Leukaemia and lymphoma risks derived from solvents

Med. Oncol. & T, tmor Pharmacother. Vol. 4, No. 314, pp. 199-205, 1987 [)73(~1)118/87 $3.(10 + .00 Printed in Great Britain Pergamon Journals Ltd.

L E U K A E M I A A N D L Y M P H O M A R I S K S D E R I V E D F R O M S O L V E N T S

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

(Received 22 May 1987; accepted 1 June 1987)

Results of epidemiologic studies indicating an association between solvent exposure and the development of malignancies affecting haematopoietic and lymphatic tissues are reviewed. Clinical and cytogenetic data support- ing this association are discussed. A variety of malignant disorders have been associated with solvent exposure, i.e. acute leukaemia, Hodgkin's disease (odds ratio 2.8-6.6), non-Hodgkin's lymphoma (odds ratio 3.3) and myeloma, and there are some indications that solvent exposure may be a risk factor for myelofibrosis. The carcinogenic effect of benzene is epidemiologically and experimentally well documented and there are some indications that other solvents may also be hazardous. Possible mechanisms bringing about malignant transformation are discussed. The need for further epidemiologic, cytogenetic and clinical studies on the association between solvent exposure and malignant diseases is emphasised.

Key words: Organic solvents, Malignancies, Haematopoietic and Lymphatic tissues.

INTRODUCTION

As early as 1897, Santesson reported that heavy exposure to solvents may have toxic effects on the bone marrow. The toxicity was observed in eight female workers handling a rubber solvent and four of them died with symptoms suggesting aplastic anaemia.t Although Santesson found that benzene was the main component of the solvent used, he could not rule out the possibility that other compo- nents were also hazardous. Later it has been well documented that aplastic anaemia may be caused by benzene exposure. Since the 1920s evidence has accumulated that occupational handling of organic solvents may also be a risk factor for haematological malignancies and benzene has been the solvent incriminated. There are, however, some indications that exposure to other solvents may also be hazardous. The present review deals with the relation between exposure to solvents and development of haalignant disorders affecting haematopoietic and lymphatic tissues. The reason for limiting the discus- sion to haematological malignancies is that other human tumours have only sporadically been associated with solvent exposure.

ACUTE LEUKAEMIA

Nowadays it is generally accepted that occupa-

199

tional exposure to benzene is a risk factor for acute leukaemia (AL). Delore and Borgomano reported the first case associated with heavy benzene exposure in 1928. 2 Aksoy et al. 3 found a more than two-fold increase in AL among Turkish shoe workers exposed to benzene, and Vigliani 4 described an association between heavy occupational exposure to benzene and AL in Italy. Rinsky et al. 5

assessed the mortality from AL in rubber industry workers and found a relative risk of 5.6 for those who had been exposed to benzene for at least 1 day. For those who had been exposed for 5 or more years a relative risk of 21 was calculated. In a comprehen- sive Chinese cohort study of benzene exposed workers Yin et al. 6 found a standardized mortality rate of 5.74 for leukaemia. Nearly 80% of the cases were acute leukaemia. Although the Turkish and Italian workers were exposed to high concentrations of benzene, mostly 200-500 ppm, considerably lower concentrations may be hazardous. The Chinese workers were generally exposed to 16-160 ppm and Infante et

al. 7 found a significant association between exposure to average concentrations of 10-50 ppm and development of acute leukaemia. Recently Rinsky et

al. s described a strongly positive exposure-response relation between benzene and leukaemia. On the basis of their model even exposure to 1 ppm for pro- longed periods may be significant.

It must be suspected that exposure to other or-

200 Lar s B r a n d t

ganic solvents than benzene may be associated with AL. In a Swedish case--control study by Flodin et al. '~

occupational exposure to a variety of solvents was more common in patients with AL compared to controls with an odds ratio of about 6. In another, and more recent, Swedish study of 125 adults with AL, Lindquist et al. found an odds ratio of 13 for patients reporting daily exposure to various aromatic and aliphatic solvents. I~ In Sweden, benzene was de- clared a poison in 1972 and the patients were seen in 1980-83. The average latency period from start of exposure to benzene until diagnosis of AL seems to be 10-11 yr. 3"4"6 For a considerable proportion of the patients studied by Lindquist et a l . , heavy benzene exposure would therefore be an unlikely etiologic factor. It is possible, however, that some exposure to benzene occurred even after 1972 because other solvents, e.g. toluene and xylene, may contain small amounts of benzene as a contaminant.

