Meal. Oncol. & TumorPharmacother. Vol. 2, No. 1, pp. 7-10, 1985 0736-0118~5 $3.00 + .00 Printed in Great Britain Pergamon Press Ltd.

R E V I E W

E N V I R O N M E N T A L F A C T O R S A N D L E U K A E M I A

LARS BRANDT Department of Oncology, University Hospital, S-221 85 Lund, Sweden

(Received for publication 19 December 1983)

Investigations on the association between environmental hazards and the development of various types of leukaemia are reviewed. Regarding acute non- lymphocyt ic leukaemia (ANLL) exposure to ionizing radiation is a well-documented risk factor. According to several recent studies exposure to strong electromagnetic fields may be suspected to be of etiologic importance for ANLL. There is evidence that occupational handling of benzene is a risk factor and other organic solvents may also be leukaemogenic. Occupational exposure to petrol products has been proposed to be a risk factor although the hazardous substances have not yet been defined. Results of cytogenetic studies in ANLL suggest that exposure to certain environ- mental agents may be associated with relatively specific clonal chromosome aberrations. These results are of interest because it has been proposed that chromosomal rearrangements may play a role in the activation of cellular oncogens.

Exposure in utero to ionizing radiation has been proposed to be a risk factor for acute lymphocyt ic leukaemia (ALL) in children. Unlike ANLL there seems at present to be little evidence that ALL is related to exposure to some chemicalS.

Chronic m.yeloid leukaemia (CML) may follow exposure to high doses of ionizing radiat ion whereas such exposure seems to be of insignificant importance for the development of chronic lymphocyt ic leukaemia (CLL). According to some studies an abnormally high incidence of CLL may be found among farmers in the USA. These results have not been confirmed in Scandinavian studies. There seems to be little evidence that CML or CLL are related to occupational handling of some chemicals.

Although several epidemiologic studies suggest a relation between exposure to environmental agents and the development of haematological malignancies it is difficult to estimate the quanti tat ive role of environ- mental hazards for this group of disorders. A closer collaboration between epidemiology, occupational medicine, haematology, oncology and cytogenetics should probably improve our knowledge about the relation between environmental factors and haematological malignancy.

INTRODUCTION

Results of epidemiological studies indicate that expo- sure to some environmental hazards is associated with an increased risk of leukaemia and that other external agents may be suspected. In many studies the diagnosis ' leukaemia ' has been used without further definit ion o f the type o f malignancy. It is obvious that the informa- tion obtained from such studies is of l imited value because it cannot be postulated that a malignant trans- formation in myeloid tissue and lymphoproliferat ive malignancies are due to common agents. The present review will therefore concentrate on studies where the

different types of leukaemia have been kept separated.

ACUTE NON-LYMPHOCYTIC LEUKAEMIA (ANLL)

It is well known that exposure to high doses o f ionizing radiation will increase the risk o f ANLL. An

increasing incidence o f ANLL was noted among sur- vivors after the atomic bombs in Hiroshima and Nagasaki beginning about 3---4 years after the exposure. It was observed that the incidence was related to the dose of irradiation and that the latency time was shorter in survivors exposed to large doses compared to those exposed to smaller doses. 1 Studies o f the exposed populations in Hiroshima and Nagasaki have allowed fairly detailed conclusions regarding dose- response and t ime- response relations and the results were recently summarized in a comprehensive rev iew) An increased risk of ANLL has also been found in patients with ankylosing spondylit is t reated wi th X- rays ) Although there is an obvious relation between exposure to high

doses of ionizing radiation and ANLL there is still considerable controversy about the relation between low-dose irradiation and A N L L In a case-control s tudy Gibson et al. 4 found that in males exposed to 41 or more X-ray Films the relative risk for ANLL was 2.3.

8 Lars B r a n d t

Examination of the trunk with 41 or more films was associated with a relative risk of 5.1. Interestingly a comparable exposure of females did not cause a significantly increased risk of ANLL. The risk of diagnostic irradiation has been questioned by Linos et al. s They found that irradiation of the bone marrow with 300 tad (3 Gy) was not associated with any increased risk of leukaemia. This study has, however, also been criticized and the possible risk of diagnostic irradiation for the development of ANLL must await further evaluation.

Recently the possible importance of exposure to strong electric and magnetic fields for the development of acute leukaemia has been discussed. A relation between such exposure and cancer in children and adults has been proposed s'7 and four studies have been published which point to an increased risk of A N L L in electrical workers. 8-11 There seems to be little biological evidence that exposure to non-ionizing electromagnetic radiation is mutagenic or carcinogenic and therefore other exo- genous factors common to these workers may be operat- ing. So far, however, no such factor has been defined.

