target population. Controls were frequency matched to cases by age and gender. Outcomes and their measurement as well as procedures of the study were adequately described. Data was collected using a 69-item food frequency questionnaire that determined the frequency, not portion size of the foodstuffs. Risks were reported for both sexes combined and the exposure was 2 years.

Lam et al. 2009

Study quality was moderate and case and control selection was well described. The study population were Italians living in Lombardy. Controls were matched to cases by age (5 year group), by residence and by gender. Data was collected using a 58-item food frequency questionnaire. Confounding factors were considered appropriately. Outcomes measures and statistical methods were adequately described. Duration of exposure not reported.

Linseisen et al. 2011

The description of the study and the eligibility criteria for subjects included in the study was clear and subjects appeared representative of target population. Outcomes and their measurement were adequately described. Statistical methods were described well. Risk ratios (RRs) and 95% CIs were estimated using Cox proportional hazards regression with time since entry (person years) as the underlying time metric. Sub analyses were performed by sex and smoking status. Although there appeared to be slight differences between participant recruitment and data collection methods between countries, this did not result in statistically significant heterogeneity, when tested using standard Chi square test.

Tasevska et al. 2009

The methods and objectives were clearly stated in this study, with clear eligibility criteria. The comparability with general population was described and the population participating in the study was representative of target population. Data was collected using a self-administered 124-item food frequency questionnaire. Outcomes and their measurement as well as procedures of the study were adequately described. Sex-specific Cox proportional hazards regression models, with age as the underlying time metric, were used to estimate HRs and 95% CIs by gender.

Tasevska et al. 2011

The description of the study design and setting and the eligibility criteria for subjects included in the study was clear and subjects appeared representative of target population. Outcomes and their measurement were adequately described. Statistical methods were described well. Sex-specific Cox proportional hazards regression models, with age as the underlying time metric, were used to estimate risk HRs and 95% CI.


19 Risk factor: Alcohol consumption19.1 IntroductionAccording to AIHW data, in 2001, 8.3% of Australians aged 14 years and over consumed alcohol on a daily basis, and males were more likely to consume alcohol both daily and weekly (11% and 46% respectively) compared to females (6% and 33% respectively).242 High-risk level alcohol consumption is found to be strongly associated with oral, throat and oesophageal cancer.243 Data suggest that men in Australia with high-risk level of alcohol consumption normally prefer beer, whereas women prefer wine.27 The apparent consumption of alcohol by those aged 15 years and over in Australia in 2004-05, was 9.8 litres of alcohol per year per person.244 Binge drinking, which is drinking at or above high-risk level in the short term was found to be associated more with young people aged 18-24 years.244 According to the International Agency for Research on Cancer,245 there is no conclusive epidemiological evidence to show causal association between consumption of various types of alcoholic beverages and lung cancer.

The search of the literature identified 21 relevant studies including one recent IARC monograph (2010).245 Of these 21 studies, one (thesis) could not be retrieved. Included were two meta-analyses that included nine of the 20 full-text articles retrieved. Two of the papers were identified in the IARC monograph. The monograph itself was not subjected to appraisal based on the selection criteria. A further 50 studies were identified relevant to this risk factor from the IARC monograph (2010).245 Out of these 50 studies, there was a meta-analysis paper246 that included 36 of the identified studies on full-text examination. Of the remaining 13 papers, two more were excluded due to language and population limitations. In all, a further 12 papers were retrieved and following full-text examination, one paper was excluded as it did not report any measure of association. One paper was excluded after critical appraisal.

Fourteen studies were ultimately included in the report. The focus of all the included studies varied. Studies conducted in Netherlands,247 Sweden,248 US Breslow et al. 2000,249 Denmark,250 Japan251, Hawaii252 and Finland253 were cohort study designs. Other studies conducted in US,254 Australia255 and Poland256 were case-control study designs. Two meta-analyses papers246, 257 were from the US and one meta-analysis paper258 was from Italy.

The method employed to collect data of alcohol consumption by the majority of included studies was self-administered questionnaires. Some of the other data collection methods included personal interviews for exposure assessment by trained investigators, cancer registries, and death certificates for outcome assessment. Exposure assessment varied, with alcohol consumption measured in different ways including total alcohol consumption per day, frequency of alcohol consumption, alcohol consumed during a specified time period, and assessment using the Nordic alcohol consumption inventory. The average length of follow-up period varied from seven to 17 years. Risk of lung cancer was the major outcome measured in all of the studies, with lung cancer mortality being the other outcome. There was a clear description of potential confounding factors and their adjusted findings in the statistical analysis in most of the studies. Age, smoking status, diet, socioeconomic status and body mass index (BMI) were consistently found to be the major confounding factors. Most of the studies did not clearly present their findings separately for smokers, non-smokers and former smokers, except for one meta-analysis.258 Characteristics of included studies are detailed in Table 19.1.


Table 19.1 Study characteristics relevant to the association between alcohol consumption and lung cancer




Bagnardi et al 2011Meta-analysis

Meta-analysis based on a total of 1913 never smoker lung cancer cases

Ten included studies; three cohort studies, one pooled analysis and six case-control studies.

Total alcohol consumption

Description unclear Fixed-effects model. Random-effects model in case of significant heterogeneity.Potential confounding factors adjusted: diet, gender, BMI, socioeconomic status and education

Lung cancer incidenceMortalityAlcohol consumption not associated with lung cancer risk in never smokersDrinkers vs non drinkers: Summary RR for never smoked regularly – 1.01 (0.88-1.17) and <100 cigarettes lifetime – 1.23 (0.57-2.65)

Balder et al.2005NetherlandsProspective Cohort

58 279 men in 204municipalities inNetherlands, aged55–69 yearsFollow-up from 1986–95

Netherlands Cohort Study on Diet and CancerMailed questionnaire

Alcohol median intake (g/day) – quintile of consumptionQ1 0Q2 2.2Q3 9.3Q4 23Q5 42

Lung cancer ascertained fromNetherlands CancerRegistry and Netherlands Pathology Registry

Adjustment factors: Age, total energy intake, current cigarette smoker, number of cigarettes smoked per day, years of smoking cigarettes, higher vocational or university education, family history of lung cancer, physical activity, BMI

Lung cancer incidenceRRQ1 (n=183) 1.0Q2 (n=241) - 1.11 (0.8–1.54)Q3 (n=337) - 1.23 (0.91–1.67)Q4 (n=333) - 1.08 (0.8–1.47)Q5 (n=311) - 1.56 (1.11–2.18)p for trend=0.03

Boffetta et al 2001Sweden,Cohort of Alcoholics

173 665 (138 195 men,35 470 women) patientswith a hospital dischargeof alcoholism, aged≥20 years;

Study based on a linkage between the Swedish In-patientRegister and the National Cancer Register

Alcoholic Lung cancer cases identified as those that occurred among the patients in the cohort either before or after the first hospital discharge with diagnosis of alcoholism.

Adjustment factors: Age, gender, calendar year

Lung cancer incidenceSIRMen (n=1613) - 2.24 (2.13–2.35)Women (n=267) - 4.16 (3.68–4.7)Total (n=1880) - 2.4 (2.29 –





mortalityfollow-up, 1965–95;case ascertainment 98%

Cancers classified according to the ICD-7

2.51)

Breslow et al.2000USAProspective Cohort

Sub-cohort of20 004 adults, 18years or older,who completed theCancer EpidemiologySupplement (8363men, 11 641 women);follow-up, 1987–95;

National HealthInterview SurveyCancer EpidemiologySupplement questionnaire (in-home interview)

Alcohol Servings/weekQuartiles of intakeQ1 0Q2 0.02–0.5Q3 0.5–4.4Q4 >4.4

Case ascertainment,National Death Indexand Death certificate

— Lung cancer mortalityAdjustment factors: Age, gender, smoking duration (years), packs per day smokedRRQ1 (n=52) - 1.0Q2 (n=23) - 0.7 (0.4–1.3)Q3 (n=32) - 1.0 (0.6–1.6)Q4 (n=50) - 1.3 (0.8–2.0)p for trend <0.101

Chao et al 2007Meta-analysis

4,119 lung cancer cases arose from N = 453,751 participants

Ten case-control studies and four cohort studies.

Amount of alcohol consumed over a time period (e.g. no: of drinks per week)

Description unclear Random-effects model.Potential confounding factors adjusted: age, sex, BMI, smoking, residence, family history, dietary intake and education

Lung cancer incidenceAvg beer and liquor consumption of one drink or greater/day increased lung cancer risk. (1.23, 1.06-1.41) & (1.33, 1.10-1.62)Modest wine consumption of one drink or greater/day decreased lung cancer risk. (0.78, 0.60-1.02)

Djoussé et al. 2002Population-based cohort studyMassachusetts,USA

In 1948, 5209 subjects aged 28–62 years at first examination; in 1971, 5124 childrenof the original cohort participated;

Framingham Cohort Study (1948) andFramingham Offspring Study (1971)Mean follow-up: original cohort, 32.8

Total alcohol consumption (g/day) - multiplying the average content of alcohol in beer, wine, and mixed drinks by number

Cancer case ascertainment, self report, hospitalisationsurveillance andNational Death Index;100% histologically

Adjustment factors: Age, sex, smoking status, pack–years of cigarette smoking, year of birth

Incidence of lung cancerNo: of cases/deaths (n=269)RR (95%CI)0 g/day (n=44) - 1.00.1–12g/day (n=100) - 1.2 (0.7–2.1)





studyincluded 4265 subjects from the original cohort and 4973 from the offspring cohort

years; offspring cohort, 16.2 years

of drinks consumedAlcohol intake in g/day calculated as ([0.57 × the number of cocktails per week] + [0.44 × the number of beers per week] + [0.40 × the number ofglasses of wine per week]) × 28.35/7; the latter representing 28.35 g of alcohol per fluid ounce divided by 7 days in a week

confirmed 12.1–24 g/day (n=39) - 1.1 (0.6–2.1)>24 g/day (n=86) - 1.3 (0.7–2.4)

Korte et al 2002Meta-analysis of four study designs

Description unclear Case-control and cohort studies of alcoholics (11 studies) and general population (12 cohort, 10 case control)

Ethanol consumption (g/month)

Description unclear Adjustment factors: smoking

Incidence of lung cancerRR (95%CI)Cohort studies (smoking adjusted)Non-drinker 1.01–499 g/mth - 0.98 (0.79–1.21)500–999 g/mth - 0.92 (0.81–1.04)1000–1999 g/mth - 1.53 (1.04–2.25)≥2000 g/mth 1.19 (1.11–1.29)Case-control studies (smoking adjusted)





Non-drinker 1.01–499 g/mth - 0.63 (0.51–0.78)500–999 g/mth - 1.3 (0.98–1.7)1000–1999 g/mth - 1.13 (0.46–2.75)≥2000 g/mth - 1.86 (1.39–2.49)Overall - 1.39 (1.06–1.83)

Mayne et al 1994Case-control USA,

413 (212 men,201 women) non-smokers identified via themedical recordsdepartment,pathology department and the tumour registry, aged31–80 years413 controlsSelected from drivinglicense files; individually matched on age, sex, countyof residence, smoking history

Interviewer administeredQuestionnaire (homeinterview, food-frequency questionnaire for alcohol use)

Beer /monthQuartile of consumptionQ1Q2Q3Q4

Lung cancer confirmed histologically

Conditional Logistic RegressionAdjustment factors: Age, sex, county ofresidence, smoking history, cigs/ day smoked by former smokers, religion, education, body-mass index, income

Lung cancer incidenceORBeer /monthQ1 1.0 (ref)Q2 1.06Q3 0.87Q4 1.18P for linear trend Non significant

Pierce et al 1989Case Control

Cases - 71 hospitalised

In-hospitalinterview

Alcohol assessed as Drinks/week

Lung cancer cases confirmed

Adjustment factors: Age; not clear whether

Incidence of lung cancerOR





Melbourne,Australia1984–85

men; mean age,67.3 yearsControls - 70 hospitalised cancer-free men; mean age, 66.5 years individually matched to cases by age

Duration (years) cytologically or histologically

smoking was adjusted Drinks/week - 1.0 (0.99–1.01)Duration (years)- 1.0 (0.96–1.03)

Rachtan & Sokolowski 1997Case ControlCracow, Poland1991–94

Cases - 118 hospitalisedwomen; age notreportedControls - 141 healthywomen selected among next of kin of patientsadmitted to thesame hospital without tobacco related cancer; age not reported

Interviewer administeredstructuredquestionnaire

Frequency of alcohol consumptionBeerWineVodka

Lung cancer cases confirmed histologically

Cox proportional hazards regression model used to estimate hazard ratios (HR) and 95% confidence intervals. Adjusted potential confounding factors: Age, smoking status, passive smoking and family history

Lung cancer incidenceRRFrequency of consumptionBeerNon-drinker 1.0Rarely 1.07 (0.49–2.34)1–2/month 1.83 (0.50–6.69)At least once/week 3.3 (0.62–17.48)p for trend=0.125WineNon-drinker 1.0Rarely 0.9 (0.5–1.81)1–2/month 1.08 (0.48–2.45)At least 1/week 1.16 (0.16–8.45)p for trend=0.957VodkaNon-drinker 1.0Rarely 3.18 (1.80–5.61)1–2/month 2.56 (1.18–5.56)





At least 1/week 10.32 (1.17–91.47)p for trend = 0.0005

Shimazu et al 2008Large scale population-based cohort study

46,347 men between 40-59 years of age from 10 prefectural public health centre areas in Japan

Two cohort studies launched in 1990 and 1993 respectively. Data obtained from questionnaires including baseline self-administered questionnaires14 year follow-up period

Frequency and amount of alcohol consumption in cohort 1 and drinking status in cohort 2

Incident cases of lung cancer cases identified by voluntary reports from local hospitals and cancer registries.Diagnosis of lung cancer confirmed by histological or cytological examinationMortality data confirmed and obtained from Ministry of Health, Labour and Welfare.

Cox proportional hazards regression model used to estimate hazard ratios (HR) and 95% confidence intervals. Adjusted potential confounding factors: Age, smoking status, passive smoking and family history.

Lung cancer incidenceRRPositive association between alcohol consumption and lung cancer in current smokers. (1.69, 1.05-2.72, p for trend = 0.02)

Sørensen et al.1998Denmark,Cohortof 1-yearSurvivors ofCirrhosis

11 605 1-year Survivors of cirrhosis;follow-up, 1977–93; 7165alcoholic cirrhosis (5079men, 2086 women)

Survivorsof cirrhosis identifiedfrom Danish NationalRegistry of Patientsthat covered all hospitaladmissions in Denmark

Alcoholic Lung cancer ascertainment, DanishCancer Registry

Adjustment factors: Age, sex, calendar period

Incidence of lung cancerNo: of cases/deaths - 135SIR2.1 (1.8–2.5)

Stemmermann et al. 1990Prospective cohort,Hawaii

7572 Japanesemen born between1900 and 1919(also subjects forthe Honolulu Heart

Japan-HawaiiCancer StudyBaseline interviewquestionnaire

Alcohol (oz/month)0<55–14

Lung cancer ascertained withhospital records,death certificates,and the Hawaii

Adjustment factors Age, current smoking status, age started smoking, number of cigarettes smoked per day, maximum number of cigarette smoked per

Incidence of lung cancerNo: of cases/deaths (n=209)RR0 - 1.0<5 - 0.75 (0.48–1.17)





Study); follow-up,1965–68 to1989; 100% casecatchments

15–39≥40

Tumour Registry day, years of smoking with maximum number per day

5–14 - 0.93 (0.59–1.47)15–39 - 1.43 (0.99–2.06)≥40 - 1.09 (0.73–1.64)p for trend=0.09

Toriola et al 2009Prospective population-based cohort study

2,267 middle-aged men from Eastern Finland without a history of lung cancer at baseline

QuestionnairesAverage follow-up of 16.7 years

Alcohol consumption assessed with structured quantity and frequency method using Nordic alcohol consumption inventory. Binge drinking classified as >70g ethanol/drinking session.

Lung cancer incidence identified by Finnish cancer registry

Cox proportional hazard models used to analyse the association between binge drinking and risk of lung cancer. Potential confounding factors such as age, smoking history, family history, BMI and socio-economic status.

Lung cancer incidenceBinge drinking increased risk of lung cancer in smokers but not among non-smokers.RR 1.79 (95% CI 1.63-4.41)


19.2 Results19.2.1 Alcohol consumption and risk of lung cancer in the general population

Findings from a meta-analysis by Korte et al.246 showed that there is a significant increase in risk of lung cancer with alcohol consumption in excess of 2000g per month (i.e. more than five drinks per day) based on cohort studies (RR 1.19, 1.11-1.29) and hospital-based case-control studies (OR 1.82, 1.41-2.35), after adjusting for smoking. Similarly, a further cohort study249 of 20,195 participants reported an association between alcohol consumption and risk of lung cancer. The relative risk of lung cancer mortality among non-smokers was 2.3 (1.1-4.6) in the highest quartile (median 10.5 servings per week) compared to the lowest quartile (no drinks) of alcohol intake. There was no significant difference in lung cancer mortality across levels of drinking for individuals with longer smoking duration (25 years (1.4, 0.9-2.1) and 50 years (0.9, 0.5-1.2)).

Meta-analysis of remaining studies (presented in Figure 19.1) combining the effect estimates from the highest exposure categories suggests a non-significant association. However, in both studies (Djousse et al. 2002;259 Stemmermann et al. 1990),252 the upper exposure category represents alcohol consumption lower than that investigated by Korte et al.246 or Breslow et al.249 Considered together, these results would indicate that the effect of alcohol is dose dependent and high alcohol consumption is necessary to increase risk of lung cancer.

Figure 19.1 Meta-analysis of risk of lung cancer (RR) in individuals with high alcohol consumption

Djousse et al, 2002 – Adjusted for age, gender, smoking status, pack-years of cigarette smoking & year of birth. Exposure >24 g/dayStemmermann et al, 1990 – Adjusted for age, smoking status & no: of cigarettes smoked/day in current smokers, maximum no: of cigarettes smoked/day and years of smoking with maximum number/day in ex-smokers. Exposure in oz/month (1oz = 28 gms) ≥40oz.

Two case–control studies254, 255 reported no significant association between any level of alcohol consumption and risk of lung cancer (Table 19.2),even at similar levels of consumption to that reported by Korte et al.246

Table 19.2 Risk of lung cancer incidence in general population by lowest and highest alcohol intake categories

Study Category Risk

Mayne et al 1994 Highest quartile of consumption 1.18

Pierce et al 1989 Highest intensity of drinking (38±4.0 drinks/week)

1.00 (0.99-1.01)


19.2.2 Alcohol consumption, smoking status and risk of lung cancer

A meta-analysis of 10 studies found that alcohol consumption was not associated with lung cancer risk in never-smokers (RR 1.21, 0.95-1.55).258

Despite this, Korte et al.246 in a meta-analysis paper, also reported unpublished data from the Cancer Prevention Study (CPS) I and II and found that there was an increased risk of lung cancer with alcohol consumption of ≥500 g per month among both men and women who had never smoked (Table 19.3).

Table 19.3 Risk ratios for alcohol consumption and lung cancer risk in non-smokers (Korte et al. 2002)

Alcohol consumption Males OR (95% CI) Females OR (95% CI)

1-499 g/month 1.08 (1.00-1.18) 1.16 (0.83-1.61)

≥500 g/month 1.38 (1.23-1.53) 1.98 (1.23-3.17)

Similarly, in a study by Shimazu et al.,251 the findings showed a positive association between alcohol consumption (rice wine, white spirits, ethanol, beer, whisky and wine) and risk of lung cancer in current smokers. This significant association with lung cancer was found among current smokers with an alcohol consumption of ≥300 g/week. In contrast to these results, there was no positive association between alcohol consumption and risk of lung cancer among non-smokers, even with an average alcohol intake of ≥450 g/week (Table 19.4).

Table 19.4 Multivariate adjusted Hazard ratio for lung cancer incidence by smoking status (Shimazu et al 2008)

Alcohol consumption ethanol intake (g/week)

Occasional drinkers

1-149 150-299 300-449 ≥450 p for trend

Non-smokers 1.00 0.62 (0.33-1.19)

0.69 (0.36-1.32)

0.77 (0.38-1.58)

0.58 (0.26-1.30)

0.49

Current smokers 1.00 1.44 (0.90-2.30)

1.30 (0.82-2.06)

1.66 (1.04-2.65)

1.69 (1.05-2.72)

0.02

Adjusted for age, study area, smoking status, pack years of smoking, passive smoking at workplace & family history

Rachtan and Sokolowski256 found a significantly increased risk of lung cancer associated with a moderate level (not specified) of alcohol consumption among Polish women who were current smokers or ex-smokers (Table 19.5).

Table 19.5 Relative risk of lung cancer in women by smoking status (Rachtan & Sokolowski 1997)

Smoking status Cases Controls RR (95% CI) P value

Never smoked 33 98 1.00 —

Ex-smokers 13 10 3.80 (1.21-7.84) 0.0187

Current smokers 72 33 6.77 (3.71-12.35) 0.0000


Adjusted for age

In contrast, another case-control study in males found that there was no positive association between lung cancer risk and alcohol consumption (30 to 40 drinks per week) in non-smokers, ex-smokers and current smokers, as illustrated in Table 19.6.255

Table 19.6 Odds ratio for alcohol consumption and lung cancer risk by smoking status (Pierce et al 1989)

Smoking status Cases Controls RR (95% CI) Chi-square value

Current smokers 43 51 1.00 4.2 NS

Ex-smokers 18 12 2.40 (0.9-6.6) 4.2 NS

Non-smokers 10 8 2.5 (0.7-8.8) 4.2 NSAdjusted for age

A prospective population based cohort study found that there was increased risk of lung cancer among male binge drinkers who smoked 1-19, 20-29 and ≥ 30 cigarettes daily, but not amongst non-smokers (Table 19.7253) Binge drinking was classified as ingestion of 70g of ethanol or more in a single session (the equivalent of six beers or a bottle of wine).

Table 19.7 Binge drinking and risk of lung cancer according to smoking status (Toriola et al 2009)

Cigarette smoking RR (95% CI) P value

Nonsmokers 1.48 (0.89-2.47) 0.13

1-19/day 2.68 (1.63-4.41) ≤ 0.001

20-29/day 2.21 (1.33-3.70) 0.002

≥30/day 2.22 (1.34-3.73) 0.002

19.2.3 Alcohol consumption, gender and lung cancer risk

Toriola et al.253 assessed the risk of binge drinking on lung cancer incidence in middle-aged men. These authors compared binge-drinking smokers with non-binge drinking smokers and observed that there was no increased risk of lung cancer among non-smoking binge drinkers. A summary estimate of risk is presented below in Table 19.8 from two groups investigated, the entire cohort, and binge drinking smokers.

Table 19.8 Relative risk of lung cancer among binge drinkers compared with non-binge drinkers in men with no history of lung cancer at baseline (Toriola et al 2009)

Category RR (95% CI) P value

Whole cohort 1.89 (1.10-3.20) 0.02

Among smokers alone 1.79 (1.03-3.12) 0.04

Balder et al.247 investigated dose dependence of alcohol’s effect and reported a statistically significant risk at the highest category of alcohol consumption in men, and that lower consumption of alcohol, be it beer, wine or spirits, did not have any protective effect (Table 19.9).


Table 19.9 Increased risk of lung cancer in men with increasing amount of alcohol (Balder et al 2009)

Study Exposure in g/day No: of cases/deaths

Relative Risk (95% CI)

p for trend

Balder et al., 2005 0 183 1.0 —

Balder et al., 2005 2.2 241 1.11 (0.8–1.54) —

Balder et al., 2005 42 311 1.56 (1.11–2.18) 0.03Adjusted for age, total energy intake, current smokers, number of cigarettes per day, years of smoking cigarettes, higher education, family history, physical activity and body mass index

One hospital-based, case-control study that used non-drinkers as the baseline comparison group found that the risk of lung cancer increased with increasing frequency of consumption of vodka in women (Table 19.10).256 This risk was no longer apparent when beer or wine was consumed from three times and 1.5 times per week respectively.

Table 19.10 Risk of lung cancer with consumption of vodka in women (Rachtan et al 1997)

Vodka consumption RR & 95% CI1 RR & 95% CI2

Nondrinkers 1.00 1.00

1-2 x /month 2.56 (1.18-5.56) 2.62 (1.25-5.50)

At least 1 x /week 10.32 (1.17 -91.47) 7.51 (0.79-71.04)1 Adjusted for age. 2Adjusted for various potential confounding factors including smoking

19.2.4 Types of alcoholic beverage consumed and risk of lung cancer

Studies that examined risk estimates for the consumption of different types of alcoholic beverages (i.e. beer, wine, and liquor) indicate that different types of alcoholic beverages have different effects on the risk of lung cancer.

The results from a meta-analysis by Chao et al.257 showed a significant association between high consumption of beer and spirits and risk of lung cancer, but there was an inverse association between wine consumption and lung cancer risk. Combining the highest beer-drinking category from included studies resulted in a RR of 1.23 (1.06–1.41). Conversely, combining the highest consumption of wine across studies resulted in a RR of lung cancer incidence of 0.79 (0.65 – 0.95), suggesting a protective effect. Results describing the risk of lung cancer attributable to daily intake of alcohol by the glass are presented in Table 19.11.

Table 19.11 Relative risk for alcoholic beverage types and lung cancer risk (Chao et al. 2007)

Alcohol consumption Beer Wine Liquor

≥1 drink/day 1.25 (1.06-1.48) 0.78 (0.60-1.02) 1.25 (1.04-1.51)

≤1 drink/day 0.78 (0.64-0.95) 0.77 (0.59-1.00) 0.89 (0.74-1.08)


A population-based matched case-control study254 reported that there was no positive association between beer consumption and lung cancer risk, and the positive trend for risk was not statistically significant, as shown in Table 19.12.

Table 19.12 Odds ratio for beer consumption and risk of lung cancer (Mayne et al. 1994)

Alcohol type

Quartile of consumptionI

Quartile of consumptionII

Quartile of consumptionIII

Quartile of consumptionIV

p for trend

Beer 1.0 1.06 0.87 1.18 Non-significant

Adjusted for cigarette use, religion, education, body mass index & income

Vodka consumption was found to be positively associated with increased risk of lung cancer in a study256 that reported age-adjusted relative risk estimates for vodka consumption in women in Poland (see Table 19.10 above).

19.2.5 Alcohol consumption and risk of lung cancer in alcoholics

Korte et al.246 investigated risk of lung cancer in a meta-analysis of 12 studies including alcoholic participants. Relative risk of lung cancer was reported as 1.99 (1.66 – 2.39). However, this value was unadjusted for smoking status.

Two further studies on alcoholics also showed that excessive alcohol intake increased the risk of lung cancer.248, 250 Meta-analysis of the data from the studies confirms that alcoholics have approximately twice the risk of lung cancer (Figure 19.2), similar to the results of the earlier meta-analysis presented by Korte et al.246 above for heavy drinkers and alcoholics alike. However, in these studies, smoking was similarly not adjusted for and confounds any interpretation of the increased risk being attributable to alcoholism. The study by Boffetta et al.248 also showed that 25 years after first hospitalisation for alcoholism, the probability of developing lung cancer was 5%.

Figure 19.2 Risk of lung cancer among alcoholic male and female patients

Adjusted for age, gender and calendar period/year

19.3 SummaryEvidence suggests that alcohol does not play an independent role in lung cancer aetiology. The majority of evidence suggests that low to moderate alcohol consumption is not associated with an increased risk of lung cancer in non-smokers. It has been identified in the literature that smoking may modify the effect of alcohol consumption.

It is ideal to consider the types of alcoholic beverages consumed when examining the effect of alcohol consumption on risk of lung cancer. Evidence suggests that high


consumption of beer and liquors may be associated with an increased risk of lung cancer, but modest wine consumption may actually lower the risk.

Overall, evidence for a smoking-adjusted association between alcohol and lung cancer risk is limited to very high consumption groups (on an average, ≥ 5 drinks per day). Light to moderate alcohol consumption was not statistically significantly associated with the risk of lung cancer, even after adjustment for smoking and other major risk factors. According to many of the included studies, any associations observed with lower levels of alcohol consumption could be explained by confounding factors, and residual confounding by smoking may be most likely in the highest alcohol consumption category. The risk of lung cancer attributable to high alcohol consumption remained consistent amongst current smokers and men. There was only limited evidence available for women and alcohol consumption. Any increased risk of lung cancer due to alcoholism is difficult to conclude due to the potential impact of smoking on the results from included studies.


Alcoholic beverages have been classified as a Group 1 carcinogen by International Agency for Research on Cancer.260 Alcoholic beverages have been causally associated with cancers of the oral cavity and pharynx, oesophagus, upper aerodigestive tract (oral cavity, pharynx, larynx and oesophagus combined), colorectum, liver, and breast. The evidence was inadequate or inconsistent for causal association between consumption of alcoholic beverages and cancer of the lung.260


Consumption of alcohol does not appear to increase the risk of lung cancer. The recently published IARC monograph260 also states that a causal association between consumption of alcoholic beverages and lung cancer could not be determined based on the available evidence due to residual confounding with tobacco smoking. However, consumption of beer and spirits in excess quantities (more than 5 drinks per day) may lead to an increased risk of lung cancer. Binge drinking, particularly in men who smoke, increases the risk of lung cancer irrespective of the number of cigarettes smoked per day.


19.5 Methodological quality of studiesTable 19.13 Alcohol consumption: Methodological quality of included studies

Study Design Q1 Q2 Q3 Q4 Q5

Q6 Q7 Q8

Q9 Q10

Total (Y) Include/Exclude

Bagnardi et al.2011 Meta-analysis Y N — — U U Y Y Y U 6 Include

Balder et al. 2005 Cohort Y Y NA — U Y Y Y Y — 7 Include

Boffetta et al.2001 Cohort Y Y NA U — Y U Y Y — 6 Include

Breslow et al.2000 Cohort Y Y NA Y U Y Y Y Y — 7 Include

Chao et al.2007 Meta-analysis U N N Y U U U Y Y Y 4 Include

Djousse et al.2002 Cohort Y Y NA Y Y Y Y Y N — 7 Include

Korte et al.2002 Meta-analysis U N N Y U U U Y U U 3 Include

Mayne et al.1994 Cohort N Y Y Y Y NA Y Y Y — 7 Include

Pierce et al.1989 Case control Y Y Y Y Y NA Y U Y — 7 Include

Rachtan & Sokolowski 1997 Cohort Y Y Y U Y NA U Y Y — 6 Include

Shimazu et al.2008 Cohort Y Y NA Y Y Y N Y Y — 7 Include

Sorensen et al.1998 Cohort Y Y NA N Y Y Y Y Y — 7 Include

Stemmermann et al.1990 Cohort Y Y NA Y Y Y Y Y Y — 8 Include

Toriola et al.2009 Cohort Y Y NA Y Y Y U Y Y — 7 Include

Murata et al 1996 Nested case-control study

N Y Y N U NA U Y Y — 4 Exclude


Bagnardi et al. 2011

The objective of this meta-analysis was clearly stated and described. The search strategy was appropriate; however, the sources of studies were inadequate with only one database (Medline) searched. The criteria for including studies were adequate; however, the search was restricted to English language publications. Three independent investigators assessed the eligibility of each article for inclusion in meta-analysis. The methods used to minimise errors in data extraction were not clear. Appropriate methods were used to combine the studies for a pooled RR. The recommendations provided were congruent with the data reported; however, the authors did not provide any specific directives for further research.

Balder et al. 2005

The subject sample was clearly described and the participants were at a similar point in the course of their condition. The details of cohort selection were clearly described. Potential confounding factors were identified and adjusted for. The follow-up period was adequate with 9.3 years of follow-up and people lost to follow-up or excluded were clearly described. It was unclear whether outcomes were assessed using objective criteria; however, lung cancer incidence was measured in a reliable way with International Classification of Diseases codes. Statistical analysis was adequately described and appropriate statistical method was used to estimate RR.

Boffetta et al. 2001

The subject sample was representative of alcoholics and the participants were at a similar point in the course of their condition, which was at hospital discharge diagnosis of alcoholism. It was unclear whether potential confounding factors were identified and adjusted for. The average follow-up period was 10.2 years, which was adequate considering other studies; however, the study did not provide clear description of people lost to follow-up or people excluded from the analysis. Outcomes were assessed using objective criteria and measured using standard classifications and tools. Standardised Incident Ratio was the measure of choice and the analysis was performed using SAS statistical package.

Breslow et al. 2000

The methods and objectives were generally well described in this study. Subjects were representative of target population and exposure and methods of interview/data collection well described. Confounding factors considered appropriately Outcome measures and statistical methods used were adequately described. It was unclear whether outcomes were assessed using objective criteria. The outcomes of people who withdrew or were excluded were adequately described.

Chao et al. 2007

The objectives of this meta-analysis were clearly stated and described with identification of gap in the relevant literature. The search strategy was not described clearly and only one database (PubMed) was searched. Inclusion and exclusion criteria were described adequately; however, details were lacking on criteria for appraising studies. It is unclear whether the appraisal was conducted by two independent reviewers. The methods used to minimise errors in data extraction were not provided. Data analysis was adequately described with appropriate methods to combine studies and methods to investigate


heterogeneity when detected. Recommendations were supported by the data presented and the authors provided specific directives for future research.

Djousse et al. 2002

Overall the study was well conducted and reported. Subjects were representative of target population and their selection well addressed. Exposure well defined and recorded. Confounding factors identified and well adjusted for. Statistical methods were appropriate and adequately described. Lung cancer confirmed and assessed using criteria. There was adequate follow-up.

Korte et al. 2002

The objective of the paper was clearly stated and described. The search strategy was appropriate. The sources of studies included Medline and a bibliographic search. The criteria for appraising studies were not clearly described as well as it was unclear whether two independent reviewers conducted the appraisal. The methods used to minimise errors in data extraction were not clear. Appropriate method was used to combine the studies. The authors provided recommendations based on their data analysis and did not mention any specific directives for future research.

Mayne et al. 1994

Overall the study addressed its objectives well and was a well-designed matched case-control study. It was unclear whether cases were representative of target population. Several potential confounding factors identified which were matched by design and not included in the analysis and several other potential confounders identified and addressed in the analysis. Condition of patients included and losses adequately described. Lung cancer determined from various standard sources. Statistical methods were adequately described.

Pierce et al.1989

Overall the study addressed its objectives. Cases were representative of target population, however controls also from hospital for other surgical procedures. Potential confounding factors were identified and addressed. It was unclear whether outcomes were assessed using objective criteria. Condition of patients included and losses briefly described. Statistical methods were appropriate and adequately described.

Rachtan & Sokolowski 1997

The description of the study design and setting was clear and subjects appeared representative of target population. Cases were representative of target population and controls were also from the same hospital from the next-of-kin of other patients without tobacco-related cancers. There was no description of potential confounding factors. Outcomes and their measurement were adequately described. Risk ratios (RRs) and 95% CIs were estimated using univariate logit models. Statistical methods were adequately described

Shimazu et al. 2008

Participants’ recruitment was adequately described and the subjects were representative of target population. Statistical analysis was adequately described that included


adjustment for potential confounding factors. Exposure was well defined and described. The outcomes of people who withdrew were not described and included in the analysis.

Sorensen et al. 1998

The description of the study design and setting and the eligibility criteria for subjects included in the study was clear and subjects appeared representative of target population. Outcomes and their measurement were adequately described. Statistical methods were described well. Standardised Incident Ratios were used to estimate the risk.

Stemmermann et al. 1990

The objective and methods were clearly stated with adequate description of confounding factors and outcome measures. The study sample was representative of the population as a whole. The condition of the participants varied depending on the amount of alcohol consumed in calories per day. Lung cancer incidence was confirmed through various standard reports. People who withdrew or excluded were described in the analysis. Statistical methods were described adequately including details on statistical model and software package.

Toriola et al. 2009

Well-designed and conducted study with a cohort representative of the target population. Confounding factors were identified and adjusted in the analysis. There was sufficient follow-up period; however, it was not clear whether people who withdrew were described and included in the analysis. Statistical methods were adequately described.


20 Risk factor: Dietary cholesterol and blood cholesterol20.1 IntroductionAn Australian Diabetes, Obesity and Lifestyle study conducted between 1999 and 2000 found that more than six million adults aged 25 years and over had cholesterol levels greater than the recommended maximum circulating concentration of 5.5 mmol/L.261 Studies suggest that for every additional 100 grams of cholesterol consumed, there is a 2-3% increase in plasma cholesterol.262 High blood cholesterol levels have been shown to be a major risk factor for coronary heart disease in Australia, however, the evidence regarding an association with lung cancer is not clear.

Sixteen studies were located by the initial search and a further 21 papers were identified from the additional search. After title and abstract examination, full-text of 35 studies were retrieved, and 21 studies were considered for critical appraisal and were ultimately included in the report. These studies included: two pooled analyses, nine prospective cohort studies and ten case-control studies.

The majority of the studies focused on dietary cholesterol intake and its association with lung cancer. The major methods of data collection were self-administered structured questionnaires and food frequency questionnaires. Some of the other data collection methods included personal interviews for dietary assessment by trained investigators, and cancer registries. Five cohort studies263-267 and two case-control studies240 particularly focused on men; one cohort study268 and two case-control studies269, 270 focused on women, whilst the rest included both men and women. The age range was between 20 and 75 years across the included studies.

Dietary assessment of cholesterol intake varied, with some studies measuring cholesterol intake in mg/day and some studies in mg/week. In addition, cholesterol consumption was reported in tertiles, quartiles and quintiles of intake. The average length of follow-up period ranged from six to 24 years in the cohort studies. In the case-control studies, the selection of cases and controls was mostly unbiased. Risk of lung cancer was the major outcome measured in all studies, with lung mortality being the other outcome in only two studies. Age, smoking status, smoking history, education and body mass index (BMI) were consistently found to be the potential confounding factors and adjusted for. Most of the studies did not clearly present their findings separately for smokers, non-smokers and former smokers, except for four studies. Table 20.1 highlights the characteristics of included studies relevant to an association between cholesterol and lung cancer.


Table 20.1 Study characteristics relevant to the association between cholesterol and lung cancer




Ahn et al 2009FinlandProspective cohort study

7,545 incident cases identified in men aged between 50-69 years.18 years follow-up

Cohort follow-up from a previous clinical trial linked to the Finnish Cancer Registry

Serum Total and High-Density Lipoprotein (HDL) cholesterol

Lung cancer ascertained by medical records, histopathology & cytology specimens and Finnish Cancer Registry

Cox proportional hazard regression analysis to generate RR 95% CI using the SAS PROC PHREG procedure.Confounders adjusted for in the model: Age, intervention, level of education, systolic blood pressure, BMI, physical activity, duration of smoking, number of cigarettes smoked per day, saturated fat intake, alcohol consumption

Overall risk of lung cancer associated with total serum cholesterol.RR (95% CI) 0.81 (0.72-0.92)P for trend = 0.0006Overall risk of lung cancer associated with serum HDL cholesterol.RR (95% CI) 0.89 (0.83-0.97)P for trend = 0.01Serum total cholesterol and HDL cholesterol significantly inversely related to lung cancer.

Alavanja et al 1996USACase-control study

White non-smoking women between 30-84 years.429 cases and 1021 control subjects.

Population-based sample. Controls selected by frequency matching on age.Self-administered questionnaires and next-of-kin interviews for dietary data.

Cholesterol daily intake in mgQuintiles of consumption – lowest to highest in five categories (Q1 – Q5)

Lung cancer confirmed from cancer registry

Unconditional logistic regressionConfounders adjusted for in the model: Age, smoking history, previous lung disease, interview type and total calories per day

Overall risk of lung cancer associated with daily cholesterol intake (OR), CIs not reportedLowest quintile (1) - 1.0 (ref)Q2 - 0.63Q3 - 0.71Q4 - 1.14Q5 – 1.09P for linear trend – 0.22

Byers et al. 1987USACase-control study

General population from three counties, aged between 35-79 years.

Nurse-interviews conducted in patients’ homes.Physician

Cholesterol consumption by quartilesLow to high –Q1 – Q4.