In addition to epidemiological evidence results of cytogenetic studies suggest a relation between occupational exposure to solvents and AL. In a retrospective study of 56 adults with acute non- lymphocytic leukaemia (ANLL), we found clonal chromosome aberrations to be more common in patients occupationally exposed to potentially mutagenic/carcinogenic chemicals than in patients without any history of occupational exposure to such agents. ~t Similar results were obtained in an extended study of 162 patients from Sweden and Italy, lz and in 74 patients from Chicago, U.S.A. ~3 and in a collaborative study at the Fourth Interna- tional Workshop on Chromosomes in Leukemia.14 Moreover, these studies have shown that ANLL following occupational exposure to chemicals, mainly solvents, is more often associated with loss of chromosomes 5 and 7 in the leukaemic cells than in ANLL patients without such a history.

Various morphologic types of AL have been described in patients exposed to benzene and other organic solvents. Most leukaemias are of the myeloid or monocytic cell types. 3'4"14 No special cell type was observed in the exposed patients analysed by the Fourth International Workshop, 14 but a pre- dominance of myelomonocytic and monocytic varieties was reported by Lindquist et al. ~~

There are some indications that ANLL in patients exposed to solvents may be more aggressive than ANLL in non-exposed patients. It is known that if all metaphases analyzed in the bone marrow of ANLL patients contain clonal chromosome aberrations the survival is poorer than if some normal metaphases are present.15 In a group of ANLL patients aged 55 yr or older with an occupation indicating exposure to potential mutagenic chemicals, 50%

had entirely abnormal bone marrow metaphases. The corresponding figure for unexposed patients was 11%. In the exposed group survival was poorer than in the non-exposed patients. No such differences were observed in ANLL patients younger than 55 yr of age.t6

HODGKIN'S DISEASE

In 1976 Olin observed that the mortality from HD was unexpectedly high in Swedish chemistry graduates. 17 In an extended study the mortality from HD proved to be higher in chemistry graduates than in a cohort of architects and in the general population. 18 Occupational exposure to chemicals, including solvents, was suspected as a risk factor for HD. In accordance with Olin's findings we observed an over-representation of occupations indicating exposure to chemicals in a consecutive series of men with HD.19 In an English case-control study of HD an increased risk was found for rubber and plastic workers. 2~ Although no statistical evaluation was performed, Aksoy et al. 2~ suggested that exposure to benzene may be a risk factor for HD. Vianna and Polan found in a cohort of workers exposed to benzene and other solvents an over-representation of deaths due to HD. 22 A relation between heavy exposure to organic solvents and HD, with an odds ratio of 2.8, was found by Hardell et al. in a case- control study in northern Sweden. 23 In male HD patients with a daily occupational exposure to solvents for 1 yr or longer, we found an odds ratio of 6.6 in a case-control study. 24 The exposed patients had handled a variety of aromatic and aliphatic solvents. The latency period from start of exposure until diagnosis was on an average 10.5 yr which is similar to the mean duration of exposure reported by Aksoy et al. for six benzene-exposed HD patients. 2~

The age specific incidence curve for HD has a characteristic bimodal shape with one peak between 25-35 yr of age and a second increase beginning about the age of 35, and it has been proposed that this phenomenon may indicate differences in etiology between younger and older age groups. 2s The over-representation of occupations indicating exposure to chemicals in male HD patients observed by us was only evident in patients over the age of 30.19 Vianna and Polan found the increased risk of HD for solvent exposed workers only in patients older than 45 yr. z2 Similarly, we found no significant difference in number of solvent exposed HD patients and controls aged 20-35, whereas over the age of 35 the difference in exposure between patients and controls was significant. 24 It therefore seems probable that

exposure to organic solvents is a less important risk factor for HD found in young patients than for HD diagnosed after the age of 35.

