Leukemia Research Vol. 16, No. 1, pp. 67-70, 1992. 0145-2126/92 $5.00 + .00 Printed in Great Britain. Pergamon Press plc

E X P O S U R E T O O R G A N I C S O L V E N T S A N D R I S K O F

H A E M A T O L O G I C A L M A L I G N A N C I E S

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

Abstraet--Epidemiological studies indicating that exposure to organic solvents is a risk factor for haematological malignancies are reviewed. Exposure to benzene is a risk factor for ANLL. A preleukaemic phase with pancytopenia is common and may be associated with a normo- or hypercellular marrow with morphological characteristics suggesting MDS. There are indications that other organic solvents than benzene may be leukaemogenic. Certain chromosome aberrations are characteristic in leukaemic cells from solvent exposed ANLL patients. The average latency time from start of occupational exposure until diagnosis is about 10--11 years. There is epidemiological evidence that exposure to organic solvents may also increase the risk of lymphoproliferative malignancies, i.e. ALL, NHL, HD and myeloma.

Key words: Organic solvents, leukaemia, lymphoma, myeloma.

INTRODUCTION

MORE than 90 years ago it became evident that injury to the bone marrow may be caused by heavy exposure to the organic solvent benzene [1]. The anaemia, infections and bleedings initially reported were prob- ably due to toxic effects of the solvent but later on it was suspected that malignant transformation of blood-forming tissue could also follow exposure to benzene [2]. In more recent years an increasing amount of data has accumulated indicating that occupational exposure to organic solvents may be a risk factor for various types of haematological malignancies, i.e. acute leukaemia, lymphomas and myeloma.

ACUTE NON-LYMPHOCYTIC LEUKAEMIA (ANLL) OR MYELODYSPLASTIC

SYNDROME (MDS)

Exposure to benzene is a generally accepted risk factor for acute leukaemia (AL). Aksoy et al. [3] ob- served a more than two-fold increase in AL among Turkish shoe workers exposed to benzene. A similar association between heavy occupational exposure to benzene and AL was observed in Italy by Vigliani [4]. In the U.S.A. Rinsky et al. [5] assessed the mortality

Abbreviations: AL, acute leukaemia; A L L , acute lym- phocytic leukaemia; A N L L , acute non-lymphocytic leukaemia; HD, Hodgkin's disease; NHL, non-Hodgkin's lymphoma; MDS, myelodysplastic syndrome.

67

from AL in rubber industry workers and found a relative risk of 5.6 for those exposed to benzene for at least 1 day. Following exposure for 5 or more years a relative risk of 21 was calculated. In a large Chinese cohort study of benzene exposed workers Yin et al. [6] found a standardized mortality rate of 5.7 for leukaemia and about 80% of the cases were AL. For the Turkish and Italian workers exposure to high concentrations of benzene, 200-500 ppm, was re- ported [3, 4]. The Chinese workers were generally exposed to 16-1600 ppm [6]. However, lower levels of exposure to benzene may be hazardous. Infante et al. [7] found a significant association between ex- posure to average concentrations of 10-50 ppm and AL. Rinsky et al. [8] described a strong exposure- response relation and concluded that even exposure to 1 ppm of benzene for prolonged periods may be significant. The average latency period from start of exposure and until diagnosis of AL seems to be about 10-11 years [3, 4, 6].

Most of the acute leukaemias associated with benzene exposure are of myeloid or monocytic cell types [3, 4, 9]. In many patients a preleukaemic phase with anaemia, leukopenia and thrombocytopenia has been reported. Some of these patients have a hypo- cellular bone-marrow indicating aplastic anaemic [10]. Vigliani and Forni [11] observed that for ben- zene exposed patients with pancytopenia, leukaemia may become evident only a few weeks before death. Gougel et al. [12] reported that the pancytopenia in the preleukaemic phase was often associated with a

68 L. BRANDT

partial blastic infiltration in the bone marrow and with disturbances in the erythrocytic series. Similarly Aksoy and Erdem [10] found a normo- or hyper- cellular bone marrow in some pancytopenic patients prior to the development of AL. Such clinical and morphologic observations strongly suggest that a MDS may precede the development of overt AL in benzene exposed patients.