Lung cancer confirmed by histology

Multiple logistic regression analysisSmoking adjusted RRs by quartiles:

Risk of lung cancer associated with daily cholesterol intake, by gender(OR). CIs not reported.Males:





Males: 296 cases & 587 controlsFemales: 154 cases & 315 controls

approvals for casesInterviewers’ performance monitored by periodic observation by a field supervisor

Q1 - 0.7; Q2 - 0.9; Q3 - 1.2; Q4 - 1.0P for trend = 0.17Females:Q1 - 1.1; Q2 - 1.7; Q3 - 1.2; Q4 - 1.0P for trend = 0.91

Chang et al.1995USAProspective cohort study

2,011 men and 2,327 women. Older adults.Follow-up 18 years

Survey and interviews using standardised questionnaire and limited physical examination

Low plasma cholesterol (<160 mg/dl)

Lung cancer ascertainment by review of medical records and mortality data from death certificates and ICD classification.

Cox proportional hazard analysis and analysis of covarianceAdjustment factors: Age, BMI, smoking

Risk of lung cancer mortality at <160mg/dl plasma By gender. RH (95% CI)Men: RH 1.81 (0.38–3.95)Women: RH 3.28 (1.17 – 9.19)(P = 0.02)Risk of lung cancer (lowest level <160 mg/dl compared to highest level ≥240 mg/dl)Men: RH 1.62 (0.66-3.92)Women: RH 3.45 (1.13 – 10.42)

De Stefani et al. 2002UruguayCase-control study

Male population200 cases & 600 controls recruited from the same hospital.Controls frequency matched to age, residence & urban/rural status

Detailed questionnaires including food frequency questionnaire

Cholesterol - tertiles of intakeLow to high – TI, TII, & TIII

Adenocarcinoma of the lung confirmed by histology

Unconditional multiple logistic regressionPotential confounders adjusted for in the model: age, residence, urban/rural status, education, BMI, smoking status, smoking duration & total energy intake

Overall risk of lung cancer associated with cholesterol intake. OR (95% CI)TI – 1.0 (reference)TII – OR 1.24 (0.80 - 1.92)TIII – OR 1.83 (1.20 – 2.79)P for trend = 0.004

Eichholzer et al. 2000

2974 men who worked in major chemical and

Description unclear

Plasma cholesterol

Lung cancer ascertained from ICD

Inferential analysis of the explanatory variables was based on the Cox proportional hazards

Overall risk of lung cancer associated with plasma cholesterol





SwitzerlandProspective cohort study

pharmaceutical companies.17 year follow-up

concentrations classification and death certificates to identify causes of deaths

regression model.Potential confounders adjusted for: smoking habits and age

levels and age.RR (95% CI)Low cholesterol and age > 60 yearsRR 1.99 (1.18 - 3.37)Low cholesterol and age ≤ 60 yearsRR 0.54 (0.21 - 1.38)Definition of low cholesterol not provided.

Goodman et al. 1988USACase-control study

Males: 226 cases & 597 controlsFemales: 100 cases & 268 controlsFive ethnic groups – Caucasian, Japanese, Chinese, Filipino & Hawaiian

Population-based.Random selection through telephone directory for control selection.Structured interviewing for data collection in subjects’ homes

Cholesterol consumption in quartilesLow to high – QI - QIV

Lung cancer confirmed by histology through pathologic records and admission records from Hawaii Tumour Registry

Multiple logistic regressionPotential confounders adjusted for: age, ethnicity & pack-years of cigarette smoking

Overall risk of lung cancer associated with dietary cholesterol levels by gender.RR (95% CI)Q1 reference categoryHighest quartile:Males: OR 2.2 (1.3 - 3.8)Females: OR 0.9 (0.4 - 2.1)P for trendMales: 0.04Females: 0.86

Hinds et al. 1983aUSACase-control study

Males: 261 cases & 444 controlsFemales: 103 cases & 183 controlsFive ethnic groups – Caucasian, Japanese, Chinese, Filipino & Hawaiian

Interviews Weekly dietary cholesterol intake in mg

Lung cancer ascertained from pathology logs, physician confirmation & Hawaii Tumour Registry. Next of kin interviews.

Multiple logistic regression analysisPotential confounders adjusted for: age, ethnicity, pack-years of cigarette smoking, occupational status, vitamin A intake and gender.

Overall risk of lung cancer associated with weekly cholesterol intake.0-750 mgSmoking subjects, males & females OR 1.0 (reference)2071+ mgSmoking subjects (both genders) OR (95% CI) 2.1 (1.2 - 3.4)Males – 2.3 (1.4 - 4.0)





Females – 1.2 (0.5 - 3.0)

Hinds et al. 1983bUSACase-control study

Hawaiian men: 188 cases & 294 controls

Random digit telephone surveys and structured questionnaires

Weekly dietary cholesterol intake in mg

Lung cancer ascertained from Hawaii Tumour Registry

Multiple logistic regression analysisPotential confounders adjusted for: age, ethnicity, pack-years of cigarette smoking & occupational exposure to lung carcinogens

Overall risk of lung cancer associated with weekly cholesterol intake (mg).0-999 - OR 1.00 (reference)1000-1999 - OR (95% CI) 1.65 (1.00 - 2.75)2000-3499 - OR 2.28 (1.28 - 4.09)3500+ - OR 3.50 (1.70 - 7.21)

Hu et al 2011CanadaCase-control study

19732 cases (10725 males & 9007 females). Number of controls not given.

Random selection of cases and controls from each of the eight provinces in Canada.Data collection by questionnaires and interviews.

— Diagnosis through pathology reports and confirmation through cancer registries.

Unconditional logistic regression.Potential confounders adjusted for: gender, education, age, BMI, alcohol drinking, pack years smoking, fruit and vegetable intake.

Risk of lung cancer by dietary cholesterol intake in mg/week in quartiles (low-high)1.01.17 (0.98-1.40)1.30 (1.07-1.59)1.61 (1.28-2.03)

Jain et al. 1990CanadaCase-control study

Men & women aged between 20 & 75 yearsMen: 401 cases & 362 controlsWomen: 438 cases & 410 controls

Random selection of one female and one male for each pair of cases.Interviews and diet history

Mean daily intake of cholesterol

Histological confirmation of lung cancer diagnosis

Conditional logistic regressionPotential confounders adjusted for: cumulative cigarette smoking

Overall risk of lung cancer by unit of consumption of cholesterol intakeOR (95% CI) 1.51 (1.165- 1.97)

Keys et al. 1985Seven countriesProspective cohort study

11,325 healthy men aged between 40-59 years.15 year follow-

Seven countries study with a common protocol, standardised methods and

Serum cholesterol concentrations

Mortality ascertained by death certificates, information from local hospitals,

Multivariate analysisPotential confounders adjusted for: age, blood pressure, smoking habit, BMI, physical activity and serum cholesterol

Overall risk of lung cancer associated with low serum cholesterol RRNumbers of men with low cholesterol dead from lung cancer





up agreed diagnostic criteria.

physicians, relatives and witnesses and hospital discharge records

in years 6-15 in a cohort from seven countriesObserved – 35 Expected – 24.93Observed/Expected – 1.40RR = 1.58

Knekt et al. 1991FinlandProspective cohort study

5,304 men aged between 20-69 years and randomly recruited from a large survey on dietary intake.20 years follow-up.

Self-administered questionnaires and Structured interviews by trained interviewers.Finnish food composition values considered

Mean daily intake of dietary cholesterol

Lung cancer incidence ascertained from Finnish Cancer Registry with data on histological type collected

Cox proportional hazard model used to estimate the associationMultivariate analysisAdjustment factors: age, smoking and energy intake

Overall risk of lung cancer associated with cholesterol intake RR between the highest and lowest tertilesRR (95% CI) 1.0 (0.6 - 1.9)

Kucharska-Newton et al. 2008USAProspective cohort study

15, 972 men and women, aged 45-64 years recruited as a probability sample.13 years follow-up

Atherosclerosis Risk in Communities (ARIC) cohort study.Physical examination and risk factor assessment conducted at baseline visit and at three subsequent visits

Plasma HDL cholesterol levels

Incidence ascertained on the basis of self-report by cohort participants and cancer registries.

Adjusted Cox proportional Hazard Ratios for low vs high HDL and incidencePotential confounding factors adjusted for: age, race, gender, BMI, smoking status, cigarette pack years of smoking, exercise and alcohol consumption

Overall risk of lung cancer associated with HDL cholesterol levels and smoking statusTotal sample HR (95% CI) – 1.45 (1.10-1.92)Current smokers – 1.04 (0.74-1.47)Former smokers – 1.77 (1.05-2.97)Never smokers – 1.56 (0.41-5.86)

Law et al 1991Pooled Analysis of studies mostly from USA and some

4,661 subjects with cancer diagnosed within two years of the

Analysis based on 33 prospective studies

Level of serum cholesterol

Description unclear

Standard techniques to compare the average case-control cholesterol differences in individual studies. Der-Simonian and Laird method to adjust for heterogeneity.

Overall risk of lung cancer associated with serum cholesterol levels. RR (95% CI)Low serum cholesterol associated with long-term lung cancer risk in





from Europe cholesterol measurement or causing death within five years

Not clear if potential confounding factors adjusted

men; however, confounded by smoking. Mean (SE) case-control cholesterol difference (mmol/l): -0.101 (0.022)

Shekelle et al. 1991USAProspective cohort study

1,878 men employed at Western Electric Company, Chicago for at least 2 yrs and aged between 40-55 years in 1958.24 year follow-up

Complete physical examination, detailed medical history and measurement of serum cholesterol.Standardised interviews and questionnaires

Intake of dietary cholesterol in mg/day

Cancer ascertained from medical and hospital records and death certificates.

Proportional hazards regression analysis.Potential confounding factors adjusted for: cigarette smoking, intake of beta-carotene and other confounding variables

Overall risk of lung cancer associated with cholesterol intake mg/day RRNo CI reported198-604 mg/day - 1.00 (reference)605-794 mg/day - 1.30795-1,909 mg/day - 1.94

Smith-Warner et al 2002Pooled analysis of studies from USA, Netherlands and Canada

280,419 female and 149,862 male participants. 3,188 lung cancer cases.Follow-up 6-16 years

Analysis based on eight prospective cohort studies

Intake of dietary cholesterol

Lung cancer identified based on ICD classification and histological confirmation within individual studies

Random-effects model by Der-Simonian and Laird method.Potential confounding factors adjusted: age, BMI, smoking history, total fruit and vegetable consumption and energy intake

Overall risk of lung cancer associated with cholesterol intakePooled multivariate RR (95% CI) was 1.01 (0.97 - 1.05) for an increment 100mg/dayQ1 – 1.00Q2 – 1.02 (0.89-1.18)Q3 – 1.03 (0.90-1.17)Q4 – 1.06 (0.94-1.20)

Steenland et al. 1995USACase-control study

657 male & 593 female cancer casesControls – 11, 804 men & women

National Health and Nutrition Survey I follow-up dataCollection of interviews and medical exam data

Cholesterol consumption in quartiles as continuous variable<190190-216217-246247+

Lung cancer diagnosis by ICD classification on a hospital discharge record & for those not on record, death certificates

Cox regression and multivariate analysesPotential confounding factors considered: age, smoking, alcohol consumption, BMI & income

Overall risk of lung cancer associated with cholesterol intake mg/dayHighest quartile compared to three other quartiles<190 vs 247+OR (95% CI) 1.48 (0.96 - 2.29)190-216 vs 247+





OR 0.89 (0.55 - 1.42)217-246 vs 247+OR 0.93 (0.59 - 1.46)P for trend = 0.14

Swanson et al. 1997USACase-control study

Women aged between 35 and 84 years587 cases and 624 controls

Probability matching and two-stage randomised recruitment process for controlsInterviewers received standardised training

Quintiles Intake of cholesterol in mg/1000 kcal<102102-126127-148149-176177+

Lung cancer diagnosis identified from Missouri Cancer RegistryHistological confirmation from pathologists

Logistic regressionPotential confounding factors considered: education, pack-years of smoking, BMI, veg & fruit intake

Overall risk of lung cancer associated with cholesterol intake mg/1000kcal RR (95% CI)by lowest and highest categories< 102 = 1.0102-126 = 1.21 (0.8-1.8)127-148 = 0.88 (0.6-1.3)149-176 = 1.04 (0.7-1.6)177+ = 1.22 (0.8-1.8)

Veierod et al. 1997NorwayProspective cohort study

25,965 men and 25,496 women aged 16-56 years15-17 years follow-up

Norwegian National Health Screening Service.Self-administered questionnaires

Dietary cholesterol intake in mg/day

Cancer cases identified from Norway Cancer Registry

Poisson regression analysis used to estimate associationPotential confounders adjusted for: smoking status, gender, age at inclusion and time-scale variable attained age

Overall risk of lung cancer associated with cholesterol intake mg/dayRR (95% CI)Q1 - ≤ 154.9 RR 1.0 (reference)Q2 – 155.0-196.1 RR 1.4 (0.9 - 2.3)Q3 – 196.2-240.5 RR 1.3 (0.8 - 2.1)Q4 - ≥ 240.6 RR 1.2 (0.8 - 1.9)

Wu et al. 1994USAProspective cohort study

41,837 postmenopausal women.Six years follow-up

Population-based prospective cohort study

Dietary cholesterol intake

Cancer cases identified through Health Registry of Iowa and based on ICD classification and histological confirmation

Proportional hazards regression used to estimate association, Cox regression analysis to minimise potential confounding effectsPotential confounding factors adjusted for: smoking status, pack-years of cigarette smoking, physical activity, occupation, age and energy intake

Overall risk of lung cancer associated with cholesterol intake in non-smokers and according to intake of cholesterol in quartilesRR (95% CI)Q1 (low) – 1.0 (reference)Q2 – RR 1.0 (0.4 - 2.7)Q3 – RR 1.4 (0.6 - 3.4)





Q4 – RR 0.9 (0.3 - 2.5)P for trend = 0.98


20.2 Results20.2.1 Dietary cholesterol intake and overall risk of lung cancer

In a pooled analysis271 of eight prospective cohort studies, dietary cholesterol was reportedly not associated with lung cancer incidence. There was no statistically significant heterogeneity among studies or by sex. Similarly, a cohort study found no association between dietary cholesterol and lung cancer risk in either men or women.272 Other data are indicative of an important relationship between fat or cholesterol intake and lung cancer risk. High (highest quartile) dietary cholesterol intake was positively and significantly associated with risk of lung cancer, and there was a statistically significant trend present overall.273, 274 Risk estimates are presented in Table 20.2.

Table 20.2 Risk of lung cancer and dietary cholesterol intake in quartiles of consumption

Study I (ref) II III IV P for trend

Veierod et al 1997(mg/day)IRRs & 95% CIs

1.0 1.4 (0.9-2.3) 1.3 (0.8-2.1) 1.2 (0.8-1.9) 0.8

Smith-Warner et al. 2002 (RRs & 95% CIs)

1.0 1.02 (0.89-1.18) 1.03 (0.90-1.17) 1.06 (0.94-1.20) 0.31

Hu et al.2011(mg/wk) ORs & 95% CIs

1.0 1.17 (0.98-1.40) 1.30 (1.07-1.59) 1.61 (1.28-2.03) <0.0001

Jain et al. 1990(mg/day) ORs

1.0 0.87 0.99 1.58 0.02

20.2.2 Risk of lung cancer and dietary cholesterol intake by smoking status

The large pooled analysis revealed no association between dietary cholesterol intake and risk of lung cancer within any of the smoking groups,271 as shown in Table 20.3.

Table 20.3 Pooled multivariate-adjusted RRs and 95% CIs of lung cancer for dietary cholesterol (for 100mg/day increases), (Smith Warner et al. 2002)

Current smokers Past smokers Never smokers

0.99 (0.93-1.05) 1.06 (0.99-1.13) 1.00 (0.87-1.15)

Remaining studies that presented data by smoking status did so only for single genders. As with the results reported for combined genders above, no significant association was observed between dietary cholesterol intake and the risk of lung cancer in both non-smoking and smoking, postmenopausal women.268 These estimates of risk are summarised in Table 20.4.


Table 20.4 RRs and 95% CIs of lung cancer by smoking status according to quartile intake of dietary cholesterol among postmenopausal women (Wu et al. 1994)

Dietary cholesterol

Non-smokers Ever smokersSquamous/small cell lung cancer

Ever smokersAdenocarcinoma

Q1 (low) 1.0 1.0 1.0

Q4 (high) 0.9 (0.3-2.5) 1.1 (0.6-2.0) 0.6 (0.3-1.3)

P for trend 0.98 0.72 0.39

When subjects were grouped by cigarette smoking status, there was no apparent effect of cholesterol in men who were current or past smokers.275 These risk estimates are shown in Table 20.5. Risk of cancer was reportedly increased where high cholesterol intake was linked with heavy smoking (>40 pack years, p=0.01).275

Table 20.5 ORs and 95% CIs for the development of lung cancer among males, by quartiles of cholesterol consumption, (Goodman et al. 1988)

Category I (low) 2 3 4 (high) P for trend

Current smoker 1.0 2.8 (1.2-6.5) 2.1 (0.9-4.7) 2.4 (1.1-5.2) 0.18

Past smoker 1.0 1.6 (0.8-3.5) 0.9 (0.4-2.2) 1.1 (0.5-2.6) 0.78Adjusted for age, ethnicity and pack years

20.2.3 Dietary cholesterol intake, gender and risk of lung cancer

Men

Meta-analysis of a comparable cohort and a case-control study that assessed lung cancer risk in relation to similar tertiles of cholesterol consumption indicates dietary cholesterol does not increase risk of lung cancer in men who consume large amounts of dietary cholesterol relative to those who do not (Figure 20.1). The cohort study by Knekt et al.266 found that dietary cholesterol intake was not associated with lung cancer risk, whilst in the included case-control study,240 high consumption of dietary cholesterol was found to contribute to a high risk of adenocarcinoma of the lung.

Figure 20.1 Risk of lung cancer and dietary cholesterol intake by highest tertile of consumption in men

De Stefani - Only exposure categories stated, no specific details on exposure. Knekt – Highest exposure category >609 mean daily intake of dietary cholesterol

A further case-control study compared the highest quartile of cholesterol consumption to other quartiles in men.276 No significant difference in risk of lung cancer between the highest and lowest intake groups was reported. No significant trend was observed across


groups to indicate any detrimental effect of high cholesterol intake (as presented in Table 20.6).

Table 20.6 ORs and 95% CIs for lung cancer risk with highest quartile of cholesterol intake compared to other quartiles in men, (Steenland et al. 1995)

<190 vs 247+ mg/dl 190-216 vs 247+ mg/dl 217-246 vs 247+ mg/dl

P for trend

1.48 (0.96-2.29) 0.89 (0.55-1.42) 0.93 (0.59-1.46) 0.14

Conversely, studies that investigated high dietary cholesterol intake in men reported a positive and significant association with lung cancer risk.275, 277, 278 A further study reported a weak, but not statistically significant, direct association between dietary cholesterol and lung cancer in men (Byers et al, 1987).265 Risk estimates are presented in Table 20.7.

Table 20.7 Risk of lung cancer and dietary cholesterol consumption in quartiles

Study Weekly intake of cholesterol (mg)

Weekly intake of cholesterol (mg)



Hinds et al. 1983a 0-750 751-1230 1231-2070 2071+

ORs & 95% CIs 1.0 1.2 (0.7-2.1) 1.4 (0.9-2.4) 2.3 (1.4-4.0)

Hinds et al. 1983b 0-999 1000-1999 2000-3499 3500+

RRs & 95% CIs 1.0 1.65 (1.00-2.75) 2.28 (1.28-4.09) 3.50 (1.70-7.21)

Study 1 (low) 2 3 4 (high)

Byers et al 1987RRs

0.7 0.9 1.2 1.0

Study Daily Cholesterol intake (mg)

Daily Cholesterol intake (mg)



Goodman et al. 1988 ORs & 95% CIs

1.0 2.3 (1.4-4.0) 1.8 (1.0-3.1) 2.2 (1.3-3.8)*

(* = 0.04)

A further study by Shekelle et al.,267 similarly indicates that increasing intake of dietary cholesterol was associated with increased risk of lung cancer; however, results from this study suggested that the association was specific to cholesterol from eggs and not to consumption of other sources of dietary cholesterol (Table 20.8).

Table 20.8 Risk of lung cancer and dietary cholesterol consumption in tertiles for men. No CIs reported, (Shekelle et al. 1991)

Category 198-604 mg/d 605-794 mg/d 795-1909 mg/d

RRs 1.00 1.30 1.94


Women

Dietary cholesterol was not associated with lung cancer risk in women,269, 270, 278 as shown in Table 20.9.

Table 20.9 Risk of lung cancer and dietary cholesterol consumption in women in quintiles

Cholesterol intake in mgAlavanja et al. 1996

≤119 120-162 163-214 215-302 ≥303 P

ORs 1 (ref) 0.95 (0.84-1.07)

0.87 (0.77-0.98)

0.92 (0.82-1.03)

0.81 (0.72-0.92)

0.22

Cholesterol intake in mg/1000 kcalSwanson et al. 1997

<102 102-126 127-148 149-176 177+

RRs 1.0 1.21 (0.8-1.8) 0.88 (0.6-1.3) 1.04 (0.7-1.6) 1.22 (0.8-1.8)

Three case-control studies272, 275, 279 did not show any significant positive association between dietary cholesterol and the risk of lung cancer in women. Risk estimates can be found in Table 20.10.

Table 20.10 Risk of lung cancer and dietary cholesterol consumption in quartiles

Study 1 (low) 2 3 4 (high) P for trend

Veierod et al 1997IRRs & 95% CIs

1.0 1.4 (0.9-2.3) 1.3 (0.8-2.1) 1.2 (0.8-1.9) 0.8

Byers et al. 1987 RRs

1.1 1.7 1.2 1.0 0.91

Goodman et al. 1988 ORs & 95% CIs

1.0 0.6 (0.2-1.5) 1.5 (0.7-3.3) 0.9 (0.4-2.1) 0.86

Similarly, when the relationship was investigated in quartiles, there was no significant association (Table 20.11) between lung cancer risk and dietary cholesterol intake when the highest quartile of consumption was compared to other quartiles.276

Table 20.11 ORs and 95% CIs for lung cancer risk with highest quartile of cholesterol intake compared to other quartiles in women (Steenland et al. 1995)

<186 vs 252+ 186-216 vs 252+ 216-251 vs 252+ P for trend

1.29 (0.70-2.40) 0.50 (0.20-1.30) 1.18 (0.51-2.74) Not provided


20.3 Risk of lung cancer and blood cholesterol concentration1

Whilst the results from studies investigating dietary cholesterol intake are varied and may indicate a potential risk of lung cancer attributable to this risk factor, those studies that measured circulating cholesterol, both plasma and serum, are generally uniform in their results.

In a recent individual cohort study conducted by Ahn et al.,263 higher total serum cholesterol concentration was associated with a decreased risk of lung cancer, as summarised in Table 20.12. The association was no longer significant however, upon inclusion of only those cases diagnosed more than nine years previous. This analysis indicated that lower serum cholesterol may be a marker of existing malignancy and not a causal factor. Greater serum HDL cholesterol was not significantly associated with lung cancer.263

Table 20.12 RRs and 95% CIs of lung cancer in relation to serum total cholesterol (mg/dL) in quintiles (Ahn et al. 2009)

1 (<203.9) 2 (203.9-227.6) 3 (227.7-249.2)

4 (249.3-276.6)

5 (>276.7) P

1 (ref) 0.95 (0.84-1.07) 0.87 (0.77-0.98) 0.92 (0.82-1.03) 0.81 (0.72-0.92) 0.0006

Similarly, a study conducted by Kucharska-Newton et al.280 indicated a relatively weak inverse association of plasma HDL-cholesterol with lung cancer that was dependent on smoking status, with risk increased in former smokers but not current smokers. These risk estimates are presented in Table 20.13.

Table 20.13 Association of plasma HDL-cholesterol quartiles with incidence of lung cancer (RRs & 95% CIs) (Kucharska-Newton et al. 2008)

Category 1 2 3 4 P for trend

Current smokers 0.76 (0.51-1.13) 0.78 (0.52-1.19) 0.68 (0.44-1.05) 1.00 0.35

Former smokers 1.97 (1.01-3.82) 1.44 (0.73-2.84) 1.08 (0.53-2.12) 1.00 0.02

20.4 Risk of lung cancer and blood cholesterol by genderKeys et al.,265 analysing cancer mortality amongst men in seven countries, reported evidence to suggest that as serum cholesterol concentration is reduced below 170mg/dL, risk of lung cancer is increased. Comparing ‘low cholesterol’ men with those in the upper 80% of serum cholesterol, shows the number of cancer mortalities is higher than expected if there were no relationship, as summarised in Table 20.14. The RR for lung cancer, for men with ‘low cholesterol’ was 58% higher than those men with high cholesterol.

1 NB. For the purposes of this review results of studies measuring serum or plasma cholesterol are both treated together as ‘blood’ cholesterol.


Table 20.14 Lung cancer risk and serum cholesterol level (Keys et al. 1985)

No. Observed No. expected Observed/expected RR Chi-square

35 24.93 1.40 1.58 5.24

Consistent with the above results, Chang et al. (1995) found that both men and women with baseline plasma cholesterol levels <160 mg/dl were more likely to die of lung cancer. This difference was statistically significant in women as illustrated in Table 20.15.

Table 20.15 Relative Hazards and 95% CIs of lung cancer mortality by low plasma cholesterol (<160mg/dl) compared with all other cholesterol levels (Chang et al. 1995)

Category RH (95% CI) P

Males 1.75 (0.80-3.82) 0.28

Females 3.29 (1.17-9.22) 0.02Adjusted for age, BMI, smoking and education adjusted

Low plasma cholesterol concentrations (<5.16 mmol/L) were associated with a significantly higher risk of lung cancer mortality in men greater than 60 years of age, but not in the younger age group, as shown in Table 20.16.264

Table 20.16 RRs and 95% CIs of low plasma cholesterol compared with higher concentrations for lung cancer (Eichholzer et al. 2000)

Category RRs for all cases RRs, first 2yrs of follow-up excluded

Low cholesterol and age ≤60 y 0.54 (0.21-1.38) 0.56 (0.22-1.43)

Low cholesterol and age>60 y 1.99 (1.18-3.37) 1.91 (1.11-3.31)

The results reported in men are supported by the pooled analysis conducted by Law et al,281 including data from 26 studies, which showed a long-term association between low serum cholesterol and lung cancer in men (case-control difference = -0.101 [SE = 0.022 mmol/l], P = 0.007). Whereas in women, data from five studies showed no long-term association between lung cancer and low serum cholesterol (case-control difference = + 0.010 [SE = 0.054] mmol/l).281

20.5 Summary20.5.1 Dietary cholesterol and risk of lung cancer

Evidence informing the relationship between dietary cholesterol and risk of lung cancer is mixed. Some located studies suggested that risk of lung cancer increases with high intake of dietary cholesterol. However, combined data in this review, and from pooled analysis of eight prospective cohort studies, indicate that there is no significant association between dietary cholesterol intake and risk of lung cancer incidence in both men and women. The pooled analysis also indicates that dietary cholesterol intake is not associated with lung cancer incidence in current, past and never-smokers.

Evidence from case-control studies was also inconsistent. Results from both genders combined suggest a significant and positive association with high dietary cholesterol intake and lung cancer incidence.230, 274 In men, most case-control studies indicated a


significant and positive association between high dietary cholesterol intake (ranging from 100-500mg/day across studies) and lung cancer incidence. In women, no significant association between dietary cholesterol intake and lung cancer incidence was reported.

20.5.2 Blood cholesterol concentration and risk of lung cancer

The results for blood cholesterol were generally more consistent, with higher total blood cholesterol levels associated with a significant decrease in the risk of lung cancer. This relationship was more consistently reported in men than in women.


IARC classify cholesterol as a Group 3 carcinogen, indicating the agent was unclassifiable as carcinogenic to humans due to inadequate evidence.118 Since the IARC monograph was published in 1987, further epidemiological studies investigating a causal association between cholesterol and lung cancer have been conducted.


The evidence suggests that dietary cholesterol intake does not increase the risk of lung cancer in the general population and in men. However, studies were located that appear to contradict this result, reporting a positive association, especially with high levels of cholesterol intake. Considering women alone, the results were more consistent, with no relationship reported between dietary cholesterol intake and lung cancer risk.

High blood cholesterol does not appear to impart any risk of lung cancer on individuals. Rather, the evidence suggests that high blood cholesterol may have a modest protective effect and reduce the risk of lung cancer. Conversely, if plasma cholesterol concentrations are low (<160 mg/dL), there is some evidence to suggest the risk of lung cancer is increased.


20.7 Methodological quality of studiesIndividual critical appraisal checklist items for each included study are shown below in Table 20.17

Table 20.17 Cholesterol: Methodological quality of included studies

Study Study Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Total (Y) Include/Exclude

Ahn et al.2009 Cohort Y Y NA Y Y Y Y Y Y — 8 Include

Alavanja et al. 1996 Case control Y Y Y Y Y NA U Y Y — 7 Include

Byers et al.1987 Case control Y Y Y Y Y NA Y U Y — 7 Include

Chang et al.1995 Cohort Y Y NA Y Y Y Y Y Y — 8 Include

De Stefani et al.2002 Case control Y Y Y Y U NA Y Y Y — 7 Include

Eichholzer et al.2000 Cohort Y Y NA Y N Y Y Y Y — 7 Include

Goodman et al.1988 Case control Y Y Y Y Y NA Y Y Y — 8 Include

Hinds et al (a). 1983 Case control Y Y Y Y N NA Y Y Y — 7 Include

Hinds et al (b). 1983 Case control Y Y Y Y N NA U Y Y — 6 Include

Hu et al.2011 Case control Y Y Y Y Y NA N Y Y — 7 Include

Jain et al.1990 Case control Y Y N U Y NA Y Y Y — 6 Include

Keys et al.1985 Cohort Y Y NA Y Y Y Y Y Y — 8 Include

Knekt et al.1991 Cohort Y Y NA Y U Y N Y Y — 6 Include

Kucharska-Newton et al.2008

Cohort Y Y NA Y N Y U Y Y — 6 Include

Law et al.1991 PooledAnalysis

Y NA N Y NA NA U U Y NA 3 Include



Shekelle et al.1991 Cohort Y Y NA Y N Y Y U Y — 6 Include

Smith-Warner et al.2002 Pooled analysis Y NA Y Y NA NA U Y Y NA 5 Include

Steenland et al.1995 Case control Y Y Y Y U NA U Y Y — 6 Include

Swanson et al.1997 Case control Y Y Y Y Y NA Y Y Y — 8 Include

Veierod et al.1997 Cohort Y Y NA Y Y Y U U Y — 6 Include

Wu et al.1994 Cohort Y Y NA Y Y N Y Y Y — 7 Include


Ahn et al. 2009

The sample was clearly described and the participants were at a similar point with regards to baseline cholesterol levels. Potential confounding factors were identified and adjusted for in a multivariate analysis model. The follow-up period was adequate with 18 years of follow-up and people excluded from analysis were described. Outcomes were assessed and measured using Cancer Registry, medical records, physician and pathologists’ reports. Cox proportional hazard and regression analysis were used to estimate RRs.


The subject sample was representative and the participants were at a similar point with regards to cholesterol daily intake. Multiple potential confounding factors were identified and adjusted for in the analysis. The study did not provide a clear description of people lost to follow-up or people excluded from the analysis. Outcomes were assessed and measured using WHO classification scheme, histologic and cytologic reports. Logistic regression method was used to estimate RR.

Byers et al. 1987

The methods and objectives were generally well described in this study. Cases and controls were representative of target population and controlled were matched to individual cases by age, sex and neighbourhood residence. Exposure and methods of interview/data collection well described. Confounding factors considered appropriately. Lung cancer cases confirmed histologically or by bronchial washings. Statistical methods used were adequately described. It was unclear whether outcomes were measures in a reliable way. The outcomes of people who were excluded were adequately described.

Chang et al. 1995

Participants’ recruitment was adequately described and the subjects were representative of target population. Statistical analysis was adequately described that included adjustment for potential confounding factors. Exposure was well defined and described. The outcomes of people who were excluded were described. Lung cancer was ascertained by record reviews and lung cancer mortality ascertained by death certificates and as coded by ICD classification.


The study was a well-designed matched case-control study with adequate description of data collection. Several potential confounding factors identified and included in the analysis. Patients excluded adequately described. Lung cancer cases ascertained histologically but unclear about their measurement using objective criteria. Statistical methods were adequately described.

Eichholzer et al.2000

Overall the study was well conducted and reported. Subjects were representative of target population and their selection well addressed. Exposure well defined and recorded. The usual confounding factors identified and well adjusted for. Statistical methods were appropriate and adequately described. Lung cancer confirmed using ICD classification but


it was not reported whether the measurements were assessed using objective criteria. There was adequate follow-up.

Goodman et al.1988

Overall the study addressed its objectives. Cases and controls were representative of target population and controls were matched to cases by age and sex. Methods of data collection well described that included description of trained interviewers. Potential confounding factors were identified and addressed. Lung cancer cases ascertained by pathological logs, admission records, cancer registry and by histological confirmation. Patients excluded were adequately described. Statistical methods were adequately described.

Hinds et al. 1983a

Overall the study addressed its aims well. Cases and controls were representative of target population and matched for age and sex. Multiple potential confounding factors identified and addressed. Patients excluded from the analysis well described. Lung cancer determined from cancer registry. Statistical methods were adequately described.

Hinds et al. 1983b

Cases and controls were representative of target population and matched for age and sex. Potential confounding factors identified and addressed in multiple logistic regression analysis. It was unclear whether patients excluded were accounted for in the analysis. Lung cancer determined from cancer registry but it was unclear in regards to measurement using objective criteria. Statistical methods were adequately described.

Hu et al. 2011

Overall the study addressed its objectives well and was a well-designed case-control study where cases and controls were matched by age and sex. Data collection was well described. Several potential confounding factors identified and included in the analysis. It was not reported whether patients were excluded included in the analysis. Lung cancer ascertained by from cancer registries based on pathological and histologically as defined by ICD classification. Statistical methods were appropriate and adequately described.

Jain et al. 1990

The description of the study design and setting was clear. Cases were representative of target population; however, some of the controls were not matched appropriately and therefore excluded from the analysis. Potential confounding factors identified included only cigarette smoking, beta-carotene and retinol. Lung cancer was ascertained through pathology, surgery and other medical records with a histological confirmation of diagnosis in 98% of cases. ORs and 95% CIs estimated using conditional logistic regression models.

Keys et al. 1985

The objective and methods were adequately described. Confounding factors were identified and adjusted for in the analysis. The study sample was representative of the population as a whole. Lung cancer mortality was confirmed through death certificates, physician reports, relatives and witnesses. People excluded were excluded from the analysis. Statistical methods were described adequately.


Knekt et al. 1991

The study sample was representative of target population. Exposure was well defined and described. The outcomes of people who withdrew were not described and included in the analysis. Statistical analysis was adequately described that included adjustment for potential confounding factors. It was not clear whether outcomes were measures using objective criteria. The follow-up period was adequate.

Kucharska-Newton et al. 2008

Overall the study addressed its objectives. The study sample was representative of the population as a whole. Potential confounding factors were identified and addressed. Outcomes were assessed based on self-reports and ascertained from cancer registries. It was unclear whether people who withdrew or excluded were included in the analysis. Statistical methods were appropriate and adequately described.

Law 1991

The objective of this analysis was well stated and described; however, it was not a traditional meta-analysis or systematic review. The criteria for including studies were unclear and it was also unclear if two or more than two independent investigators assessed the eligibility of each article for inclusion in the analysis. Minimal data provided. Methods used to combine the studies were clear. The recommendations provided were congruent with the data reported.

Shekelle et al. 1991

The description of the study design and setting and the eligibility criteria for subjects included in the study was clear and subjects appeared representative of target population. Outcomes and their measurement were not described clearly and it was unclear whether outcomes were assessed and measured objectively and in a reliable way. Statistical methods described were adequate. Potential confounding factors were addressed.

Smith-Warner et al. 2002

The objective of this pooled analysis were clearly stated and described. The include cohorts were all identified and their characteristics described. No clear details on data extraction provided. Data analysis was adequately described; however, it was unclear whether methods used to combine studies were appropriate. Recommendations were supported by the data presented.

Steenland et al. 1995

The study sample was representative of target population. Cases were representative of target population and controls were matched for race and gender. Potential confounding factors were addressed in the analysis. Outcomes were assessed using objective criteria. Odds ratios were estimated using multivariate analysis models. Statistical methods were adequately described. It was not clear whether people excluded or id those who withdrew were included in the analysis.


Swanson et al.1997

The description of the study design, setting and recruitment was well described. Cases were representative of target population and controls were matched appropriately. Potential confounding factors identified and included in the analysis. Lung cancer ascertained through histological confirmation and cancer registries. RRs and 95% CIs estimated using conditional logistic regression models.

Veierod et al.1997

The objective and methods were clearly stated with adequate description of confounding factors and outcome measures. The study sample was representative of the population as a whole. Lung cancer incidence was confirmed through cancer registries. People who withdrew or excluded were not described in the analysis. Statistical methods were described adequately.

Wu et al.1994

Well designed and conducted study with a cohort representative of the target population. Confounding factors were identified and adjusted in the analysis. Lung cancer incidence was ascertained histologically and by ICD classification. People who were excluded were described in the analysis. Statistical methods were described adequately described. The follow-up period was not adequate when considering other similar studies.


21 Risk factor: Avian exposure21.1 IntroductionPet ownership, including birds, is common in Australia. Some 8.4 million birds were estimated to be kept as pets in Australia as of 1999.282 The potential for pet birds to increase indoor air pollution and spread pathogens has stimulated some research into their association with various disease states, including lung cancer.

Of citations identified during study selection as relevant to this risk factor, no syntheses of previous research or prospective studies were located. Seven case-control studies were selected that aimed to establish the degree to which avian exposure is an independent risk factor for lung cancer. Following appraisal of these studies, two were excluded (see Appendix D). Of the included studies, three were conducted in Europe283-285 and two in the US.286, 287 All of the included studies investigated exposure to pet birds in the domestic environment, either in the house itself or outdoors in an aviary or similar enclosure. No studies were located that investigated occupational exposure to birds as a risk factor for lung cancer. In all reports, cases and controls were matched for at least age and sex, and all studies measured smoking status. The study by Alavanja et al. (1996)273 investigated risk of lung cancer due to exposure to different types of birds in US women. Morabia et al. (1998)274 investigated a subset of pet bird species (parakeets, canaries, finches and parrots) and risk of lung cancer according to tobacco exposure in men and women. The study by Gardiner et al. (1992)270 investigated a range of bird species similar to that by Morabia et al. (1998),274 including pigeons, kept in the domestic environment in Scotland. The remaining studies from Germany284, 285 both investigated the duration of household exposure to birds and risk of lung cancer. The study by Jöckel et al. (2002)272 investigated household avian exposure as part of an ongoing study into a range of occupational risk factors for lung cancer. All of the included studies were of moderate quality. The important characteristics of each study are detailed in Table 21.1.


Table 21.1 Study characteristics relevant to the association between avian exposure and lung cancer




Gardiner et al 1992ScotlandCase Control

143 cases, 97% smokers (65.4 yrs (mean); 286 controls, 78% smokers; 143 cardiac controls (65 yrs), 143 orthopaedic controls (64.9 yrs)

Cases from 1 hospital. 2 x Controls from same hospital, 1 cardiac, 1 orthopaedic. Data collected by interview with subject or next of kin

Lived with birds at least for 1 yr, anytime up to 15 yrs prior. Investigated type of bird, duration of exposure, location (indoor/outdoor), other pets.

Majority Squamous cell. Histological diagnosis in 89% of cases remainder clinical.

Conditional logistic regression

No significant association overall. Adj. OR (95% CI) 1.29 (0.79 - 2.12)Significant association with keeping pigeons. Adj. OR 3.9 (1.2 - 12.62). Maintained for Men and women and across age groups.

Alavanja et al 1996USACase Control

652 cases, 629 controls. Women only. Median age 67 yrs.

Recruited Cases from Missouri cancer registry 12mth period. Randomised selection of controls on basis of smoking status. Data collected by interview questionnaire only to period prior diagnosis (also next of kin).

> 6 mths up to 82 yrs. Type and number of birds and location kept in home also investigated.

Histological diagnosis of 86% of cases.

Multivariate logistic regression

No significant association overall. Adj OR (95% CI) 0.84 (0.65 - 1.09). Relationship did not change with increasing number of years or birds.