NON-HODGKIN'S LYMPHOMA

An association between occupational exposure to organic solvents and non-Hodgkin's lymphoma (NHL) was reported by Vianna and Polan. 2-~ Hardell et al. also found that heavy solvent exposure increased the risk of NHL. 23 Zoloth et al. 26 analysed the proportionate mortality ratios (PMR) for various malignancies in a cohort of 1401 commercial pressmen with a high level of solvent exposure. They found a significantly elevated ratio for NHL and this was particularly evident for men under 65 yr of age, with a PMR of 388. In a recent case-control study of 167 consecutive men with NHL, we found an increased risk following a daily occupational handling of organic solvents for at least 1 yr with an odds ratio of 3.3 (95% confidence interval 1.9-5.8). 27 There was a considerable variation in the latency periods from start of exposure until diagnosis, 2-60 yr with a median of 2I yr.

Results of a previous preliminary study TM suggested that a history of occupational exposure to solvents may be especially common in patients with an initially supradiaphragmatic location of NHL. This was confirmed in our recent extended study. The odds ratio for localized supradiaphragmatic lym-

�9 phoma was 6.5 and for other lymphoma presenta- tions 2.3. 27 Since organic solvents are volatile, inhalation may cause a considerable exposure of the mucous membranes in the upper and lower respira- tory tract. It is reasonable to assume that lymphoid tissue regional to these areas is exposed to higher concentrations of the substances than such tissue in other parts of the body. If some solvents promote the development of NHL, the initial lesion should be found in lymphoid tissue above the diaphragm rather than in lymphoid tissue located elsewhere.

Some recent cytogenetic findings in NHL may also point to an association between solvent exposure and NHL. In the NHL patients with a history of daily occupational exposure to solvents for at least 1 yr, multiple clonal chromosome aberrations in the Iymphoma cells were more common than in unexposed patients. Moreover, some recurrent clonal abnormalities ( - 8 and 14q+ without transloeation from chromosome 18) were more common in the exposed patients, whereas other aberrations (+ 12 and 6 q - ) occurred more often in patients without any history of solvent exposure. 29

Solvent exposure and malignancies 201

MYELOMA

In 1970 Tortes e t al . TM reported two cases of myeloma with a preceding exposure to benzene, and Aksoy 3~ has presented three other cases. Kyle and Greipp a2 reported two men with myeloma who were successive husbands of the same wife. Both had a history of benzene exposure. The significance of the relation between benzene exposure and myeloma in these case reports is uncertain. Recently Rinsky et al. studying a cohort of 1165 men occupationally exposed to benzene, found a statistically significant excess of deaths from myeloma with a standardized mortality ratio of 409. 8

In a cohort study of printing plant workers, Greene et al. 33 found a significant excess mortality from myeloma. The workers had been exposed to a variety of chemicals and solvent exposure was not especially incriminated. Excess mortality from myeloma has also been observed in machinists handling cutting oils and f lu ids 34 and in cosmetologists exposed to a variety of organic and inorganic chemicals, as It thus appears that a possible relation between myeloma and exposure to chemicals other than benzene should be further explored. Tollerud et al . 36 found an elevated mortality from myeloma in furniture workers suggesting exposure to some environmental hazard. Interestingly, the excess mortality was only seen in workers under the age of 65. The major risk indicator for myeloma is age, but the results mentioned suggest that it might be worth- while to explore environmental risk factors for myeloma in patients belonging to relatively young age groups.

HAIRY CELL LEUKAEMIA

In a case-control study of 45 patients with hairy cell leukaemia the reported exposure to organic chemicals in the workplace was significantly greater among patients than controls with an odds ratio of 3.1.37 The effect of exposure to organic solvents was not specifically evaluated.

MYELOFIBROSIS (MYELOID METAPLASIA)

In 1941 Rawson e t al . reported six patients with myeloid metaplasia and a history of benzene exposure, but the statistical significance of their find, ings cannot be evaluated. 38 Since then occasional cases associated with benzene exposure have been described. 3t'39'4~ In an analysis of cause of death in 1401 commercial pressmen, Zoloth et al. 26 observed three deaths attributed to myelofibrosis. The pos-

202 L a r s B r a n d t

sible association between solvent exposure and myelofibrosis should be further explored. This is a difficult task, however, because myelofibrosis is a very rare condition.

observation that NHL in patients with a heavy occupational exposure to solvents have a predominantly supradiaphragmatic location also support the concept that exposure to solvents has some bearing on the development of lymphomas. 27"28

IS THE ASSOCIATION BETWEEN SOLVENT EXPOSURE AND HAEMATOLOGICAL

MALIGNANCIES CONCLUSIVE?

