Formaldehyde and Nasopharyngeal Cancer by Gary Marsh

8/2/2019 Formaldehyde and Nasopharyngeal Cancer by Gary Marsh

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Graduate School of Public Health

Department of BiostatisticsCenter for Occupational Biostatistics & Epidemiology

Formaldehyde and Nasopharyngeal

Cancer: What Have We Learned fromthe Epidemiology Studies?

Gary M. Marsh, Ph.D., F.A.C.E.

Department of BiostatisticsGraduate School of Public Health

University of Pittsburgh

Formaldehyde International Science ConferenceMadrid, Spain (April 2012)


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Department of Biostatistics

Center for Occupational Biostatistics & Epidemiology

NPC is a Very Rare Cancer andDifficult to Study Epidemiologically

Site

Males Females

< 65 yrs 65+ yrs < 65 yrs 65+ yrs

NPC 1.0(0.18%)

0.4(0.10%)

All Leukemia 7.4 (3.4%) 76.2 (2.7%) 5.1 (2.2%) 41.6 (2.5%)

Lung 21.6 (9.9%) 446.2 (16.1%) 17.4 (7.6%) 293.8 (17.6)

All Cancer 219.1 2,776.2 229.6 1,669.7

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Source: U.S. SEER incidence rates per 100,000 (2004-2008)


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Center for Occupational Biostatistics & Epidemiology

FA-NPC Epidemiology:Investigations and Evaluations

Epidemiology Studies

Professionals who use FA

Population-based, case-control studies

Cohort studies of industrial workers

Reviews and Meta-Analyses

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Center for Occupational Biostatistics & Epidemiology4

Industrial Workers Have Much HigherAverage (TWA) HCHO Exposures

PPM

Job TWA Peak

Foundry 2.8 10

Plywood Manufacture 2.2 10

Resins Operation 2.0 10

Garment Manufacture 1.9 8

Monomer Production 0.7 3

Pathologists 0.4 4

Embalmers 0.2 6

Source: IARC, 1995


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Experimental studies show HCHO causes nasalsquamous cell carcinoma in rats at high (6 ppm)prolonged exposures (e.g., Swenberg et al., 1982; Kernset al., 1983)

Early epidemiology studies

Mostly PMR, population-based case-control, small cohort studies

Included professionals who use FA (pathologists, anatomists,embalmers)

Many w/o direct measures of FA FA exposures relatively low and infrequent compared with

industrial workers

Many did not report results for NPC

1980s - The Beginning of Research


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U.S. National Cancer Institute (NCI)

(Blair et al., 1986; Hauptmann et al., 2003; 2004;

Beane Freeman et al., 2009; in review)

British Medical Research Council (MRC)(Acheson et al., 1984; Gardner et al., 1993;

Coggon et al., 2003)

U.S. Natl. Institute for Occupational Safety & Health(NIOSH)

(Stayner et al, 1988; Pinkerton et al., 2003)

1980s-date: 3 Largest CohortStudies of Industrial Workers


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1980, 1994 & 2004 follow-ups of cohort of 25,619 workers in 10 U.S.industrial plants that made or used HCHO

(~ 1 million pyrs, 42 yr. avg. obs. time)

Only cohort study to quantitatively estimate past HCHO exposures

Study Conclusions for NPC

(Blair et al., 1986)

Elevated risks for NPC (4/7 NPCs in Plant 1), not exposure-related,

(Hauptmann et al, 2004)

A possible causal association between HCHO and NPC andpossibly other upper respiratory sites (6/10 NPCs in Plant 1)

(Beane Freeman et al., 20??)Remains Unpublished)????

U.S. NCI Cohort Study


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2000 follow-up of cohort of 14,014 workers from6 British chemical plants (Coggan et al., 2003)

Highest estimated worker exposures (28% of subjectshad TWA FA >2ppm vs. 4% in NCI study)

Study Conclusions: . . . a small effect on sino-nasal or NPC cannot be ruledout.

(1 NPC deathamong worker classified as lowFAexposure vs. 2.0 deaths expected)

British Cohort Study


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1998 follow-up of cohort of 11,039 garmentworkers from 3 U.S. plants (Pinkerton, et al.,2003)

Study Conclusions:

No nasal cancers or NPCs observed

U.S. NIOSH Cohort Study


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1998 and 2003 follow-ups of expanded cohort of7,328 plastics producing workers

Nested case-control study of 22 pharyngeal cancersincluding 7 NPCs with info on external exposures

Includes 6 of 10 NPCs in NCIs 10 plant study

Study Conclusions (Marsh et al, 2007) Corroborated Plant 1 NPC excess in NCI study

Little evidence of HCHO exposure-response Possible role of risk factors external to study plant, in

particular, silversmithing, brass plating and metal work

UPitt Independent Study of NCI Plant 1


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Recent Reviews / Meta-Analyses