Kohlmeier et al 1992GermanyCase Control

239 cases, 55.3 yrs (78.2% men) 95.4% smokers; 429 controls, 55.2 yrs (77.6% men), 55% smokers.

Cases from 3 hospitals. < 65 yrs old. Controls from same city. Data collected by interview with computerised questionnaire.

> 6 months at least 5 yrs prior in the home. Neither number of birds nor location determined.

Primary malignant neoplasms of lung and airways by ICD, clinician and pathologist report

Conditional logistic regression

Adj OR (95% CI) 1.92 in men; 2.44 in women. Overall 2.14 (1.35 - 3.4). Risk increased 2x with 1-5 yrs and 3x >10 yrs exposure.





Morabia et al 1998USACase Control

887 cases (53% men) 57.1 yrs for men (mean) 56.6 yrs for women; 1350 controls (55.3% men). 365 owners of birds incl.

Newly diagnosed cases and controls from hospitals. Data collected by interview with structured questionnaire

No minimum exposure. Type of bird and duration of exposure recorded.

Histological diagnosis according ICD-7

Multivariate logistic regression assessed based on smoking status

No significant association overall. Adj OR (95% CI) for never smokers 0.7 (0.15 - 3.17) in men; 1.32 (0.65 - 2.7) for women. For ever smokers 1.28 (0.88 - 1.86) in men; 1.17 (0.83 - 1.64) in women. Relationship did not change with increasing exposure up to >8yrs. OR for trend 0.99 (0.69 - 1.44).

Jöckel et al 2002GermanyCase Control

144 cases (78% men) 57.1 yrs for men (mean) 56.6 yrs for women; 253 controls (80% men). 365 owners of birds incl.

Newly diagnosed cases and randomly selected controls from same region. Data collected by interview with structured questionnaire.

No minimum exposure detailed. Duration of exposure recorded as <10 yrs to >20 yrs during lifetime and adulthood only.

Histological or cytological diagnosis according ICD-7. Majority (52%) adenocarcinoma.

Unconditional logistic regression.

No significant association overall. Adj OR (95% CI) 0.85 (0.53 - 1.35) across all ages; 0.87 (0.56 – 1.36) for adulthood exposure. Increasing duration of exposure showed no evidence for trend.


21.2 Results21.2.1 Avian exposure and risk of lung cancer

The results reported by the individual included studies varied from no risk of lung cancer due to avian exposure in the domestic environment285-287 to twice the risk relative to no exposure.284 Smoking was identified as an independent risk factor for lung cancer in all of the included studies.

Risk of lung cancer attributable to avian exposure reported by the included studies is summarised in Table 21.2. Gardiner et al. (1992)270 investigated exposure to several bird species that included pigeons, canaries, finches and a variety of parrot species. A statistically significant risk of lung cancer was associated with exposure to pigeons only. The study by Alavanja et al. (1996)273 was only conducted with female participants. Morabia et al. (1998)274 was the only study to investigate and report risk by smoking status.

Table 21.2 Risk of lung cancer due to avian exposure

Study Adjusted OR (95% CI)

Kohlmeier et al 1992 2.14 (1.35 – 3.40)

Gardiner et al 1992 3.9 (1.2 – 12.62) (pigeons only)

Alavanja et al., 1996 0.84 (0.65 – 1.09) (women only)

Jöckel et al 2002 0.85 (0.53 – 1.35)

Figure 21.1 displays the overall effect estimate (RR 95% CI) of 1.14 (0.65 – 1.99) calculated with the combination of available studies. Note, Gardiner et al. (1992)270 was not included, as individual bird species were investigated separately. The results of studies combined suggest avian exposure does not increase risk of lung cancer.

Figure 21.1 Meta-analysis of risk of lung cancer (RR) and avian exposure

All studies matched for at least age and sex, and adjusted for other important confounding factors including smoking. Only one study adjusted for other pets kept in the house,285 whilst two considered occupational exposure to carcinogens.284, 285 Some studies adjusted for education,286, 287 race286 and socio-economic status285 whilst others also included marital status, a range of dietary factors,284, 286 and passive smoking.284, 286 Two studies used controls with other diseases rather than healthy matched controls.283, 287


21.2.2 Duration of avian exposure and risk of lung cancer

Four of the included studies reported risk according to duration of exposure to birds in the domestic environment.284-287 Presentation of categories by years was variable across all studies. Kohlmeier et al. (1992)271 was the only study to report any statistically significant dose response relationship with increasing exposure to birds, though the relationship was not linear, with no risk observed between six and 10 years of exposure (Adj OR 1.20 (0.57 – 2.53)), which was apparent at between one and five years of exposure (Adj OR 2.63 (1.79 – 3.2)). The most comparable exposure categories, being also those of longest duration are detailed in Table 21.3. All studies expressed risk against a reference of no exposure to birds except for Morabia et al. (1998),274 in which baseline exposure was less than two years.

Table 21.3 Risk of lung cancer with long duration of avian exposure

Study Duration in years Adjusted OR (95% CI)

Kohlmeier et al., 1992 >11 3.10 (1.48 – 8.21)

Alavanja et al., 1996 10-82 (women only) 1.13 (0.72 – 1.78)

Morabia et al., 1998 >8 (men only) 1.31 (0.59 – 2.91)

Morabia et al., 1998 >8 (women only) 1.11 (0.57 – 2.18)

Jöckel et al., 2002 10-20 0.70 (0.34-1.44)

Jöckel et al., 2002 >20 0.82 (0.40 – 1.67)

21.2.3 Avian exposure, smoking status and risk of lung cancer

All of the included studies collected data related to smoking status in subjects; however, only two studies presented the risk of lung cancer due to avian exposure for at least one year (Morabia et al. 1998)274 and more than six months (Alavanja et al. 1996)273 by smoking status. Table 21.4 summarises this data for men and women separately.

Table 21.4 Lung cancer risk by smoking status, (Morabia et al. 1998)

Smoking status Men Adjusted OR (95% CI) Women Adjusted. OR (95% CI)

Never 0.7 (0.15 – 3.17) 1.32 (0.65 – 2.7)

Ever 1.34 (0.91 – 1.97) 1.1 (0.75 – 1.62)Adjusted for age and education

21.2.4 Avian exposure, gender and risk of lung cancer

Morabia et al. (1998)274 was the only included study to present risk of avian exposure, smoking status and lung cancer risk by gender. Table 21.5 summarises this data.

Table 21.5 Lung cancer risk for women by smoking status (Alavanja et al., 1996)

Smoking status Adjusted OR (95% CI)

Never smoked 1.15 (0.48 – 2.74)

Former smoker 0.85 (0.53 – 1.37)


Smoking status Adjusted OR (95% CI)

Light to moderate 0.92 (0.65 – 1.32)

Heavy smoker 0.57 (0.27 – 1.18)Adjusted for raw vegetables, red meat, age, marital status, education, race, driving license, and passive smoking.

Combined data for risk of lung cancer in never-smoking women is presented in Figure 21.2. The combined RR of 1.24 (0.72 – 2.15) indicates no increased risk of lung cancer in this group.

Figure 21.2 Meta-analysis of risk of lung cancer (RR) in never smoking women from avian exposure

21.3 SummaryIn summary, the few studies located indicate that there is no increased risk of lung cancer with exposure to birds, even with long duration of exposure. There appeared to be no differences in risk of lung cancer apparent between men and women exposed to birds, nor any differences in risk dependent on smoking status. However, one case-control study conducted in Germany suggests there may be some risk of lung cancer due to general exposure to birds in the household environment, and that this risk increases with duration of exposure (Kohlmeier et al. 1992).271

Due to the moderate quality of included studies, the marked variability in selection of cases and controls and confounding factors adjusted for, and the likelihood of the residual effect of smoking, the results are not definitive and such a conclusion must be interpreted with caution.


Exposure to birds is not recognised as a carcinogen in humans.


The evidence suggests that exposure to birds is not likely to increase risk of lung cancer. Furthermore, the evidence suggests household exposure to birds at any age or for any period greater than six months, as investigated across the studies included here, is unlikely to create significant risk for the development of lung cancer.


21.5 Methodological quality of studiesIndividual critical appraisal checklist items are shown in Table 21.6.

Table 21.6 Avian exposure: Methodological quality of included studies

Study Study/ Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Total (Y) Include/Exclude

Alavanja et al. 1996 case-control Y U Y Y Y N/A Y Y Y 7 Include

Gardiner et al. 1992 case-control U Y N U Y N/A Y Y U 4 Include

Holst et al. 1988 case-control N N U U U N/A Y U U 1 Exclude

Jockel et al. 2002 case-control Y Y Y U Y N/A U U Y 5 Include

Kohlmeier et al. 1992 case-control Y Y U Y U N/A Y U Y 4 Include

Modigh et al. 1996 case-control Y U N Y U N/A N U Y 3 Exclude

Morabia et al. 1998 case-control U Y U N Y N/A N Y Y 4 Include



The methods and objectives were generally well stated in this study. Subjects were representative of target population and exposure and methods of interview/data collection well described though next of kin included in 33% which increase bias. Confounding factors considered appropriately Outcome measures and statistical methods used were adequately described. Duration of exposure established over lifetime.

Gardiner et al. 1992

It was unclear why controls also had disease, including one associated to smoking (heart disease). Exposure well established and defined as was disease however selection of controls not randomised. Although measured and adjusted for range of confounders, many bundled with smoking alone on basis of association, unclear on association with bird keeping. Outcomes and their measurement were adequately described. Exposure established for 15yrs prior admission. Statistical methods and presentation were unclear.

Jöckel et al. 2002

Overall the study was well conducted and reported. Subjects were representative of target population and their selection well addressed though any omissions not reported. Exposure well defined and recorded. Confounding factors accounted for though no protective factors considered. Smoking addressed only as binary outcome, therefore no impact of amount of smoking. Statistical methods were adequately described. Lung cancer confirmed but no detail how or according to what criteria.

Kohlmeier et al. 1992

Subjects were representative of target population and exposure and methods of interview/data collection well described. It was unclear how or by whom diagnosis of lung cancer conducted. Smoking accounted for only as binary outcome, therefore no impact of amount of smoking. Duration of exposure established in children and adults and both though age at exposure not considered in final analysis. Other confounders addressed well. Statistical methods were adequately described.

Morabia et al. 1998

Overall the study addressed its aims well. Cases were representative of target population, however controls also from hospital with diseases. Smoking was the only confounding factor addressed in relation to bird keeping. Other potential confounders not addressed. Condition of patients included and losses not well described. Lung cancer determined from pathological reports. Statistical methods were adequately described.


22 Risk factor: Wood dust22.1 IntroductionIn 2007-2008 the turnover of Australia’s forest product industries was more than $21 billion, or 6.2% of total manufacturing output.288 The kinds of occupational environments in which wood exposure is high include; furniture factories, pulp and paper mill factories. In addition to occupational wood dust exposure, wood dust exposure may also result from hobby-related woodwork activities.

The nature of the association between wood dust exposure and lung cancer is difficult to establish. This is for two main reasons. Firstly, the duration and intensity of wood dust exposure is difficult to measure accurately. Wood dust exposure is most commonly measured in research studies using records of occupation status. In some cases, self-reported wood dust exposure data is used, but even this is a poor measure as there is the potential problem of accurate recall. Secondly, the problem of confounding factors is particularly problematic in the case of wood dust exposure. This is because in the environment in which wood dust exposure affects individuals, there are a range of other exposures that are also known to raise the risk of mortality from lung cancer. These include chemicals and various kinds of organic and inorganic dusts, for example, asbestos, paper dust, pulp dust, coal dust, lime dust, and kaolin dust. These difficulties imply a need for caution when drawing conclusions from the findings of primary research studies on the association between lung cancer and wood dust exposure.

In 1995 IARC classified wood dust as carcinogenic to humans, with nasal cancer highlighted as the type of cancer most commonly associated with wood dust exposure. The IARC Working Group concluded that occupational exposure to wood dust played no role in the causation of lung cancer.289 However, due to the variable nature of evidence available, the need for more research on wood dust and the association with lung cancer was highlighted.290 Common limitations of the studies relating to lung cancer and wood dust exposure, as noted by the IARC Working Group, included; that participants were mostly white males, that study sizes were small, the inadequacy of comparison groups, and insufficient control of confounding factors such as smoking.291 The approach adopted to inform this risk factor was to only consider studies undertaken since the 1995 IARC review for potential critical appraisal.

In the initial search of the literature, eight potentially relevant citations were identified relevant to wood dust exposure and lung cancer risk. Two additional studies were subsequently identified by hand searching. No syntheses of previous research were located. Ten full-text papers were retrieved and of these, two were excluded before critical appraisal.

Eight studies were included for critical appraisal; three retrospective cohort studies292-294 and five case control studies.289, 291, 295-297 Two of the case-control studies291, 295 were excluded during critical appraisal. Of the remaining six studies, three were undertaken in the US;289, 292, 296 one in Finland,294 one in Estonia293 and one in Poland. 297 All of the included studies were rated as being of moderate quality. Characteristics of the included studies are presented in Table 22.1.


Table 22.1 Study characteristics relevant to the association between wood dust exposure and lung cancer




Bhatti et al. 2010Case control/Rural Washington State USA

Males440 cases (mean age 61.8 years)845 controls (mean age 61.1 years).Over 95% of subjects Caucasian. 60% of cases current smokers compared to 19% of control groups.

Controls: identified from same geographical area through random-digit dialling, using a modified Waksberg method. Frequency matched to cases by 5-year age group.Cases: identified from a rapid reporting mechanism of the Fred Hutchinson Cancer Research Centre Surveillance System. Included men diagnosed with lung cancer between 1 May 1993 and 31 July 1996, aged 18-74 years and resided in an 11-county area of western Washington.Data collected from cases and controls by experienced interviewers. Subject or next of kin interviewed.

Data collected on occupational exposure to wood dust and woodwork hobby. Exposure estimation based on algorithm informed by typical concentrations of wood dust specific to the occupational and recreational processes.Individual cumulative exposure calculated by summing the product of duration (months) working in or near the process, the proportion of a 40h work week typically spent in or near the process, the average exposure intensity (mg/m3) and the modifying factors.

Clinical information regarding the types of lung cancer was determined from medical records by trained registry personnel.Most common histological groups adenocarcinoma, squamous cell and small cell carcinoma.

RRs estimated by calculation of ORs and 95% CIs. Unconditionallogistic regression.Quartiles exposure based on the distribution of cumulative wood dust exposure among controls. Age and smoking status (never, former, current) included as covariates in all models. Race, education and pack-years of smoking also examined as potential confounding factors. No impact observed. Possible interactions between smoking and wood dust exposure examined by stratum-specific analyses and evaluating interaction terms in the logistic model.

MalesNo significant association. OR (95% CI): 0.9 (0.6 - 1.3) for all categories of wood dust exposed workers. Based on the highest quartile exposure measured (>344.7 to 16469.4 months-mg/m3), compared with the lowest quartile of exposure.SmokingNot reported.

Laakkonen et al. 2006Retrospective Cohort Study /Finland.

Cohort of all economically active Finns born between 1906 and 1945 who participated in the national population census on 31

Incident cases of cancer established using data in Finish Cancer Registry. Good coverage; accuracy high.

Occupations of cohort established from population census in 1970 and converted into exposures to eight dust exposure types,

Various types of cancers: nasal, laryngeal, lung and mesothelioma studied. Types of lung cancer not

RRs estimated by calculation of standardized incidence ratios (SIR) and 95% confidence intervals.SIR defined as ratio of observed to expected

MalesNo significant association for all measures.Low exposure: SIR 1.11 (1.04-1.18)





December 1970 (667 121 men; 513 110 women). Followed up for 30 million person-years during 1971-95.

including wood dust exposure.Cumulative Wood dust exposure (and other dust exposure types) calculated as a product of prevalence, level of exposure and estimated duration of exposure. Three exposure measures calculated: low (<3 mg/m3 -year); medium (3-50 mg/m3 -year) high (>50 mg/m3 – year).In Finland wood dust exposure mainly softwood dust (pine, spruce).

stated. number of cases (based on studying reference group / economically active population).Poisson regression analysis.RRs adjusted for age, social class and period.Risk measures not adjusted for smoking.

Med. exposure : 1.02 (0.97-1.06)High exposure: 0.85 (0.70-1.02)FemalesNo significant association for all measures.Low exposure: 0.92 (0.57-1.41)Med. exposure: 1.03 (0.76-1.37)High exposure: 0.95 (0.49-1.66)

Innos et al. 2000Retrospective Cohort Study/Estonia.

Cohort of 6 786 male (n=3723) and female (n=3063) furniture workers employed (1946 – 1988) at 2 furniture factories in Tallinn, Estonia. Subjects employed at either factory for at least 6 months between Jan. 1 1946 and Dec. 31 1988 and lived in Estonia on

Cohort followed up for vital status and cause of death from date of fist employment until December 31 1995. Lung cancer incidence (SIR) of cohort compared to that in the general population of Estonia. Wood dust exposure data extracted from employment records. Lung Cancer Register

Data on job titles corresponding to work tasks and workplaces used as a basis for wood dust exposure estimation. Task completed in consultation with an industrial hygienist. Three different levels of exposure defined based on three different occupational

Type of lung cancer studied not stated.

RRs estimated by calculation of SIR and 95% CI. SIR calculated by dividing the observed number of cases by the corresponding number of expected cases. Expected number of cases computed by applying the 5-year age, 5-year calendar period and gender specific registration rates for the population of Estonia to the person-year

No significant association overall or in males. Is for females but restricted to short-term workers.OverallSIR 1.07 (0.87-1.28) for the cohort (all job categories).MalesSIR 1.02 (0.82-1.26) for the cohort (all job categories).





1 January 1968 when follow up for lung cancer incidence commenced.51.9% non-smokers in cohort. 48.1% current or previous smokers.

and questionnaire (1988) used to attain data on smoking.

categories.Measurements of exposure levels for the different categories not reported.

distribution of the cohort. 95% CI derived assuming Poisson distribution.Risk measures not adjusted for smoking.

SIR 0.79 (0.36-1.50) for medium exposure jobs.SIR 1.01 (0.79-1.27) for high exposure jobs.FemalesSIR 1.43 (0.83-2.29) for the cohort (all job categories).SIR 1.12 (0.36-2.61) for medium exposure jobs.SIR 1.62 (0.81-2.89) for high exposure jobs.SmokingLung cancer risks not reported by smoking status.

Jayaprakash et al 2008Hospital based case-control study/USA (Buffalo City New York).

All males. Mostly Caucasian. 809 cases (mean age 62.3 years). 1 522 controls (mean aged 61.4 years).4.6% never smokers in cases compared to 10.8% never smokers in controls.

Cases and controls from database developed by the Cancer Institute at a hospital in Buffalo New York. Diagnosis of lung cancer confirmed by medical examination. Controls (no lung cancer confirmed by medical examination) randomly selected and frequency matched to cases at a ratio of 1:1 based on 10-year age groups and smoking history (never smoked/ever smoked).Questionnaire used to gather smoking and

Self reported wood dust exposure data used to determine exposure levels. Questionnaire asked subjects to grade wood dust exposure into never, occasional and regular. No clear definition of these terms in questionnaire.Lung cancer risk measures reported for different exposure measures based on intensity and duration of exposure.

Squamous cell; carcinoma and adenocarcinoma of the lung.

RRs estimated by computing OR and 95% CI. Unconditional logistic regression.Risk measures adjusted for age, education, pack years of smoking, BMI, family income and year of enrollment in study.

Significant association between regular exposure to wood dust and lung cancer risk (all types).MaleModerate exposure: (occasionally exposed or regularly exposed for less than 20 yrs): OR 1.12 (0.89-1.42)High exposure: (regularly exposed for 20 yrs or more): OR 2.15 (1.31-3.56).





wood dust exposure data.

Szadkowska-Stanczyk & Szymczak et al. 2001Case control nested within a cohort of pulp and paper workers/Poland

79 lung cancer cases and 237 healthy controls. Male and female. Cases employed in pulp and paper factory for at least a year between 1968 and 1990 who were deceased and had lung cancer classified as the cause of death. Must have deceased between entry and 31 December 1995. Controls selected from the cohort of factory workers and matched to each case by sex, year or birth and year of hire.

Follow up until then end of 1995. Study measured lung cancer risk associated with wood dust and other dust exposure.Questionnaire used for additional data including on smoking. Interviews with participants or next of kin (if diseased).Lung cancer mortality the outcome measure used for risk measurement.Diagnosis of death cause checked with National and Regional Cancer Registry. In 72% of cases lung cancer as cause of death histological and/or radio logically confirmed.

Occupational wood dust exposure measured using employment files for each participant and expert opinion. Measured using personal records of workers and expert opinion. Following exposure groups adopted: Non-exposed; exposed to low concentrations (0.1-1 mg/m3); exposed to moderate concentrations (1-5 mg/m3); exposed to high concentrations (>5 mg/m3). Cumulative dose index used to study dose-response.

RRs estimated by calculating ORs and 95% CI. Conditional logistic regression.RRs estimated by calculating ORs and 95% CI. Conditional logistic regression.Adjusted for smoking.

OverallLow: OR = 2.077 (0.88-4.92).Moderate and high: OR=2.08 (0.8-6.31)

Stellman et al. 1998Retrospective cohort study/USA.

Sample included 45 399 wood dust exposed males. Subjects selected from those enrolled in 1982 in the USA Cancer Prevention Study II. Followed up for a relatively short period of 6

Lung cancer risk calculated using cause of mortality data.Data on exposure to wood dust and other risk factors for lung cancer gathered via questionnaire. Asked also about lifestyle, health and family

Exposure measures derived for two partially overlapping groups: woodworkers and wood dust-exposed men. The former group those who reported yes to working in a wood related occupation.

Not stated. Mortality. RRs estimated using maximum likelihood methods. 95% CI based on the standard error of the coefficients were derived using Poisson regression.Adjusted for age and smoking status (never, past, current, missing).

MalesGroup who reported wood dust exposure: RR = 1.17 (1.04-1.31).Group who reported working in a wood-related occupation: RR=1.14 (0.94-1.37).





years. cancer history.Lung cancer mortality risk of wood dust exposed in sample compared with those in sample who responded no in the questionnaire to the questions on wood dust exposure.Death certificates used to determine cause of death (ICD-9 followed). For about one quarter of reported cancer deaths the primary site of diagnosis was checked through cancer registries, physicians or hospitals.

Latter those who reported regular exposure to wood dust.

All RR comparisons relative to participants in the USA Cancer Prevention Study II who did not report either employment in a wood occupation or regular exposure to wood dust.

Significant trend (P=0.02) of increasing risk of lung cancer with increasing duration of wood dust exposure.


22.2 Results22.2.1 Wood dust exposure and risk of lung cancer

The six studies investigating the association suggest there is little or no relationship between wood dust exposure and risk of lung cancer. Four found no association289, 293, 294, 297 and two found a positive significant association with exposures of approximately 20 years duration.292, 296 The majority of the studies included only male populations. In one study,293 a positive significant association was found for females but not for males. Two of the studies, Laakkonen et al.294 and Innos et al.,293 did not adjust for smoking in risk measurement. The remaining studies did adjust for smoking, as well as age and in some instances other confounding factors including socio-economic status.

Only two of the studies presented results for samples of males and females.293, 297 Both studies reported no significant association. The results of these studies are presented in Table 22.2.

Table 22.2 Risk of lung cancer due to wood dust exposure

Study Risk

Innos et al (2000) SIR (95% CI): 1.07 (0.87-1.28). Calculated for all job categories of workers employed in a furniture factory for at least six months. No precise measure of exposure level provided.

Szadkowska-Stanczyk & Szymczak (2001)

OR (95% CI): 2.1 (0.9-4.9) for low exposure (0.1-1 mg/m3)OR (95% CI): 2.08 (0.8-6.31) for medium (1-5 mg/m3) and high exposure (>5 mg/m3).

22.2.2 Wood dust exposure and risk of lung cancer by gender

Five of the studies reported results for lung cancer risk due to wood dust exposure for males and two for females in addition to males. The risks for males are presented in Table 22.3 and for females in Table 22.4.

Table 22.3 Risk of lung cancer due to wood dust exposure for males

Study Risk

Bhatti et al. 2010 OR (95% CI): 0-9 (0.6-1.3) for all categories of wood dust exposed workers based on highest quartile of exposure measured (>344.7 to 16469.4 months-mg/m3) compared with lowest quartile of exposure.

Laakkonen et al. 2006 SIR (95% CI): 1.11 (1.04-1.18) for low exposure defined as <3 mg/m3 – yr; 1.02 (0.97-1.06) for medium exposure defined as 3-50 mg/m3 – year; 0.85 (0.70-1.02) for high exposure defined as >50 mg/m3 – year.

Innos et al. 2000 SIR (95% CI): 1.02 (0.82-1.26) for all job categories in the cohort of furniture workers studies; 0.79 (0.36-1.50) for workers in jobs classified as having medium wood dust exposure; 1.01 (0.79-1.27) for workers in jobs classified as having high wood dust exposure.

Jayaprakash et al. 2008 OR (95% CI): 1.12 (0.89-1.42) for moderate exposure defined as regularly exposed to wood dust for less than 20 years; 2.15 (1.31-3.56) defined as regularly exposed to wood dust for more than 20 years.

Stellman et al. 1998 RR (95% CI): RR 1.17 (1.04-1.31) for the group who reported having been exposed to wood dust; RR 1.14 (0.94-1.37) for the group who reported working in a wood related occupation.


Innos et al.293 found no significant association for males nor females. The greater imprecision amongst females may be explained by the female group being characterised by greater levels of smoking. The Laakkonen et al.294 study found no significant risk of lung cancer due to wood dust exposure for either males or females, with the exception of males in the low exposure class (Table 22.4).

Table 22.4 Risk of lung cancer due to wood dust exposure for females

Study Risk

Laakkonen et al 2006 SIR (95% CI): 0.92 (1.57-1.41) for low exposure defined as <3 mg/m3 – yr; 1.03 (0.76-1.37) for medium exposure defined as 3-50 mg/m3 – year; 0.95 (0.49-1.66) for high exposure defined as >50 mg/m3 – year.

Innos et al 2000 SIR (95% CI): 1.43 (0.83-2.29) for all job categories in the cohort of furniture workers studies; 1.12 (0.36-2.61) for workers in jobs classified as having medium wood dust exposure; 1.62 (0.81-2.89) for workers in jobs classified as having high wood dust exposure.

22.2.3 Wood dust exposure and risk of lung cancer by smoking status

Whilst all of the studies collected data on smoking status and four adjusted for smoking in computing lung cancer risk, none presented risk measures by smoking status.

22.2.4 Dose response relationship between wood dust exposure and lung cancer

Stellman et al.292 investigated risk of death among males due to different types of cancer (including lung cancer) in their sample drawn from the US Cancer Prevention II study. These authors found a significant trend for lung cancer (P = 0.03). Their results for those in the sample who reported wood dust exposure are presented in Table 22.5.

Table 22.5 Risk of death among men by duration (yrs) of wood dust exposure, (Stellman 1998)

Cause of death (P-value trend)

RR (95% CI)Less than 10 years

RR (95% CI)10 – 19 years

RR (95% CI)20 or more years

Lung Cancer (P=0.03) 1.03 (0.82) 1.31 (1.01-1.70) 1.16 (0.96-1.40)

Bhatti et al.289 examined how lung cancer risk is affected by cumulative wood dust exposure, taking into account both hobby and occupational sources of wood dust exposure. They found no indication of any dose-response relationship.Similarly, Szadkowska-Stanczyk and Szymczak297 also reported no evidence of a dose-response relationship. Their results are presented in Table 22.6.

Table 22.6 Lung cancer risk among pulp and paper industry workers exposed to wood dust by cumulative dose (Szadkowska-Stanczyk & Szymczak 2001)

Category Exposure by cumulative indexNon exposed

Exposure by cumulative indexLower

Exposure by cumulative indexHigher

OR (95% CI) 1.0 2.10 (0.48-9.20) 1.97 (0.72-5.40)


22.3 SummaryIn 1995 IARC reviewed a number of studies that examined the link between lung cancer and wood dust exposure. It concluded that the studies presented mixed results and cautioned that the evidence was not unequivocal regarding an association between wood dust exposure and risk of lung cancer. The results presented here suggest that wood dust is not a significant risk factor for lung cancer though may present some risk at high concentrations or with long duration (more than 20 years) of exposure. Any consideration of wood dust as a risk factor for lung cancer from the present review is limited almost exclusively to males.

These results must be considered in light of the difficulties involved in the accurate measurement of wood dust exposure and in isolating the impact of wood dust exposure from other kinds of exposures known increase the risk of lung cancer. The results of the studies presented above are reflective of an array of different types of wood dust exposure measurement techniques.

22.4 Conclusion22.4.1 Hazard Identification

There is sufficient evidence in humans to indicate that wood dust causes cancer of the nasal cavity and paranasal sinuses, and of the nasopharynx. Weaker evidence exists for other sites such as the pharynx, larynx and lung, where positive associations were observed in some, but not all, case-control studies, and not supported by findings of cohort studies (IARC, 1995).290


Exposure to wood dust does not appear to present a significant increased risk of lung cancer. There is some evidence to suggest risk may be apparent for exposures of more than 20 years duration.


22.5 Methodological quality of included studiesIndividual critical appraisal checklist items for wood dust are shown below in Table 22.7.

Table 22.7 Wood dust: Methodological quality of included studies

Wood dust study Design Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Total (Y)

Included/excluded

Barcenas et al (2005)

Case control

No No Un. Un. No NA Un. Un. Yes NA 1 Excluded

Bhatti et al (2010) Case control

No No Un. Un. Yes NA Yes Yes Yes NA 4 Included

Innos et al (2000) Cohort No Un. NA Un. Yes Yes Un. Yes Yes NA 4 Included

Jayaprakash et al (2007)

Case control

No Un. Yes Un. Yes NA Un. Yes Yes NA 4 Included

Laakkonen et al (2006)

Cohort Yes Un. NA Un. Yes Yes Un. Un. Yes NA 4 Included

Schraub et al (1989) Case Control

No Un. Un. Un. Yes NA Un. Yes Yes NA 3 Excluded

Stellman et al (1998)

Cohort No No NA No Yes Yes Un. Yes Yes NA 4 Included

Szadkowska-Stanczyk & Szymczak (2001)

Case Control

No Un. Yes Un. Yes NA Yes Un Yes NA 4 Included


Bhatti et al. 2010

This was a good quality case control study with respect to matching of cases and controls. The measurement of outcomes was also very good compared to the other studies reviewed. However, a weakness in this context is the sample, which was 95% Caucasian and from a particular rural area in the USA. The two primary weaknesses to note, which are similar to the other studies, are poor measurement of exposure to wood dust exposure and insufficient addressing of confounding factors. Whist the study did not report lung cancer risk measures by smoking status it did test how smoking status affected findings and found the effect of smoking insignificant.

Innos et al. 2000

This study was a cohort study that looked at the association between wood dust exposure and various cancers, including lung cancer in a cohort of furniture workers in the capital of Estonia. Like all the other studies the study dealt insufficiently with confounding factors. The study did not address smoking as a confounding factor. A strength of the study was its relatively large sample and long period of follow up. Another was that the cohort of furniture workers studies is comprised of males and females and lung cancer risk measures were presented by sex and different work categories (which are linked to different wood dust exposure levels).

Jayaprakash et al. 2008

This was a hospital based case control study, undertaken in Buffalo city New York. The sample (n=809 lung cancer cases and n=1522 controls) was all male and largely Caucasian sample. The study examined a range of different measures of wood dust that were based on self-reported exposure data. A strength of the study relative to the others reviewed was the range of confounding factors, in addition to smoking, adjusted for in the analysis.

Laakkonen et al (2006)

This was a retrospective case control study that studied the association between lung cancer and wood dust exposure using data on lung cancer incidence in the economically active population of Finland. The study sample was relatively large and the follow up time was relatively long: all economically active Finns born between 1906 and 1945 were followed up from 1971-1995. Presentation of results for three different levels of wood dust exposure is strength of the study. Like the other studies the results presented in this study are weakened by inability to separate out clearly the effect of WD exposure form other lung cancer risk factors. Similar to the Innos et al. (2000) study this study did not adjust for smoking when calculating lung cancer risk measures and hence the results of the study should be read with caution.

Stellman et al. 1998

This study used data from a large cohort study called the Cancer Prevention II study, which was undertaken by the American Cancer Society. A sample of males who reported yet to either being exposed to wood dust or working in a wood related occupation in a questionnaire was drawn from the study of cancer risk factors. Strengths of the study are that comparisons were made with an appropriate reference group, the large sample that was drawn from over 50 states in the USA, the District of Columbia and Puerto Rico and adjustment for a smoking and some other confounders. Another is that self-reported data on wood exposure was used rather than simply drawing on occupational records of work


and then using this to derive exposure levels based on different activity classifications. However, even this self-reported data is unlikely to generate accurate measurement of wood dust exposure.

Szadkowska-Stanczyk & Szymczak et al. 2001

This was a relatively small case control study nested within a cohort study of pulp and paper workers in Poland. It forms part of a larger study on association between various other kinds of dust exposure and lung cancer risk. The study has a number of strengths relative to the other studies including good matching of cases and controls, adjustment for smoking, testing of different exposure levels, good verification of cause of death and the development of a cumulative exposure index to test dose response.


23 Risk factor: Physical activity23.1 IntroductionPhysical activity is normally associated with daily living, work and leisure-time activities.298 Physical activity in Australia has been recognised as a major beneficial factor in preventing chronic diseases. The National Physical Activity Guidelines for adults in Australia recommend at least 30 minutes of moderate-intensity physical activity and for children and adolescents, recommend at least 60 minutes of moderate to vigorous physical activity every day.299 In 2004-05, 70% of Australians aged 15 years and over were classified as sedentary or having low exercise levels. Of these, just under half (48%) recorded no or very little exercise in the previous two weeks (sedentary exercise level) and 52% recorded a low level of exercise. The proportions reporting sedentary or low exercise levels have not changed significantly over the last ten years, based on age-adjusted estimates from the last three National Health Surveys (69% in 1995, 69% in 2001, and 70% in 2004-05).299

The search identified 11 studies. Of these studies, one was a synthesis of existing research (meta-analysis) that included four of the other identified studies.298 Therefore, seven studies underwent critical appraisal and are included in this report. Six of the included studies were prospective cohort study designs and one was a meta-analysis. The majority of the studies focussed on investigating the protective effect of physical activity on the incidence or development of lung cancer. Two of the studies investigated a range of cancer types including lung cancer.300, 301 Four of the six prospective cohort studies were conducted in the US,300-303 one in Denmark304 and another was conducted across 10 European countries.305 The most common method of data collection across these studies was self-administered questionnaires/surveys. Other data collection methods included in-person interviews for exposure assessment, cancer registries, and death certificates for outcome assessment.

The participants recruited were large cohorts of men and women with an age range between 20 and 70 years. Four studies 300, 302, 304, 305 included men and women as participants, one study301 recruited only men and one study303 recruited only women as participants. Participants recruited in the majority of the studies were caucasian/white, except in a few studies conducted in US that included both white and non-white people.

The average length of follow-up period varied from 10 to 15 years. Incidence of lung cancer was the major outcome reported in all the studies, with mortality due to lung cancer also reported in three studies.298, 300, 305 The included studies were of high quality with a clear description of potential confounding factors and their adjusted findings in the statistical analysis. Most of the studies did not clearly present their findings separately for smokers, non-smokers and former smokers. The important characteristics of the included studies are presented in Table 23.1.


Table 23.1 Study characteristics relevant to the association between physical activity and lung cancer




Alfano et al 2004USAProspective cohort study

7,045 men (59%) and womenAged between 54-78 years at recruitment

Participants recruited from six centres across the United States from β-carotene and Retinol Efficacy Trial (CARET).Completed a PA questionnaire for the purpose of this study. 17 yrs follow up.

PA measured as average weekday and weekend day hours during the past year in five categories: sleeping, vigorous activity, moderate activity, light activity and sitting.

Incident cases of lung cancer identified as reported by the participants, cancer registries, state boards of health and the National Death Index.

Cox regression model predicting cancer incidence. Potential confounding factors adjusted for: age, smoking history, gender and BMI

Total PA 70.4 ± 19.09 hr/wk: Age 54-62 yrs HR 0.84, (95%CI 0.69 - 1.03), Age 63-78 yrs HR 1.11, (95%CI 0.95 - 1.29).

Bak et al 2005DenmarkProspective cohort study

57,053 participants (aged 50-64 years)

Study conducted between 1993 and 1997 and followed up till 2002 in Denmark. 5 - 9 yrs follow up. All participants filled in questionnaires.

PA in leisure time Incident cases of LC were identified as reported by cancer registries.

Cox proportional hazard model stratified according to age at entry and adjusted for smoking status.

Lower risk of LC incidence in physically active women than non-active women for all types of PA. For men, lower risk observed only for sports and gardening.

Lee et al 1994USAProspective cohort study

17,607 males only, 30-79 years at recruitment.15,216 of cohort available for investigation in relation to lung cancer.

Participants: undergraduates at Harvard University between 1916 and 1950. Follow-up: 22 - Two prospective assessments of PA, modes A and B, separated by 11 or 15 yr, to predict cancer risk in college alumni. Model B established more precise measure of referent inactivity

PA based on self-reported stair climbing, walking and participation in sports or recreational activities

Nonfatal occurrences of LC ascertained by means of mailed questionnaires and fatal occurrences from death certificates to determine cause-specific mortality.

Proportional hazards regression used to estimate RR associated with different activity levels. Adjusted confounding factors: age, Quetelet’s index, parental history of any cancer and cigarette smoking habit.

High PA had 0.39 (95% CI, 0.18-0.85) to 0.62 (0.45-0.85) times the lung cancer risk of their low PA counterparts.





Leitzmann et al 2009USAProspective cohort study

501,148 subjects, 50-71 years at recruitment.

The National Institutes of Health-AARP Diet and Health studyEstablished in 1995-1996, recruited subjects from six different states in USA who were followed up through December 31, 2003. 7 - 8 yr follow up.

PA assessed and categorised based on the frequency each week spent at activities that lasted 20 minutes or more and caused either increases in breathing or heart rate or working up a sweat.

Incident cases of LC were identified through probabilistic linkage to the state cancer registries. The study also examined the main histologic types of LC defined by anatomic and histologic code of ICD for Oncology.

Cox proportional hazards regression with person-time follow-up as the time scale was used to estimate the relative risks and the corresponding 95% confidence intervals of lung cancer.

Participants engaged in PA 5 or more times per week RR 0.50 (95%CI 0.46 - 0.54) compared with their inactive counterparts.

Sinner et al 2006USAProspective cohort study

36,929 women 55 - 69 yrs at recruitment.

The Iowa Women’s Health Study USA. Subjects administered a questionnaire regarding PA, smoking, BMI and other life-style factors in 1986. Follow-up questionnaires sent out in 1987, 1989, 1992 and 1997. 16 yr follow up.

Four PA measures for assessment: PA (yes, no), level of PA (low, medium, high), moderate activity level (never, less than once a week, more than once a week) and vigorous activity level (never, less than once a week, more than once a week).

Incident cases of LC identified through State Health Registry.

Cox proportional hazards regression model used to compute age-adjusted and multivariate-adjusted HR and confidence intervals. Adjusted potential confounding factors: BMI, smoking status, pack-years of smoking, education, marital status, alcohol intake, coffee intake and vegetable intake.

Women with high PA level 23% (0.77, 0.64-0.94) less likely to be diagnosed with LC than women with low PA level.

Steindorf et al 2006European multicentreprospective cohort study

521,457 male and female participants, 35-70 years were initially recruited; 416,227 subjects were included in the current analysis. Males, 31%, mean age 53.1 yrs. females mean age 51.5 yrs.

The European Investigation on Cancer and Nutrition (EPIC) project was conducted in 23 centres in 10 European countries. Mean 6.3 yr follow up.PA data obtained at baseline in either in-

PA, Occupational PA, Recreational PA, Household PA and Vigorous no-occupational PA.

LC incidence identified by population cancer registries and by active follow-up, which included health insurance records and direct contact of participants.

As the intensity of recreational and household activities was not directly recorded, a metabolic equivalent (MET) value was assigned to each reported activity.