Among chemical hazards promoting the development of A N L L benzene has been most thoroughly investigated. Delore and Borgomano described the first case of acute leukaemia associated with heavy benzene exposure in 1928) a Aksoy et al. ~a have reported a significantly greater incidence of acute leukaemia in Turkish shoe workers exposed to benzene and Vigliani found an association between heavy occupational exposure to benzene and acute leukaemia in I ta ly) 4 Although the Turkish and Italian workers were exposed to high concentrations of benzene, mostly 200-500 ppm, there is evidence that considerably lower concentrations may be hazardous. Thus Infante et al. is found a signifi- cant association between exposure to average concen- trations of 10-50 ppm and the development of acute leukaemia. The median time from the start of exposure until the development of acute leukaemia seems to be about 10 years although great variations have been reported) a,14

Recently it has been proposed that occupational exposure to other organic solvents than benzene may increase the risk of A N L L . In a Swedish case-control study Flodin e t al. 16 found that occupations implying exposure to organic solvents were about twice as com- mon in a group of adults with A N L L compared to a control group. Because in 1972 benzene was declared poison in Sweden exposure to this solvent should be rare. However, it is well known that other solvents, e.g. toluene and xylene, may contain small amounts of benzene as a contaminant and it is therefore possible that some exposure to benzene may occur in occupa- tions where toluene and xylene were used as solvents.

Occupational exposure to petrol products or their

combustion residues may also be a risk factor for ANLL. In a case-control study of men with ANLL aged 20 -64 years 36% of the patients had occupations indicating such exposure, e.g. service-men at petrol filling stations, truck drivers and motor-saw workers. In various control materials the corresponding figure was 10-11%. 17 Petrol may contain about 5% of benzene and this admixture might therefore be hazardous. However, it is also known that the combustion residues of petrol products contain mutagenic/carcinogenic agents, e.g. benzo(a)pyrene and other polyaromatic hydrocarbons. In a group of road tanker drivers who delivered petrol Fredga e t al. ~8 noted an increased frequency of chromosome aberrations in blood lymphocytes. However, a similarly increased frequency of aberrations was observed in a control group of road tanker drivers distributing milk. These observa- tions may indicate that other risk factors than benzene may be genotoxic to blood cells in persons exposed to petrol products.

According to results from a Finnish study some contagious agent causing acute or chronic myeloid leukaemia might be suspected. The leukaemia patients reported a significantly larger extent of previous contact with hospitals than control patients with acute cardio- vascular illnesses. In most leukaemia patients contact was through nurses working in haematological wards) 9 However, these results were not confirmed in a Swedish study from two hospitals. Hospital contacts were com- pared among 33 patients with acute leukaemia and a group of 32 age-matched patients with lung cancer or benign disorders. The number of hospital contacts in these groups were similar, 33 and 30%, respectively. 2~

About 50% of patients with ANLL have clonal chromosome aberrations in the bone marrow cells at diagnosis, tn a retrospective Swedish study of 56 adults such abnormalities were significantly more common in patients previously occupationally exposed to potentially mutagenic/carcinogenic agents than in those with no history of occupational exposure to such agents. 2~ A more recent evaluation of 162 patients from Sweden and Italy 22 and 74 patients from Chicago, USA, z~ confirmed the initial observation and also indicated that certain specific karyotypic aberrations were more frequent in patients for whom a previous occupational exposure to chemical solvents, insecticides and/or petroleum products was evident. In a prospective study recently analysed by the Fourth International Workshop on Chromosomes in Leukemia loss of chromosomes No. 5 and/or No. 7 ( -5 / -7 ) was found in 10 out of 39 patients with a history of occupational exposure to chemicals, mainly organic solvents. Among 260 other patients without such exposure none had - 5 / - 7 in their bone marrow cells. =4 The high incidence of clonal chromosome aberrations associated with a history of exposure to potential mutagenic/carcinogenic agents

may be less evident in young ANLL patients than in older ones. 2s In an analysis of 361 adults with ANLL no different incidence of cytogenetic abnormalities was observed in exposed and non-exposed patients before the age of 30. 24 This finding may indicate that a certain latency period from the beginning of occupational exposure is needed before the disease becomes apparent.

The relation between occupational exposure to mutagenic/carcinogenic chemicals and certain specific chromosome aberrations in ANLL suggests that a com- bination of epidemiologic and cytogenetic investigations may be worth while to clarify pathogenetic mechanisms in ANLL. The recent finding that chromosomal trans- locations may be related to cellular oncogens 26 indicates that chromosomal aberrations caused by exposure to environmental mutagenic]carcinogenic agents may con- tribute to a malignant transformation.