Although there is little doubt that exposure to benzene is a risk factor for AL the possible haemato- logical hazards of other organic solvents are less obvious. Girard and Revel [13] found some evidence that, in addition to benzene, exposure to toluene might be leukaemogenic. Inhalation of toluene has occasionally been associated with aplastic anaemia [14, 15] and AL [16]. In a Swedish case-control study of 125 patients with AL, Lindquist et al. [17] found a significant odds ratio of 4.9 for patients occupation- ally exposed to a variety of organic solvents. In Sweden benzene was declared poison in 1972 and the patients were diagnosed in 1980-1983. The average latency period from start of exposure until diagnosis of AL seems to be 10-11 years [3, 4, 6]. For a considerable proportion of the patients studied by Lindquist et al. heavy benzene exposure would there- fore be an unlikely etiologic factor and other solvents must be suspected. Checkoway et al. [18] found indications that benzene may not be the only solvent used in the rubber industry capable of causing haemo- poietic malignancies. A problem often encountered in epidemiological studies of the association between solvent exposure and haematological malignancies is that the exposed patients almost invariably have handled several solvents [17, 19-21]. It is therefore extremely difficult to incriminate any single agent as the cause of the malignancy studied. Moreover, it is well known that commonly used solvents like toluene and xylene may contain small amounts of benzene as an impurity. Thus, even if replaced by other pre- sumably less hazardous solvents, the risk of benzene exposure is not negligible. Regarding MDS there are also indications that exposure to chemicals other than benzene may be a risk factor. In an epidemiological study by Farrow et al. [22] MDS patients reported significantly more exposure to petrol and diesel fumes or liquids compared to controls.

In addition to epidemiological evidence, results of cytogenetic studies suggest a relationship between occupational exposure to solvents and ANLL. Thus clonal chromosome aberrations are more common in ANLL patients occupationally exposed to potentially mutagenic/carcinogenic chemicals than in patients without any history of occupational exposure to such agents. Moreover, a complete or partial loss of chromosomes 5 and 7 are characteristic findings in

leukaemic cells from patients with a history of occupational exposure to chemicals, mainly solvents [9, 23-25]. An interesting parallel is that the same aberrations have been observed in a majority of patients with ANLL secondary to treatment with alkylating cytostatic drugs [26, 27]. Alkylating agents may result from the metabolism of benzene and to a lesser extent from toluene and xylene [28, 29]. It is possible that such metabolites may cause cell damage and mutation-like events in bone marrow cells and that the pathogenesis of ANLL is similar following exposure to alkylating drugs and to aromatic solvents.

OTHER HAEMATOLOGICAL MALIGNANCIES

Most of the acute leukaemias associated with occupational exposure to solvents are various types of ANLL [3, 4, 17]. However, a considerable number of patients with ALL following such exposure have been reported. McMichael et al. [30] found a seven-fold increased risk of ALL in workers exposed to solvents. Lindquist et al. [17] reported 12 patients with ALL among 43 patients with acute leukaemia associated with such exposure. In a subgroup of 13 patients with acute leukaemia and a heavy solvent exposure, 5 were of ALL type.

Results of epidemiological studies of NHL also indicate that occupational exposure to solvents is a risk factor for malignant transformation of lymphoid cells [20, 31, 32]. In a case-control study including 167 men with NHL, Olsson and Brandt [21] found an odds ratio of 3.3 (95% CI 1.9-5.8) for patients with a daily occupational handling of solvents for at least one year. There was an especially strong association between such exposure and initial supradiaphrag- matic location of the lymphomas with an odds ratio of 6.5 (95% CI 3.2-13.3). For other lymphoma presen- tations the ratio was only 2.3 (95% CI 1.3-4.3). Since organic solvents are volatile, inhalation may cause a considerable exposure of the mucous membranes in the upper and lower respiratory tract. Lymphoid tissue regional to these areas is exposed to higher concentrations of the substances than such tissue in other parts of the body. It therefore seems reasonable to assume that the initial malignant transformation should be observed in lymphoid tissue above the diaphragm rather than in such tissue located elsewhere.