Vigorous PA in women in the first and second tertile show a reduction in risk 0.65 (0.43, 0.98) and 0.60 (0.40, 0.89) respectively when compared to women with no vigorous non-occupational activity.





person interviews or self-administered questionnaires.Participants recruited between 1992 and 2000.

Cox proportional hazard models used to analyse the association between PA and risk of lung cancer separately for male and female subjects. Potential confounding factors such as age, smoking status, education, BMI, alcohol and vegetable and fruit consumption were adjusted for in the analysis. Heterogeneity between different countries was assessed by chi-square tests

Tardon et al 2005Meta-analysis

Total N=185,279; mainly from USA and EuropeParticipant age range not reported.

Nine included studies; two case-control and seven cohort studies. Data collected by questionnaires and interviews.Search details: MEDLINE (1966 to October 2003) and EMBASE (1974 to October 2003). No language or age restrictions.

Three components of leisure-time PA – type, duration and/or intensity

Not specified DerSimonian and Laird’s random-effects method.

Protective effect for both moderate leisure time PA (OR = 0.87, 0.79-0.95) and high leisure time PA (OR = 0.70, 0.62-0.79).


23.2 Results23.2.1 Physical activity and risk of lung cancer

Evidence from the included studies suggested that physical activity reduced the risk of lung cancer incidence and mortality, in particular in smokers. However, the findings presented in each study varied based on type, frequency and duration of physical activity, amount of energy expended and intensity of physical activity.

Findings from the meta-analysis298 showed an inverse relationship between leisure time physical activity (LPA) and lung cancer risk. The estimated risk was found to be protective for both moderate and high LPA and is summarised in Table 23.2.

Table 23.2 Leisure time physical activity (LPA) and lung cancer (Tardon et al. 2005)

LPA level Total OR (95% CI) Males OR (95% CI) Females OR (95% CI)

Moderate 0.87 (0.79 - 0.95) 0.93 (0.85 - 1.00) 0.77 (0.66 - 0.89)

High 0.70 (0.62 - 0.79) 0.75 (0.66 - 0.86) 0.62 (0.48 - 0.79)

Trend (p = ) 0.00 0.01 0.01Adjusted for smoking

Investigating physical activity and risk of lung cancer, Lee et al., 1994301 reported risk across a range of defined levels of physical activity:

Inactive (expending <1000 kcal/wk)

Moderately active (expending 1000 to <2500 kcal/wk)

Highly active (expending >2500 kcal/wk)

Table 23.3 summarises the risk of lung cancer by level of physical activity.

Table 23.3 Relative Risk of lung cancer at different levels of physical activity (Lee et al. 1994)

Category <1000 (kcal/wk)

1000-2499 (kcal/wk) ≥2500 (kcal/wk)

P for trend

PA level assessed both in 1962/66 & updated in 1977 (Model B)

1.00 (referent) 0.79 (0.44-1.43) 0.39 (0.18-0.85) 0.02

Adjusted for age, parental history, no: of cigarettes smoked/day

Leitzmann et al.302 reported that increased frequency of physical activity was associated with a decreased risk of lung cancer. This study classified participants into five categories according to their frequency of physical activity: 0 (inactive), less than 1, 1-2, 3-4, and 5 or more times per week. Analysis of the trend indicated that individuals who engaged in physical activity more often were less likely to develop lung cancer, compared with their inactive counterparts.302 Table 23.4 summarises the relative risk according to frequency of physical activity.


Table 23.4 Relative Risk of lung cancer according to frequency of physical activity/week (Leitzmann et al. 2009)

0 (none) <1 1-2 3-4 ≥5 P trend

1.0 0.89 (0.82, 0.96) 0.86 (0.81, 0.93) 0.81 (0.76, 0.87) 0.77 (0.71, 0.83) <0.001Adjusted for age, gender and smoking status

Similarly in women, a statistically significant inverse association was found between physical activity and lung cancer after adjusting for potential confounding factors.303 Highly active women were 23% less likely to be diagnosed with lung cancer than women who had a low level of physical activity. Women who participated in moderate activity more than once a week were 21% less likely to develop lung cancer than women who never participated in moderate physical activity. Women who participated in vigorous physical activity more than once a week were 29% less likely to develop lung cancer than women who never participated in vigorous physical activity.303 The results of this study are summarised in Table 23.5.

Table 23.5 Lung cancer risk in women with different measures of leisure time physical activity (LPA) (Sinner et al. 2006)

Regular LPAPhysical activity variable Multivariate-adjusted HR

No 1.00 (ref)

Yes 0.92 (0.79, 1.07)

LPA levelPhysical activity variable Multivariate-adjusted HR

Low 1.00 (ref)

Medium 0.84 (0.70, 1.00)

High 0.77 (0.64, 0.94)

Moderate LPAPhysical activity variable Multivariate-adjusted HR

Never 1.00 (ref)

≤1/wk 0.90 (0.75, 1.09)

>1/wk 0.79 (0.66, 0.94)

Vigorous LPAPhysical activity variable Multivariate-adjusted HR

Never 1.00 (ref)

≤1/wk 0.80 (0.60, 1.07)

>1/wk 0.71 (0.51, 0.99)Adjusted for age, BMI and smoking


23.2.2 Physical activity, gender and risk of lung cancer

Non-active men and women had a higher risk of lung cancer than individuals who spent the least time being physically active. Among men, an additional one-hour per week of sports activity was associated with a non-significant lower lung cancer risk (IRR = 0.89; 95% CI 0.77-1.04).304 For all types of activity (except for do-it-yourself work), physically active women had a lower risk of lung cancer than non-active women (Bak et al. 2005).304

Table 23.6 is a summary of the risk of lung cancer by gender broken down by physical activity and by time spent on that activity.

Table 23.6 Incident rate ratios (IRR) for lung cancer in relation to categories according to time spent on each of the different types of physical activity in leisure time (Bak et al. 2005)

MenPhysical activity in leisure time

Time spent on activityNon active IRR(95% CI)

Time spent on activityLittle

Time spent on activitySome IRR (95% CI)

Time spent on activityMuch (95% CI)

Sport 2.43 (1.47-4.02) 1.00 1.16 (0.59-2.30) 0.59 (0.29-1.22)

Cycling 1.30 (0.91-1.84) 1.00 0.77 (0.49-1.23) 1.23 (0.79-1.89)

Walking 1.37 (0.82-2.31) 1.00 1.27 (0.89-1.82) 1.43 (1.00-2.05)

Gardening 2.11 (1.44-3.09) 1.00 1.31 (0.87-1.98) 2.36 (1.57-3.57)

Housework 0.77 (0.48-1.23) 1.00 1.03 (0.66-1.59) 0.99 (0.71-1.38)

Do-it-yourself work 1.44 (0.96-2.15) 1.00 1.29 (0.87-1.93) 1.49 (1.04-2.13)

WomenPhysical activity in leisure time

Time spent on activityNon active IRR(95% CI)

Time spent on activityLittle

Time spent on activitySome IRR (95% CI)

Time spent on activityMuch (95% CI)

Sport 1.92 (1.29-2.85) 1.00 0.83 (0.46-1.49) 1.13 (0.67-1.93)

Cycling 2.14 (1.43-3.20) 1.00 0.95 (0.59-1.52) 1.39 (0.81-2.41)

Walking 2.31 (1.36-3.95) 1.00 1.18 (0.81-1.73) 1.33 (0.90-1.95)

Gardening 1.62 (1.11-2.37) 1.00 1.02 (0.62-1.68) 1.14 (0.72-1.81)

Housework 1.00 1.00 (0.71-1.42) 0.84 (0.58-1.23)

Do-it-yourself work 1.29 (0.88-1.91) 1.00 0.76 (0.37-1.54( 1.55 (0.89-2.67)All categories of physical activity ranged from a minimum of 1.5 - 8.5 hrs/week. Adjusted for smoking, school education, occupational exposure & intake of fruits & vegetables

Steindorf et al.305 reported that the type of physical activity was not associated with a significant reduction in lung cancer risk in a male cohort. This was not the case in a female cohort, where vigorous physical activity was associated with a reduction in lung cancer risk. The results of this study are presented as adjusted relative risk with 95% CIs, and are summarised by category of physical activity and by gender in Table 23.7. Standard metabolic equivalent or MET, is a unit used to estimate the amount of oxygen consumed by the body during physical activity. One MET would be the equivalent of the oxygen used whilst sedentary, for example sitting and reading a book. As activity increases, so too does the MET level.


Table 23.7 Risk of lung cancer by type of physical activity (PA) and by gender (Steindorf et al. 2006)

Occupational PACategory Adjusted HR Males Adjusted HR Females

Sitting 1.0 1.0

Standing 1.35 (1.02, 1.79) 1.14 (0.83, 1.57)

Heavy (manual) 1.25 (0.94, 1.66) 1.09 (0.76, 1.56)

Non-occupational PA (MET-hrs/wk)Category Adjusted HR Males Adjusted HR Females

0-<33.7 1.0 1.0

33.7-<56.6 0.89 (0.70, 1.13) 0.99 (0.77, 1.26)

56.6-<86.6 1.20 (0.96, 1.51) 0.99 (0.76, 1.30)

≥86.6 0.97 (0.76, 1.25) 1.00 (0.75, 1.35)

Recreational PA (MET-hrs/wk)Category Adjusted HR Males Adjusted HR Females

0-<13.5 1.0 1.0

13.5-<27.5 1.09 (0.88, 1.35) 0.99 (0.77, 1.280

27.5-<45.0 0.85 (0.67, 1.08) 0.99 (0.76, 1.30)

≥45.0 1.00 (0.79, 1.27) 0.99 (0.76, 1.30)

Household PA (MET-hrs/wk)Category Adjusted HR Males Adjusted HR Females

0-<11.0 1.0 1.0

11.0-<23.8 0.77 (0.60, 1.01) 1.04 (0.81, 1.33)

23.8-<43.6 0.86 (0.67, 1.10) 0.90 (0.68, 1.18)

≥43.6 1.04 (0.82, 1.31) 0.95 (0.70, 1.30)

Vigorous non-occupational PA (MET-hrs/wk)Category Adjusted HR Males Adjusted HR Females

None 1.0 1.0

>0-<15.0 0.94 (0.69, 1.28) 0.65 (0.43, 0.98)

15.0-<40.0 0.86 (0.65, 1.15) 0.60 (0.40, 0.89)

≥40.0 0.87 (0.65, 1.16) 0.92 (0.65, 1.32)Adjusted for smoking, weight, height, education, total energy intake, alcohol, vegetable and food intake, red and processed meat, and occupational exposure to lung carcinogens.

23.2.3 Physical activity, smoking status and risk of lung cancer

Alfano et al. (2004)285 reported that as the percentage of vigorous compared to moderate physical activity increased, a reduced association with lung cancer incidence may be


present in individuals with a lower history of smoking duration and intensity (<44 pack-years; HR 0.83, 95% CI 0.66 - 1.05). This association was not statistically significant and even less likely in individuals with smoking histories of 45 - 185 pack-years (HR 1.04 (0.91 - 1.21).

Considering women alone, Sinner et al.303 reported that in women who were current smokers, a moderate level of physical activity was associated with a 0.65-fold (95% CI, 0.51-0.83) lower risk of developing lung cancer, compared with those with a low level of physical activity. In addition, a high level of physical activity was associated with a 0.72-fold (95% CI, 0.55-0.94) lower risk. Former smokers who had moderate or high levels of physical activity were also at lower risk of developing lung cancer (2006). The lowest level of physical activity was used as the reference for other categories of activity.

23.3 SummaryA research synthesis and six research studies have been used to inform on the association between physical activity and risk of lung cancer, with most, but not all, suggesting an inverse association between higher levels of physical activity and lung cancer risk. Variability in the presentation of data between included studies precluded any meta-analysis. The included studies suggest any effect is more pronounced for recreational than occupational activity, and is stronger in men than in women. In one study on women, there was either no effect or a diminished effect of physical activity on risk of lung cancer amongst non-smokers.

Some of the limitations of these studies include the influence of factors outside the control of the investigators, non-response, dropouts and subjective interpretation of questionnaires.


According to the IARC Handbook of Cancer Prevention,306 physical activity is not considered to be a risk factor for cancer, including lung cancer, but rather provides benefits in terms of risk reduction.


Increased physical activity is not associated with an increased risk of lung cancer but may rather reduce the risk of the disease. Males and females who participate in some physical activity may be at a reduced risk of developing lung cancer when compared to those who are physically inactive. Among current and former smokers (both male and female), the risk of developing lung cancer is lowered with moderate to high physical activity levels.


23.6 Methodological quality of studiesScoring of each study for individual critical appraisal items is shown in Table 23.8.

Table 23.8 Physical activity: Methodological quality of included studies


Alfano et al 2004 Cohort Y Y U Y Y Y N Y Y — 7 Include

Bak et al. 2005 Cohort Y Y U Y Y Y Y Y Y — 7 Include

Lee et al 1994 Cohort N U U Y Y Y N Y Y — 5 Include

Leitzman et al 2009 Cohort Y Y U Y Y Y U Y Y — 7 Include

Sinner et al 2006 Cohort Y Y U Y Y Y N Y Y — 7 Include

Steindorf et al 2006 Cohort Y Y U Y Y Y U Y Y — 7 Include

Tardon et al 2005 Meta-analysis Y Y Y Y Y U U Y Y Y 8 Include


Alfano et al. 2004

The subject sample was clearly described with subjects having similar condition i.e. they were all heavy smokers. The details of cohort selection were unclear although it was stated that the sample was drawn from a previously conducted randomised controlled trial. The sample was predominantly Caucasian and middle-aged and hence cannot be generalisable to other ethnic or age groups. Confounding factors were identified but only one factor described in the analysis. Loss to follow-up was not well described. Outcome measurement tools were reviewed and validated. Statistical methods were described in detail.

Bak et al. 2005

Subject recruitment was well described; however, selection of cohort was unclear. The follow-up period was adequate. The outcomes of people who withdrew were not included in the analysis. Confounding factors were identified and adjusted for. Statistical methods were clearly described.

Lee et al. 1994

The sample selected was not representative of the population as a whole. It was also unclear whether the subjects selected had similar conditions and the selection was prone to bias. The study identified confounding factors but only age and smoking status were included in the analysis. Data analysis was adequately described. Loss to follow-up was not well described.

Leitzmann et al. 2009

The objective and methods were clearly stated with adequate description of confounding factors and outcome measures. The condition of the study participants was unclear. It was unclear whether people who withdrew were described in the analysis. Outcome measurement instrument was validated and adequately described. Statistical methods were described adequately.

Sinner et al. 2006

Participant recruitment was adequately described and the subjects were representative of the target population. However, it was unclear whether there was any bias in relation to selection of participants. Statistical analysis was adequately described that included adjustment for potential confounding factors. Exposure was well defined and described. The outcomes of people who withdrew were not well described.

Steindorf et al. 2006

Well designed and conducted study with a large cohort representative of the target population; however, the selection of the cohort was not well addressed. Confounding factors were identified; however, only gender and smoking status were described in the analysis. There was sufficient follow-up period; however, it was not clear whether people who withdrew were described. Statistical methods were clearly described.


Tardon et al. 2005

The objective of the paper was clearly stated and described. The search strategy was appropriate, as were the criteria for appraising studies however, it was unclear whether two independent reviewers conducted the appraisal. The methods used to minimise errors in data extraction were not clear. Appropriate method was used to combine the studies. The authors provided recommendations based on their data analysis and briefly mentioned specific directives for future research.


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286 Alavanja MC, Brownson RC, Berger E, et al. Avian exposure and risk of lung cancer in women in Missouri: population based case-control study. British Medical Journal. 1996;313 (7067):1233-1235.

287 Morabia A, Stellman S, Lumey LH and Wynder EL. Parakeets, canaries, finches, parrots and lung cancer: no association. British Journal of Cancer. 1998;77 (3):501–504.

288 Growing Careers. Australia’s Forest and Wood Products Industry. .

289 Bhatti P, Newcomer L, Onstad L, et al. Wood dust exposure and risk of lung cancer. Occupational and Environmental Medicine. 2011;68 (8):599-604.

290 IARC. Wood Dust and Formaldehyde. International Agency for Research on Cancer, Lyon, France, 1995.

291 Barcenas CH, Delclos GL, El-Zein R, et al. Wood Dust Exposure and the Association With Lung Cancer Risk. American Journal of Industrial Medicine. 2005;47 (4):349–357.

292 Stellman SD, Demers PA, Collin D and Boffetta P. Cancer mortality and wood dust exposure among participants in the American Cancer Society Cancer Prevention Study-II (CPS-II). American Journal of Industrial Medicine. 1998;34 (3):229–237.

293 Innos K, Rahu M, Rahu K, et al. Wood dust exposure and cancer incidence: A retrospective cohort study of furniture workers in Estonia. American Journal of Industrial Medicine. 2000;37 (5):501–511.

294 Laakkonen A, Kyyronen P, Kauppinen T and Pukkala EI. Occupational exposure to eight organic dusts and respiratory cancer among Finns. Occupational and Environmental Medicine. 2006;63 (11):726-33.

295 Schraub S, Leneure-B M and Bourgeois P. A brief original contribution: adenocarcinoma and wood. American journal of epidemiology. 1989;130 (6):1164-1166.

296 Jayaprakash V, Natarajan KK, Moysich KB, et al. Wood dust exposure and the risk of upper aerodigestive and respiratory cancers in males. Occupational and environmental medicine. 2008;65 (10):647-654.


297 Szadkowska-Stańczyk I and Szymczak W. Nested case-control study of lung cancer among pulp and paper workers in relation to exposure to dusts. American Journal of Industrial Medicine. 2001;39 (6):547-56.

298 Tardon A, Lee WJ, Delgado-Rodriguez M, et al. Leisure-time physical activity and lung cancer: a meta-analysis. Cancer Causes and Control. 2005;16 (4):389-397.

299 AIHW. Australia's Health 2006. cat. no. AUS 73. Australian Institute of Health and Welfare, Canberra, 2006.

300 Alfano CM, Klesges RC, Murray DM, et al. Physical activity in relation to all-site and lung cancer incidence and mortality in current and former smokers. Cancer Epidemiology Biomarkers & Prevention. 2004;13 (12):2233-2241.

301 Lee IM and Paffenbarger Jr RS. Physical activity and its relation to cancer risk: a prospective study of college alumni. Medicine and Science in Sports and Exercise. 1994;26 (7):831.

302 Leitzmann MF, Koebnick C, Abnet CC, et al. Prospective study of physical activity and lung cancer by histologic type in current, former, and never smokers. American journal of epidemiology. 2009;169 (5):542-553.

303 Sinner P, Folsom AR, Harnack L, et al. The association of physical activity with lung cancer incidence in a cohort of older women: the Iowa Women's Health Study. Cancer Epidemiology Biomarkers & Prevention. 2006;15 (12):2359-2363.

304 Bak H, Christensen J, Thomsen BL, et al. Physical activity and risk for lung cancer in a Danish cohort. International Journal of Cancer. 2005;116 (3):439-444.

305 Steindorf K, Friedenreich C, Linseisen J, et al. Physical activity and lung cancer risk in the European Prospective Investigation into Cancer and Nutrition Cohort. International Journal of Cancer. 2006;119 (10):2389-2397.

306 IARC. IARC handbook of cancer prevention, volume 6: weight control and physical activity. International Agency for Research on Cancer, Lyon, France, 2002.


25 Appendices25.1 Appendix A NHMRC Levels of Evidence19 – AetiologyLevel Aetiology

Level I A systematic review of level II studies

Level II A prospective cohort study

Level III - 1 All or none1

Level III - 2 A retrospective cohort study

Level III - 3 A case-control study

Level IV A cross-sectional study or case series1All or none of the people with the risk factor(s) experience the outcome; and the data arises from an unselected or representative case series which provides an unbiased representation of the prognostic effect 19. For example, no smallpox develops in the absence of the specific virus; and clear proof of the causal link has come from the disappearance of small pox after large-scale vaccination.

25.2 Appendix B Search history25.2.1 PubMed Cancer Lit

http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&orig_db=PubMed&cmd_current=Limits&pmfilter_Subsets=Cancer

http://www.cancer.gov/cancertopics/cancerlibrary/cancerliterature

#76 Search (#75) AND #45 Limits: Cancer

#75 Search (#74) OR #48 Limits: Humans, English, Cancer

#74 Search ((((((((((((((((((((((((#49) OR #50) OR #51) OR #52) OR #53) OR #54) OR #55) OR #56) OR #57) OR #58) OR #59) OR #60) OR #61) OR #62) OR #63) OR #64) OR #65) OR #66) OR #67) OR #68) OR #69) OR #70) OR #71) OR #72) OR #73 Limits: Cancer

#73 Search folic acid/analogs Limits: Cancer

#72 Search xanthophylls Limits: Cancer

#71 Search beta carotene derivatives Limits: Cancer

#70 Search beta carotene/analogs Limits: Cancer

#69 Search carotenoids/blood Limits: Cancer

#68 Search beta carotene/blood Limits: Cancer

#67 Search alpha-tocopherol/blood Limits: Cancer

#66 Search vitamin a/blood Limits: Cancer

#65 Search vitamin a Limits: Cancer


http://www.cancer.gov/cancertopics/cancerlibrary/cancerliterature



#64 Search environmental risk factors Limits: Cancer

#63 Search pollution Limits: Cancer

#62 Search agriculture Limits: Cancer

#61 Search pesticides Limits: Cancer

#60 Search heavy metals Limits: Cancer

#59 Search silica Limits: Cancer

#58 Search asbestos exposure Limits: Cancer

#57 Search asbestos Limits: Cancer

#56 Search radon exposure Limits: Cancer

#55 Search radon Limits: Cancer

#54 Search indoor air pollution Limits: Cancer

#53 Search alcohol Limits: Cancer

#52 Search marijuana Limits: Cancer

#51 Search smoking Limits: Cancer

#50 Search antioxidants Limits: Cancer


#48 Search (#46) OR #47 Limits: Cancer

#47 Search risk factor$ Limits: Cancer

#46 Search risk factors Limits: Cancer

#45 Search ((#5) OR #39) OR #44 Limits: Cancer

#44 Search (((#40) OR #41) OR #42) OR #43 Limits: Cancer

#43 Search schneeberg adj disease Limits: Cancer

#42 Search pancoast tumor Limits: Cancer

#41 Search non small cell lung cancer Limits: Cancer

#40 Search small cell lung cancer Limits: Cancer


#38 Search (((((((((((((((#22) OR #23) OR #24) OR #25) OR #26) OR #27) OR #28) OR #29) OR #30) OR #31) OR #32) OR #33) OR #34) OR #35) OR #36) OR #37 Limits: Cancer


#37 Search metast$ Limits: Cancer

#36 Search tumor$ Limits: Cancer

#35 Search tumo?r$ Limits: Cancer

#34 Search carcinogenesis Limits: Cancer

#33 Search microcytic$ Limits: Cancer

#32 Search blastoma$ Limits: Cancer

#31 Search angiosarcoma$ Limits: Cancer

#30 Search sarcoma$ Limits: Cancer

#29 Search teratoma$ Limits: Cancer

#28 Search lymphoma$ Limits: Cancer

#27 Search adenocarcinoma$ Limits: Cancer

#26 Search carcinoma$ Limits: Cancer

#25 Search cancer$ Limits: Cancer

#24 Search neoplasm$ Limits: Cancer

#23 Search neoplasm$.tw Limits: Cancer

#22 Search neoplasms Limits: Cancer

#21 Search ((((((((((((((#6) OR #7) OR #8) OR #9) OR #10) OR #11) OR #12) OR #13) OR #14) OR #15) OR #16) OR #17) OR #18) OR #19) OR #20 Limits: Cancer

#20 Search alveobronchial.tw. Limits: Cancer

#19 Search pulmon$.tw. Limits: Cancer

#18 Search bronchio-alveolar Limits: Cancer

#17 Search bronchoalveolar Limits: Cancer

#16 Search bronchioaveolar Limits: Cancer

#15 Search alveobronchial$ Limits: Cancer

#14 Search alveobronchial Limits: Cancer

#13 Search peribronchial$ Limits: Cancer

#12 Search peribronchial Limits: Cancer

#11 Search peribronch$ Limits: Cancer


#10 Search bronch$ Limits: Cancer

#9 Search pneumo $ Limits: Cancer

#8 Search pulmon $ Limits: Cancer

#7 Search lung $ Limits: Cancer

#6 Search lung $.tw. Limits: Cancer

#5 Search (((#1) OR #2) OR #3) OR #4 Limits: Cancer

#4 Search lung adenocarcinoma Limits: Cancer

#3 Search non small cell lung carcinoma Limits: Cancer

#2 Search carcinoma Limits: Cancer

#1 Search lung neoplasms Limits: Cancer

25.2.2 Embase

http://ovidsp.tx.ovid.com/sp-3.3.la/ovidweb.cgi

The same Synonyms, related terms, variant spellings, truncation and wildcards were used as search strategies for both General and Specific Risk Factors in Embase. In the specific risk factors, some terms are not supported in Embase.

#75 74) AND #45

#74 (#73) OR #48 Limits: Humans, English

#73 ((((((((((((((((((((((((#49) OR #50) OR #51) OR #52) OR #53) OR #54) OR #55) OR #56) OR #57) OR #58) OR #59) OR #60) OR #61) OR #62) OR #63) OR #64) OR #65) OR #66) OR #67) OR #68) OR #69) OR #70) OR #71) OR #72)

#72 folic acid/analogs

#71 xanthophylls

#70 beta carotene derivatives

#69 beta carotene

#68 carotenoids

#67 beta carotene

#66 alpha-tocopherol

#65 vitamin a

#64 environmental risk factors

#63 pollution


http://ovidsp.tx.ovid.com/sp-3.3.la/ovidweb.cgi

#62 agriculture

#61 pesticides

#60 heavy metals

#59 silica

#58 asbestos exposure

#57 asbestos

#56 radon exposure

#55 radon

#54 indoor air pollution

#53 alcohol

#52 marijuana

#51 smoking

#50 antioxidants

#49 (#45) AND #48

#48 (#46) OR #47

#47 risk factor$

#46 risk factors

#45 ((#5) OR #39) OR #44

#44 (((#40) OR #41) OR #42) OR #43

#43 schneeberg adj disease

#42 pancoast tumor

#41 non small cell lung cancer

#40 small cell lung cancer

#39 (#21) AND #38

#38 (((((((((((((((#22) OR #23) OR #24) OR #25) OR #26) OR #27) OR #28) OR #29) OR #30) OR #31) OR #32) OR #33) OR #34) OR #35) OR #36) OR #37

#37 metast$

#36 tumor$


#35 tumo?r$

#34 carcinogenesis

#33 microcytic$

#32 blastoma$

#31 angiosarcoma$

#30 sarcoma$

#29 teratoma$

#28 lymphoma$

#27 adenocarcinoma$

#26 carcinoma$

#25 cancer$

#24 neoplasm$

#23 neoplasm$.tw

#22 neoplasms

#21 ((((((((((((((#6) OR #7) OR #8) OR #9) OR #10) OR #11) OR #12) OR #13) OR #14) OR #15) OR #16) OR #17) OR #18) OR #19) OR #20 Limits: Cancer

#20 alveobronchial.tw.

#19 pulmon$.tw.

#18 bronchio-alveolar .tw.

#17 bronchoalveolar .tw.

#16 bronchioaveolar .tw.

#15 alveobronchial$ .tw.

#14 alveobronchial .tw.

#13 peribronchial$ .tw.

#12 peribronchial .tw.

#11 peribronch$ .tw.

#10 bronch$ .tw.

#9 pneumo $ .tw.


#8 pulmon $ .tw.

#7 lung $ .tw.

#6 lung $.tw.

#5 (((#1) OR #2) OR #3) OR #4

#4 lung adenocarcinoma /

#3 Non small cell lung carcinoma/

#2 Carcinoma/

#1 lung neoplasms.mp.or exp Lung Neoplasms/

25.2.3 Lung Cancer search histories (minor databases)

JBI Library (1998 – 28/03/2011)

Search strategy

Lung cancer AND risk factors

Lung cancer AND risk

Bandolier (1995 - 28/03/2011)

Search strategy


Lung cancer AND risk factor$

Index to Theses (1970 – 29/03/2011)


Fade: The Northwest Grey literature Service


Lung cancer AND risk factor*

The Networked digital library of Theses and Dissertations (1900-2012)

Scirus ETD


Lung cancer AND risk

VTLS visualiser



Australian Digital Theses


DART-Europe E-theses Portal



25.3 Appendix C Critical appraisal instruments25.3.1 JBI Critical Appraisal Checklist for Comparable Cohort/ Case Control

Reviewer Date

Author Year Record Number

Criteria Yes No Unclear1. Is sample representative of patients in the population as a whole?

2. Are the patients at a similar point in the course of their condition/illness?

3. Has bias been minimised in relation to selection of cases and of controls?

4. Are confounding factors identified and strategies to deal with them stated?

5. Are outcomes assessed using objective criteria? 6. Was follow up carried out over a sufficient time period?

7. Were the outcomes of people who withdrew described and included in the analysis?

8. Were outcomes measured in a reliable way? 9. Was appropriate statistical analysis used?

Overall appraisal: Include Exclude Seek further info

Comments (Including reason for exclusion)


25.3.2 JBI Critical Appraisal Checklist for Systematic Reviews

Reviewer Date

Author Year Record Number

Criteria Yes No Unclear1. Is the review question clearly and explicitly stated? 2. Was the search strategy appropriate? 3. Were the sources of studies adequate? 4. Were the inclusion criteria appropriate for the review question?

5. Were the criteria for appraising studies appropriate?

6. Was critical appraisal conducted by two or more reviewers independently?

7. Were there methods used to minimise error in data extraction?

8. Were the methods used to combine studies appropriate?

9. Were the recommendations supported by the reported data?

10. Were the specific directions for new research appropriate?

Overall appraisal: Include Exclude Seek further info

Comments (Including reason for exclusion)


25.4 Appendix D Excluded studies 25.4.1 Risk factor – Asbestos

Finkelstein 2010

The study was excluded because it failed to deal with smoking as a confounding factor.

Pira et al 2009

The objective of this prospective cohort study, undertaken in Italy that focused on a cohort of chrysotile asbestos miners is well stated. It was to provide further information on mortality from cancer and other causes among chrysotile asbestos miners several years after exposure ceased. The study updated the analyses updated an earlier study with an extended follow up period. Whilst the study findings, that chrysotile exposure does present a significant risk of lung cancer are interesting, their usefulness is limited by a question mark over whether they are influenced by failure to adjust for smoking in the analysis. This study was excluded from the review for this reason.

Menegozzo et al 2011

This study used data from a cohort of male asbestos-cement workers employed in an asbestos-cement planted located in Naples Italy. It focused on measuring mortality from lung cancer and a number of other diseases, including asbestosis and estimated relative risks using Standardized Mortality Ratios (SMRs). The study found a significant increase in lung cancer mortality for the cohort. Whilst the study obtained a score on the JBI critical appraisal test the met the requirements for inclusion it was exclude as it did not adjust for smoking in the computation of risk measures.

Weiss 1999

This review and meta-analysis focused on the question of whether excess lung cancer risk in worker cohorts exposed to asbestos only occurs among those with asbestosis. It used data only from cohort studies. The lung cancer risk measures (SMRs) of seven cohort studies that used cohorts with no asbestosis deaths were examined and a summary indicator computed. In addition, lung cancer rates in 38 cohorts were correlated with asbestosis rates and cumulative asbestos exposure and the results of these two exercises compared. One weakness of this study was that some of the studies it extracted data from and used in the analysis did not adjust adequately for smoking. Another was no explanation of inclusion criteria (aside from excluding case-controls) and linked to this a rather small sample of studies used to develop the summary risk indicator in cohorts without confirmed asbestosis. The study was excluded due to failure to adjust for the smoking confounder.

25.4.2 Risk factor – Avian exposure

Holst et al. 1988

Subjects did not appear representative of the population; the sample size was small and despite the stated number of inhabitants cases and controls only related to one general practice. Controls were randomly selected. Despite being recorded, duration of exposure defined was broad and not included in analysis; only self completed questionnaire used; delivered by 57 different people. Confounding factors were addressed, though no occupational exposure nor exposure to other pets considered. Duration of exposure was


considered by observation of increased bird keeping by patients; it was unclear if this was increased duration or intensity. Outcomes classified according to international criteria, however no information provided how identified. Exposure established over 14 yr period and any losses to group and reasons well described. All cases were smokers, matching may be more appropriate.

Modigh et al. 1996

Subjects were representative of target population. Condition of patients included and duration of exposure is ill defined. Selection of controls was consecutive rather than random and cases of lung cancer for inclusion were confirmed post interview leaving the study at risk of bias. Confounders well accounted for. It was unclear how or by whom the suspected diagnosis of lung cancer was confirmed. Statistical methods were adequately described.

25.4.3 Risk factor – Red meat and processed meat consumption

Chui et al 2010

The study quality was moderate, with the methods and objectives being clearly stated. Section criteria were well reported for both cases and controls. The study population were Chinese women living in Hong Kong. Controls were aged matched to cases (by 10 year age groups) and were also from Hong Kong. Data was collected using a food frequency questionnaire (number of items not reported). Meat was considered as a whole food group, with no distinction between meat types as such the study was excluded from analysis. Confounding factors were considered appropriately. Outcomes measures and statistical methods were adequately described. Duration of exposure was 5 years.

Brinton et al 2011

Examined potential risk factors for lung cancer in women identified from the NIH-AARP Diet and Health Study Cohort, with a particular focus on reproductive hormones. The study reports positive associated higher levels of consumption of red meat and processed meat, however no estimates of risk is provided to support this statement.

Sinha and Rothman 1999

This study examined the association between red meat and various cooking techniques with the risk of colorectal cancer. This study was excluded as it did not address the risk of lung cancer.

De Stefani et al 2011

This study examined the potential association of dietary patterns and the risk of lung cancer in Uruguayan men. This study was excluded because the exposure was an overall diet and data specific to red meat could not be isolated.

25.4.4 Risk factor – Family history

Matakidou et al 2005

This research synthesis combined primary data from 53 (28 case control, 17 cohort and 7 twin studies) studies identified through a search of PubMed (1963 – May 2005). The review aims were well defined. The search strategy was appropriate, however only the PubMed database was searched for studies, raising the possibility that relevant studies


were not identified. Unpublished studies were not sought, possibly introducing publication bias. The review included any study located by the search and details of methodological quality assessment (if any) were not reported. No distinction was made between studies that estimated familial risk from mortality or incidence data, respectively. The characteristics analysed included publication year (before or after 1993; the mean year of publication of studies), type of control group used, verification of the data collected, type of relative studied, sex of cases, adjustment for smoking habits in study subjects, adjustment for smoking habits in relatives and adjustment for family size. Data from this study was included in the more recent review by Lissowska et al 2010.

25.4.5 Risk factor – Wood dust

Barcenas et al 2005

The questions where the study was rated ‘yes’ were on the objectivity of criteria used for outcome assessment, the reliability of measurement of outcomes and the appropriateness of statistical analysis used. The sample use in this study was relatively large (1368 cases and controls) but it was comprised of particularly ethnic groups and not at all representative of the USA population, where the study took place. The sample is also poorly matched to the Australian population. As with all the other studies there is the problem of confounding factors not being sufficiently addressed. Another weakness in this study was poor matching of cases and controls.

Schraub et al 1989

This study was only awarded a yes to the quality check for the questions on appropriateness of statistical analysis, objectivity and accuracy of outcome measurement. There was insufficient explanation of how the controls and cases were matched in this study, the sample was very small and there was vagueness around the measurement of wood dust exposure.


25.5 Appendix E Tables of included studies 25.5.1 Air PollutionStudy Exposure/ Risk

factorDesign Population Type of

LCAdjusted for Risk (Measure of Association) Adjusted

Beelen et al 2008Nested case controlThe Netherlands

Air pollution measured as sum of background & local elements.Exposure to black smoke, nitrogen dioxide (NO2), sulphur dioxide (SO2), & particulate matter ≥2.5 µm (PM2.5)Local traffic contributions also measured as motor vehicles per hour (MVH).Duration of exposure: 90% of participants 10yrs+

Netherlands Cohort Study on Diet & Cancer (NLCS). Mean 11.3 yr follow up.Demographic data (inc. smoking) collected via questionnaire.Exposure assessed using data from monitoring stations in routine air quality monitoring networks.Distance & proximity to heavy traffic roads also determined

114,378 participantsAged 55-69yrs at enrolment, living throughout the NetherlandsFollow-up from September 1986 to December 1997

Type not stated.Lung cancer incidence confirmed by Cancer registry.

Age, gender, smoking status, indicators of socioeconomic status.Education, fruit consumption also considered.

Adj. RR (95% CI) (95th vs 5th percentile of distribution for each category):NO2 (30µm/m3):0.86 (0.70-1.07)PM2.5(10µm/m3):0.81 (0.63-1.04)SO2 (20µm/m3):0.90 (0.72-1.11)Overall risk associated with air pollution by traffic intensity:Traffic intensity (10,000 MVH/24h):1.05 0.94-1.16Traffic intensity in a 100m buffer(335,000 MVH/24h):1.05 (0.92-1.19)Living near a major road: 1.11 (0.91-1.34)Living near heavy traffic roads – by smoking status adj. RR (95% CI)Never smokers: 1.11 (0.88 - 1.41)Ex smokers: 0.98(0.77 - 1.25)Current smokers: 1.04 (0.91 - 1.19)Living near heavy traffic roads with a 100m buffer – by smoking status. Adj. RR (95% CI)Never smokers : 1.55 (0.98 - 2.43)Ex smokers: 1.24 (0.85 - 1.81)Current smokers : 0.95 (0.73 - 1.23)

Chen et al 2008Systematic Review

Exposure to environmental air pollution on annual basis.Gaseous

Systematic review of 32 studies. 9 cohort & 1 case-control studies had controlled

Adults older than 18 years of age, both genders.Both genders, mean age: 42 yrs

Lung cancer incidence and mortality was coded

Age, gender, occupation, indoor smoking, interviewer, employment in risk occupation,

Pooled RR (95%CI) or pooled RR associated with a 10µg/m3 increase (RR10), by pollutant, rel. lowest category in each case:NOx: (2 studies)


Study Exposure/ Risk factor

Design Population Type of LC

Adjusted for Risk (Measure of Association) Adjusted

Several countries

pollutants (SO, CO, O3, NO, NOx)Particulate pollutants (PM10 & PM2.5).Definitions of what constitutes “near to” a “busy” or “major” road were not reported.

for smoking & were relevant to the association between long term exposure to ambient pollution & lung cancer.Medline, Embase & Risk abstract databases searched for papers published 1950-2007.

(range 25-59yrs)Median follow up: 17 yrs

by ICD 9: 162.Types of lung cancer not specified

population density 1.08 (1.02-1.15) (incidence)1.11 (1.03-1.19) (mortality)NO2: (mortality, 4 studies)Pooled RR10associated with a 10µg/m3 increase:1.01 (0.94 - 1.09)(Incidence, 3 cohort studies)Pooled RR10 = 1.11 (0.99-1.24)SO2: (5 studies)Pooled RR10: 1.07 (0.96-1.19) (mortality)Pooled RR10: 1.12 (0.98-1.29) (Incidence)Both genders (4 studies):1.12 (0.97-1.30)Men only (1 study):1.00 (0.92-1.08)USA (2 studies): 1.58 (0.66-3.76)Europe (3 studies):1.00 (0.96-1.19)Particulate matter PM2.5:(Incidence, 4 studies)Pooled RR10: 1.15 (1.06-1.24)Both genders (4 studies):1.20 (1.08-1.33)Men only (1 study): 1.39 (0.79-2.46)USA (3 studies):1.15 (1.07-1.25)Europe (2 studies):1.23 (0.98-1.54)Living near a “major road” – highest category vs lowest:RR 1.31 (0.82-2.09) (incidence, 1 study)RR 1.44 (0.94-2.21) (mortality, 1 study)Living near a “busy road” highest category vs lowest:RR 1.07 (0.93-1.23)

Pope et al 2011

Daily exposure estimates

CohortACS-CPS II

794,784 male (49%) & female

Types of lung

Smoking, gender, education, marital

Overall risk with ambient exposure to 10µg/m3 PM2.5, Adj RR (95%CI):





CohortUSA

PM2.5 ranged from 5-µg/m3/day measured at residences in the study areas. Exposure detection method not reported.

studyDemographics (inc. smoking data) collected by self-reported questionnaires.