ACUTE LYMPHOCYTIC LEUKAEMIA (ALL)

Already in 1958 it was suggested that exposure in

utero to diagnostic ionizing radiation may be a risk factor for the development of. malignant tumours including acute leukaemia in children 27 and these findings have later been confirmed. 2s However, only a minute fraction of ALL in childreh seems to be related to such exposure. 2s Unlike ANLL there seems to be little evidence at present that the development of ALL is related to exposure to some chemicals.

CHRONIC MYELOID LEUKAEMIA (CML)

It is well established that exposure to high-dose ionizing radiation constitutes a risk factor for CML. Among survivors after the atomic bomb explosions in Japan there was an increasing incidence of CML 4 - 5 years following the exposure. 1'2 Evidence of high-dose irradiation as a risk factor for CML also comes from studies of patients with ankylosing spondylitis treated with X-rays. 3 As in ANLL there is still considerable controversy about the role of low-dose irradiation for the development of CML. Thus Gibson et al. 4 found that in males an exposure of 11 or more X-ray films of the trunk was associated with a relative risk of 2.2. After 41 or more films the relative risk was 7.1. Linos et al. s

could not confirm any increased risk following irradiation with a bone marrow dose of 3 Gy. As in ANLL there may be sex differences in the susceptibility to ionizing radiation because Gibson et al. 4 found no association between diagnostic irradiation and CML in females.

CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)

Exposure to ionizing radiation is probably of insignifi- cant importance for the development of CLL 3'4 and no

Environmental factors and leukaemia 9

firm evidence of an association between exposure to chemical agents and CLL has been presented. Milham 29 reported that CLL was unduly common as a cause of death among farmers. Because the lymphoproliferative malignancy bovine leukosis is of infectious origin it has been suggested that the disease may be transmitted to man. 3~ However, in an area where bovine leukosis is especially prevalent the incidence of leukaemia has not been found to be increasedJ 1 In a case-control study of occupations among 67 consecutive men with CLL in southern Sweden 17 had worked with farming (25%). The corresponding frequency of such occupations in a sex- and age-matched control group without malig- nant disorders was 27 out of 142 (19%). The differ- ence is not significant and it therefore seems that the relation between farming and CLL is not consistent in different areas (L. Brandt and P. G. Nilsson, un- published observations).

Although there are several epidemiologic studies suggesting a relation between exposure to environ- mental agents and the development of haematological malignancies it is still difficult to estimate the quanti- tative role of environmental hazards for this group of disorders. According to available epidemiologic and cytogenetic data the relation between environmental mutagenic/carcinogenic factors and haematological malig- nancy seems to be especially strong for ANLL, suggest- ing that myeloid tissue is especially susceptible to geno- toxic agents. There is, however, increasing evidence that malignant lymphoproliferative disorders may also follow exposure to environmental hazards. Thus occu- pational exposure to organic solvents may be of some importance for the development of non-Hodgkin lym- phoma 32-a4 and Hodgkin's disease, a4'as The substances that may be responsible for this oncogenic effect are still poorly defined and their mechanism of action largely unknown. A closer collaboration between occu- pational medicine, haematology, ontology, cytogenetics and epidemiology should probably improve our know- ledge about the relation between environmental factors and haematologic malignancy.

REFERENCES

1. Bizzozero O J, Johnson K G, Ciocco A: Radiation- related leukemia in I-Iiroshima and Nagasaki 1946- 1964. New Engl J Med 274, 1095 (1966).

2. Hiroshima and Nagasaki: the physical, medical and social effects o f the atomic bombings, pp. 255-273. London, Hutchinson.

3. Doll R: Radiation hazards: 25 years of coUaborative research. Br J Radiol 54, 179 (1981).

4. Gibson R, Graham S, Lilienfeld A, Schuman L, Dowd J E, Levin M L: Irradiation in the epidemiology of leukemia among adults. J Natn Cancer Inst 48, 301 (1972).

10 Lars Brandt

5. Linos A, Gray J E, Orris A L, Kyle R A, O'Fallon W M, Kurland L T: Low-dose radiation and leu- kemia. N e w E n g l J M e d 302, 1 I01 (1980).

6. Wertheimer N, Leeper E: Electrical wiring configura- tions and childhood cancer. A m J Epidemiol 109, 273 (1979).

7. Wertheimer N, Leeper E: Adult cancer related to electrical wires near the home. ln t J Epidemiol 11, 345 (1982).

8. Milham S: Mortality from leukemia in workers exposed to electrical and magnetic fields. N e w E n g l J M e d 307,249 (1982).

9. Wright W E, Peters J M, Mack T M: Leukemia in workers exposed to electrical and magnetic fields. Lancet ii, 1160 (1982).