Collins et al, JOEM-1997 (47 studies)

We conclude that the available studies do not support a

causal relation with FA and NPC

Duhayon, et al, Int Arch Env Hlth -2008 (25 studies)Human studies fail to raise a convincing conclusion

concerning the carcinogeneityof FA

Bosetti et al, Annals of Oncology -2008 (30 studies)

This review shows no appreciable excess risk for cancers of theoralcavity and pharynx The slight excess risk of NPC found inindustry workers based on 9 deaths is due to a cluster of 6 deaths in asingleplant

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Recent Reviews / Meta-Analyses

Bachand et al., Critical Rev Toxicol -2010 (18 studies)

. . . Our meta-analyses provide little support for a causalrelationship between FA exposure and NP

IARC (2010) Monograph 100F

Formaldehyde causes cancer of the nasopharynx

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Recent IARC Evaluations

June 2004 (Monograph 88)- IARC upgradedformaldehyde from: Group 2a (probably carcinogenic tohumans) to Group 1 (known human carcinogen)

Based on new epidemiology findings available since lastreview in 1994

NPC judged sufficient evidencebased largely on findings inNCI U.S. cohort study (moved from limited)

Oct 2009 (Monograph 100F) Few new studies, additional re-analyses of NCI data and

meta-analyses (included UPitt 2003 Plant 1 update)

Formaldehyde causes cancer of the nasopharynx


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3 plants, USNIOSH Cohort

N= 11,039

10 plants, US

NCI Cohort

N= 25,616

6 plants, UKMRC Cohort

N=14,014

Blair et al.(1986)

Stayner et al.(1985, 1988)

Acheson et al.(1984)

Blair et al. (1990)

Robins et al. (1988)

Sterling, Weinkam(1988, 1989, 1994)

Stewart (1990)

Marsh et al. (1992a,b)

Collins et al.(1988)

Marsh et al.(1996, 2002)

Marsh et al.(1994)

Gardner et al.(1993)

IARCEvaluation

1994

Marsh et al.(1996, 2002)

Hauptmann et al.(2003, 2004)

Marsh and Youk(2004, 2005),Marsh et al. (2007)

Marsh et al.(2007)

IARC

Evaluation1994

IARCEvaluation

2004

Stayner et al.(1985, 1988)

Coggan et al.(2003)

Pinkerton et al.(2004)

Acheson et al.(1984)

Beane Freeman

et al. (2009, in review)

Marsh et al.

(2004, 2005, 2007)Marsh et al. (2010)

Gardner et al.(1993)

Main study and updated studies

Substudies on Wallingford Plant

Reanalyses of data

3 Largest FA Studies

Adapted from: Duhayon et al.

2008

IARCEvaluation

2009

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Assessing Causality:

Main Issues

The results of NCI cohort study weigh heavily on allevaluations of the potential carcinogenicity of

formaldehyde (e.g., IARC 2004, 2009; EPA IRIS;NTP 12th RoC; NAS)

Several recent (2004+) reports challenged the validity ofNCIs recent findings for NPC on grounds of inadequate

or questionable methods of data analysis


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Problems with NCI NPC Data

1. NCI cohort findings for NPC driven

entirelyby anomalous findings forPlant 1 (6/10 deaths)


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No Excess NPC among FA-ExposedWorkers with Plant 1 Excluded

Study Obs Exp SMR

British 1 2.00 --

NIOSH 0 0.96 --

NCI Plants 2-10 2 3.15 --

Combined 3 6.11 0.50 (.1, 1.4)

NCI Plant 1 6 0.66 9.10 (3.3, 19.8)

Source: Tarone and McLaughlin, Am J Epid 2005

FA-Exposed workers, U.S. comparison


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NPC - NCIs Highest PeakAssociation Driven by Plant 1

0.0

0.5

1.0

1.5

2.0

2.5

Unexposed >0 - 1.9 2.0 - 3.9 4.0+

Highest Peak HCHO Exposure (ppm)

Relative

Risk

All Plants

Plant 1

Plants 2-10

Basis of NCI

Finding forPlants 1-10

UPitt Findingfor Plant 1

UPitt Finding forPlants 2-10

zero deaths


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2. Independent UPitt study of Plant 1 found

little association with HCHO, but strongassociation with prior work in silversmithing and brass plating industry


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5/7 Plant 1 NPC Cases Had Very BriefEmployment and Low FA Exposures

NPC Case Number

FA Metric 1 2 3 4 5 6 7 Median

Duration ofExposure(yrs) 0.62 0.25 17.87 4.28 0.15 0.01 35.20 0.62

AverageExposure(ppm)