(61%) participants aged 30yrs+ at enrolment. Mean age 56yrs (+/-10.5yrs)Cohort includes 3194 lung cancer deaths.6yr follow up

cancer not reported.ICD-9 162 classification used.Cardiovascular disease also examined

status, BMI, alcohol consumption, as well as various dietary factors and several occupational dust/fumes

1.14 (1.04-1.23)Risk with ambient exposure to 10µg/m3 PM2.5 by smoking status Adj RR (95%CI), relative to never smokers.≤3 cigs/day:10.44 (7.30-14.94)8-12 cigs/day:11.63 (9.51-14.24)28-32 cigs/day:26.82 (22.54-31.91)≥43 cigs/day: 39.16 (31.13-49.26)

Raaschou-Nielsen et al 2011CohortDenmark

Time weighted average levels of NOx and NO2 estimated for each residence based on actual & calculated measurements from the Danish AirGIS modelling system.Traffic load within 200m & whether a major road was within 50m also noted.

Demographics (inc. smoking data) collected by self-reported questionnaires.National records used to determine cause of death & loss to migration from the area.20yr follow up

52,970 residents of Copenhagen & Aahus areas of Denmark. Men & women aged 50-64yrs at enrolment,

Types of lung cancer not stated

Smoking, ETS, education, fruit intake, employment, age

Overall risk with NOx concentration (µg/m3)Adj. IRR (95%CI)<17.2: 1.0017.2-21.8: 1.09 (0.84-1.40)21.8-29.7: 0.93 (0.73-1.13)>29-7: 1.30 (0.79-1.51)Risk with NOx concentration (µg/m3), by smoking status. Relative to <17.2µg/m3 for each category. Adj. IRR (95%CI)Non-smokers:17.2-21.8 µg/m3:1.07 (0.59-1.94)21.8-29.7µg/m3:0.83 (0.46-1.51)>29-7 µg/m3: 1.91 (1.10-3.30)Current Smoker:17.2-21.8 µg/m3:1.09 (0.82-1.45)21.8-29.7µg/m3: 0.95 (0.73-1.23)>29-7 µg/m3: 1.21 (0.95-1.45)Males:17.2-21.8 µg/m3: 1.14 (0.80-1.62)21.8-29.7µg/m3: 0.97 (0.70-1.34)>29-7 µg/m3: 1.16 (0.85-1.57)





Females:17.2-21.8 µg/m3:0.95 (0.65-1.37)21.8-29.7µg/m3: 0.85 (0.60-1.20)>29-7 µg/m3: 1.45 (1.06-1.99)Overall risk associated with a major road within 50m or residence Adj. IRR (95%CI)No:1.00Yes:1.21 (0.95-1.55)Overall risk associated with traffic load within 200m (103 vehicle km/day) Adj. IRR (95%CI)<0.88:1.000.88-2.61:0.98(0.76-1.27)2.61-6.73:1.05 (0.83-1.34)>6.73:1.17 (0.92-1.47)

Turner et al 2011Cohort studyUSA

Chronic exposure to ambient fineparticulate matter (PM2.5) air pollution.Mean (1yr, measured 1999-2000) 17.6 µg/m3 (range; 14.3-21.1µg/m3).Data on exposure obtained from aerometric information retrieval system.

Population-based cohort study Data collected via mailed questionnaire (inc. smoking status).

188,699 lifelong never smokers.Data from the American Cancer Society Cancer Prevention Study II (CPS-II)26yr follow up.

Types of lung cancer not reported.

Smoking, age, race, education, marital status, BMI, passive smoking, veg/fruit/fibre & fat intake, as well as various occupational factors (asbestos: chemicals/acids/solvents, coal or stone dusts, coal tar/pitch/asphalt, formaldehyde, diesel engine exhaust), mean county-level residential radon concentrations, prevalent chronic lung disease (CLD)

Overall risk with chronic exposure PM2.5. Adj. HR (95%CI)1 yr exposure:1.27 (1.03 – 1.56)11 yr exposure: 1.25 (1.01-1.55)21yr exposure: 1.27 (1.02-1.56)Chronic exposure to ambient PM2.5 - by gender. HR( 95%CI)Male: 1.19 (0.83 - 1.73)Female: 1.30 (1.01 - 1.68)Chronic exposure to ambient PM2.5 & industrial exposureExposed:1.17 (0.66-2.09)Non-exposed: 1.29 (1.03-1.61)Chronic exposure to ambient PM2.5 & passive smoking





(asthma, chronic bronchitis, or emphysema) or hay fever at enrolment.

None: 1.39 (1.03-1.87)Any: 1.17 (0.88-1.57)

25.5.2 Alcohol ConsumptionStudy Exposure/

Risk factorDesign Population Type of LC Adjusted

forRisk (Measure of Association) Adjusted

Bagnardi et al 2011

Total alcohol consumption

Meta-analysis of ten included studies; three cohort studies, one pooled analysis and six case-control studies.

Meta-analysis based on a total of 1913 never smoker lung cancer cases

Description unclear

Diet, gender, BMI, socio-economic status and education

Pooled RRs and 95% CIs of lung cancer for drinker versus non-drinkers by gender and non-smokers

Definition of never smokers

Never smoked regularly

<100 cigarettes lifetime Unspecified

1.01 (0.88-1.17) 1.23 (0.57-2.65) 1.60 (0.90-2.85)

Gender

Male Female Male and female

1.22 (0.83-1.80) 1.26 (0.81-1.95) 1.07 (0.64-1.80)

Balder et al 2005Nether-lands

Alcohol median intake (g/day) – quintile of consumptionQ1 0Q2 2.2Q3 9.3Q4 23

Cohort Study on Diet and Cancer.Follow-up from 1986–95

58 279 men in 204 municipalities in Netherlands, aged 55–69 years

Lung cancer ascertained fromNetherlands CancerRegistry and Netherlands Pathology Registry

Age, total energy intake, current cigarette smoker, number of cigarettes smoked per day, years of smoking cigarettes, higher

RR and 95% CI of lung cancer according to quintiles of alcohol consumptionp for trend=0.03

Q1 Q2 Q3 Q4 Q5

1.0 1.11 (0.8–1.54)

1.23 (0.91-1.67)

1.08 (0.8–1.47)

1.56 (1.11–2.18)



Design Population Type of LC Adjusted for

Risk (Measure of Association) Adjusted

Q5 42 vocational or university education, family history of lung cancer, physical activity, BMI

Boffetta et al 2001Sweden

Alcoholics Cohort study based on a linkage between the Swedish In-patientRegister and the National Cancer Register

173 665 (138 195 men, 35 470 women) patients with a hospital discharge of alcoholism, aged ≥20 years; mortality follow-up, 1965–95; case ascertainment 98%

Lung cancer cases identified as those that occurred among the patients in the cohort either before or after the first hospital discharge with diagnosis of alcoholism.Cancers classified according to the ICD-7

Age, gender, calendar year

Standardised incident ratios and 95% CI of lung cancer among alcoholic patients

Men Women Total

2.24 (2.13–2.35) 4.16 (3.68–4.7) 2.4 (2.29 –2.51)

Breslow et al 2000USA

Duration of birdOwnership, the number and type of birds owned>6 months

Cohort studyFollow-up, 1987–95

Sub-cohort of 20 004 adults, 18 years or older who completed theCancer Epidemiology Supplement (8363 men, 11 641 women)

Case ascertainment, National Death Index and Death certificate

Age, gender, smoking duration (years), packs per day smoked

RR and 95% CI for lung cancer mortality by quartiles of alcohol consumption

Age-adjusted (p for trend <0.0001)

Q1 Q2 Q3 Q4

1.0 0.9 1.2 21

Multivariate adjusted (p for trend <0.101)

Q1 Q2 Q3 Q4





1.0 0.7 (0.4–1.3) 1.0 (0.6–1.6) 1.3 (0.8–2.0)

Chao et al 2007

Amount of alcohol consumed over a time period (e.g. no: of drinks per week)

Meta-analysis of ten case-control studies and four cohort studies.

4,119 lung cancer cases arose from N = 453,751 participants

Description unclear

Age, sex, BMI, smoking, residence, family history, dietary intake and education

Smoking adjusted summary RR and 95% CI for lung cancer according to type of alcoholic beverage

<1 drink/day

Beer Wine Liquor

0.85 (0.67-1.08) 0.72 (0.52-0.99) 0.89 (0.69-1.16)

≥1 drink/day

Beer Wine Liquor

1.20 (0.90-1.58) 0.80 (0.65-0.99) 1.20 (0.98-1.48)

Highest category

Beer Wine Liquor

1.10 (0.83-1.49) 0.83 (0.70-1.00) 1.13 (0.98-1.32)

Djoussé et al 2002USA

Alcohol average intake (g/day) on follow-up examination

Framingham Cohort Study (1948) andFramingham Offspring Study (1971)

In 1948, 5209 subjects aged 28–62 years at first examination; in 1971, 5124 children of the original cohort participated; study included 4265 subjects from the original cohort and 4973

Cancer case ascertainment, self report, hospitalisation surveillance andNational Death Index; 100% histologically confirmed

Age, sex, smoking status, pack–years of cigarette smoking, year of birth

RR and 95% CI for average alcohol intake (g/day) and risk of lung cancer

0 0.1-12 12.1-24 >24

1.0 1.2 (0.7-2.1) 1.1 (0.6-2.1) 1.3 (0.7-2.4)





from the offspring cohort

Korte et al 2002

Ethanol consumption (g/month)

Meta-analysis of four study designs.Case-control and cohort studies of alcoholics (11 studies) and general population (12 cohort, 10 case control)

Description unclear

Description unclear

Smoking Pooled RR and 95% CI of lung cancer risk according to different categories of alcohol consumption (g/month)

Cohort studies

Nondrinker

1-499 500-999 1,000-1,999

≥2,000 Overall

1.0 0.98 (0.79–1.21)

0.92 (0.81–1.04)

1.04 (0.88-1.22)

1.53 (1.04–2.25)

1.19 (1.11–1.29)

Case-control studies

Nondrinker

1-499 500-999 1,000-1,999

≥2,000 Overall

1.0 0.63 (0.51–0.78)

1.3 (0.98–1.7)

1.13 (0.46–2.75)

1.86 (1.39–2.49)

1.39 (1.06–1.83)

Mayne et al 1994USA

Beer /monthQuartile of consumptionQ1Q2Q3Q4

Case-control study

413 (212 men, 201 women) nonsmokers identified via the medical records department, pathology department and the tumour registry, aged 31–80 years


Age, sex, county of residence, smoking history, cigs/ day smoked by former smokers, religion, education, body-mass index, income

ORs and 95% CI of lung cancer risk and quartiles of beer consumption

Q1 Q2 Q3 Q4

1.0 (ref) 1.06 0.87 1.18





413 controlsSelected from driving license files; individually matched on age, sex, county of residence, smoking historyCases - 71 hospitalised men; mean age, 67.3 yearsControls - 70 hospitalised cancer-free men; mean age, 66.5 years individually matched to cases by age

Pierce et al 1989Australia

Alcohol assessed as Drinks/weekDuration (years)

Case Control study

— Lung cancer cases confirmed cytologically or histologically

Age, smoking status

ORs and 95% CI of lung cancer and alcohol consumption by smoking status

Current smoker Exsmoker Nonsmoker

1.00 2.40 (0.9-6.60) 2.50 (0.7-8.80)

Rachtan & Sokolowski 1997

Frequency of alcohol consump-tion

Case Control study

Cases - 118 hospitalised women; age not reported

Lung cancer cases confirmed

Age, smoking status, passive

RR and 95% CI for lung cancer risk by frequency of consumption of alcohol beverages

Non-drinker





Poland BeerWineVodka

Controls - 141 healthy women selected among next of kin of patients admitted to the same hospital without tobacco related cancer; age not reported

histologically smoking and family history

Beer, p for trend=0.125

Wine, p for trend=0.957 Vodka, p for trend = 0.0005

1.0 1.0 1.0

Rarely



1.07 (0.49–2.34) 0.9 (0.5–1.81) 3.18 (1.80–5.61)

1–2/month



1.83 (0.50–6.69) 1.08 (0.48–2.45) 2.56 (1.18–5.56)

At least once/week



3.3 (0.62–17.48) 1.16 (0.16–8.45) 10.32 (1.17–91.47)

Shimazu et al 2008Japan

Frequency and amount of alcohol consumption in cohort 1 and drinking status in cohort 2

Large scale population-based cohort study.14 year follow-up period

46,347 men between 40-59 years of age from 10 prefectural public health centre areas in Japan

Incident cases of lung cancer cases identified by voluntary reports from local hospitals and cancer registries.Diagnosis of lung cancer confirmed by histologic or cytologic

Age, smoking status, passive smoking and family history

Adjusted hazard ratios and 95% CI for lung cancer incidence according to alcohol consumption stratified by smoking status(*p for trend (MV adjusted – 0.02)

Nonsmokers

Age, area adjusted Multivariate adjusted

Nondrinkers 1.33 (0.76-2.35) 1.23 (0.70-2.17)

Occasional drinkers 1.00 1.00

1-149 g/wk 0.66 (0.35-1.26) 0.62 (0.33-1.19)





examinationMortality data confirmed and obtained from Ministry of Health, Labour and Welfare.

150-299 g/wk 0.78 (0.41-1.49) 0.69 (0.36-1.58)

300-449 g/wk 0.90 (0.44-1.83) 0.77 (0.38-1.58)

≥450 g/wk 0.70 (0.31-1.57) 0.58 (0.26-1.30)

Current smokers

Age, area adjusted Multivariate adjusted

Nondrinkers 1.67 (1.07-2.60) 1.61 (1.03-2.52)

Occasional drinkers 1.00 1.00

1-149 g/wk 1.38 (0.87-2.21) 1.44 (0.90-2.30)

150-299 g/wk 1.30 (0.82-2.07) 1.30 (0.82-2.06)

300-449 g/wk 1.74 (1.09-2.77) 1.66 (1.04-2.65)

≥450 g/wk 1.86 (1.16-2.98) 1.69 (1.05-2.72)

Sørensen et al 1998Denmark

Alcoholics Cohort study of 1-yearSurvivors of Cirrhosis

11 605 1-year Survivors of cirrhosis;follow-up, 1977–93; 7165alcoholic cirrhosis (5079 men, 2086 women)

Lung cancer ascertainment, DanishCancer Registry

Age, sex, calendar period

Incidence of lung cancerNo: of cases/deaths - 135Standardised Incident Ratio (SIR) & 95% CI

2.1 (1.8–2.5)

Stemmermann et al. 1990

Alcohol (oz/month)0

Prospective cohort studyFollow-up,

7572 Japanese men born between

Lung cancer ascertained with hospital

Age, current smoking status, age

Covariates adjusted RR and 95% CI for lung cancer by level of alcohol consumption (oz/month)P value 0.09





Hawaii <55–1415–39≥40

1965–68 to 1989

1900 and 1919 (also subjects for the Honolulu Heart Study)

records, death certificates, and the Hawaii Tumour Registry

started smoking, number of cigarettes smoked per day, maximum number of cigarette smoked per day, years of smoking with maximum number per day

0 <5 5-14 15-39 40+

1.0 0.75 (0.48-1.17)

0.93 (0.59-1.47)

1.43 (0.99-2.06)

1.09 (0.73-1.64)

Toriola et al 2009Finland

Alcohol consumption assessed with a structured quantity and frequency method using Nordic alcohol consumption inventory. Binge drinking classified as >70g ethanol/drinking session.

Prospective population-based cohort studyAverage follow-up of 16.7 years

2,267 middle-aged men from Eastern Finland without a history of lung cancer at baseline

Lung cancer incidence identified by Finnish cancer registry

Age, smoking history, family history, BMI and socio-economic status

RR and 95% CI for lung cancer and binge drinking according to smoking categoriesMultivariate adjusted

Number of cigarettes smoked per day

Nonsmokers 1-19/day 20-29/day ≥30/day

1.49 (0.88-2.56)

2.70 (1.61-4.53) 2.35 (1.38-3.96) 2.24 (1.29-3.80)

Duration of smoking (in years)

Nonsmokers <30 ≥30

1.62 (0.96-2.72)

2.76 (1.64-4.62) 1.72 (1.02-2.91)


25.5.3 Arsenic exposureStudy Exposure/

Risk factorDesign Population Type of LC Adjusted for Risk (Measure of Association) Adjusted

Baastrup et al 2008Cohort studyDenmark

Two exposures for arsenic in drinking water calculated for each participant. First one included time-weighted average exposure and second included cumulated arsenic exposure.

Cohort study.

Danish cohort of 57,053 persons, including 27,178 men and 29,875 women. 6-10 years follow-up.

All lung cancers, type not stated.

Data adjusted for various confounding factors.

Adj IRRTime-weighted average exposure (median exposure 0.7-1.2 µg/L) – 0.99 (0.92-1.07)Cumulated exposure (5mg) – 1.0 (0.98-1.02)

Ferreccio et al 1998Case ControlChile

Data collected on arsenic levels in drinking water from utility companies from 1950 to 1996.

Case-control study.

151 lung cancer cases and 419 controls enrolled in three regions of Northern Chile.


Unconditional regression analysis with univariate and multivariate models.

Adj OR for mean arsenic concentrations (mg/L)0-0.01 – 10.01-0.029 – 1.7 (0.5-5.1)0.03-0.049 – 3.9 (1.2-13.4)0.05-0.199 – 5.5 (2.2-13.5)0.20-0.40 – 9.0 (3.6-22.0)

Hughes et al 1988Pooled analysis of studies mostly from USA

Arsenic exposure in communities surrounding arsenic-producing industries.

Pooled analysis based on 12 cohort studies.

Large population-based cohorts in communities residing around copper

Description unclear

Regression modelNot clear if potential confounding factors adjusted

Pooled OR:Overall – 1.08 (0.66 -1.43)Mortality – 1.14 (0.69-1.88)Incidence – 1.02 (0.46-2.28)



Design Population Type of LC Adjusted for Risk (Measure of Association) Adjusted

smelters.

Lundstrom et al 2006Nested Case ControlSweden

Cumulative airborne arsenic exposure estimated (mg As/m3 X 10 m3/d X 250 days/yr X number of exposed years) as a cumulative air arsenic exposure index (CAAEI).

Nested Case Control.

Men - 46 cases and 141 age-matched controls. Mortality followed from 1955 to 1987 and incidence followed from 1958 to 1987.Primary smelter workers.


Multiple linear logistic regression with adjustment for potential confounding factors.

Adj OR (95% CI)1.07 (1.02-1.11)Significant association with CAAEI and smoking.

Pershagen et al 1985Case ControlSweden

Arsenic community exposure but further details unclear.

Case Control study.

Men - 212 cases and 424 controls. Cases constituted men who died between 1961 and 1979.Men living near arsenic-emitting smelter

All lung cancers, type not stated. Histological diagnosis (77.8%), cytological diagnosis (9.1%) and clinical and radiological evidence (13.1%).

Smoking. Data analyses as described by Mantel and Haenszel and Miettinen.

RR and 95% CI:Nonsmokers – 2.3 (0.7-7.6)Smokers – 2.2 (1.3-3.9)Relative risk of 2.0 for lung cancer among both nonsmokers and smokers in the exposed area compared to reference area.

Qiao et al 1997CohortChina

Cumulative individual worker’s exposure to arsenic estimated using an

Cohort study 8346 members (7,867 men and 479 women). Four year follow-up with 241 lung


Proportional hazard model for relative risk and SMR computed using Poisson distribution.Age-adjusted

RR & 95% CIQ1 (0.062-1.731) = 1.00Q2 (1.733-7.287) = 3.15 (1.23-8.05)Q3 (7.288-16.090) = 5.55 (1.95-12.54)Q4 (16.093-) = 4.94 (1.95-12.54)




index for arsenic exposure – Index of Arsenic Exposure Months, IAEM), calculated as a time-weighted average of arsenic concentration X time exposure months.

cancer cases diagnosed.Tin miners

P = 0.0002

‘t Mannetje et al 2011Multi-centre case controlCentral/Eastern Europe and UK

Indices to assess exposure included expert’s confidence in the presence of exposure, frequency of exposure and the intensity of exposure. Three cut-points used for exposure intensity.

Multi-centre case control study.

2852 cases (men -2,197 & women – 655) and 3104 controls (men -2,295 & women – 809).Workers employed in smelters, foundries, metal plating and manufacturing & processing of metals and metal containing products.


Unconditional logistic regression.Adjusted for age, gender, tobacco consumption and other potential confounding factors.

No significant trend with exposure to arsenic in terms of duration in years.Adj OR & 95& CI:Arsenic dustNot exposed - 1.001-6 - 2.12 (0.84-5.34)6-17 - 1.71 (0.66-4.45)17- 1.02 (0.43-2.40)Linear trend p - 0.33Arsenic fumes/mistNot exposed - 1.001-5 - 2.18 (0.66-7.18)5-10 - 1.45 (0.45-4.68)10 - 1.20 (0.45-3.19)Linear trend p - 0.31

Taylor et Individual Case control Men – 107 All lung Univariate and multivariate Multivariate adjusted RR & 95% CI in quartiles




al 1989Case controlChina

worker’s exposure to arsenic estimated using an index for arsenic exposure – Index of Arsenic Exposure Months, IAEM.

study. cases and 107 controls between 35-80 years and who were alive in 1985.Tin miners

cancers, type not stated.

regression analyses. of exposure:Q1 – 0 = 1.0Q2 – 0.003-24.3 = 6.8 (2.0-23.9)Q3 – 24.4 – 66.5 = 23.9 (5.5-104.0)Q4 – 66.6 – 255.6 = 22.6 (4.8-106.4)Risk increased with exposure to high levels of arsenic.

Tsuda et al 1989Retrospective cohortJapan

Cohort divided into three groups according to arsenic concentration of well water:≥0.5 ppm – high0.05ppm – 0.5ppm – medium<0.05ppm – low1ppm = 1mg/L

Retrospective cohort study.

281 people, 126 men and 155 women from 49 families. Follow-up from 1959 to 1987.

Description unclear.

Description unclear SMRHigh-concentration group = 16.41 (7.15-36.34)SMRSmokers in the ‘high concentration’ group = 10.14 (.52-58.38)The mortality rate was in excess among residents in both the groups.

25.5.4 AsbestosStudy Exposure/ Risk

factorDesign Population Type of LC Adjusted for Risk (Measure of Association) Adjusted

IARC Non - Review of 64 Presents lung Studies cover a — Range in risk estimates reported for occupational and non-




Monograph – 100C/ IARC Review (2011)

occupational and occupational exposure.Occupational exposure cohort studies grouped by occupation type.Exposure measured in various ways across studies.Exposure categories (duration and intensity) relating to risk estimates also different across studies.Type of asbestos exposure stated for some but not all studies.

case control and cohort studies.

cancer risk estimates from 64 studies (case control and cohort studies) published through 2009.Most (not all) all use all male samples.Multi-country coverage.

range of lung cancers.For most, type not specified.

occupational exposure.Overall risk occupational exposure from cohort studies – RR (95% CI)

Lowest risk: 1.12 (0.56-2.0).

Highest risk: 4.2 (p<0.01)

Overall risk occupational exposure from case controls– OR (95% CI)≥ 10 yrs exposure

Lowest risk: 1.5 (1.0-2.4)

Highest risk: 2.1 (1.6-2.9)

Overall risk non-occupational exposure from case controls and cohort studies

Lowest risk: SMR 0.99(95% CI 0.78-1.25)

Highest risk: OR 6.8(95% CI 2.0-23.1)

Risk estimates for gender and smoking status are reported in the text.

Lenters et al 2011

Occupational exposure.Cumulative exposure categories and corresponding risks extracted from 19 studies.The relative risk and exposure

Review with meta-analysis

19 cohort studies with quantitative estimates of cumulative asbestos exposure.Studies incrementally excluded

Not specified. — Meta-analysis - RR (95% CI)

For each 100 fibre-years/mL of exposure

1.66 (1.53-1.79)

Meta-KL X 100 (95% CI)

0.13 (0.04 – 0.22)

Meta-analysis based on the two highest quality exposure measurement studies:




response slope are calculated for each 100 fibre/years/mL of exposure.Stratification by exposure measurement quality undertaken to determine whether source of difference in the exposure response slope.

based on different aspects of quality of exposure.

Meta-KL X 100 (95% CI)

0.55 (0.11-0.99)

Suggests that higher quality exposure measurement increases lung cancer risk estimates.

Yano et al 2010

Occupational exposure to chrysotile.Duration of exposure,M =25yrs.Overall, subjects heavily exposed:Dust concentrations exceeded 3mg/m3Personal samples exceeded3 fibres/ml (except in the cement workshop where fibre count was low)

Nested case control study/ China

41 male textile worker cases from seven workshops (90% smokers all died from lung cancer) 205 male controls (73% smokers).Matched for age (+-5 yrs).Ave age (cases and controls) 66 yrs.Worked (1972-1976) in a textile plant where high chrysotile

Not specified. — Overall OR (95% CI)

Low exposure 1.00 (reference)

Medium exposure 1.25 (0.47-3.31)

High exposure 3.66 (1.61-8.29)

Risk by smoking status OR (95% CI)Low-exposure non-smoking group used as reference.

Smoking group high exposure 10.39 (1.34-82.4)

Non-smoking group high exposure 5.23 (0.50 -54.58)

Synergy index (S) 1.55 (95% CI 0.43-5.67)

Implying a combined effect that is greater than additive

No exposure duration effect except for smokers in high exposure category.




Three exposure categories: low, medium and high.

exposure.Cohort recruitment over same period.

Reid et al 2005

Occupational and non-occupational exposure to crocidolite.Cumulative exposure measured in fibre-years per ml.Used data from measurement of dust in mine and mill and job history records.Cumulative exposure on average 11 fibre/ml-year.

Prospective cohort study/Wittenoom Western Australia

Former male and female workers (n=1196) and residents (n=792) of the crocidolite mining and milling town of Wittenoom who were also participants in a cancer prevention programme (1990-1996).

Not specified. — Risk by smoking status (OR 95% CI)

Never-smoker 1.00 (ref)

Past smoker (no. of cigarettes per day not stated)

9.53 (1.29-70.6)p= 0.027

Current smoker (no. of cigarettes per day not stated)

26.5 (3.54-198.5)p= 0.001

Reid et al 2006

Occupational exposure to crocidolite asbestos.Cumulative exposure measured in fibre-years per ml.Used data from measurement of dust in mine and

Retrospective cohort study/Wittenoom Australia

2935 former workers of the crocidolite mine and mill at Wittenoom, Western Australia

Not specified. — Risk by smoking status OR (95% CI)Never smokers used as the comparator.

Past smokers (ceased smoking within 6 years of survey)

22.1 (5.6-87.0)

Past smokers (ceased smoking 20 yrs or more ago)

1.9 (0.50-7.2)

Current smokers (<20 cigs per day)

6.8 (2.0-22.7)

Current smokers (>20 cigs per 13.2 (4.1-42.5)




mill and job history records.No further details provided.

day)

Wang et al 2011

Occupational chrysotile exposure.Risks for 3 categories of exposure: low medium; high.Defined based on measures of exposure in different job categories and stations.No further details provided.Ave. exposure duration 25 years

Prospective cohort study/ChinaAir samples taken in 1999 from the workshops in factory to measure chrysotile fibre and dust concentrationsPersonal and area samples taken in 2002. > exposure in raw material and textile sections relative to rubber and cement.Data used to classify workers into 3 exposure categories

577 asbestos (chrysotile) factory workers and 435 controls (no work with asbestos) followed up from 1972-2008.Males.

Not specified. — Overall risk HR (95% CI)Control workers (smokers and non-smokers) used as reference.

All exp. categories: 3.31 (1.60-6.87)

Low exp.: 1.94 (0.84-4.46)

Med exp.: 3.49 (1.41- 8.67)

High exp.: 6.01 (2.74-13.19)

Risk by smoking status HR (95% CI)Non-smoking control workers used as reference: 1.00 (ref)All exp. categories

Non smokers 7.52 (0.9-62.79)

Smokers(1 cig/day for six years)

17.35 (2.38-126.57)

Exposure-response trend found in smokers and non-smokers.

Synergy index 1.4 (95% CI 0.73-3.98)

Frost et al 2011

3 occupational (various duration) exposure categories:

Retrospective cohort studyRisk of lung cancer

98, 912 asbestos workers recruited into asbestos

Not specified. — Risk by smoking status (RR 95% CI)

Never smokers

Low exp.: 1.00




Low < 10 yrs low exposure jobs

Medium 10-29 yrs

High ≥ 30 yrs.

Average exposure for cohort, 11 years.

estimated using cause of mortality data and general population as a reference.Risk by smoking status (former, current never) calculated.Interaction between smoking and asbestos exposure.Smoking information by interview.

worker survey in the UK from 1971 and followed up to December 2005.

Med exp.: 1.9 (0.8-4.3)

High exp.: 1.6 (0.6-4.2)

Former smokers (1 pack/day on ave for 17 yrs)

Low exp.: 5.6 (2.7-11.7)

Med exp.: 6.5 (3.2-13.3)

High exp.: 9.7 (4.7-20.0)

Current smokers (1 pack/day on ave for 35 yrs)

Low exp.: 18.8 (9.4-37.9)

Med exp.: 22.7 (11.3-45.6)

High exp.: 26.2 (13.0-53.1)

Synergy index 1.4 (95% CI 1.2-1.6)

25.5.5 Avian Exposure Study Exposure/ Risk

factorDesign Population Type of LC Adjusted


Gardiner et al 1992ScotlandCase Control

Lived with birds at least for 1 yr, anytime up to 15 yrs prior. Investigated type of bird, duration of exposure, location

Cases from 1 hospital. 2 x Controls from same hospital, 1 cardiac, 1 orthopaedic. Data collected by interview with subject or

143 cases, 97% smokers (65.4 yrs (mean); 286 controls, 78% smokers; 143 cardiac controls (65 yrs), 143

Majority Squamous cell. Histological diagnosis in 89% of cases remainder clinical.

— Overall Pigeons

No significant association overall.

Significant association with keeping pigeons. Maintained for men and women and across age

groups.

Adj. OR (95% CI) 1.29 (0.79 - 2.12)

Adj. OR 3.9 (1.2 - 12.62).





(indoor/outdoor), other pets.

next of kin orthopaedic controls (64.9 yrs)

Alavanja et al 1996USACase Control

> 6 mths up to 82 yrs. Type and number of birds and location kept in home also investigated.

Recruited Cases from Missouri cancer registry 12mth period. Randomised selection of controls on basis of smoking status. Data collected by interview questionnaire only to period prior diagnosis (also next of kin).

652 cases, 629 controls. Women only. Median age 67 yrs.

Histological diagnosis of 86% of cases.

— No significant association overall.

Adj OR (95% CI) 0.84 (0.65 - 1.09).

Relationship did not change with increasing number of years or birds.

Kohlmeier et al 1992GermanyCase Control

> 6 months at least 5 yrs prior in the home. Neither number of birds nor location determined.

Cases from 3 hospitals. < 65 yrs old. Controls from same city. Data collected by interview with computerised questionnaire.

239 cases, 55.3 yrs (78.2% men) 95.4% smokers; 429 controls, 55.2 yrs (77.6% men), 55% smokers.

Primary malignant neoplasms of lung and airways by ICD, clinician and pathologist report

— Overall Men Women

OR (95% CI) 2.14 (1.35 -

3.4).

OR (95% CI) 1.92 in men

OR (95% CI) 2.44 in women.

Risk increased 2x with 1-5 yrs and 3x >10 yrs exposure.

Morabia et al 1998USACase Control

No minimum exposure. Type of bird and duration of exposure recorded.

Newly diagnosed cases and controls from hospitals. Data collected by interview with structured

887 cases (53% men) 57.1 yrs for men (mean) 56.6 yrs for women; 1350 controls (55.3% men).

Histological diagnosis according ICD-7

— Adj OR (95% CI)No significant association overallOR for trend 0.99 (0.69 - 1.44).

Never Smokers Ever Smokers

Men 0.7 (0.15 - 3.17) 1.28 (0.88 - 1.86)





questionnaire 365 owners of birds incl.

Women 1.32 (0.65 - 2.7) 1.17 (0.83 - 1.64)

Relationship did not change with increasing exposure up to >8yrs.

Jöckel et al 2002GermanyCase Control

No minimum exposure detailed. Duration of exposure recorded as <10 yrs to >20 yrs during lifetime and adulthood only.

Newly diagnosed cases and randomly selected controls from same region. Data collected by interview with structured questionnaire.

144 cases (78% men) 57.1 yrs for men (mean) 56.6 yrs for women; 253 controls (80% men). 365 owners of birds incl.

Histological or cytological diagnosis according ICD-7. Majority (52%) adenocarcinoma.

— Adj OR (95% CI)No significant association overall

Across all ages Adulthood exposure

0.85 (0.53 - 1.35) 0.87 (0.56 – 1.36)

Increasing duration of exposure showed no evidence for trend.

25.5.6 Beryllium exposureStudy Exposure/ Risk


Ward et al 1992Retrospective cohort studyUSA

Occupational exposure in 1 one or more of 7 beryllium processing plants.No exposure quantification. RR estimated for any level and duration of exposure.


9225 male workers (8905 white 320 non white) employed for at least 2 days between 1 Jan 1940 and 31 Dec 1969. Follow up through Dec 1988.


Smoking.Indirect method used to adjust for smoking due to poor data on smoking in exposed population.

SMR, US population as the referenceAll 7 plants 1.12 (0.99-1.25)Lorain plant (oldest): 1.49Reading plant (2nd oldest): 1.09

Levy et al 2002Retrospective cohort study/USA

Occupational exposure in 1 or more of 7 beryllium processing


Same population as study by Ward et al (1992):


Smoking.Indirect method used to adjust for smoking due to poor data on

SMR, US population as the referenceAll 7 plants: 1.04 (0.92-1.17)Lorain plant: 1.39 (1.05-1.79)




plants.No exposure quantification. RR estimate for any level and duration of exposure.

9225 male workers (8905 white 320 non white) employed for at least 2 days between 1 Jan 1940 and 31 Dec 1969. Follow up through Dec 1988.

smoking in exposed population. Different level of smoking assumed in exposed population compared to reference than Ward et al (2002).

Reading plant: 1.02 (0.84-1.22)Lucky plant: 0.67 (0.31-1.28)Cleveland plant: 0.89 (0.64-1.19)Elmore: 0.81 (0.45-1.34)Hazelton plant: 1.14 (0.61-1.95)Multiple plants: 1.37 (0.73-2.34)Unknown plants: 1.09 (0.50-2.07)

Sanderson et al 2001Nested case control studyUSA

Occupational exposure due to work in the Reading beryllium processing plant.RR estimated for any level and duration of exposure for different types of beryllium exposure and beryllium exposure.RR also estimated for exposure to quantified beryllium exposure categories.

Case control nested within retrospective cohort of males workers who worked in beryllium processing plant (Reading).

Population a sub-group of the population studied by Ward et al (1992) and Levy et al (2002) but with longer follow up, through Dec 1992. Lung cancer cases (n=142) and controls (n=710) all worked in the Reading beryllium processing plant for 2 or more days between 1 Jan 1940 and 31 Dec 1969. 60% of cases and controls


Smoking.Due to poor collection of smoking data in the cohort, indirect method and assumptions about smoking used to adjust for smoking.

ORs for any level of exposure to Be and Be types, 20 yr time lag from first exposure to Be, US pop refBe Ore: 1.50 (p<0.05)Be OH: 1.48 (p<0.05)BeF: 1.59 (p<0.05)BeO: 1.93 (p<0.01)BeCu: 1.80 (p<0.01)BeAl: 0.91Be: 1.09ORs for quartiles of maximum beryllium exposure (ug/m3) from analysis with 20 yr since first exposure to Be, US pop ref≤1.0: 1.001.1-23.0: 1.95 (p<0.05)23.1-56: 2.89 (p<0.01)>56.0: 1.67ORs for quartiles of cumulative beryllium exposure (ug/m3) from analysis with 20 yr since first exposure to Be, US pop ref≤20:1.00




hired during 1941-1945 and worked for > 1 yr in the plant.

21-2 195: 2.18 (p<0.01)2 196-12 376: 1.89 (p<0.05)>12 376: 1.89 (p<0.05)ORs for average beryllium exposure(ug/m3) in analysis with 20 yrs since first exposure to Be1.0: 1.001.1-19.3: 1.92 (p<0.05)19.4-25.5: 3.06 (p<0.01)Lagged analysis showed a significant positive relation in the exposure-response relationship.

Schubauer-Berigan et al 2011aRetrospective cohort studyUSA

Occupational exposure in 1 or more of 7 beryllium processing plants.RR estimated for any level of exposure for the cohort overall and by plant.RR for quantified exposure categories also estimated for a sub-group of workers who worked in 3 plants.


Same population studied by Ward et al (1992) & Levy (2002) but with additional years of follow up:9 199 workers employed for 2 or more days between 1 Jan 1940 and 31-Dec 1969) at 1 or more of 7 beryllium processing facilities in USA. Follow up through Dec 2005. Sub-group of population for which RR

All lung cancers, type not state.

Smoking, birth cohort and race adjusted for in RR estimation. Confounding by cigarette smoking accounted for using indirect external and within-cohort adjustments.

SMR any level of exposure, US pop refAll 7 facilities: 1.17 (1.08-1.28)Lorain plant: 1.45 (1.17-1.78)Reading plant: 1.20 (1.04-1.37)Lucky: 0.92 (0.59-1.37)Cleveland: 1.09 (0.88-1.33)Elmore: 1.01 (0.74-1.36)Hazelton: 1.03 (0.70-1.47)Multiple plants: 1.64 (1.06-2.43)SMR for maximum exp. categories, US pop ref3 plants, Elmore, Reading, Hazleton:All workers (unlagged)<10 ug/m3: 0.83 (0.67-1.02)10 to <25 ug/m3: 1.45 (1.06-1.94)25 to <70 ug/m3: 1.49 (1.19-1.83)≥ 70 ug/m3: 1.27 (0.98-1.62)All ≥ 10 ug/m3: 1.40 (1.21-1.61)Excluding short term workers (unlagged)




developed for quantified exposure categories comprised of 5 436 male workers exposed in the Reading, Hazleton and Elmore plants.

<10 ug/m3: 0.85 (0.66-1.07)10 to <25 ug/m3: 1.80 (1.13-2.73)25 to <70 ug/m3: 0.96 (0.60-1.47)≥ 70 ug/m3: 1.40 (0.97-1.97)All ≥10 ug/m3: 1.32 (1.04-1.65)SMR for cumulative exp. categories, US pop ref3 plants, Elmore, Reading Hazleton:All workers (lagged 10 yrs)0 to <550 ug/m3:1.08 (0.85-1.36)550 to <2500 ug/m3:1.12 (0.88-1.41)2500 to 10300 ug/m3: 1.10 (0.86-1.38)≥10 300 ug/m3: 1.31 (1.03-1.65)Excluding short term workers (lagged 10 yrs)0 to <550 ug/m3:0.63 (0.32-1.13)550 to <2500 ug/m3:0.91 (0.60-1.32)2500 to 10300 ug/m3: 1.04 (0.75-1.39)≥10 300 ug/m3: 1.26 (0.97-1.61)Significant positive trend in dose response relation (cumulative exposure measure) when short term workers (< 1 yr work) excluded.

Schubauer-Berigan et al 2011bRetrospective cohort studyUSA

Occupational exposure, quantified for workers exposed in 1or more of 3 beryllium processing plants in USA between 1 January 1940 and 31 Dec


Same population studied as in Schubauer-Berigan et al (2011a). See directly above.Different confounders addressed in Schubauer-


Smoking (adjusted for using an indirect method) race, plant, professional work and short-term work status, and exposure to acid mist,

HR for mean DWA exposure categories, Us pop refExcluding asbestos exposed and professionals (3 plants)<0.6 (ug/m3): 1.00.6- <2.0 (ug/m3): 1.30 (0.59-3.11)2.0 to <8.0 (ug/m3):2.41 (1.06-5.82)8.0 to <12 (ug/m3): 7.22 (2.62-21.4)12 to <50 (ug/m3): 6.68(2.81-18.0)≥50: (ug/m3): 4.80 (1.74-14.2)




1979.RR estimated for daily weighted average ug/m3 exposure categories.