There is also some evidence that occupational exposure to organic solvents is a risk factor for HD [19, 20, 31, 33-35]. The age-specific incidence curve for HD has a characteristic bimodal shape with one peak between 25 and 35 years of age and a second

Solvents and haematological malignancies 69

increase beginning about the age of 35-40 and it has been proposed that this phenomenon may indicate differences in etiology between younger and older age groups [36]. In line with this assumption Vianna and Polan [19] found a significant association be- tween solvent exposure and H D only for patients older than 45 years. Similarly we found such exposure to be a significant risk factor only for HD patients over the age of 35 [20].

Excess mortality from myeloma has been reported for printing plant workers [37] and machinists hand- ling cutting oil and fluids [38] suggesting that ex- posure to solvents may be a risk factor also for myeloma. This assumption is supported by a signifi- cant excess of deaths from myeloma (standardized mortality rate 409) recorded in a cohort of 1165 men occupationally exposed to benzene [8].

In summary, exposure to benzene is a risk factor for the development of ANLL. The association between benzene exposure and MDS has not, to the reviewer's knowledge, been studied separately. However , reports on clinical and morphological characteristics in the preleukaemic phase of ANLL in benzene exposed patients suggest that a MDS may often precede the development of overt ANLL. There are indications that exposure to other organic solvents than benzene may also increase the risk of ANLL and MDS. The mutagenic/carcinogenic hazards of exposure to organic solvents are supported by epidemiological results indicating that such ex- posure may also increase the risk of lymphoprolifer- ative disorders, i.e. ALL, NHL, HD and myeloma.

R E F E R E N C E S

1. Santesson C. G. (1897) Ueber chronische Vergiftungen mit Steinkohlentheerbenzin. Vier Todesf~ille. Archiv far Hygiene, Manchen u. Leipzig 31, 3.

2. Delore P. & Borgomano C. (1928) Leucemie aigue au cours de l'intoxication benzenique: sur l'origine toxique de certaines leucemies aigues et leurs relations avec les anemies graves. J. Med. Lyon 9, 222.

3. Aksoy M., Erdem S. & Dincol G. (1976) Types of leukemia in chronic benzene poisoning: a study in 34 patients. Acta Haemat. 55, 65.

4. Vigliani E. C. (1976) Leukemia associated with ben- zene exposure. Ann. N Y Acad. Sci. 271, 143.

5. Rinsky R. A., Young R. J. & Smith A. B. (1981) Leukemia in benzene workers. Am. J. Ind. Med. 2, 217.

6. Yin S. N., Li G. L., Tain F. D., Fu Z. I., Jin C., Chen Y. J., Luo S. J., Ye P. Z., Zhang J. Z., Whang G. Z., Zhang X. C., Wu H. N. & Zhong Q. C. (1987) Leukaemia in benzene workers: a retrospective cohort study. Br. J. Ind. Med. 44, 124.

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

8. Rinsky R. A., Smith A. B., Hornung R., Fillon T. G., Young R. J., Okun A. H. & Landrigan P. J. (1987)

Benzene and leukemia. An epidemiologic risk assess- ment. New Engl. J. Med. 316, 1044.

9. Fourth International Workshop on Chromosomes in Leukemia (1984) Karyotype and occupational ex- posure to potential mutagenic/carcinogenic agents in acute non-lymphocytic leukemia. Cancer Genet. Cytogenet. 11, 326.

10. Aksoy M. & Erdem S. (1978) Follow up study on the mortality and the development of leukemia in 44 pancytopenic patients with chronic exposure to ben- zene. Blood 52, 285.

11. Vigliani E. C. & Forni A. (1976) Benzene and leu- kemia. Environ. Res. 11, 122.

12. Goguel A., Cavigneaux A. & Bernard J. (1967) Les leucemies benzeniques au cours des hemopathies graves. Nouv. Rev. Franc. Hemat. 7, 465.

13. Girard E. & Revel L. (1970) La frequence d'une exposition benzenique au cours des hemopathies graves. Nouv. Rev. Franc. Hemat. 10, 477.