0.13 0.03 0.60 0.16 0.14 0.07 0.19 0.19

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Unlikely to be relevant to FA-NPC association


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UPitt Plant 1 Study: NPC Not Related toAverage Intensity of FA Exposure

0

2

4

6

8

10

12

14

16

Unexposed >0 - < .03 .03 - .159 .16+

Average Int. HCHO Exposure (ppm)

SMR

1945-1998

1945-2003

*

*

*p < .05

0 Deaths

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UPitt Plant 1 Nested Case-Control Study - NPCAssociated with Smoking and Prior Employment

But Not HCHO

Risk Factor (ever vs. never)OddsRatio 95%CI p-value

Smoking 3.04 .33- .022Long-term worker(1+ yr) 1.06 .14-6.8 .999HCHO exposure 1.51 .20- .407

Pre/post silversmithingemployment

14.41 1.30-757 .024

Other metal work 3.61 .50-22.7 .360


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Plant 1 NPC Cases: Prior Silver Smithing andMetal Work among 7 NPC Cases

Time Employed

NPC Cases

No. Cum % EOG

< 1 month 1 14.3 1

1 - 4.9 months 2 42.3 1, 2

5 12 months 1 57.1 (1, 2)

1 4.9 years 1 71.4 --

5 + years 2 100.0 (1, 2)

Total 7

1= EOG 1 (silver smithing, brass plating, etc.)

2= EOG 2 (other metal working)

(x, x) EOGs for single subject

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Excess Deaths in Plant 1 from Respiratory System andSinonasal Cancers (Not Found in NCI Study)

Cancer site

1945-2003

Obs SMR-L

Respiratory system 341 1.20*

Sinonasal 3 2.64

Nose (internal) & nasal cavities 0 --

Eustachian tube & middle ear 0 --Maxillary sinus 0 --

Other specified sinus 2 10.57*

Sinus site (unspec.) 1 4.14

Larynx 15 1.51

Bronchus, trachea, lung 322 1.18*

*p < .05

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FA does not penetrate sinuses (Heck et al, 1989)


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3. In 1994 update, NCI missed 995 (12%) deaths

disproportionately among unexposed, and hasnot provided corrected data and risk estimatesfor specific solid tumors, including NPC


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Cause of Death

Observed Deaths(Hauptmann et

al.,2003)

CorrectedDeaths (BeaneFreeman et al,

2009)

Change inObserved

DeathsPercentChange

All Causes

UnexposedExposedTotal

82776598486

100284799481

175820995

21%11%12%

All Cancers


18319162099

22821472375

45231276

25%12%13%

All Solid Cancers


16617551921

20819672175

42212254

25%12%13%

All Leukemia

UnexposedExposed **Total

46569

47276

077

--11%10%

Differential Under-Ascertainment of Deaths in NCI Study *

* from Marsh et al, Reg Tox Pharm, 2010

** lowest exposure baseline category for RRs


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0

0.5

1

1.5

2

2.5

3

Unexp >0-


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Uncorrected NCI Data for Solid Tumors (esp.NPC) Have Misinformed Risk Assessments

Several agencies have conducted reviews classifyingHCHO as known human carcinogen based in part on NCI1994 follow-up (Hauptmann et al., 2004)

Baan et al., 2009; Euler et al., 2009; National Academies Press,

2007; NIEHS, 2009; Schulte et al., 2006; SCOEL, 2008

Recent meta-analyses and reviews have useduncorrected NPC risk estimates from Hauptmann et al.,2004):

Bachand et al., 2010; Bosetti et al., 2008; Duhayon et al., 2008;Zhang et al., 2009)


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Future EpidemiologyResearch / Directions?

NCI should correct 1994 data on solid tumors includingNPC and publish their 2004 update

Update the NIOSH and British cohorts?

Update of the UPitt Plant 1 cohort and case-controlstudies?

Additional re-evaluations of data from the NCI 2004update (Marsh, Youk, Morfeld) sponsored byFormaCare

Studies of new or extant FA-exposed cohorts?


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Conclusions

The results of NCI cohort study weigh very heavily onall evaluations of the potential carcinogenicity offormaldehyde (e.g., IARC 2004; 2009, NTP 12th RoC;EPA IRIS)

Reanalyses of the NCI cohort data and UPittindependent study of NCIs Plant 1 cast considerabledoubt on the validity of the NCI findings for NPC

The cumulative epidemiological evidence for NPC todate, including the NCI cohort study and UPitt study ofPlant 1, does not support reclassifying formaldehyde asa known human carcinogen


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Collaborators and Sponsors

Ada Youk

Peter Morfeld

Formaldehyde Council Inc. (U.S.)

CEFIC Formacare (Europe)

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Department of Biostatistics 32

Questions?

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Formaldehyde and Nasopharyngeal Cancer by Gary Marsh