Berigan et al 2011b compared to Schubauer-Berigan et al 2011 b. RR estimated for different quantified exposure categories across the two studies.

asbestos, cadmium, chromium, nickel and silica.

25.5.7 CadmiumStudy Exposure/ Risk



Adams et al. 2011Cohort studyUSA

Lifetime residential cadmium exposure determined by urine analysisMean uCd was 0.252µg/g for men and 0.352µg/g for womenNo details given on potential occupational exposure but results were not materially changed after adj for

Cadmium conc. of spot urine samples was measured and corrected for urine creatinine (uCd)Vital stats and cause of death through 2006 were obtained for NHANES III participantsFollow-up for mortality averaged 13.4yrs for men and 13.8yrs for women

Population study of stratified sample representative of non-institutionalised US populationThird National Health and Nutrition Examination survey (NHANES III) cohort (1988-1994)Aged ≥17yrs7455 men and 8218 women (after exclusions)


Stratified by smoking history, never-smokers considered as those who had smoked <100 cigarettes totalAdj for age, smoking history, education, BMI, and

HR (95%CI) of mortality per twofold increase in uCdEntire populationMen: 1.81 (1.49-2.21)Women: 1.21 (0.79-1.84)Never-smokersMen: 2.16 (1.39-3.36)Women: 0.57 (0.33-0.97)





occupation or industry

race

Beveridge et al. 2010Pooled analysisCanada

Lifetime occupational exposure to cadmium determined from interviews

Pooled data from 2 population based case control studiesExposure assessment based on worker’s occupation, industry, job title & individual characteristics of the workplace and tasks as reported by the participants

Males only1598 cases and 1965 controls residing in MontrealCategories of high-risk occupations for exposureCases matched on age & residential area. One study had 2 sets of controls: gen population & other non-lung cancer

Lung cancer type not stated, however diagnosis histologically confirmed

Adj for age, yrs education occupation, smoking, and study

OR (95%CI), reel to unexposed in all categoriesOverallAny level exposure: 1.5 (0.9-2.7)Non-substantial exposure: 1.1 (0.6-1.9)Substantial exposure: 2.9 (0.7-11)By duration (any level of exposure)<5yrs exposure: 1.0 (0.4-2.1)5-20yrs exposure: 0.8 (0.4-1.7)>20yrs exposure: 1.4 (0.7-2.8)By smoking status (any cadmium exposure)Non-smokers: 4.7 (1.5-14.3)Smokers: 1.4 (0.8-2.4)

IARC Monograph 2012GlobalResearch synthesis

Most studies included participants with >1yr occupational exposureSome studies provide details on intensity of exposure

MonographDerived from expert panel discussion, search terms and inclusion criteria not detailedTabular data presented for 15 cohort studies of occupational exposure

Several cohort studies with occupational exposure includingNi-Cd battery manufacture (UK),Ni-Cd battery factory (Sweden),Cu-Cd alloy plants (UK), Cd recovery (USA), Cd processing plants (UK)Includes data from Nawrot et al 2006 for residential exposure


Adj not clearly stated in monograph, some studies did not adj for smoking or exposure to other occupational agents

No statistical synthesis provided, see Table 1.3 for relative risk determined for each studyThe IARC view is that there is sufficient evidence in humans for the carcinogenicity of Cd and Cd compounds and state that Cd and Cd compounds cause cancer of the lung





Navarro Silvera et al. 2007Systematic reviewIncludes cohort studies from UK, Sweden and USA

Occupational exposureExposure levels determined by job history for most studies

Systematic search of Medline (1966-present)Epidemiologic studies of men and women includedExcluded studies not published in English or not peer-reviewedData taken from seven occupational cohort studies

Includes studies of same cohorts as in IARC Monograph with occupational exposure to Cd or Cd compounds


Adj not clearly stated in review

Data not synthesisedSix of the seven cohort studies reported statistically significant increased risks of lung cancer associated with relatively high Cd exposure

Nawrot et al. 2006Cohort studyBelgium(Reported in IARC Monograph 2012)

Lifetime residential exposureCd in soil ranged from 0.8 mg/kg to 17 mg/kgMean uCd was 12.3nm/day in high-exposure area, 7.7nm/day in low-exposure area42 participants with history of occupational exposure (and significantly raised Cd excretion compared to case-controls),

Cadmium conc. of soil from participants gardens measuredAt baseline and follow up: Validated

questionnaire

Urinary excretion of cadmium (uCd) over 24h used as a biomarker of lifetime exposure

Blood

Population sample (n=994) living in north-east Belgium, comparison of residents living near zinc smelters to reference area away from smeltersRandom sample stratified by gender and age from high-exposure (>3 mg cadmium/kg soil) and low-exposure (<1 mg cadmium/kg soil) areas on basis of a preliminary soil screenHigh-exposure area:


Adj for gender, age and smoking statusAdditional explan. variables: no. of pack yrs, time since ceased smoking, baseline serum creatinine, and 24h urinary arsenic excretionResults presented

Risk resulting from Cd exposure, HR (95%CI):Per twofold increase in uCd (unadj for arsenic):Total cohort: 1.70 (1.13-2.57)Resid. exp: 1.73 (1.09-2.72)Per twofold increase in uCd (adj for arsenic):Total cohort: 1.57 (1.01-1.35)Resid. exp: 1.57 (0.96-2.56)Per twofold increase in soil Cd:Total cohort: 1.57 (1.11-2.24)Resid. exp: 1.49 (1.04-2.14)High exposure vs low exposure area:Total cohort: 4.17 (1.21-14.4)Resid. exp: 3.58 (1.00-12.7)Occupational vs resid. exp:3.23 (1.00-10.8)Smokers vs non-smokers:





39 of these lived in high-exposure area

sampleParticipants recruited between 1985-89 and incidence of cancer followed until 2004, median follow up 17.2yrs (range 0.6-18.8)

Total pop. 9840Study pop. 521Low exposure area:Total pop. 9390Study pop. 473

for total cohort & excluding participants with occ. exp. (i.e. resid. exposure only)

3.69 (1.31-10.3)Ex-smokers (pack yrs):1.76 (1.17-2.63)Ceased smoking <10yrs vs ≥10yrs:1.68 (1.12-2.52)

‘t Mannetje et al. 2011Multicentre case-control study17 centres, 7 countries (Romania, Hungary, Poland, Russia, Slovakia, Czech Republic, and UK)

Occupations held for at least 1yrIndustries included: steel industry, coke manufacture, foundry, glass industry, mechanic, wood worker, painter, welder, chemical industry, tannery, toolmaker and machine tool operator, miner or quarryman, insulation worker, printing, meat workers, farmer, rubber industry, and asbestos compound production

A job-specific matrix was constructed using interview, questionnaire and an expert panel

2853 cases and 3104 controls. Both males and femalesCases (age <75yrs), controls frequency matched based on gender and age (±3yrs)


Adj for smoking, age, centre, gender, and exposure to other occupational agents

OR (95% CI), relative to unexposed (all categories)Overall: 1.18 (0.83-1.67)Cadmium dust: 1.13 (0.74-1.73)Cadmium fumes/mist: 1.19 (0.77-1.82)Duration of exposure:Dust1-8yrs: 1.67 (0.88-3.15)8-19yrs: 0.71 (0.32-1.56)19+yrs: 0.95 (0.45-2.02)p for trend = 0.9530Fumes/mist1-9yrs: 1.11 (0.56-2.19)9-25yrs: 1.32 (0.67-2.57)25+yrs: 1.13 (0.54-2.35)p for trend = 0.4606Cumulative exposure (mg/m3-h):Dust0.001-28: 1.86 (0.94-3.68)28-97: 0.96 (0.49-1.91)97+: 0.67 (0.30-1.51)





p for trend = 0.7569Fumes/mist0.001-28: 1.15 (0.56-2.35)28-65: 0.52 (0.24-1.14)65+: 2.04 (1.07-3.90)p for trend = 0.2087

Verougstraete et al. 200360606060626161616160148148148148148148

Systematic reviewIncludes cohort studies from UK, Sweden and USA

Occupational exposure duration ranging from 1 to >30 yrsVarious methods used to estimate occupational Cd exposureCumulative index for exposure provided for some studies

Searched Medline, database of Unit of Occ. and Environ.Med. in Zurich, and contacts with European Union experts in Cd risk assessmentDetailed inclusion criteria, studies published after IARC monograph (1993) were included, when no follow-up had been published since IARC evaluation the latest update was used

Includes studies of five separate cohorts with occupational exposure to Cd or Cd compounds as detailed under IARC MonographAlso includes several residential exposure cohorts


Some studies adj for smoking and other confounders (e.g. arsenic exposure) but not all

Data presented separately for each study, not synthesisedOverall, the literature indicates a small increase in the relative risk of lung cancer in workers exposed to Cd and Cd compoundsThe risk appears lower in groups exposed to Cd in the absence of arsenicNone of the studies of residential cohorts show clear evidence of association between Cd exposure and lung cancer

25.5.8 Chromium IVStudy Exposure/ Risk



Beveridge et Lifetime occupational

Pooled data from two

1598 cases & 1965 controls, males

Lung cancer

Age, years education,

Adj OR (95%CI), relative to unexposed in all





al. 2010Pooled analysisCanada

exposure according to detailed job history determined by an expert group blind to subjects’ disease status.Unexposed (<5yrs occ exp to Cr VI)Substantial (med-high lvls of Cr VI for >5% of work week, > 5yrs)No definition provide for non-substantial exp.

population based case control studies.Interviews & questionnaire.Lifetime occupational exposure to chromium VI from 0 - >20 yrs as determined from interviews.

residing in Montreal.15 categories of occupations including; sheet metal workers, mechanics, printers, construction & painters.Cases matched on age & residential area. One study had 2 sets of controls: gen population & other non-lung cancer.Non-smokers defined as having smoked <100 cigarettes in lifetime or quit >20yrs.

type not stated, however diagnosis histologically confirmed

occupation, smoking and study

categories:Overall risk associated with exposure to chromium:Any exposure: 1.1 (0.9-1.5)Non-substantial: 1.1 (0.8–1.5)Substantial: 1.1 (0.5–2.0)Risk associated with exposure to chromium for any exposure (by duration):<5yrs: 1.3 (0.7–2.2)5-20yrs: 1.1 (0.7–1.7)>20yrs: 1.1 (0.7–1.6)Risk associated with exposure to chromium for any exposure (by smoking status):Non-smokers: 2.4 (1.2–4.8)Smokers: 1.0 (0.7 – 1.3)

Birk et al. 2006Cohort studyGermany

Lifetime occupational exposure to Cr VI, reconstructed from medical records & job descriptions.Exposure >1yr-30yrMale workers at one of two chromate production

Levels of urinary Cr (µg/L yr) were used a biomarker to estimate exposure.

— Lung cancer type not stated.

Age and smoking status.

SMR (95%CI) calculated relative to the general German population.Overall risk associated with chromium exposure:1.48 (0.93–2.25)Risk associated with chromium exposure by duration of exposure:1-4 yrs: 0.78 (0.16-2.29)5-9 yrs: 1.45 (0.53-3.16)10-19yrs: 1.19 (0.57-2.19)20+yrs: 1.79 (0.37-5.23)Risk associated with chromium - exposure





plants measured by urinary concentration (g/L-yr Cr):- no lag:0–39.9: 0.36 (0.01-2.00)40–99.9: 0.95 (0.26–2.44)100–199.9: 0.94 (0.31–2.20)>200: 2.09 (1.08–3.65)Urinary chromium concentration following a 10yr lag:0–39.9: 0.93 (0.34–2.01)40–99.9: 0.78 (0.16–2.28)100–199.9: 1.31 (0.43–3.07)>200: 2.05 (0.88–4.04)Urinary chromium concentration following a 20yr lag:0–39.9: 1.10 (0.60–1.84)40–99.9: 1.01 (0.12–3.65)100–199.9: 1.10 (0.13–3.96)>200: 2.74 (0.75–7.03)

Boice et al. 1999Cohort studyUSA

Lifetime occupational exposure to Cr VI, reconstructed from company & medical records.Mean exp. 24.2yrs, range 1-40yrs.Routine exposure as part of normal

Risk estimates based on standardised job descriptions and interviews.

77965 Aircraft manufacturing factory workers (inc. electroplaters, painters & process equipment operators), employed f>1yr as of Jan 1960.87% male, 13% female88% Caucasian8.4% routine exp & 8.0% intermittent

Cancer of the bronchus, trachea & lung (ICD 162)

Date of birth, date starting & finishing employment, gender and race.

SMR (95%CI) calculated relative to general population of California for Whites and whole USA for Non-whites (due to small number of Non-whites):Overall risk associated with exposure to chromium:1.02 (0.82-1.26)Risk associated with any level of exposure to chromium by duration:gender & race combined)<10yrs: 1.23 (1.11–1.36)10-19yrs: 1.08 (0.96–1.22)





working day intermittent exp. was non-routine.

exp. 20-29yrs: (0.80-1.01)>30yrs: 0.70 (0.61–0.80)

Cole et al. 2005Systematic review with meta-analysesSetting not reported

Overall risk resulting from occupational exposure to Cr VI – no details on length or intensity of Cr VI exposure or occupations.

Medline & other (not detailed) databases searched for English language studies published between 1950 – Jan 2005.Independent critical appraisal (2 reviewers), detailed inclusion criteria.

Data extracted from 47studies (84 papers) published. between 1950-2003.Participant demographics not reported. Only 26 of the included studies adj. for smoking.


Most studies were retrospective follow-up and used the standardised mortality ratio (SMR). An overall SMR was calculated in the meta-analysis.Smoking was adjusted for, no details on other confounders.

SMR (95%CI) calculated relative to the general population. Risk resulting from occupational exposure to Cr:Overall risk associated with chromium exposure (All 47 included studies):1.41 (1.35 – 1.47)Overall risk associated with chromium exposure – adjusted for smoking (26 studies):1.18 (1.12 – 1.25)Overall risk associated with chromium exposure – not adjusted for smoking (21 studies):1.81 (1.71 – 1.92)

Hara et al 2010Cohort studyJapan

Occupational exposure to Cr VI through working in Cr plating industry.Exposure duration 1 - >21yrs

Self reported questionnaires & company health records

1190 Males employed >6mo in a plating factory in Tokyo. Aged >35yrs in 1976.626 >6mo chromium exp, 564 were unexposed to chromium but were exp to other metals

Lung cancer type ICD C33-C34

Confounders not detailed, however smoking and drinking statistics were assumed from national statistics.

SMR (95%CI) calculated relative to the general Japanese population.Overall risk associated with chromium exposure:Cr exposed platers: 1.46 (0.98 – 2.04)Non-Cr exposed platers: 1.09 (0.67 – 1.60)Risk associated with any level of exposure to chromium by duration:1-10yrs 1.50 (0.85–2.34)11-20yrs 1.50 (0.61–2.79)>21yrs 1.32 (0.49–2.56)

IARC monograph 2012Research

Not detailed, however most studies focused on lifetime

Monograph derived from expert panel discussion.

No sample demographics detailed. Included: manufacturing (of


Details mainly narrative, no statistical synthesis or confounders

Overall risk associated with chromium exposure:Overall SMR for 10 studies not included in Cole et al 2005 SR. None of the studies were conducted in Australia and only 2 studies provide some measure of





synthesisGlobal

occupational exposure, as determined by questionnaire.Exposure duration estimates provided for only 3 studies & intensity levels for 6 studies.

Search terms & inclusion criteria not detailed.Research syntheses, cohort and case control studies lifetime occupational exposure (duration not specified) were included.

textile dyes, paints, inks & plastics), metal finishing & chrome plating and welders.Tabular data presented for 37 cohort studies, (duration & exposure data incomplete for most). Significant overlap of studies with Cole et al 2005 SR.

reported. exposure.3/10 studies report Cr VI represents an increased risk, however details are limited and CI’s wide, making the results difficult to interpret.

Luippold et al. 2005Cohort studyUSA

Occupation >1yr, mean 12.4yrs (plant 1) & 7.8yrs (plant 2). Risk estimates based on standardised job descriptions.Cr VI levels across both plants, mean annual Cr VI conc. <1.5µg/m3 range 0.36-4.36µg/m3

Interviews, company records & medical records.

Total of 617 workers at one of two US chromate production plants.84% male, 16% female.74% Caucasian44% ever smokers, 44% never smokers, 12% unknown.Exp. determined for workers employed 1972-1998

Cancer of the bronchus, trachea and lung (ICD 162)

Age, residential area, gender and smoking.

SMR (95%CI) compared with general USA population.Overall risk associated with exposure to any level of chromium:0.84 (0.17-2.44)

’t Mannetje et al 2011Multicentre case–control study(17 centres, 7

Occupations held for at least 1yr. Industries included:steel industry,coke

A job-specific matrix was constructed using interview, questionnaire & an expert panel.

2,852 cases & 3,104 controls. Both males & females.Cases (age <75yrs), controls


Age, centre, sex, tobacco consumption.Occupational exp. to asbestos, silica, wood dust, welding

Adj OR (95%CI), relative to unexposed (all categories).Overall risk associated any exposure to any level of chromium:1.20 (0.93-1.55)





countries (Romania, Hungary,Poland, Russia, Slovakia, Czech Republic, and UK).

manufacture, foundry, glass industry, mechanic, wood worker, painter, welder, chemical industry, tannery, toolmaker& machine tool operator, miner or quarryman,insulation worker, printing, meat workers, farmer, rubber industry, & asbestos compound production.

frequency matched based on sex & age (±3 years).

fumes, chromium, nickel, cadmium, & arsenic were also considered as confounders.

Risk associated with exposure to any level of chromium dust:Overall: 1.25 (0.95-1.65)1-5yrs: 1.16 (0.75-1.79)5-17yrs: 1.04 (0.65-1.65)17+yrs: 1.53 (1.00-2.34)Risk associated with exposure to any level of chromium mist/fumes:Overall: 1.02 (0.75-1.39)1-9yrs: 1.10 (0.71-1.72)9-25yrs: 0.97 (0.62-1.53)25yrs+: 0.93 (0.58-1.49)Risk associated with exposure to cumulative levels of chromium dust (mg/m3-h):0.001-25: 1.19 (0.74-1.91)25-175: 1.24 (0.80-1.92)175+: 1.32 (0.85-2.05) )P for trend: 0.1148Risk associated with exposure to cumulative levels of chromium fumes/mist (mg/m3-h):0.001-38: 0.97 (0.59-1.59)38-280: 0.80 (0.48 1.33)280+:1.31 (0.80-2.15)P for trend: 0.6356

25.5.9 Dietary Cholesterol and Blood CholesterolStudy Exposure/



Ahn et al Serum Total Prospective 7,545 incident Lung cancer Age, RR and 95% CI for lung cancer and total serum cholesterol and serum





2009Finland

and High-Density Lipoprotein (HDL) cholesterol

cohort study18 years follow-up

cases identified in men aged between 50-69 years

ascertained by medical records, histo-pathology & cytology specimens and Finnish Cancer Registry

intervention, level of education, systolic blood pressure, BMI, physical activity, duration of smoking, number of cigarettes smoked per day, saturated fat intake, alcohol consump-tion

HDL cholesterol according to quartiles of consumption (mg/dL)

Q1 (<203.9)

Q2(203.9-227.6)

Q3(227.7-249.2)

Q4(249.3-276.6)

Q5(>276.7)

Total serum cholesterol (P = 0.0006)

1 (ref) 0.95 (0.84-1.07)

0.87 (0.77-0.98)

0.92 (0.82-1.03)

0.81 (0.72-0.92)

Q1(<36.2) Q2(36.2-41.6)

Q3(41.7-47.2)

Q4(47.3-55.2)

Q5(>55.3)

Serum HDL cholesterol (P = 0.19)

1 (ref) 0.92 (0.81-1.05)

0.91 (0.80-1.03)

0.96 (0.85-1.09)

0.89 (0.78-1.01)

Alavanja et al 1996USA

Cholesterol daily intake in mgQuintiles of consumption – lowest to highest in five categories (Q1 – Q5)

Case-control study

Population-based sample. Controls selected by frequency matching on age.White non-smoking women between 30-84 years.429 cases and 1021 control subjects

Lung cancer confirmed from cancer registry

Age, smoking history, previous lung disease, interview type and total calories per day

ORs (CIs not reported) for lung cancer by quintile of weekly intake of dietary cholesterol - P for linear trend – 0.22

Lowest quintile(Q1) - 1.0 (ref)

Q2 - 0.63 Q3 - 0.71 Q4 - 1.14 Q5 – 1.09

Byers et Cholesterol Case-control General Lung cancer Smoking Smoking adjusted RRs (CIs not reported) for lung cancer by quartiles





al 1987USA

consumption by quartilesLow to high –Q1 – Q4.

study population from three counties, aged between 35-79 years.Males: 296 cases & 587 controlsFemales: 154 cases & 315 controls

confirmed by histology

of dietary cholesterol consumption

MalesP for trend = 0.17

FemalesP for trend = 0.91

Q1 0.7 1.1

Q2 0.9 1.7

Q3 1.2 1.2

Q4 1.0 1.0

Chang et al 1995USA

Low plasma cholesterol (<160 mg/dl)

Prospective cohort studyFollow-up 18 years

2,011 men and 2,327 women. Older adults.

Lung cancer ascertain-ment by review of medical records and mortality data from death certificates and ICD classification

Age, BMI, smoking

Risk of lung cancer - RH (95% CI)

Mortality at <160mg/dl plasma by gender

Lowest level <160 mg/dl compared to highest level ≥240 mg/dl by gender

Men Women Men Women

1.81(0.38–3.95)

3.28(1.17 – 9.19)(P = 0.02)

1.62(0.66-3.92)

3.45(1.13 – 10.42)

De Stefani et al 2002Uruguay

Cholesterol - tertiles of intakeLow to high – TI, TII, & TIII

Case-control study

Male population200 cases & 600 controls recruited from the same hospital.Controls frequency matched to age,

— Age, residence, urban/rural status, education, BMI, smoking status, smoking duration & total energy

Overall risk of lung cancer associated by tertiles of cholesterol intake - OR & 95% CI

TI TII TIII

1.0 (reference) 1.24 (0.80 - 1.92) 1.83 (1.20 – 2.79)

P for trend = 0.004





residence & urban/rural status

intake

Eichholzer et al 2000Switzer-land

Plasma cholesterol concentrations

Prospective cohort study17 year follow-up

2974 men who worked in major chemical and pharma-ceutical companies

Lung cancer ascertained from ICD classification and death certificates to identify causes of deaths

Smoking habits and age

Overall risk of lung cancer associated with plasma cholesterol levels and age - RR & 95% CI

Low cholesterol and age > 60 years

Low cholesterol and age ≤ 60 years

1.99 (1.18 - 3.37) 0.54 (0.21 - 1.38)

Goodman et al 1988USA

Cholesterol consump-tion in quartilesLow to high – QI - QIV

Population-basedCase-control study


Lung cancer confirmed by histology through pathologic records and admission records from Hawaii Tumour Registry

Age, ethnicity & pack-years of cigarette smoking

Overall risk of lung cancer associated with plasma cholesterol levels in quartiles by gender - OR & 95% CI

Men Women

I (low) 1.0 1.0

II 2.3 (1.4-4.0) 0.6 (0.2-1.5)

III 1.8 (1.0-3.1) 1.5 (0.7-3.3)

IV (high) 2.2 (1.3-3.8) 0.9 (0.4-2.1)

Hinds et al. 1983aUSA


Case-control study


Lung cancer ascertained from pathology logs, physician confirmation & Hawaii Tumour Registry. Next of kin

Age, ethnicity, pack-years of cigarette smoking, occupational status, vitamin A intake and gender

Dose response relation of dietary cholesterol to lung cancer risk


All subjects Smoking subjects

Male subjects Female subjects

0-750 1.0 1.0 1.0 1.0

751-1230 1.3 (0.9-2.0) 1.3 (0.8-2.1) 1.2 (0.7-2.1) 1.7 (0.9-3.5)

1231-1270 1.4 (0.9-2.1) 1.4 (0.8-2.2) 1.4 (0.9-2.4) 1.3 (0.6-3.0)





interviews 2071+ 2.0 (1.3-3.1) 2.1 (1.2-3.4) 2.3 (1.4-4.0) 1.2 (0.5-3.0)

Hinds et al 1983bUSA


Case-control study

Hawaiian men: 188 cases & 294 controls

Lung cancer ascertained from Hawaii Tumour Registry

Age, ethnicity, pack-years of cigarette smoking & occupational exposure to lung carcino-gens

Overall risk of lung cancer in men associated with weekly cholesterol intake (mg) - RR & 95% CI

0-999 1000-1999 2000-3499 3500+

1.00 (reference) 1.65 (1.00 - 2.75)

2.28 (1.28 - 4.09) (1.70 - 7.21)

Hu et al. 2011Canada

Mean intake of dietary cholesterol mg/week in quartiles (I, II, III & IV)

Case-control study

Confirmed cases of 1736 men & 1605 women from eight Canadian provinces

Lung cancer ascertained histologically as defined by ICD classification

Gender, total alcohol drinking, province, education, pack years smoking, veg and fruit intake, saturated fat and total energy

ORs & 95% CI for lung cancer by quartiles of dietary cholesterol intake

I II III IV

1.0 1.17 (0.98-1.40)

1.30 (1.07-1.59) 1.61 (1.28-2.03)

Jain et al 1990Canada

Mean daily intake of cholesterol

Case-control study

Men & women aged between 20 & 75 yearsMen: 401 cases & 362 controlsWomen: 438 cases & 410 controls

Histological confirmation of lung cancer diagnosis

Cumula-tive cigarette smoking

OR (95% CI not reported) for lung cancer by unit (400mg) of consumption of dietary cholesterol

Women Men Non-smokers Smokers Overall

1.69 1.44 1.39 1.40 1.51





Keys et al. 1985Seven countries

Serum cholesterol concentrations


11,325 healthy men aged between 40-59 years.

Mortality ascertained by death certificates, information from local hospitals, physicians, relatives and witnesses and hospital discharge records

Age, blood pressure, smoking habit, BMI, physical activity and serum cholest-erol

Overall risk of lung cancer associated with low serum cholesterol.Numbers of men with low cholesterol dead from lung cancer in years 6-15 in a cohort from seven countries

Observed Expected Observed/Expected

35 24.93 1.40

RR = 1.58

Knekt et al 1991Finland

Mean daily intake of dietary cholesterol

Prospective cohort study20 years follow-up

5,304 men aged between 20-69 years and randomly recruited from a large survey on dietary intake

Lung cancer incidence ascertained from Finnish Cancer Registry with data on histological type collected

Age, smoking and energy intake

RR & 95% CI for lung cancer by cholesterol intake in tertiles

<441 441-609 >609

1.0 0.80 (0.49-1.30) 1.03 (0.58-1.85)

Kucharska-Newton et al 2008USA

Plasma HDL cholesterol levels

Prospective cohort study13 years follow-up

15, 972 men and women, aged 45-64 years recruited as a probability sample.

Incidence ascertained on the basis of self-report by cohort participants and cancer registries

Age, race, gender, BMI, smoking status, cigarette pack years of smoking, exercise and alcohol consumption

Hazard ratio and 95% CI for lung cancer and the association of low HDL and high HDL cholesterol

Overall Current smokers

Former smokers

Never smokers

Low vs high HDL cholesterol

1.45(1.10-1.92)

1.04(0.74-1.47)

1.77(1.05-2.97)

1.56(0.41-5.86)

HDL cholesterol as a continuous variable

0.92(0.78-1.08)

1.07(0.90-1.28)

0.87(0.62-1.22)

0.78(0.39-1.56)





Law et al 1991

Level of serum cholesterol

Pooled Analysis of 33 prospective studies mostly from USA and some from Europe

4,661 subjects with cancer diagnosed within two years of the cholesterol measurement or causing death within five years

Description unclear

Not clear if potential confounding factors adjusted

Overall risk of lung cancer associated with serum cholesterol levels. RR (95% CI)Low serum cholesterol associated with long-term lung cancer risk in men; however, confounded by smoking. Mean (SE) case-control cholesterol difference (mmol/l): -0.101 (0.022)

Shekelle et al 1991USA

Intake of dietary cholesterol in mg/day


1,878 men employed at Western Electric Company, Chicago for at least 2 yrs and aged between 40-55 years in 1958

Cancer ascertained from medical and hospital records and death certificates

Cigarette smoking, intake of beta-carotene and other confound-ing variables

Overall risk of lung cancer associated with cholesterol intake (mg/day) - RR, no 95% CI reported

198-604 605-794 795-1,909

1.00 1.30 1.94

Smith-Warner et al 2002

Intake of dietary cholesterol

Pooled analysis of eight prospective cohort studiesFollow-up 6-16 years

280,419 female and 149,862 male participants. 3,188 lung cancer cases.

Lung cancer identified based on ICD classification and histological confirmation within individual studies

Age, BMI, smoking history, total fruit and vegetable consumption and energy intake

Pooled RRs & 95% CI for lung cancer by quartiles of dietary cholesterol intakes

Q1 Q2 Q3 Q4

1.00 1.02 (0.89-1.18) 1.03 (0.90-1.17) 1.06 (0.94-1.20)

Steenland et al 1995

Cholesterol consump-

Case-control study

657 male & 593 female

Lung cancer diagnosis by

Age, smoking,

OR and 95% CI for lung cancer associated with cholesterol intake mg/day. Highest quartile compared to three other quartiles





USA tion in quartiles as continuous variable<190190-216217-246247+

cancer casesControls – 11, 804 men & women

ICD classification on a hospital discharge record & for those not on record, death certificates

alcohol consumption, BMI & income

<190 vs 247+ 190-216 vs 247+ 217-246 vs 247+

1.48 (0.96 - 2.29) 0.89 (0.55 - 1.42) 0.93 (0.59 - 1.46)

P for trend = 0.14

Swanson et al 1997USA

Quintiles Intake of cholesterol in mg/1000 kcal<102102-126127-148149-176177+

Case-control study

Women aged between 35 and 84 years587 cases and 624 controls

Lung cancer diagnosis identified from Missouri Cancer RegistryHistological confirmation from pathologists

Education, pack-years of smoking, BMI, veg & fruit intake

RR & 95% CI for lung cancer according to intake of cholesterol (mg/1,000 kcal)

< 102 102-126 127-148 149-176 177+

1.0 1.21 (0.8-1.8) 0.88 (0.6-1.3) 1.04 (0.7-1.6) 1.22 (0.8-1.8)

Veierod et al 1997Norway

Dietary cholesterol intake in mg/day

Prospective cohort study15-17 years follow-up

25,965 men and 25,496 women aged 16-56 years

Cancer cases identified from Norway Cancer Registry

Smoking status, gender, age at inclusion and time-scale variable attained age

Incident rate ratios and 95% CI for lung cancer according to quartiles of dietary cholesterol intake (mg/day)

Q1 ≤ 154.9 Q2 – 155.0-196.1 Q3 – 196.2-240.5 Q4 ≥ 240.6

1.0 (reference) 1.4 (0.9-2.3) 1.3 (0.8-2.1) 1.2 (0.8-1.9)

Wu et al 1994USA

Dietary cholesterol intake

Prospective cohort studySix years

41,837 postmenopausal women.

Cancer cases identified through Health

Smoking status, pack-years of cigarette

RR and 95% CI for lung cancer by smoking status according to cholesterol intake in quartiles

Quartiles Nonsmokers Ever smokers





follow-up Registry of Iowa and based on ICD classification and histological confirmation

smoking, physical activity, occupation, age and energy intake

Squamous cell/small cell

Adenocarcinoma

Q1 1.0 1.0 1.0

Q2 1.0 (0.4-2.7) 0.8 (0.4-1.6) 0.4 (0.2-0.9)

Q3 1.4 (0.6-3.4) 0.9 (0.5-1.7) 0.6 (0.3-1.3)

Q4 0.9 (0.3-2.5) 1.1 (0.6-2.0) 0.6 (0.3-1.3)

25.5.10 Family history Study Exposure/



Lissowska et al 2010Original Case control study combined with meta-analysis of 41 other studies.Case controls: 36Prospective Cohort: 6Multinational

Self-reports of the prevalence of lung cancer in first degree relatives.Exposure determined as being first degree relatives, e.g. parents and siblings.Number of first degree relatives ranged from 2 – 26 (median= 6)

Case control study In person structured interviews used to collect data on lung cancer prevalence of family members.Self-reports of cancer in relatives were not confirmed by checking medical records.Smoking history of relatives was not obtained.

Demographics only reported for the case control study, not for the meta-analysis.Ages ranged from 20 - 79 years2861 cases2205 – men656 – women3118 controls matched by age, gender and geographical area.

Cytologically or histologically confirmed lung cancer (all types).

— General exposureFamily member with lung cancer RR/OR (95%)

Cohort studies Case control studies Combined

RR= 1.95 (1.63 - 2.33)

OR= 1.66 (1.50 - 1.85) 1.72 (1.56 – 1.88)

Lung cancer risk by gender

Males: Female:

RR = 1.50 (1.08 – 2.08) RR = 1.73 (1.50 – 2.00)

Case Control: General exposureFamily member with lung cancer OR (95%)

Mother Father Siblings Any family member

1 family member

2 + family members

2.24 1.45 1.75 1.63 1.54 3.60





Number of siblings ranged from 0-17 (median = 2)

Meta-analysisSearch of PubMed (inception – 2009). Data pooled using random effects model

2305 – men813 - women

(1.26-4.00)

(1.10-1.91)

(1.23-2.48)

(1.31-2.01)

(1.24-1.92)

(1.56-8.31)

Exposure by smoking status – ever smokersFamily member with lung cancer OR (95%)Adjusted for smoking, gender and:

Parents Siblings Any family member

1.53 (1.18 – 2.00) 1.65 (1.13 – 2.39) 1.55 (1.24 – 1.95)

25.5.11 Iron and Steel Study Exposure/


Ahn et al. 2010Cohort studyKorea

Exposure assessment done to classify job categories: production & office workNo exposure assessment of individual carcinogens

Cohort identified by contacting employers of 388 iron foundries, out of which 208 companies provided details.Follow-up from 1 January 1992 to 31 December 2005Cancer morbidity ascertained from Cancer Registries

17,098 workers, 14,611 men & 2,487 women from 208 small-sized iron & steel foundries who worked anytime between 1992-2000

Not specified Adj for; gender, age & calendar year.

Risk by job classification.SIR (95% CI)Both genders:Overall: 1.33 (1.03-1.69)Production: 1.45 (1.11-1.87)Office: 0.71 (0.26-1.54)Men:Overall: 1.28 (0.98-1.64)Production: 1.38 (1.04-1.80)Office: 0.75 (0.27-1.63)Women:Overall: 2.29 (0.83-4.98)Production: 2.79 (1.02-6.07)Office: no employees




Risk by duration of employmentSIR (95% CI)Both genders:≤ 10yrs: 1.12 (0.66-1.77)≤ 10yrs: 1.66 (1.20-2.24)Men:>10yrs: 1.12 (0.65-1.79)≤ 10: 1.55 (1.09-2.12)Women:>10yrs: 1.15 (0.02-6.40)≤ 10: 3.90 (1.26-9.09)Risk from working in production in an iron foundry (rel. to office) SRR (95% CI), both genders:2.91 (1.25-6.80

Bosetti et al. 2007Research synthesis with pooled analyses & meta-analysesUSA, Canada, Finland, Denmark, UK & France

Occupational exposure to PAH resulting from being a foundry worker.PAH exposure intensity &duration not reported

Review included cohort studies identified through Medline, published between 1997 & 2005.11 cohort studies relevant to risk of lung cancer. 9 of which also included in IARC (2012)

Workers from iron and steel foundries with high exposures to Polycyclic Aromatic Hydrocarbons (PAH)

Not specified Pooled RRs & 95% CI computed as weighted average of SMR/SIR using inverse variance of the logarithm of SMR/SIR as weight (fixed-effect model)Potential confounders adj. for: smoking, age, sex, calendar period

Risk from working in production in an iron foundry. Overall SMR & pooled RR (95%CI) for exposure to PAHSMR: 1.39Pooled RR (9 studies) :1.40 (1.32-1.49)Individually, 7 of 11 studies reported an increased lung cancer risk resulting from occupational exposure to PAH as an iron/steel foundry worker.

Bourgkard Occupational Historical 16 742 males & Not specified Two series of Risk from working in production in an iron foundry.




et al. 2008Cohort studyFrance

exposures assessed by a factory-specific job exposurematrix (JEM) validated with atmosphericmeasurements.

cohort study of all workers ever employed in a French carbon steel-producing factory for at least 1 year between 1 January 1959 and 30 June 1997.Data collected from administrative records, medical records & occupational physicians

959 females ever employed for at least 1 year between 1959 & 1997 were followed up for mortality from January 1968 to December 1998

internal statistical analyses : 1) a Poisson regression in which age & time period effects were taken into account by including expected numbers of cases as offsets.2) Cox regression with age as the main time variable & time-varying exposure variables.Data adjusted for smoking and other occupational exposures

RR & 95% CI for iron oxide exposures among menDuration of exposure (yrs) (intensity level >2)Non-exposed: 1.001–10yrs: 0.87 (0.58 to 1.29)>11yrs: 0.64 (0.35 to 1.15)Frequency weighted cumulative index(intensity level.freq.years)Non-exposed: 1.00≤0.02: 1.30 (0.86 to 1.95)0.02–0.41: .35 (0.90 to 2.03)0.41–3.81: 0.99 (0.63 to 1.56)>3.81 = 1.03 (0.63 to 1.70)Smoking habitNever = 1.00Former = 6.82 (1.58 to 29.4)Current = 26.22 (6.50 to 105.8)

IARC 2012MonographGlobal

Employment in an iron or steel foundry given as exposure. No summary details of exposure duration & intensity reported

Cohort & case control studies published up to 2006. Studies incl. based on consensus of expert opinion.17 cohort & 4 case control studies

Workers from iron & steel foundries. Risk by Individual carcinogens not detailed.No demographic details.

Type of lung cancer not specified

No overall summary estimate reported. SMRs or OR reported for individual studies

Of the 17 included cohort studies, smoking status data was unavailable for 10 studies and only detailed in 3 other studies.Of the 4 case control studies, smoking status data was unavailable for 1 study




relevant to risk of lung cancer. 9 of which also included in IARC (2012) monograph

25.5.12 Red Meat and Processed Meat Consumption Study Exposure/


Alavanja et al 2001USACase control study

Food frequency of red meat consumption as part of usual diet for the 2-3 years prior to study enrollment


Female Iowa residents aged between 40 – 84 years, newly diagnosed between 1993-1996360 cases, 574 aged matched controlsMean age: 67 years for both groups

Primary invasive (not in situ) lung carcinoma

Age, pack–years of smoking, yellow–green vegetable intake, fruit and fruit juice intake, nutrient density calories, BMI and alcohol, non-malignant lung disease, years of education completed.

Highest (>9.8 serves per week) compared with lowest quintile of red meat intake (<3.5 times per week). Serve size not reported.

Overall Former/never smoked:

Current smokers:

OR =3.3 (1.7-7.6) OR= 2.8 (1.4-5.4) OR= 4.9 (1.1-22.3)

Cross et al 2007USAProspective cohort


Part of the National Institute of Health American Association for Retired Persons (NIH-AARP) Diet and Health Study. Mean follow up 6.8 yrs.

494,036 persons: Male (294,724)Female (199,312)Members of AARP aged between 50-71 at baseline,

All types. Incident cases of lung cancer identified as reported by the participants, cancer registries, state boards of health and the

— Highest quintile compared with lowest quintile of consumption.

Red Meat In Men median (mdn)

= 67.0g/1000kca vs 12.2g/1000kcal

In women mdn = 54.7g/1000 kcal vs 8.0g/1000kcal

HR=1.2095% CI=1.10–1.31 (both genders combined)





residing in 1 of 8 named regions of the US

National Death Index.

Processed Meat Both genders

combined mean =22.6g/1000kcal vs 1.6g/1000kcal

HR = 1.16; 95% CI = 1.06–1.26


Food frequency of meat, processed meat and egg consumption as part of usual diet for the year prior to study enrollment (controls) or becoming ill (cases).