14. Powars D. (1965) Aplastic anemia secondary to glue sniffing. New Engl. J. Med. 273, 700.

15. Isager H. (1975) Fatal aplasia of the bone marrow following inhalation of the vapour from toluene- containing glue. Ugeskr Laeg. 137, 2197.

16. Caliguri M. A., Early A. P., Marinello M. J. & Preisler H. D. (1985) Acute non-lymphocytic leukemia in a glue sniffer. Am. J. Hemat. 20, 89.

17. Lindquist R., Nilsson B., Eklund G. & Gahrton G. (1987) Increased risk of developing acute leukemia after employment as a painter. Cancer 60, 1378.

18. Checkoway H., Wilkosky T. & Wolf P. (1984) An evaluation of the associations between leukemia and rubber industry solvent exposures. Am. J. Med. 5,239.

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

20. Olsson H. & Brandt L. (1980) Occupational exposure to organic solvents and Hodgkin's disease in men. Scand. J. Work. Environ. Health 6, 302

21. Olsson H. & Brandt L. (1988) Risk of non-Hodgkin's lymphoma among men occupationally exposed to organic solvents. Scand. J. Work. Environ. Health 14, 246.

22. Farrow A., Jacobs A. & West R. R. (1989) Myelo- dysplasia, chemical exposure, and other environmental factors. Leukemia 3, 33.

23. Mitelman F., Brandt L. & Nilsson P. G. (1978) Relations among occupational exposure to potential mutagenic/carcinogenic agents, clinical findings and bone marrow chromosomes in acute nonlymphocytic leukemia. Blood 52, 1229.

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

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

26. Arthur D. C. & Bloomfield C. D. (1984) Banded chromosome analysis in patients with treatment- associated acute non-lymphocytic leukemia. Cancer Genet. Cytogenet. 12, 189.

27. Pedersen-Bjergaard J., Philip P., Pedersen N. T., Hou-Jensen K., Svejgaard A., Jensen G. & Nissen N. (1984) Acute non-lymphocytic leukemia, preleukemia

70 L. BRANDT

and acute myeloproliferative syndrome secondary to treatment of other malignant diseases. II. Bone marrow cytology, cytogenetics, results of HLA-typing, response to antileukemic treatment and survival in a total series of 55 patients. Cancer 54, 452.

28. Dean B. J. (1978) Genetic toxicology of benzene, toluene, xylenes and phenols. Mutat. Res. 47, 75.

29. Dean B. J. (1985) Recent findings on the genetic toxicology of benzene, toluene, xylenes and phenols. Mutat. Res. 154, 153.

30. McMichael A. J., Spirtas R., Kupper L. L. & Gamble J. F. (1975) Solvent exposure and leukemia among rubber workers: an epidemiologic study. J. Occup. Med. 17, 234.

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

32. Zoloth S. R., Michaels D. M., Villalbi J. R. & Lacher M. (1986) Patterns of mortality among commercial pressmen. J. natn. Cancer Inst. 76, 1047.

33. Aksoy M., Erdem S., Dincol K., Hepuksel T. & Dincol G. (1974) Chronic exposure to benzene as a possible contributory etiologic factor in Hodgkin's disease. Blut 28, 293.

34. Olin R. & Ahlbom A. (1980) The cancer mortality among Swedish chemists graduated during three decades: a comparison with the general population and with a cohort of architects. Environ. Res. 22, 154.

35. Bernard S. M., Cartwright R. A., Darwin C. M., Richards I. D. G., Roberts B., O'Brien C. & Bird C. C. (1987) Hodgkin's disease: case control epidemiological study in Yorkshire. Br. J. Cancer 55, 85.

36. MacMahon B. (1966) Epidemiology of Hodgkin's disease. Cancer Res. 26, 1189.

37. Greene M. H., Hoover, R. N., Eck R. L. & Fraumeni J. F. (1979) Cancer mortality among printing plant workers. Environ. Res. 20, 66.

38. Gallagher R. P. & Threlfall W. J. (1983) Cancer mortality in metal workers. Can. Med. Ass. J. 129, 1191.