10. McDowall M E: Leukaemia mortality in electrical workers in England and Wales. Lancet i, 246 (1983).

11. Coleman M, Bell J, Skeet R: Leukaemia incidence in electrical workers. Lancet i, 982 (1983).

12. Delore P, Borgomano C: Leuc6mie aigue au cours de l'intoxication benz6nique: sur l'origine toxique de certaines leuc6mies aigues et leurs relations avec les an6mies graves. J. Med Lyon 9,227 (1928).

13. Aksoy M, Erdem S, Dincol G: Types of leukemia in chronic benzene poisoning: a study in thirty- four patients. A eta haemat 55, 65 (1976).

14. Vigliani E C: Leukemia associated witla benzene eJ, posure. Ann N Y A c a d Sci 271,143 (1976).

15. Infante P F, Rinsky R A, Wagoner J K, Young R J: Leukemia in benzene workers. Lancet ii, 76 (1977).

16. Flodin U, Andersson L, Anjou C-G, Palm U-B, Vikrot O, Axelsson O: A case-referent study on acute myeloid leukemia, background radiation and exposure to solvents and other agents. Scand J WorkEnviron Hlth 7,169 (1981).

17. Brandt L, Mitelman F, Nilsson P G: Occupational exposure to petroleum products in men with acute non-lymphocytic leukemia. Br Med J 1,553 (1978).

18. Fredga K, Reitalu J, Berlin M: Chromosome studies in workers exposed to benzene, in Berg K (ed): Genetic Damage in Man Caused by Environmental Agents, pp. 187-203. New York, Academic Press (1979).

19. Timonen T, Uvonen M: Contact with hospital, drugs and chemicals as aetiological factors in leu- kaemia. Lancet i, 350 (1978).

20. Brandt L, Nilsson P G, Nyberg G, Reizenstein P: Hospital contacts apparently no etiologic factors in leukaemia. Abstract in Swedish. XIV Nordic Haematologic Meeting, Oslo, 27-28 May 1983.

21. Mitelman F, Brandt L, Nilsson P G: Relations among occupational exposure to potential muta-

genic/carcinogenic agents, clinical findings and bone marrow chromosomes in acute non- lymphocytic leukemia. Blood 52, 1229 (1978).

22. Mitelman F, Nilsson P G, Brandt L, Alimena G, Gastaldi R, DaUapiccola B: Chromosome pattern, occupation, and clinical features in patients with acute non-lymphocytic leukemia. Cancer Genet Cytogenet 4, 197 (1981).

23. Golomb H M, Alimena G, Rowley J D, Vardiman J, Testa J R, Sovik C: Correlation of occupation and karyotype in adults with acute non-lymphocytic leukemia. Blood 60,404 (1982).

24. Fourth International Workshop on Chromosomes in Leukemia: Karyotype and occupational exposure to potential mutagenic/carcinogenic agents in acute nonlymphocytic leukemia. Cancer Genet Cytogenet (in press).

25. Brandt L, Mitelman F, Nilsson P G: Chromosome pattern and survival in acute nonqymphocytic leu- kaemia in relation to age and occupational exposure to potential mutagenic/carcinogenic agents. Scand JHaemato l 30,227 (1983).

26. Rowley J D: Human oncogenelocations and chromo- some aberrations. Nature 301,290 (1983).

27. Stewart A, Webb J, Hewitt D: A survey of childhood malignancies. Br Med J 1, 1495 (1958).

28. Bross I D J, Natarajan N: Leukemia from low-level radiation. New Engl J Med 287, 107 (1972).

29. Milham S: Leukemia and multiple myeloma in farmers. A m J Epidemiol 94,307 (1971).

30. Donham K J, Berg J W, Sawin R S: Epidemiologic relationships of the bovine population and human leukemia in Iowa. A m J Epidemiol 112, 80 (1980).

31. Kvarnfors E, Henricson B, Hugosson G: A statistical study on farm and village level on the possible relations between human leukemia and bovine leukosis. Acta vet scand 16,163 (1975).

32. Vianna N J, Polan A: Lymphomas and occupational benzene exposure. Lancet i, 1394 (1979).

33. Olsson H, Brandt L: Supradiaphragmatic presenta- tion of non-Hodgkin's lymphoma in men occupa- tionally exposed to organic solvents. A cta med scand 210,415(1981).

34. Hardell L, Eriksson M, Lenner P, Lundgren E: Malignant lymphomas and exposure to chemical agents, especially to organic solvents, chlorophenols and phenoxy acids: a case control study. Br J Cancer 43,169 (1981).

35. Olsson H, Brandt L: Occupational exposure to organic solvents and Hodgkin's disease in men: a case-referent study. Stand I Work Environ Hlth 6,302 (1980).