Male Montevideo residents aged between 30 – 89 years, newly diagnosed who had been residents of Montevideo for at 10 years.377 cases, 377 aged and residential area matched controls

All types Age, residence, education, family history oflung cancer, body-mass index, total energy intake, cigarettesmoking (in pack-years), alpha-carotene and fat intake

Overall lung cancer

Never/ex smokers

Smokers

Red Meat Upper quartile (388 or more serves per year) compared with lowest quartile (178 or less serves per year). Serve size not reported

OR = 1.250.78-1.89

OR = 1.160.55-2.47

OR = 1.320.71-2.46

Processed meatUpper quartile (282 or more serves per year) compared with lowest quartile(79 or less serves per year)

OR = 1.190.75-1.89

- -

De Stefani et al 2002UruguayCase control

Food frequency of red meat, processed meat and egg


Male Montevideo residents aged between 30 – 89 years, newly

Adenocarcinoma

Potential confounders included in the model: age, residence,

Upper tertile compared with lowest tertile for each factor, however frequency/portion size not reported.

Red Meat Processed meat

OR=1.92: 1.27-2.90 OR=0.83: 0.55-1.26




study consumption for the 5 years prior to study commencement.

diagnosed between 1994-1999.200 cases, 600 aged & residential area matched controls

Education, family history of lung cancer, BMI, body mass index smoking status, total energy intake, total vegetables and fruits, reduced glutathione and nonmeat fatty foods intakes.


Food frequency of red meat, and processed meat consumption as part of usual diet for the 5 years prior to study commencement


Male Montevideo residents aged between 30 – 89 years, newly diagnosed between 1996-2004.846 cases, 846 aged and residential area matched controls

Adenocarcinoma

Potential confounders included in the model: age, residence,Education, family history of lung cancer, BMI, smoking status, total energy, intake, total vegetables and reduced glutathione and nonmeat fatty foods intakes.

Overall Former smoker

Smoker

Red MeatUpper quintile (>9.1 serves/week) compared with lowest quintile (5 or less serves/week). Serve size not reported

OR = 2.331.63 - 3.32)

OR = 3.531.92 - 6.48)

OR = 2.331.57 - 3.47

Processed meatUpper quintile (>4.6 serves/week) compared with lowest quintile (1.1 or less serves/week). Serve size not reported

OR = 1.791.22 - 2.65

OR = 1.881.13 - 3.12

OR = 1.230.86 - 1.74

Hu et al 2011

Food frequency of

Population based Case Control

Cases - 19,732 (men:10725,

All types Potential confounding

Processed meatUpper quartile (5.42 or more serves per

OR = 1.41.1-1.7




CanadaCase control study

processed meat consumption as part of usual diet for the 2 years prior to study commencement

National Enhanced Cancer Surveillance System (NECSS) study.Data collected by self-report questionnaire

women: 9007), newly diagnosed.Mean age: 60.1 +/- 13.4 yearsControls - 5039 (men: 2547, Women: 2492), sex stratified and aged stratified sampling. Mean age: 57.1 +/- 13.4 years.

variables included: age province, education, BMI, sex, total alcohol drinking, pack-years smoking, consumption of total vegetables and fruit and total energy.

week) compared with the lowest quartile (.94 or less serves per week). No serve size reported.

(both genders combined)

Lam et al 2009ItalyCase control study

Food frequency of red meat, and processed meat consumption as part of usual diet. Exposure length not reported.

Population based Case ControlEnvironmental and Genetics in Lung cancer Etiology (EAGLE) studyData collected by self-report questionnaire

1903 CasesMean age: upper tertile (65 +/- 8.9 years)lower tertile (67.8 +/- 7.6 years)2073 ControlsMean age: upper tertile (65 +/- 8.9 years)lower tertile (67.8 +/- 7.6 years)Information on gender not reported.

All types Potential confounding variables included: age, gender, and area of residence, BMI, education, alcohol consumption, smoking status, dietary intake of fruits and vegetables and different meat groups.

Stratified by smoking status:

Overall Never Former smoker

Smoker

Red MeatUpper tertile (>3.0 serves/week) compared with lowest tertile (0.7 or less serves/week)

OR = 1.81.5-2.2

OR=2.4;1.1-4.0

OR=1.7;1.3-2.2

OR=1.7;1.3-2.2

Processed meatUpper tertile (>8.6 serves/week) compared with lowest

OR=1.7; 1.4-2.1

OR=2.5;1.5-4.2

OR=1.6;1.3-2.1

OR=1.77;1.32-2.4




tertile (1.8 or less serves/week)

Linseisen et al 2011Denmark, France, Germany, Greece, Italy, Netherlands,Norway, Spain, Sweden, and United Kingdom.Prospective cohort

Frequency of meat and processed meat consumption. Portion size was estimated in grams(g)/day.

This data is derived from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. European men and women. Median follow-up of 8.7yrs.Data collected by self-report questionnaire

478,427 persons (142,602 men and 335,825 women) who were aged between 25--70 at baseline, residing in 1 of 10 named European countries.

All types Lung cancer cases were classified using International Classification of Diseases-Oncology (ICD-O) criteria.Four major histological types: squamous cell carcinoma, small cell carcinoma, large cell carcinoma & adenocarcinoma.

Red MeatMen or women consuming >80 g red meat per day compared with those consuming less than 10 g/day.

RR = 1.19 95% CI 0.94–1.50

Processed meatMen or women consuming >80 g processed meat per day compared with those consuming less than 10 g/day.

RR = 0.92, 95% CI 0.73–1.17



Part of the National Institute of Health American Association for Retired Persons (NIH-AARP) Diet and Health Study. 8yr follow up.Data collected by food frequency questionnaire

467,976 persons Male (278,380) and female (189,596) members of AARP aged between 50-71 at baseline, residing in 1 of 8 named regions of the US

All types. Incident cases of lung cancer identified as reported by the participants, cancer registries, state boards of health and the National Death Index

— Highest quintile compared with lowest quintile of consumption.

Men Women

Red MeatMen: median (mdn) = 67.0g/1000kca vs 12.2g/1000kcalWomen: median = 54.7g/1000 kcal vs 8.0g/1000kcal

HR= 1.22; 95% CI: 1.09 - 1.38

HR= 1.13; 95% CI: 0.97 - 1.32

Processed Meat HR= 1.23; 95% HR = 1.00;




Men: median (mdn) = 24.8/1000kca vs 2.3g/1000kcalWomen mdn = 18.3g/1000 kcal vs 1.2g/1000kcal

CI: 1.10 - 1.37 95% CI: 0.87 - 1.15


Food frequency of meat and processed meat consumption

Data from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.5yr follow up.

99579 persons, Male (48,229) and Female (51,350) aged between 55-74 years aged at baseline, residing in one of 10 centres in the USA

All types — Highest quintile compared with lowest quintile of consumption.

Men Women

Red MeatMen: median (mdn) = 67.1g/1000kca vs 14.5/1000kcalWomen: mdn = 52.8g/1000kcal vs 9.4g/1000kcal

HR=1.11; 95% CI: 0.79 - 1.56

HR=1.30; 95% CI: 0.87 - 1.95

Processed MeatMen median (mdn) = 18.0/1000kca vs 5.6g/1000kcalWomen mdn = 12.6g/1000 kcal vs 3.8g/1000kcal

HR=1.12; 95% CI: 0.83 - 1.53

HR=1.98; 95% CI: 0.68 - 1.41

25.5.13 NickelStudy Exposure/ Risk



Anderson et al 1996

Occupational exposure:

Data collected from 82

Male employees working at the

Lung cancer incidence

Age specific incidences

Overall SIR (95%CI) resulting from occupational exp. to Ni





NorwayCohort study

Concentrations of airborne and different forms of nickel were estimated by an expert group for 82 different work areas derived from previous job exposure matrix. Work history from plant records; nickel exposures from 5 900 measurements for total nickel 1973–1994 and estimates of specific nickel compounds leading to job exposure matrix.Exposure duration not reported.

different working areas. Follow-up started after 3 (1916-40) or 1 (1946-83) years of total employment.Cancer incidence coded from The Cancer Registry of Norway since 1953.

Falconbridge nickel refinery. 379 workers with 1st employment 1916-40 & 3 years of employment & 4385 workers with one year of employment 1946-83, and alive at 1/1/1953.

identified according to The NorwayCancer RegistryCancer type not specified

were calculated, relative to the 1953 to 1993 Norwegian male population, RR relative to unexposed workers.Multivariate Poisson regression analysis used to calculate RRs, adj. for age, smoking status (available in 95% of entire cohort), and birth cohort

(rel. Norwegian male popln.)3.0 (2.6-3.4)Cumulative exp. to Nickel (mg/m3),rel. to unexposed workers). RR (95%CI)Soluble nickel<1 : 1.0 (ref)1-4 : 1.2 (0.8–1.9)5-14 : 1.6 (1.0–2.8)≥15 : 3.1 (2.1-4.8)Nickel oxide (mg/m3)<1 : 1.0 (ref)1-4 : 1.0 (0.6–1.5)5-14 : 1.6 (1.0–2.5)≥15 : 1.5 (1.0-2.2)RR (95%CI)Unexposed: never-smoker: 1 (ref)ever smoker:2.9 (0.6-2.3)Exposed:never-smoker:1.1 (0.2-5.1)ever smoker:5.1 (1.3-20.5)

Antilla et al 1998FinlandCohort study

Occupational exposure. Air measurements available beginning in 1966

Data collected from company employment records and follow-up of cancer from 1953 according to Finnish Cancer Registry

1 388 workers employed at a nickel refinery & copper/nickel smelter 3 month+ 1945–1985, follow-up 31/12/19951,339 men(34,320 person-yrs)

Type not detailed, ICD 7, 162

Adj. for age, gender, and calendar period

Overall SIR (95%CI)1.22 (0.65-2.08)Refinery workers (n=418, inc 49 women)Overall: 2.61 (0.96-5.67)5yrs+ exposed: 1.99 (0.41-5.80)20+yrs latency: 3.38 (1.24-7.36)Smelter workers (n=566 males)





49 women (1,081,person-yrs)Mean follow-up 25.5 years.

Overall: 1.39 (0.78-2.28)5yrs+ exposed: 1.01 (0.43-1.98)20+ys latency: 2.00 (1.07-3.42)

Beveridge et al 2010CanadaPooled analysis

Lifetime occupational exposure according to detailed job history determined by an expert group blind to subjects’ disease status.Unexposed (<5yrs occ exp to Ni)Substantial (med-high lvls of Ni for >5% of work week, > 5yrs)No definition provide for non-substantial exp.Basis for categories not reported

Pooled analysis of 2 population based case control studies. Population controls randomly selected from electoral listsInterviews & questionnaires (self-reported or surrogate)Data collected for socio-demographic, lifestyle characters, and detailed job history

1598 cases & 1965 controls, male residents of Montreal.15 categories of occupations including; sheet metal workers, mechanics, printers, construction & painters.Cases matched on age & residential area. One study had 2 sets of controls: gen popln & other non-lung cancer

Histologically confirmed lung cancer, type not specified

Unconditional logistic regression adjusted for smoking, age, respondent status, years of education, occupations & study.

Adj. OR (95%CI), rel. to unexposed in all categories.OverallAny exposure: 1.3 (1.1-1.7)Non-substantial:1.3 (0.9–1.6)Substantial1.5 (0.7–3.1)By duration (any exposure)<5yrs:0.9 (0.5-1.6)5-20yrs :1.2 (0.8-2.0)>20yrs :1.6 (1.1-2.3)Smoking status (any exposure)Non-smokers:2.5(1.3-4.7)Smokers: 1.1 (0.9-1.4)

Grimsrud et al 2002NorwayNested case-control study

Occupational nickel exposures from 5 900 measurements for total nickel between 1973–

Nested case-control study of 213 lung cancer cases identified in Cancer Registry between 1952–

5389 male workers employed at a Kristiansand nickel refinery ≥ 12 months between 1910–1994 & alive at 1/12/1952

Lung cancer incidence identified according to NorwayCancer Registry

Conditional logistic regression adjusted for smoking status & work duration.

Adj. OR (95%CI) (rel to unexposed, all categories)Water soluble NickelLow: 1.3 (0.5-3.5)Low-medium:1.8 ( 07-4.5) Medium:1.9 (0.8-4.6)Medium-high: 2.5 (1.0-6.0)





1994.Relative concentrations of four forms of nickel were estimated on the basis of speciation analyses of refinery dusts & aerosols conducted during 1990s.Risk estimates due to specific nickel compounds categorised on basis of cumulative exp based on a job exposure matrix.

1995 & 525 controls from workforce matched by age, sex and year of birth (94% of all originally identified cases & controls)

Nested within the cohort utilised by Grimsrud et al. 2003.

Alloy data unadjusted for exposure to water soluble Ni.

High:3.8 (1.6-9.0)p-trend: 0.002Ni oxideLow:1.7 (0.7-4.2)Low-medium:2.3 ( 0.9-5.8) Medium: 2.7 (1.1-6.6)Medium-high: 2.3 (1.0-5.7)High: 2.2 (0.9-5.4)p-trend: 0.201Ni sulphideLow: 1.6 (0.6-4.2)Low-medium:2.8 ( 1.1-6.9) Medium: 2.5 (1.0-6.3)Medium-high: 2.3 (0.9-5.5)High: 2.8 (1.1-6.7)p-trend: 0.119Metallic nickelLow: 1.4 (0.6-3.3)Low-medium:1.3 ( 0.6-3.0) Medium: 1.3 (0.6-3.0)Medium-high: 1.7 (0.8-3.8)High: 2.4 (1.1-5.3)p-trend: 0.126Nickel exp. and smoking<0.75mg/m3/yr:Non & ex(>5yrs) smokers:1 (ref)Smokers (1-20g/day):12.3 (3.6-42.3)Smokers (>20g/day):37.6 (9.3-151)>0.75mg/m3/yr:





Non & ex(>5yrs) smokers:5.0 (1.4-17.3)Smokers (1-20g/day):22.1 (6.7-72.8)Smokers (>20g/day):34.4 (9.3-121)

Grimsrud et al 2003NorwayCohort study

Nickel exposures from 5 900 measurements for total nickel between 1973–1994 and estimates of specific nickel compounds leading to job exposure matrix

Work history from plant records; lung cancer incidence followed up until 12/31/2000 from The Cancer Registry of Norway. Age specific incidences from 1953 to 1993 for entire Norwegian male population was used to calculate SIRs

Cohort of 5 297 male workers employed at a Kristiansand nickel refinery ≥ 12 months between 1910–1989 and alive at 1/1/1953

Lung cancer incidence identified according to The NorwayCancer Registry

Multivariate Poisson regression analysis adjusted for age and smoking status (available in 89% of entire cohort

SIR (relative to Norwegian male population)Overall (any exp): 2.6 (2.3-2.9)Roasting:3.4 (2.3-4.8)Smelting:2.7 (2.1-3.6)Ni electrolysis:4.0 (3.3-4.8)Cumulative exposure (mg/m3X yr)(relative to unexposed in all categories)Adj. RR (95%CI)Total Nickel:0.01-0.41:1.2 (0.6-2.3)0.42-1.99: 2.1 (1.1-3.9)≥2.0: 2.4 (1.3-4.5)Water soluble nickel0.01-0.34: 1.3 (0.7–2.4)0.35-1.99: 1.8 (1.0–3.2)≥2.0: 3.1 (1.7-5.5)Nickel oxide:0.01-0.12: 1.7 (1.0–3.1)0.13-1.99: 2.5 (1.4–4.4)≥2.0: 2.1 (1.2-3.8)Nickel exp. and smoking <1.0mg/m3/yr Nickel:





Never: (ref)Ever smokers: 5.6 (2.0-15.0)>1.0mg/m3/yr Nickel:Never: 1.8 (0.5-6.2)Ever smokers: 9.1 (3.4-25.0)

Grimsrud & Peto 2006Wales (UK)Pooled analysis

Minimum of 15 yrs exposure (exp. type not detailed)

Not detailed Two cohorts of male workers with 5+ yrs of employment hired 1902–1969 or between 1953–1992 and followed through 1985 and 2000, respectively.No demographics reported,


Pooled standardised mortality ratios compared (SMRs), based on national mortality rates.Confounders not detailed.

Pooled SMR (95%CI)1.33 (1.03-1.72)

25.5.14 Polycyclic Aromatic Hydrocarbons (PAH) exposureStudy Exposure/ Risk



Armstrong et al 1994Case-cohort studyQuebec, Canada

Two indices of cumulative exposure (average concentration x time): benzene soluble matter (BSF) (mg/m3 – years) & benzo-a-pyrene (BaP) (µg/m3 – years). Job-exposure matrix used.

Case-cohort study design, where exposure information is required from a random sample of entire cohort, rather than for matched controls.Lung cancer ascertained from cancer and

338 lung cancer deaths & a random sample (sub-cohort)of 1,138 from among 16,297 men employed for at least one year between 1950 & 1979 in an aluminium production plant


Data adjusted for age, calendar period & smoking

Lung cancer mortality: Rate ratios & 95% CI, by smoking habit:Never reported smoking = 1.00Ever smoked = 3.00 (1.62-5.59)Ever smoked, by pack years<20 = 0.95 (0.45-2.02)20-39 = 3.00 (1.59-5.69)40-59 = 3.44 (1.79-6.62)≥60 = 6.20 (3.11-12.38)Never smoked more than 20 cigarettes per day = 3.05





tumour registries and records of patients from a hospital.

(1.46-6.35)Unknown smoking habit = 2.33 (1.06-5.17)Lung cancer mortality: Rate ratios & 95% CI, by cumulative exposure:BSF (mg/m3 – years):<1 = 1.001-9 = 1.15 (0.84-1.59)10-19 = 2.25 (1.50-3.38)20-29 = 1.90 (1.22-2.97)≥30 = 2.08 (1.30-3.33)BaP (µg/m3 – years):<10 = 1.0010-99 = 1.48 (1.09-2.00)100-199 = 2.23 (1.46-3.39)200-299 = 2.10 (1.40-3.15)≥300 = 1.87 (1.05-3..33)

Armstrong et al 2009CohortQuebec, Canada

Job-exposure matrix using estimates of BaP for each job combined with work histories to give estimates of cumulative exposure in µg/m3 - years

Large cohort study with follow-up from 1950 until the end of 1999.Exposure-response relationship

16431: 5977 men at one very large & two small aluminium smelters, and 9726 men and 728 women who completed one year employment before 1989. 677 lung cancer cases.


Data adjusted for age, calendar period & smoking

Overall lung cancer mortalitySMR & 95% CI = 1.32 (1.22-1.42)RR & 95% CI for lung cancer incidenceBy cumulative exposure to BaP (µg/m3 – years):0 = 1.000.0000001-= 1.75 (1.23-2.48)20- = 3.02 (2.01-4.52)40- = 1.94 (1.27-2.97)80- = 3.09 (2.12-4.51)160- = 2.86 (1.96-4.18)320- = 3.77 (2.23-6.38)By no: of cigarettes per day:





0 = 1.001-= 1.49 (1.12-1.98)21-= 2.89 (2.18-3.84)41-=1.48 (0.83-2.66)61-= 1.99 (0.72-5.49)Unknown = 1.02 (0.73-1.41)SMR & 95% CI for lung cancer mortalityBy cumulative exposure to BaP (µg/m3 – years):0 = 0.62 (0.44-0.87)0.0000001-= 1.09 (0.96-1.23)20- = 1.88 (1.47-2.38)40- = 1.21 (0.91-1.59)80- = 1.93 (1.59-2.32)160- = 1.79 (1.48-2.15)320- = 2.36 (1.49-3.54)By no: of cigarettes per day:0 = 0.80 (0.61-1.04)1-= 1.19 (1.04-1.36)21-= 2.32 (2.05-2.61)41-=1.19 (0.65-2.00)61-= 1.60 (0.44-4.09)Unknown = 0.82 (0.66-1.00)

Bertrand et al 1987CohortLorraine, France

Exposure assessment by two methods:Duration of exposure in years and according to individual

Cohort design, follow-up from 1963 to 1982.Mortality ascertained from medical records

Cohort of 534 male manual workers from two coke oven plants between 1963 & 1982.


Wilkinson’s signed rank test & Armitage’s statistical test of homogeneity of proportions for duration of exposure.

Lung cancer mortality between two coke oven plantsPlant A – 3.05 (p<1%)Plant B – 1.75 (NS)Cohort mortality in comparison with French male mortality





exposures O/E = 2.51 (p<1%)

Bosetti et al 2007Meta- analysis & pooled analysisMultinational

Occupational exposure to PAHPAH exposure intensity and duration not reported

57 cohort studies published between 1997 & 2005.

Workers from all relevant industries with high exposures to PAH: coal gasification, coke production, aluminium production, carbon black, coal tar related & carbon electrode

Description unclear

Smoking, age, sex, calendar period

Overall SMR & pooled RR (95%CI) for various industriesAluminium productionSMR = 1.01RR = 1.03 (0.95-1.11)Coal gasificationSMR = 2.14RR = 2.29 (1.98-2.64)Coke productionSMR = 1.49RR = 1.58 (1.47-1.69)Tar distillationSMR = 1.19RR = 1.21 (0.95-1.55)CreosoteSMR = 1.11RR = 1.14 (0.85-1.51)Carbon blackSMR = 1.21RR = 1.30 (1.06-1.59)Carbon electrodeSMR = 0.96RR = 1.00 (0.82-1.23)

Olsson et al 2010Multicentre Case Control

Two exposure indices: duration of exposure across all job periods in

2861 newly diagnosed lung cancer cases & 2936 population or hospital

2197 men & 655 women from six Central & Eastern European (CEE) countries and UK

All types of lung cancer including squamous

Age groups, gender, tobacco pack-years & other occupational exposures.

Occupational exposure to PAH & lung cancer risk, OR & 95% CIOccupational PAH exposureNever





Six Central and East European Countries and UK

years; cumulative exposure calculated as product of frequency (mid-interval values of average work time: 3%, 17.5%, 65%), intensity of airborne BaP (mid-interval values: 0.075, 0.55, 3 µg/m3) & duration of exposure in years summed all over work periods in the person’s job history

controls.Nine cases & 13 controls excluded from final analysisData collection from interviews and questionnaires

aged between 40 and 74 years in various industries classified as exposed to PAH

cell carcinoma, small cell carcinoma & adenocarcinoma

CEE = 1.00UK = 1.00EverCEE = 0.93 (0.77-1.14)UK = 1.97 (1.16-3.35)Maximum intensity to PAH (µg/m3)0.05-0.1CEE = 0.82 (0.65-1.04)UK = 2.12 (1.12-4.00)0.1-1CEE = 1.17 (0.84-1.64)UK = 1.42 (0.57-3.52)1-5CEE = 1.11 (0.60-2.05)UK = 2.68 (0.74-9.77)Cumulative exposure<0.04CEE = 0.73 (0.50-1.06)UK = 1.79 (0.82-3.90)<0.15CEE = 0.99 (0.69-1.44)UK = 1.68 (0.67-4.20)<0.77CEE = 0.89 (0.62-1.29)UK = 2.14 (0.75-6.110≥0.77CEE = 1.13 (0.80-1.58)UK = 2.77 (0.94-8.11)





Years exposed to PAH<5CEE = 0.90 (0.64-1.26)UK = 1.30 (0.60-2.82)6-10CEE = 1.12 (0.75-1.68)UK = 1.40 (0.55-3.58)11-20CEE = 0.76 (0.51-1.13)UK = 15.11 (2.05-74.89)21-30CEE = 0.94 (0.60-1.47)UK = 1.18 (0.32-4.23)30+CEE = 1.02 (0.66-1.57)UK = 3.60 (0.73-17.80)

Pastorino et al 1984Population-based case-control studyNorthern Italy

Description unclear

211 cases & 351 controls. One control chosen for each case for first two years of study & two controls for each case the following two years. Age-matched controls

Study area in Northern Italy region characterised by high density of small and medium-sized industries

Description unclear

Analysis by stratification according to potential cofounders. Adjusted risk ratios between incidence of lung cancer among exposed and unexposed

RR for PAH exposure by no: of cigarettes per day0-9 = 1.310-19 = 7.020+ = 9.9

Veglia et al 2007

CAREX=based job exposure matrix for

Large cohort study with a follow-up period

Cohort includes subjects of both genders, between

Description unclear

Adjusted for gender, smoking history, education,

Hazard ratio & 95% CIOverall = 1.42 (1.1-1.8)





Cohort10 Western European Countries

exposures to lung carcinogens

of 6 years.Data collected with questionnaires

the age range of 35 and 74 years.

BMI, fruit & vegetable consumption & leisure time physical activity

Men = 1.43 (1.2-1.8)Women = 1.24 (0.6-2.4)

25.5.15 Painting as an occupationStudy Exposure/ Risk


Bachand et al 2010Systematic review with meta-analysisMulti-country

Painting as an occupation (various durations) the exposure for which lung cancer RR estimated in the included studies. A painter / painting occupation defined slightly different across studies. RRs (study design type) are for or any duration / level of painting occupation.No quantification of exposure to particular suspected carcinogens in paints or the paint workers’ environment

Systematic review with meta-analysis based on 38 studies (23 case control and 15 cohort studies). External adjustment technique used to adjust for smoking as majority of studies did not adjust for smoking when estimating their lung cancer RR for painters compared to non-painters.

Painters (mostly male) studied in 38 studies (15 cohort and 23 case controls) that estimated RR for painting as an occupation. Majority of painters male. Subjects worked as painters in a range of countries for a range of years. Countries included Russia, New Zealand, USA, Germany, Uruguay, Canada, China, Argentina, Italy, Brazil, Sweden, Scotland.

Various lung cancer, types.

Smoking (adjusted for using an external technique as not all included studies adjusted for smoking when estimating the RR in painters compared to non-painters).

RR for painting as an occupation, any level/yrs exposure (smoking adj), ref pop non painters (15 cohort studies)Morbidity: 1.00 (0.70-1.42)Mortality: 1.19 (0.98-1.44)RR for painting as an occupation (smoking adj), any level/yrs exposure, ref pop non painters ( 23 case controls):1.29 (1.10-1.51)RR for painting as an occupation by smoking status and genderNot reported.




Guha et al 2010Systematic review with meta-analysisMulti-country

Painting as an occupation the exposure studies. Painter defined slightly different some of the included studies. Studies estimated lung cancer RR for different durations of painting employment and the RR reported from the meta-analysis are for any level of exposure/duration of work as a painter. No quantification of exposure to particular suspected carcinogens in paints or the paint workers’ environment

Systematic review with meta-analysis. RR for lung cancer in painters compared to non-painters estimated based on studies that did and did not adjust for smoking. Only the results of meta-analysis that used smoking adjusted RR from included studies reported here. Sub-group analysis undertaken to estimate RR for females compared to males and non-smokers as well as never smokers.

Study population painters who worked as painters in a range of countries including China, Finland, Norway, Denmark, UK, USA, Uruguay, Switzerland, Brazil, Argentina, Sweden.Overwhelming male painters, however seven studies reported results for female painters and their RR were used in meta-analysis to derive a summary RR for females and compared to that for males.

Various types Alls studies for which we report the meta-analysis results adjusted for at least smoking and some additional factors such as family cancer history, sex, age, education. One meta-analysis, based on 5 studies estimated a summary lung cancer RR for painting as an occupation adjusted for smoking plus other occupational exposures.

RR (smoking adj.) for painting as occupation, any yrs of employment/level of exposure, non painters the ref pop.All study designs (27 studies):1.35 (1.21-1.51)Cohort studies (4): 1.22 (0.97-1.52)Case controls (23): 1.41(1.23-1.61)RR (adjusted for smoking plus other occupational exposures) for painting as an occupation, non-painters the ref pop (5 studies):1.57 (1.21-2.04)RR in never smoking painters, non-painters the ref (3 studies):2.00 (1.09-3.67)RR in never smokers & non-smokers, never painters the ref: (3 studies):1.96 (1.15-3.35)RR for female painters, any level/duration, non-painters the ref, (7 studies):2.04 (1.59-2.62)RR for male painters, any level/duration, non painters the ref, (study number not stated):1.37 (1.29-1.44)RR by duration of exposure (5 studies) found higher RR for longer duration.

Ramanakumar et al 2011Pooled analysisMontreal Canada

RR estimated for two kinds of exposures: (i) Painting as an occupation (lifetime work history based/any duration/level of

Population controls selected using random sampling. Cases and controls matched by age & sex. For first case control

Painters studied in two case controls undertaken in Montreal Canada. Case Control 1: 857 male lung cancer cases,

Small cell, squamous cell & adenocarcinoma.

Adjusted for age, family income, ethnicity, respondent status, years of schooling, smoking, and

RR associated with work as painter, all males, any level of exposure, ref no painting work OR (95% CI)Overall risk :Painter (any duration): 1.6 (1.0-2.4)Painter ≤10 years: 2.0 (0.9-4.1)




exposure) and (ii) Exposure to wood and gypsum paints classified as substantial, non-substantial and any level, based on a job description matrix and expert opinion.

interviews from 1979-1986, for second 1996-2001. Interview undertaken with subject or next of kin/proxy informant.Detailed lifetime histories elicited in interview including information on smoking other lifestyle factors and socio-economic status.Level and duration of exposure to 3 different agents based on job history (interview) & expert opinion.

controls 533 males.Case control 2: 765 male & female lung cancer cases and 899 controls.All Canadian citizens resident in Montreal.Due to low female subject numbers RR estimated only for males. Average age of subjects older in Case Study II than I. All 35 yrs or older and most over 55 yrs.

exposure to at least one of the following carcinogenic agents, asbestos, silica cadmium compounds.

Painter >10 years: 1.2 (0.5-1.8)RR associated with exposure to wood and gypsum paints, all male subjects, ref no exposureOverall risk:Any exposure: 1.4 (0.9-1.9)Any exposure ≤15 yrs: 1.2 (0.8-2.4)Any exposure ≥15 yrs: 1.1 (0.7-1.5)Non substantial exposure:1.1 (0.8-1.9)Substantial exposure:1.4 (0.8-2.7)RR by date of first exposure to painting as occupation:First exposed ≤1965 1.5 (0.8-2.4)First exposed >1965 1.2 (0.9-1.6)

Tse et al 2011Case controlHong Kong, China

Painting as an occupation with stratification for exposure to spray painting and general painting work excluding spray painting.Exposure classified as working at least once a week for at least 6 months.

Case Control.Cases selected from oncology centre in Hong Kong (Feb2004 - 30 Sept 2006).Controls randomly selected from same districts as cases. Community referents no

Cases 132 Chinese non-smoking males (aged 35-79yrs) newly diagnosed with lung cancer. Controls 536 non-smoking male community referents.

Histologically confirmed primary lung cancer (all types). Separate analysis for adenocarcinoma.

Age, place of birth, education level, residential radon exposure, past history of lung diseases, any cancer in first degree relatives and intake of

OR for general painting work , any duration of employment, ref pop who have never done general painting work or been exposed to a range of other human carcinogens:2.79 (1.20-6.48)OR for spray painting work, any duration of employment, ref pop never done spray painting work or been exposed to a range of other human carcinogens:3.29 (1.31-8.23)RR increased with increasing yrs of spray painting work but not yrs of general painting excluding spray




history of diagnosed cancer, frequency matched in 5-yr age groups to a lung cancer case.Interviews for data on lifestyle, occupational history &other exposures namely asbestos, arsenic, nickel, chromium, tars, asphalts, silica, spray painting, non-spray painting, pesticides, diesel engine exhaust, cooking fumes, welding fumes.

meat. These confounding factors selected based on testing sensitivity of results to a range of potential confounder variables.

painting.

25.5.16 Physical ActivityStudy Exposure/


Alfano et al 2004USA

Physical activity (PA) measured as average weekday and weekend day hours during the past year in five categories:

Prospective cohort study. 1985 through 2002

7,045 men and women recruited from six centres across the United States

Incident cases of lung cancer identified as reported by the participants, cancer registries, state boards of health and the National Death

Age, smoking history, gender and BMI

Physical activity and lung cancer incidence - HRR (95% CI)

Total PA (h/wk)

Age 54-62 y Age 63-78 y

0.84 (0.69, 1.03); P = 0.04 1.11 (0.95, 1.29)

Moderate-vigorous PA (h/wk)




sleeping, vigorous activity, moderate activity, light activity and sitting

Index 0.99 (0.87-1.11); P = 0.83

Bak et al 1996Denmark

Physical activity in leisure time

Prospective cohort study.1993/1997 through 2002

57,053 participants (aged 50-64 years)

Incident cases of lung cancer were identified as reported by cancer registries

Smoking status, duration of smoking (years), number of years since quitting smoking, smoking intensity school education and consumption of vegetables and fruits

Incidence rate ratios corresponding to a difference of 1 hour/week of activity with 95% confidence intervals for lung cancer

Men – total leisure time activity

Smoking adjusted Other factors adjusted

1.00 (0.99, 1.02) 1.00 (0.99, 1.02)

Women - total leisure time activity

Smoking adjusted Other factors adjusted

1.00 (0.98, 1.01) 1.00 (0.98, 1.01)

Lee et al 1994Harvard USA

PA based on self-reported stair climbing, walking and participation in sports or recreational activities

Prospective cohort study1962/1966 through 1988

Nonfatal occurrences of lung cancer ascertained by means of mailed questionnaires and fatal occurrences from death certificates to determine cause-specific

Age, Quetelet’s index, parental history of any cancer and cigarette smoking habit.

— Adjusted Relative Risk (95% Confidence Interval)

Physical activity level assessed both in 1962/66 & updated in 1977 (Model B)P for trend 0.02

<1000 (kcal/wk) 1000-2499 (kcal/wk)

≥2500 (kcal/wk)

1.00 (referent) 0.79 (0.44-1.43) 0.39 (0.18-0.85)




mortality. NonsmokersPhysical activity level assessed both in 1962/66 & updated in 1977 (Model B)P for trend 0.60

<1000 (kcal/wk) 1.00 (referent)

1000-2499 (kcal/wk) 0.92 (0.37, 2.30)

≥2500 (kcal/wk) 0.76 (0.28, 2.05)

Leitzmann et al 2009USA

Physical activity assessed and categorised based on the frequency each week spent at activities that lasted 20 minutes or more and caused either increases in breathing or heart rate or working up a sweat

Prospective cohort study - The National Institutes of Health-AARP Diet and Health study 1995/96 through 2003

501,148 subjects recruited from six different states in USA

Incident cases of LC identified through probabilistic linkage to the state cancer registries. Main histological types of lung cancer defined by anatomic and histological code of ICD for Oncology

Age, gender, smoking status, gender and BMI.

Relative risk of lung and 95%CI according to frequency (times per week) of physical activity

Age and gender adjusted

0 1.0

<1 0.77 (0.71, 0.83)

1-2 0.67 (0.62, 0.72)

3-4 0.55 (0.51, 0.59)

≥5 0.50 (0.46, 0.54)

Age and gender adjusted + smoking

0 1.0

<1 0.89 (0.82, 0.96)

1-2 0.86 (0.81, 0.93)

3-4 0.81 (0.76, 0.87)

≥5 0.77 (0.71, 0.83)

Sinner et al 2006

Four PA measures for

Prospective cohort study

36,929 women aged between

Incident cases of LC identified

BMI, smoking status, pack-

LC associated with leisure activity by smoking status

Age-adjusted HR




USA assessment: PA (yes, no), level of PA (low, medium, high), moderate activity level (never, < once a week, > once a week) and vigorous activity level (never, < once a week, > once a week).

55 and 69 years through State Health Registry

years of smoking, education, marital status, alcohol intake, coffee intake and vegetable intake

Current smokers

Low 1.00 (ref)

Medium 0.65 (0.51, 0.82)

High 0.70 (0.54, 0.91)

Former smokers

Never smokers

Low 1.00 (ref) 1.00 (ref)

Medium 0.72 (0.50,1.04)

1.82 (1.21, 2.74)

High 0.65 (0.45, 0.94)

1.33 (0.84, 2.10)

Multivariate adjusted HR

Low 1.00 (ref) 1.00 (ref) 1.00 (ref)

Medium 0.65 (0.51, 0.83)

0.72 (0.50, 1.04)

1.83 (1.21, 2.78)

High 0.72 (0.55, 0.94)

0.63 (0.43, 0.92)

1.32 (0.83, 2.10)

Steindorf et al 2006(USA)

PA, Occupational PA, Recreational PA, Household PA and

Multicentre prospective cohort study 1985 to 1997

521,457 male and female participants, aged between 35-70 years were initially

LC incidence identified by population cancer registries and by active

Age, smoking status, education, BMI, alcohol and vegetable and fruit

Adjusted relative risk and 95% CIs of lung cancer by type of physical activity

Males Females

Smoking Full Smoking Full




Vigorous no-occupational PA

recruited for this study; however, only 416,227 subjects were included in the current analysis

follow-up, which included health insurance records and direct contact of participants

consumption adjust. adjust. adjust. adjust.

Occupational PA

Unemployed

1.82(1.40, 2.37)

1.57(1.20, 2.05)

1.39(1.05, 1.84)

1.25(0.94, 1.66)

Heavy (manual)

1.45(1.10, 1.90)

1.25(0.94, 1.66)

1.20(0.84, 1.71)

1.09(0.76, 1.56)

Non-occupational PA (quartiles in MET-hrs/week)

33.7-<56.6

0.88(0.70, 1.12)

0.89(0.70, 1.13)

0.96(0.75, 1.24)

0.99(0.77, 1.26)

≥86.6 0.96(0.75, 1.22)

0.97(0.76, 1.25)

0.99(0.74, 1.32)

1.00(0.75, 1.35)

Recreational PA(quartiles in MET-hrs/week)

13.5-<27.5

1.08(0.87, 1.34)

1.09(0.88, 1.35)

0.96(0.74, 1.23)

0.99(0.77, 1.280

≥45.0 0.99(0.78, 1.26)

1.00(0.79, 1.27)

0.93(0.72, 1.21)

0.99(0.76, 1.30)

Household PA(quartiles in MET-hrs/week)

11.0-<23.8

0.77(0.60, 1.00)

0.77(0.60, 1.01)

1.04(0.82, 1.34)

1.04(0.81, 1.33)




≥43.6 1.03(0.81, 1.31)

1.04(0.82, 1.31)

0.97(0.71, 1.32)

0.95(0.70, 1.30)

Vigorous non-occupational PA(tertiles over actives, MET-hrs/week)

>0-<15.0

0.85(0.63, 1.16)

0.94(0.69, 1.28)

0.61(0.41, 0.92)

0.65(0.43, 0.98)

≥40.0 0.84(0.63, 1.11)

0.87(0.65, 1.16)

0.90(0.63, 1.28)

0.92(0.65, 1.32)

Tardon et al 2005(USA)

Three components of leisure-time PA – type, duration and/or intensity

Meta-analysis Total sample N=185279; USA and Europe

Description unclear

Age, gender, smoking statusBMI, vegetable intake, education

Leisure time physical activity and lung cancer - OR, 95% CI

Total Males Females

Moderate 0.87 (0.79, 0.95)

0.93 (0.85, 1.00)

0.77 (0.66, 0.89)

High 0.70 (0.62, 0.79)

0.75 (0.66, 0.86)

0.62 (0.48, 0.79)

Trend 0.00 0.01 0.01

25.5.17 RadonStudy Exposure/


Darby et al 2004Sweden, Finland, Austria,

Residential exposureBetween 5 – 34 years

Meta-analysisCombination of 13 previously published case control studies conducted in 9

7148 cases and 14,208 controlsMales = 5521 cases, 10388 controls


Gender, age, smoking status, region of residence and exposure

General exposure for both genders combined OR (95% CI)

<25 Bq/m3 OR 1.00 (0.87 – 1.15)

25 - 49 Bq/m3 OR 1.06 (0.98 – 1.15)




Czech republic, France, Germany, Italy, Spain, & UKMeta-analysis

Estimates of radon (and radon progeny) exposure was detected using both air and surface monitors for a 12 month period

countriesSearch or inclusion details not reportedIncluded studies range from1992 - 2004

Females = 1627 cases, 3820 controlsGeneral population controls matched on gender and age.Age range from<55 – 65+ yrs

time

50 - 99 Bq/m3 OR 1.03 (0.96 – 1.10)

100 - 199 Bq/m3 OR 1.20 (1.08 – 1.32)

200 - 399 Bq/m3 OR 1.18 (0.99– 1.42)

400 - 799 Bq/m3 OR 1.43 (1.06 – 1.92)

>800 Bq/m3 OR 2.02 (1.24 – 3.31)

Risk was not presented by gender, smoking status or exposure duration.

Grosche et al 2006GermanyCohort study

Occupational exposureMean age at first exposure: 24.6 yrs (33% exposed for the first time < 20 yrs old)Mean duration of exposure: 11.3 yrs, 40% of cohort had worked 5–14 yrs~33% of workers exposed below 10 WLM; 9.3 % exposed exceeded1000 WLM

Cohort was identified via company recordsStratified based on high, medium, and low exposures, based on job categoryDeaths were identified via district death certificates

59,001 former male employees of the Wismut CompanyMean duration of follow-up: 30.5 yrs

Not specified

Age, smoking and calendar period

Overall exposure RR (95%CI)

Exposed, compared with unexposed miners

2.08 (1.08–2.79)

Risk estimates not presented by smoking status.

IARC 2011 Most studies Monograph No detailed sample All types of — Occupational exposure to radon




monographGlobalResearch syntheses

reported at 100 Bqm3 for >5 yrs

Derived from expert panel discussionSearch terms or selection criteria not detailedResearch syntheses, cohort and case control studies addressing bothResidential exposure and occupational exposure (5-30 yrs) includedNo inclusion criteria or search strategy was detailed

demographics providedPopulations of interest were:Miners (specifically uranium miners) and people residing in regions where they were exposed to radon

lung cancer No risk estimates provided

Occupational exposure risk to underground iron ore miners (SMR)

USA haematite (ferric oxide)

1.00

UK iron ore(type not specified)

1.53 (1948 -67)

1.13 (1967+)

China haematite (ferric oxide)

3.7

Radon level and exposure duration not reported.

Residential exposure OR (95%CI)

Risk for 5-30 year, 100 Bqm3 radon exposure

USA 1.11 (1.00 – 1.28)

China 1.33 (1.01–1.36)

Europe(adjusted for random uncertainties in measurement)

ERR 0.16 (0.05 – 0.31)

No reported risk estimates for either type of exposure by smoking status or gender.

Jonsson et al 2010Cohort study

Occupational exposureBased on WLM of 166.67 hours of usual work per month

Exposure data collected from company recordsLung cancer deaths derived from national register

5486 male workers who had worked for at least 1 year in a Swedish iron ore mine

Adenocarcinoma

— Adjusted RR (95% CI), relative to unexposed miners

16.6 WLM 1.10 (0.65 – 2.08)

105.3 WLM 2.80 (1.82 – 6.08)

159.5 WLM 4.76 (3.06 – 10.01)




Assessments based on data from 5481 radon measurements carried out during 1969-1998.

271.6 WLM 4.27 (2.68 – 9.69)

* NB WLM is in this study is based on 166.67 hours at work, not 170 hours

Kreuzer et al 2003East GermanyCase control study

Residential exposure5 – 34 yrs

Data collected via combination of methods: self-report questionnaire, interview and comprehensive radon exposure assessmentAlpha detectors in each residence used to calculate mean exposure estimate for a 12 month period

A total of 1192 cases and 1640 controlsMales = 1046 cases, 1414 controlsFemales = 146 cases, 226 controlsGeneral population controls matched on basis of gender and ageAge range from <50 – 75 yrs


Risk was adjusted for gender, age, region, smoking status and occupational asbestos exposure.Risk was not presented by gender or by smoking status.

Both genders combined OR (95%CI)0 - 50 Bq/m3 reference exposure

50 - 80 Bq/m3 OR 0.95 (0.77 – 1.18)

80 - 140 Bq/m3 OR 1.13 (0.86 – 1.50)

>140 Bq/m3 OR 1.30 (0.88 – 1.93)

Risk estimate by exposure duration

5 – 15 years

50 - 80 Bq/m3 OR 1.03 (0.81 – 1.31)

80 - 140 Bq/m3 OR 1.03 (0.77 – 1.38)

>140 Bq/m3 OR 1.37 (0.95 – 1.98)

5 – 25 years

50 - 80 Bq/m3 OR 1.14 (0.87 – 1.49)

80 - 140 Bq/m3 OR 1.05 (0.75 – 1.45)

>140 Bq/m3 OR 1.36 (0.89 – 2.08)

5 – 35 years

50 - 80 Bq/m3 OR 0.88 (0.60 – 1.27)

80 - 140 Bq/m3 OR 0.77 (0.50 – 1.19)




>140 Bq/m3 OR 1.44 (0.83 – 2.52)

Krewski et al 2005USAPooled analysis

Residential exposure5 – 30 yrsEstimates of radon (and radon progeny) exposure was detected using long term alpha track detectors for a 12 month period

Meta-analysisCombination of 7 previously published case control studies conducted in 6 states of the USA

A total of 3662 cases and 4966 controlsApprox 70% males in both cases and controlsControls matched on basis of gender and age (+/- 5 yr)Age ranged from <60 – 75+ yrs


— General Exposure for both genders combinedOdds ratio (95%CI) relative to <25 Bq/m3

25 – 49 Bq/m3 OR 1.13 (0.95 – 1.35)

50 – 74 Bq/m3 OR 1.09 (0.89 – 1.34)

75 – 99 Bq/m3 OR 1.16 (0.91 – 1.48)

100 – 149 Bq/m3 OR 1.24 (0.96 – 1.60)

150 - 199 Bq/m3 OR 1.22 (0.87 – 1.71)

>200 Bq/m3 OR 1.37 (0.98 – 1.92)

Risk was not presented by gender, smoking status or exposure duration

Lagarde et al 2001

Residential exposureExposure for 32 yrs, except for 11 subjects younger than 35 yrs of age at the end of follow-up

Research synthesis/case controlData combined from 5 previously published and 1 new case control studies conducted in Sweden

Mean time in residence was approx. 25 yrs (both cases and controls)Approx. 45% male, 55% female (cases and control)Ages ranged from 28 – 94 yrsCases were selected from a national register. Controls were matched to cases on birth year (+/- 3-years), gender and study

Primary lung cancer (ICD-7, code 162.1)

— Residential exposure and smokingGeneral Exposure for both genders combined – Odds ratio (95%CI). Risk estimate based on 5 Swedish case control studies, exposure compared with <50 Bq/m3 for at least 3 years

Never smokers

50 - 80 Bq/m3 OR 1.18 (0.75 – 1.88)

80 - 140 Bq/m3 OR 1.24 (0.80 – 1.92)

>140 Bq/m3 OR 1.44 (0.87 – 2.35)

Current smokers

50 - 80 Bq/m3 OR 1.08 (0.79 – 1.47)

80 - 140 Bq/m3 OR 1.18 (0.86 – 1.61)

>140 Bq/m3 OR 1.44 (1.00 – 2.06)




Environmental smoking in the home

Not present

50 - 80 Bq/m3 OR 0.93 (0.63 – 1.38)

80 - 140 Bq/m3 OR 0.88 (0.58 – 1.34)

>140 Bq/m3 OR 1.13 (0.70 – 1.82)

Present

50 - 80 Bq/m3 OR 1.43 (0.86 – 2.36)

80 - 140 Bq/m3 OR 1.76 (1.08 – 2.86)

>140 Bq/m3 OR 2.10 (1.21 – 3.65)

Leurand et al 2011Research synthesisCzech Republic, France and GermanyAlpha-Risk project

Occupational exposureExposure was measured in ambient air where the miners worked. Method not specified.Occupational history and exposure data were available from the cohorts.Smoking information was

Three case-control studies nested within cohorts of uranium miners

Czech cohort:2 cohorts.1) 4353 miners employed for at least 4 yrs between 1948–1959.2) 5626 miners employed for at least 1 yr between 1968–1974. Both cohorts followed until the end of 1999.French cohort:5098 miners employed for at least 1 yr between 1946–

Not specified

— Overall RR adj for level of radon exposure (95%CI)

Never smokers 1.00

Ex-smokers 1.94 (1.35 – 2.80)

Current smokers 6.41 (4.68 – 8.80)

WML adj RR (95% CI), relative to never smokers exposed to <50 Bqm3

50 - 100

Never smokers 2.08 (0.83 – 5.24)

Ex-smokers 3.94 (1.59 – 9.76)

Current smokers 12.03 (5.74 – 25.23)




provided by self-administered questionnaires and occupational medical archives.

1990 and followed from 1946 to 1994.German cohort:59,000 miners employed for at least 180 days by the Wismut Co. First employment between 1946 and 1989. Follow-up was between 1946 and 1998.

100 - 200

Never smokers 2.01 (0.81 – 4.97)

Ex-smokers 4.97 (2.14 – 11.58)

Current smokers 18.61 (8.96 - 38.64)

200 - 400

Never smokers 4.93 (1.95 – 12.49)

Ex-smokers 6.28 (2.59 – 15.23)

Current smokers 20.98 (9.97 – 44.15)

> 400

Never smokers 7.06 (2.42 – 20.57)

Ex-smokers 16.79 (6.78 – 41.59)

Current smokers 36.69 (16.92 – 70.59)

Lubin et al 2003Pooled analysis of case control studies

Residential exposureExposure was measured in ambient in residences and estimated over for 5 – 30 yrs.China – levels recorded for 1 yr at current residence in places where they have lived

Pooled analysis of case control studiesAll studies used long-term alpha-track detectors as the principal measurement device.

USA:4081 cases (2766 females and 1315 males)5281 controls (3779 females and 1502 males)China (Shenyang)301 Cases,355 Controls – females onlyChina (Gansu)

All types USA: study, sex, age, duration of smoking, no. of cigarettes smoked p/day, no. of residences and years of exposure covered with alpha-track measurements.

Overall Adjusted OR (95% CI) - both gender combined

USA (6 studies) 1.106 (1.00 - 1.28)

China (2 studies) 1.139 (1.01 - 1.37)

Risk estimate not presented by gender or by smoking status.




for at least 5 yrs

768 Cases(205 female, 563 males)1795 controls(427 female, 1232 males)No age details provided

China: age, smoking risk, no. of residences and coverage, and for the Gansu study, town, sex and socioeconomic factors.

Lubin et al 2004Research synthesisChina

Residential exposureOverall residential exposure was between 5 – 30 years.Estimates of radon (and radon progeny) exposure was detected using long term alpha track detectors for a 12 month period.

Meta-analysisCombination of 2 previously published case control studies conducted in 2 provinces of China.1 of the studies used only females.High proportion of smoking males in one study (91%)

A total of 1069 cases and 2014 controls.Males = 563 cases, 1232 controlsFemales = 506 cases, 782 controlsGeneral population controls matched on basis of gender and age.Age range from <45 – 70+ yrs.


Gender, age, smoking status, air pollution index, prefecture of residence and socioeconomic status

General exposure for both genders combinedOR(95%CI) relative to <100 Bq/m3

100 - 149 Bq/m3 1.12 OR (0.80 – 1.50)

150 – 199 Bq/m3 1.42 OR (1.00 – 2.00)

200 – 249 Bq/m3 1.13 OR (0.80 – 1.60)

250 – 299 Bq/m3 1.27 OR (0.80 – 1.90)

>/= 300 Bq/m3 1.52 OR (1.10 – 2.20)

Risk by smoking status at 100 Bq/m3

Odds ratio (95%CI)

Never smoker OR 1.00

Ever smoker OR 2.28 (1.8 – 3.0)

Current smoker

Light OR 1.77 (1.3 – 2.3)

Moderate OR 2.93 (2.2 – 4.0)

Heavy OR 4.47 (2.8 – 7.1)

Risk not presented by gender or exposure duration.




Pavia et al 2003Meta-analysisCountries not detailed

Residential exposureEstimates of radon (and radon progeny) exposure was detected using both air and surface monitors for a 12 month period for the majority of the included studies (82%).

Meta-analysisCombination of 17 previously published case control studies

A total of 9127 cases and 16,449 controlsControls matched for at least: sex, smoking status, age.Age range from 30 – 84 yrs.


— General Exposure for both genders combined – Odds ratio (95%CI)

50 Bq/m3 1.07 OR (1.04 – 1.11)

100 Bq/m3 1.15 OR (1.07 – 1.24)

150 Bq/m3 1.24 OR (1.11 – 1.38)

200 Bq/m3 1.33 OR (1.15– 1.54)

250 Bq/m3 1.43 OR (1.19 – 1.72)

Risk was adjusted for gender, age and smoking status.

Women only(based on 6 case control studies)Lung cancer risk to women exposure to 150 Bq/m3 compared with unexposed

150 Bq/m3 1.29 OR (1.04 – 1.60)

Risk was not presented by smoking status or exposure duration.

Pisa et al 2003Case controlItaly

Residential exposureEstimates of radon exposure were measured using both air monitors for a 12 month period.

Case controlData collected using a combination of methods: self-report questionnaire, face to face interview and a comprehensive radon exposure assessment.

138 cases and 291 controls. Cases were all deceased and were identified via death certificates.Males = 122 cases, 253 controlsFemales = 16 cases, 38 controlsGeneral population controls matched on basis of gender and year of birth.


Gender, age, dietary variables and smoking status.

Overall OR (95%CI)<40 Bq/m3 used as reference category

Both genders combined

40 - 76 Bq/m3 OR 2.00 (1.00 – 3.90)

77 - 139 Bq/m3 OR 1.80 (0.90 – 3.70)

140- 199 Bq/m3 OR 2.40 (0.90 – 6.2)

>200 Bq/m3 OR 1.0 (0.30 – 3.10)

Males




Age range from <55 – 65+ yrs.

40 - 76 Bq/m3 OR 2.10 (1.00 – 4.40)

77 - 139 Bq/m3 OR 2.00 (0.90 – 4.40)

140- 199 Bq/m3 OR 2.70 (0.90 – 7.90)

>200 Bq/m3 OR 1.40 (0.40 – 4.70)

Females

40 - 76 Bq/m3 OR 1.20 (0.20 – 7.40)

77 - 139 Bq/m3 OR 0.80 (0.10 – 7.30)

140- 199 Bq/m3 OR 0.30 (0.00 – 4.00)

Risk was not presented by either smoking status or exposure duration.

Schnelzer et al 2010Nested case control studyGermany

Occupational exposureUranium miners in Germany, employed for at least 180 days.

Smoking status attained from questionnaires and company records.Data on radonexposure were taken from a job-exposure matrix

Cases: 704 miners who died of lung cancerControls: 1,398 matched individually for birth year and attained age.

All types, determined from death records

Smoking, type of employment

Overall exposure (WLM)Risk RR (95% CI)

>0 - <50 0.86 (0.45 – 1.65)

>50 - <100 1.34 (0.65 – 2.73)

>100 - <500 2.14 (1.12 – 4.09)

>500 - <1000 3.63 (1.86 – 7.08)

>1000 - <1500 4.59 (2.25 – 9.37)

>1500 3.61 (1.70 – 7.68)

Occupational radon exposure, smoking and lung cancer risk

Smokers compared with non-smokers

RR 7.6 (4.4 – 13.1)




Excess relative risk due to smoking

ERR = 0.23%(0.11 – 0.46%)

Tomasek et al 2008

Occupational exposure Uranium miners in France and Czech RepublicMean exposure of 10.9 yrs. French miners exposed for at least 1 yr exposure, Czech miners, at least 4 yrs exposure.

Cohort studyMortality data from company/public records.Smoking information by questionnaire

10,000 male uranium miners aged approx. 54 yrs at follow up.

All types — Overall risk (SMR) of lung cancer resulting from occupational exposure

FranceMean Exposure WLM 36.5 (range 1- 37)

Risk SMR 1.55 (1.33, 1.79)

Czech RepublicMean Exposure WLM 57.3 (range 0.3 – 387)

Risk SMR 3.77 (2.48, 4.08)

CombinedMean exposure WLM 46.8 (0.1 – 960)

Risk SMR 2.87 (2.68, 3.08)

25.5.18 SilicaStudy Exposure/


Erren et al 201110 countries

SilicaNo details of exposure duration or intensity were reported.

Meta-analysis of 38 cohort and case control studies based on silicotics and 11 studies

An update of an earlier meta-analysis based on studies of lung cancer in both silicotics and non-silicoticsMost included

Lung cancer confirmed in individual studies by radiology, autopsy examinations, cancer registries and compensation

SmokingOther factors explored in the analysis were: record source, geographical location, periods of investigation.

Pooled estimate of overall lung cancer risk associated with silicosis RR (95%CI)

Silicotics (with silicosis, 38 studies)

Fixed effects model Random effects model

2.2 (2.0 - 2.3) 2.0 (1.8 - 2.3)

Non-silicotics (no silicosis, 11 studies)




based on non-silicotics

studies focussed on occupational exposureNo demographic information provided

lists Fixed effects model Random effects model

1.2 (1.1-1.3) 1.2 (1.0-1.4)

Lacasse et al 200511 countries

Occupational exposure to silica that led to silicosisEstimates of exposure ranged from 5 – 35 years

Meta-analysis of 27 cohort studies and 4 case-control studies.

Cohort study23,305 silicosis patients across 27 cohort studiesCase controlCases: 593Controls: 1082No demographic information provided

Description unclear

Smoking, mining sectors & cumulative radon exposure

Pooled estimate of overall lung cancer risk associated with silicosis SMR (95%CI)27 Cohort studies

2.45 (1.63-3.66)

Pooled estimate of overall lung cancer risk associated with silicosis OR (95%CI)4 Case-control studies

1.70 (1.15-2.53)

Lacasse et al 2009Six countries

Workers from diatomaceous earth, ceramic, industrial sand, mining, stone, quarrying and aluminium industries

Meta-analysis of four prospective cohort studies and 6 case-control studies.

Cohorts:8635 of which 267 had confirmed lung cancerCase control:Cases: 2161Controls: 5057Workers from diatomaceous earth, ceramic, industrial sand, mining, stone, quarrying and

Description unclear

Potential confounding factors not addressed

Pooled estimate of overall lung cancer risk associated with silica exposure RR (95%CI)10 studies

Two levels of silica exposure(no exposure reference)

1.0 mg/m3/yr 6 mg/m3/yr

RR 1.22 (1.01 - 1.47) RR 1.84 (1.48–2.28

No estimates of risk presented by smoking status or by gender




aluminium industries

Pelucchi et al. 2006Multi-national

Occupational exposure to silicaSilica exposure intensity and duration not reported

Systematic review of 28 cohort, 15 case–control and two proportionate mortality ratio (PMR) studies

Sub-cohort of 20 004 adults, 18 years or older, who completed the Cancer Epidemiology Supplement (8363 men, 11 641 women)


Smoking, age, sex, calendar period

Pooled estimate of overall lung cancer risk associated with silica exposure, RR (95%CI)

Random effects(27 cohort studies)

Fixed effects(27 cohort studies)

Random effects(15 case-control studies)

Fixed effects(15 case-control studies)

1.34 (1.25 – 1.45)

1.19 (1.16 – 1.21)

1.41 (1.18-1.67) 0.99 (0.98-1.00)

Preller et al 2010Nether-lands

Silica exposure intensity and duration not reported


Men aged 55-69 years (n=58 279)

Lung cancer ascertain-ment from cancer registry

Age, family history of lung cancer, smoking status, alcohol consumption, fruit and vegetable consumption and asbestos exposure

Overall lung cancer risk associated with silica exposure RR (95%CI)

1.65 (1.14 - to 2.41)

Overall lung cancer risk associated with silica exposure by duration (years), RR (95% CI)

1 -10 11 – 25 26 – 51

0.67 (0.43 – 1.04)

0.88 (0.60 – 1.29) 1.65 (1.14 – 2.41)

Overall lung cancer risk associated with silica exposure by silica concentration (mg/m3), RR (95%CI)

>0 0.075 – 0.2 0.2 – 0.6

<0.075 - 0.97(0.70 – 1.33)

1.21 (0.82 – 1.78) 1.14 (0.63 – 2.06)

Cumulative exposure for ≥3 vs <3 mg/m3.year), RR 95% CI




1.47

(0.93 - 2.33)

Smith et al 1995Multi-national

Silica exposure intensity and duration not reported

Meta-analysis of 14 cohort studies and 4 case-control studies

SilicoticsNo demographic details

Description unclear

Smoking Pooled estimate of overall lung cancer risk associated with silica exposure in silicotics, RR (95%CI)23 studies

2.2 (2.1-2.4)

No summary estimates of risk were presented by either smoking status or gender.

Steenland et al 2001Five countries

Pooled-exposure response analyses in silica-exposed workers.Median cumulative exposure ranged from 0.13 – 11.37 (mg/m3 -years)

Pooled analysis of 10 cohort studies with quantitative exposure data

Pooled cohort of 65,980 workers (44,160 miners and 21,820 nominees)

Description unclear

Confounders included in the model not described

Pooled risk of lung cancer associated with a cumulative exposure to silica in quintiles, OR (95%CI)

Q1 – 1.0 Q2 - 3.1 Q3 - 4.6 Q4 - 4.5 Q5 - 4.8

(reference)

(2.5 - 4.0) (3.6 - 5.9)

(3.5 - 5.8) (3.7 - 6.2)

No summary estimates of risk presented by either smoking status or gender.

Vida et al 2010Canada

Occupational exposure to crystalline silica including levels of exposure

A pooled analysis of 2 population-based case-control studies.

Study 1- men between 35 to 70 years; 857 cases, 533 population controls, 1,349 cancer controlsStudy 2 – men


Age, ancestry, smoking history

Pooled risk of lung cancer associated with exposure to silica, OR (95%CI)

Unexposed Any exposure Non-substantial level of exposure

Substantial level of exposure

1.00 (ref) 1.31 (1.08 – 1.59)

1.20 (0.97 – 1.49)

1.67 (1.21 - 2.31)




and women between 35-75 years; 738 cases and 899 controls

Pooled risk of lung cancer associated with exposure to silica, by smoking status, OR (95%CI)

0 cigarette yrs



1.0(ref) 1.28 (0.52-3.17)

0.98 (0.32-3.00)

2.25 (0.59-8.56)

>0-<400 cigarette yrs



2.19 (1.28-3.76)

3.20 (1.51-6.77)

3.09 (1.36-7.00)

3.67 (0.95-14.14)

≥400-<1000 cigarette yrs



6.91 (4.40-10.85)

6.76 (4.01-11.40)

5.98 (3.44-10.40)

9.49 (4.68-19.24)

≥1000 cigarette yrs



16.90 (10.87-26.28)

23.20 (14.41-37.36)

22.00 (13.46-35.96)

26.93 (15.16-47.84)




Yu et al. 2007Hong Kong

Retrospective exposure assessment - cumulative dust exposure (CDE) or mean dust concentration (MDC)


2,789 silicotic workers in Hong Kong diagnosed during the period 1981–1998

Cancer case ascertainment from death registry and ICD classification

Age, smoking status, calendar year of first exposure to silica

Overall lung cancer risk in silicotics by smoking status, HR (95% CI)

Never smoker Ex-smoker Current smoker

1.0 (ref) 3.43 (0.81 – 14.53)

5.89 (1.44 – 24.14)

Overall, SMR 95% CI

1.69 (1.35–2.09)

25.5.19 Smoking: Active and passive smokingStudy Exposure/


Gandini et al. 2008Meta-analysis

Active tobacco smoking investigated in former and current smokers with never smokers as the referent category.

Meta-analysis of 216 reports incl. in 2004 IARC monograph Tobacco Smoke and Involuntary Smoking. Report on 13 different cancer sites.

21 studies (26 cohorts) contribute to data for lung cancer in current smokers. 20 studies for former smokers.

Lung cancer. Not specified.

— RR (95%CI)current smokers8.96 (6.73 – 12.1)Former smokers3.85 (2.77 – 5.34)Differences in study design was most important explanatory factor for heterogeneity observed. Case control studies combined resulted in significantly greater risk estimate than cohort studies.

Boffetta et al 2000Meta-analysisAnalysis of 11 case control studies of multiple

Exposure to second hand smoke in adult never-smokers exposed during childhood. Self reported exposure to maternal or

Meta-analysis of the studies of childhood exposure to passive smoke identified from Medline database. The search covered the

2834 lung cancer cases; adult never-smokers; exposed to tobacco smoke during childhood. Both genders included; age range from 0-16 years.

Description unclear.

Potential confounding factors adjusted include: drugs and chemicals, parental occupational exposures, prenatal

Overall risk resulting from childhood exposure to passive smokeRR (95%CI)RR 0.91 (0.80 - 1.05)Risk resulting from childhood exposure to passive smoke by parentMother: RR 0.99 (0.78 - 1.26)




location worldwide; Hong Kong, Sweden, Japan, USA and Russia

paternal smoking during preconceptional, transplancental and direct smoke. Passive smoke exposure quantitatively measured as number of cigarettes/day smoked by the parents (smoker-years or pack-years). Duration of exposure not clearly reported.

publications up to the year 1998.

exposure to ionizing radiation, diet, and socioeconomic status.

Father: RR 0.83 (0.72 - 0.95)

Boffetta 2002Meta-analysis51 epidemiological studies in total. This includes 6 cohort and 45 case-control studies from several countries.However studies from

Exposure to environmental tobacco smoke exposure (ETS) in a home environment resulting from a spouse at home and/or other cohabitants

Meta-analysis.Only one database (Medline) was searched. The most recent date of publication included was December 2000.

7369 lifelong non-smokers of adult lung cancer who were exposed to second hand smoke from spouse and/or other cohabitants.Cases: 7369Males: 661Females: 6708Controls: 13281Males: 801Females: 12480661 male and 6708 female.

All histological types of lung cancer; squamous cell carcinoma, adenocarcinoma, non-adenocarcinoma, small cell carcinoma

Potential confounding factors adjusted include age, gender, occupation, diet, but not reported.

Overall risk resulting from ETS resulting from a spouseRR (95%CI)RR 1.25 (1.15 - 1.37)Risk by genderMale:RR 1.25 (0.95 - 1.65)Female:RR 1.25 (1.14 – 1.38)Histological type by exposureAdenocarcinomaRR 1.28 (1.13 - 1.44)Non Adenocarcinoma




China (including Hong Kong and Taiwan) and those from the USA each contributed more than one-third of total cases.

RR 1.14 (1.14 - 1.79)Squamous cell carcinomaRR 1.38 (0.87 - 2.20)Non squamous cell carcinomaRR 1.38 (0.87 - 2.20)Duration of exposure /dose response relationshipNo dose response relationship of exposure was apparent.Positive and cumulative relationship with estimated cumulative exposure; however; data was not clearly presented.

Stayner et al 2007Meta-analysisAnalysis of 22 case control studies from several countries: USA, Canada, Europe(Germany, Sweden, Spain Italy, France, Portugal; Russia Greece) , Hong Kong, Russia, India, and Taiwan.

Exposure to environmental tobacco smoke exposure (ETS) in a workplace context.(Excluding ETS from having a smoking spouse)Years of workplace exposure was determined as the total number of years in which the subject reported working in an environment where others were smoking.

Meta-analysis of 22 studies from multiple locations worldwide of workplace environmental tobacco smoke exposure and lung cancer risk published in Medline and Embase databases. The search time frame covered up to January 2003.

4305 persons categorised as being never smokers exposed to second hand smoke at the workplace.Both genders included; however number of male and female not reported separately.No information on ages, but all cases were non-smokers who had exposed to environmental tobacco smoke at workplace.

All histological types of lung cancer; squamous cell carcinoma, adenocarcinoma, small cell carcinoma.

Potential confounding factors adjusted for: age, diet, race, exposure to ETS from a spouse, other occupational carcinogens.

Overall workplace exposure RR (95%CI)Workers exposed to ETS have an increased risk of lung cancer RR 1.24 (1.18 - 1.29) compared with those not exposed.The measure of exposure used to categorise at work place ETS varied from study to study. Total number of years of exposure weighted for the number of hours of exposure per day and for a subjective index of level of smokiness at the workplace. Actual values of these figures were not available.Dose–Response AnalysesRR 2.01 (1.33 - 2.60)(Analysis of 7 case control studies)“highly exposed” exposure used to categorise varied across studies as judged by the authors. Highly exposed reported in the included studies varied from >4 co-workers smoked, cumulative exposures measured as >100.6 level×hours per day ×years; > 89 level×hours per day ×years; >64 smokers ×years.Duration of workplace exposure RR (95%CI)




Workers exposed to ETS over a 45 year period had an elevated risk of lung cancerRR 1.63 (1.45 - 1.82)(Analysis of 7 case control studies)Results were not reported by gender.

Taylor et al 2007Meta-analysisAnalysis of 55 studies from several countries worldwide; US, Canada, Japan, China, India, Taiwan, Singapore, Hong Kong, Europe(Germany, Sweden, Netherlands, Greece, Prague)7 cohort, 25 population-based case-control and23 non-population-based case-control studies

Exposure to environmental tobacco smoke exposure (ETS) resulting from a spouse.Context of exposure not reported

Meta-analysis of papers published between 1981 and 2006. Medline and Embase databases were searched.

Never smoking women exposed to second hand smoke from spouses.Number of women included not reported. No age estimate provided.

Confirmation of diagnosis not clear.

Potential confounding factors adjusted varied across the included studies.

Overall risk resulting from ETS resulting from a spouseRR (95%CI)RR 1.27 (1.17 - 1.37).Overall risk resulting from ETS resulting from a spouse by geographical regionRR (95%CI)North America and EuropeRR 1.31 (1.24 – 1.52).AsiaRR 1.31 (1.16 – 1.48).Duration of exposure /dose response relationshipDose–response relationship data not clearly reported.




Lee 2011Systematic reviewIn total, eight epidemiological studies included. These include 2 prospective cohort studies, 3 hospital-based case control studies and 3 population cases control studies.One case-control study was conducted in Germany, all studies were conducted in the USA

Smoking mentholated cigarettesExposure measured by self reported brand name of cigarettes and duration of exposure varied as reported by the subjects (range from 15-20 years)

Meta-analysis. Database search included Medline, Google Scholar, Scopus, Scirus, Science Direct and Academic search complete. Publication up to the year 2008. Source of data on mentholation status reported in the studies were largely self-reported.

Lung cancer cases in mentholated cigarette smokers (current smokers, ever smokers, and former smokers) in both genders of African-Americans population.Age ranged from 30-84 years.Cases= 5806Male =3856Female=1950Controls=8939Male =3765Female=4628

Cases were generally histopathologically confirmed.

Adjusted for age, gender, race and smoking.(Smoking habits, such as daily cigarette consumption and duration of smoking).Not attempted to account for the possibility that switching from non-mentholated to mentholated cigarettes, occupation or diet.Although length of use of mentholated cigarettes were investigated, brands smoked years ago was largely unclear.

Overall risk resulting from actively smoking mentholated cigarettesRR (95%CI)In ever smokers, and current smokersEver users vs no useRR 0.93 (0.84 - 1.02)Current smokers onlyEver users vs no useRR 0.92 (0.84 - 1.02)Former smokers onlyEver users vs no useRR 0.99 (0.62 - 1.56)GenderRR (95%CI)Males: RR 1.01 (0.84 - 1.22)Females: RR 0.80 (0.67 - 0.95)Duration of useLong term use (>15+ years use of mentholated cigarettes) vs <15 years useRR (95%CI)RR 0.95 (0.80 - 1.13).GenderLong term use (>15+ years use of mentholated cigarettes) vs <15 years useRR (95%CI)Males: RR 1.13(0.86 - 1.47)Females: RR 0.78 (0.60 - 1.01)

Akal, et al. 2010)

Exposure to water pipe

Total Cases=983Control=1827

Systematic reviewDatabase search

Diagnosis varied from radiology

Adjusted for age, gender,

Overall risk resulting from water pipe tobacco smoking OR (95%CI)




Systematic reviewAnalysis of 5 case control studies and 1cohort study from India, Eastern Mediterranean (Tunisia) and China

tobacco smokeself reported by the subjects no standardised measures reported. Consumption calculated varied across the studies- the number of pipe years or pack years equivalent of cigarettes or in cumulative dose quartiles.

Male and female data not reported clearly but majority of them were males.

included Medline (1950 to 2009), EMBASE (1980 to 2009) and ISI the Web of Science (no search time frame reported)

and confirmed by histology, panel of pathologist,

other types of inhaled tobacco, cigarettes

2.12 (1.32 - 3.42).

25.5.20 Wood Dust Study Exposure/ Risk


forRisk (Measure of Association)Adjusted

Bhatti et al 2010Case control/Rural Washing-ton State USA

Data collected on occupational exposure to wood dust and woodwork hobby.Exposure estimation based on algorithm informed by typical concentrations of wood dust specific to the occupational and recreation-al processes.Individual cumulative exposure

Controls: identified from same geographical area through random-digit dialling, using a modified Waksberg method. Frequency matched to cases by 5-year age group.Cases: identified from a rapid reporting mechanism of the Fred Hutchinson Cancer Research Centre Surveillance System. Included men

Males440 cases (mean age 61.8 years)845 controls (mean age 61.1 years).Over 95% of subjects Caucasian. 60% of cases current smokers compared to

Clinical information regarding the types of lung cancer was determined from medical records by trained registry personnel.Most common histological groups adenocarcinoma, squamous

Age and smoking status (never, former, current) included as covariates in all models. Race, education and pack-years of smoking

Males - OR (95% CI)No significant association.For all categories of wood dust exposed workers.0.9 (0.6 - 1.3)Based on the highest quartile exposure measured (>344.7 to 16469.4 months-mg/m3), compared with the lowest quartile of exposure.Smoking: Not reported.




Risk (Measure of Association)Adjusted

calculated by summing the product of duration (months) working in or near the process, the proportion of a 40h work week typically spent in or near the process, the average exposure intensity (mg/m3) and the modifying factors.

diagnosed with lung cancer between 1 May 1993 and 31 July 1996, aged 18-74 years and resided in an 11-county area of western WashingtonData collected from cases and controls by experienced interviewersSubject or next of kin interviewed

19% of control groups.

cell and small cell carcinoma.

also examined as potential confounding factors.

Laakkonen et al 2006Retrospective Cohort Study /Finland.

Occupations established from population census in 1970 and converted into exposures to eight dust exposure types, including wood dust exposure.Cumulative Wood dust exposure (& other dust exposure types) calculated as a product of prevalence, level of exposure and estimated duration of exposure. Three exposure measures calculated: low (<3 mg/m3 -year); medium (3-50 mg/m3 -year)

Incident cases of cancer established using data in Finish Cancer Registry. Good coverage; accuracy high.

Cohort of all economic-ally active Finns born between 1906 and 1945 who participated in the national population census on 31 December 1970 (667 121 men; 513 110 women). Followed up for 30 million person-years during 1971-95.

Various types of cancers: nasal, laryngeal, lung and mesothelioma studied. Types of lung cancer not stated.

RRs adjusted for age, social class and period.Risk measures not adjusted for smoking

Low exposure:

Med. exposure

High exposure

Males SIR 1.11 (1.04-1.18)

1.02 (0.97-1.06)

0.85 (0.70-1.02)

Females

0.92 (0.57-1.41)

1.03 (0.76-1.37)

0.95 (0.49-1.66)

No significant association for all measures.





high (>50 mg/m3 – year).mainly softwood dust (pine, spruce).

Innos et al 2000Retrospective Cohort Study/ Estonia

Data on job titles corresponding to work tasks and workplaces used as a basis for wood dust exposure estimation. Task completed in consultation with an industrial hygienist. Three different levels of exposure defined based on three different occupational categories.Measurements of exposure levels for the different categories not reported.

Cohort followed up for vital status & cause of death from date of fist employment until December 31 1995. Lung cancer incidence (SIR) of cohort compared to that in the general population of Estonia. Wood dust exposure data extracted from employment records. Lung Cancer Register & questionnaire (1988) used to attain data on smoking.

Cohort of 6 786 male (n=3723) and female (n=3063) furniture workers employed (1946 – 1988) at 2 furniture factories in Tallinn, Estonia. Subjects employed at either factory for at least 6 months between Jan. 1 1946 and Dec. 31 1988 and lived in Estonia on 1 January 1968 when follow up for lung cancer incidence commenced.51.9% non-smokers in cohort. 48.1% current or previous

Type of lung cancer studied not stated.

Risk measures not adjusted for smoking.

Overall Males Females

For the cohort (all job categories)

SIR 1.07(0.87-1.28

SIR 1.02(0.82-1.26)

SIR 1.43(0.83-2.29)

For medium exposure jobs.

— SIR 0.79(0.36-1.50)

SIR 1.12(0.36-2.61)

For high exposure jobs.

— SIR 1.01 (0.79-1.27)

SIR 1.62 (0.81-2.89)

No significant association overall or in males.Is for females but restricted to short-term workers.SmokingLung cancer risks not reported by smoking status.





smokers.

Jayaprakash et al 2008Hospital based case-control study/USA (Buffalo City New York).

Self reported wood dust exposure data used to determine exposure levels. Questionnaire asked subjects to grade wood dust exposure into never, occasional and regular. No clear definition of these terms in questionnaire.Lung cancer risk measures reported for different exposure measures based on intensity and duration of exposure.

Cases and controls from database developed by the Cancer Institute at a hospital in Buffalo New York. Diagnosis of lung cancer confirmed by medical examination. Controls (no lung cancer confirmed by medical examination) randomly selected and frequency matched to cases at a ratio of 1:1 based on 10-year age groups and smoking history (never smoked/ever smoked).Questionnaire used to gather smoking and wood dust exposure data.

All males. Mostly Caucasian. 809 cases (mean age 62.3 years). 1 522 controls (mean aged 61.4 years).4.6% never smokers in cases compared to 10.8% never smokers in controls.

Squamous cell; carcinoma and adenocarcinoma of the lung.

Risk measures adjusted for age, education, pack years of smoking, BMI, family income and year of enrollment in study.

Male - Significant association between regular exposure to wood dust and lung cancer risk (all types).

Moderate exposure:(occasionally exposed or regularly exposed for less than 20 yrs):

High exposure:(regularly exposed for 20 yrs

or more):

OR 1.12 (0.89-1.42) OR 2.15 (1.31-3.56)

Szadkowska-Stanczyk & Szymczak et al 2001Case control nested within a cohort of pulp and paper workers/Poland

Occupational wood dust exposure measured using employment files for each participant and expert opinion. Measured using personal records of workers and expert opinion. Following exposure groups adopted: Non-exposed; exposed to low concentrations (0.1-1 mg/m3); exposed to

Lung cancer risk calculated using cause of mortality data.Data on exposure to wood dust and other risk factors for lung cancer gathered via questionnaire. Asked also about lifestyle, health and family cancer history.Lung cancer mortality risk of wood dust exposed in sample compared with those in

79 lung cancer cases and 237 healthy controls. Male and female. Cases employed in pulp and paper factory for at least a year between 1968 and 1990 who were deceased and

Not stated. — Overall

Low: Moderate and high:

OR = 2.077 (0.88-4.92). OR=2.08 (0.8-6.31)





moderate concentrations (1-5 mg/m3); exposed to high concentrations (>5 mg/m3). Cumulative dose index used to study dose-response.

sample who responded no in the questionnaire to the questions on wood dust exposure.Death certificates used to determine cause of death (ICD-9 followed). For about one quarter of reported cancer deaths the primary site of diagnosis was checked through cancer registries, physicians or hospitals.

had lung cancer classified as the cause of death. Must have deceased between entry and 31 December 1995. Controls selected from the cohort of factory workers and matched to each case by sex, year or birth and year of hire.

Stellman et al 1998Retrospective cohort study/USA

Exposure measures derived for two partially overlapping groups: woodworkers and wood dust-exposed men. The former group those who reported yes to working in a wood related occupation Latter those who reported regular exposure to wood dust.

Lung cancer risk calculated using cause of mortality data.Data gathered via questionnaire. Asked also about lifestyle, health and family cancer history.Lung cancer mortality risk of wood dust exposed in sample compared with those in sample who responded no in the questionnaire to the questions on wood dust exposure.Death certificates used to determine cause of

Sample included 45 399 wood dust exposed males. Subjects selected from those enrolled in 1982 in the USA Cancer Prevention Study II. Followed up for a relatively short period of 6 years.

Not stated. Adjusted for age and smoking status (never, past, current, missing).

Males

Group who reported wood dust exposure:

Group who reported working in a wood-related occupation:

RR = 1.17 (1.04-1.31). RR=1.14 (0.94-1.37).

Significant trend (P=0.02) of increasing risk of lung cancer with increasing duration of wood dust exposure.





death (ICD-9 followed). For about one quarter of reported cancer deaths the primary site of diagnosis was checked through cancer registries, physicians or hospitals.


RFLSR 14