An association between occupational solvent exposure and an increased risk of acute leukaemia could not be verified in a Finnish study. 4~ A relation between solvent exposure and malignant lymphomas has also been called in question. In a consecutive series of male patients with Hodgkin's disease, we found 19% with occupations indicating exposure to chemicals, including solvents. The corresponding proportion in various control groups was 2-3%. ~9 Benn et al. 42 could not verify this observation in a group of English men with HD and in an Italian group of HD patients exposure to chemicals was not unduly common. 43 Smith and Lickiss 44 could not demonstrate any association between occupations indicating benzene exposure and malignant lymphomas (HD and NHL).

The reasons for these contradictory results are obscure. Apparently the studies mentioned which failed to find an association with solvent exposure were based on register data or occupational titles. It is possible that the information on exposure obtained in such studies is less reliable than in case- control studies where patients and referents are per- sonally interviewed about the exposure. In one such study of acute leukaemia solvent exposure was found to be a strong risk factor.t~ Likewise personal interviews with HD and NHL patients and their controls have revealed heavy solvent exposure as a risk factoi ' . 23"24"27 Even if different techniques used in the epidemiological studies may explain some of the different results, it is obvious that further investigations are necessary to elucidate the relation between solvent exposure and malignancies of haematopoietic and lymphatic tissues.

Some cytogenetic and clinical findings may support the epidemiological arguments in favour of a relation between solvent exposure and haematological malignancies," Thus the non-random chromosome aberrations found in acute non-lymphocytic leukaemia following exposure to potentially mutagenic/ carcinogenic chemicals may support the concept that occupational exposure to solvents is relevant for the development of acute leukaemia, ll'lza3"14 Similarly certain chromosome aberrations in NHL tissue seem to be related to exposure to solvents. 29 The clinical

WHICH SOLVENTS ARE HAZARDOUS?

There is little doubt that exposure to benzene is a risk factor for acute leukaemia. Several epidemiological studies, support this idea and experimental models have been developed which confirm that benzene or its metabolites are leukaemogenic. 45 Ex- posure to benzene may also be a risk factor for malignant lymphomas, 22 although the evidence is less convincing than for acute leukaemia.

The possible hazards of other common solvents than benzene have been studied less thoroughly. In- halation of toluene may have toxic effects on the bone marrow 46:7 and has occasionally been associated with acute ieukaemia. 48 Excess mortality from lymphoma has been found in workers handling styrene. 49 Checkoway et al. 5~ found indications that benzene may not be the only solvent used in the rubber industry capable of causing haematopoietic malignancies. They proposed that carbon tetra- chloride and carbon disulphide exposure may also be associated with leukaemia.

A problem often encountered in epidemiological studies of the association between solvent exposure and haematological malignancies is that the exposed patients and controls almost invariably have handled several solvents . 1~ 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 benzene is replaced by other presumably less hazardous solvents, the risk of benzene exposure is not negligible.

POSSIBLE MECHANISMS FOR TUMOUR INDUCTION BY SOLVENTS

Although exposure to benzene is now generally accepted as a risk factor for acute leukaemia, the mechanisms bringing about the malignant transformation remain to be determined. The biotransformation of benzene has been reviewed by Dean, 5t'52 and genotoxic properties have been described for some metabolites, i.e. benzene epoxide, phenols and hydroquinone. Ongoing studies of the leukaemogenic properties of benzene and its metabolites in mice were recently discussed by Cron-

kite. 45 Metabolites of other aromatic solvents may have mutagenic effects although this is less well documented than for benzene. The reader is referred to Dean 5t'52 for a thorough review of the metabolism of aromatic solvents and the possible genotoxic products formed during their biotransformation.

Some metabolites of aromatic solvents, e.g. epoxides, hydroquinone, may have alkylating properties. 45'5~'52 In secondary ANLL following treatment with alkylating drugs, some non-random chromosome abnormalities are especially common, i.e. loss or deletion of chromosome 5 and/or 7. 53 These aberrations are also characteristic findings in ANLL following exposure to solvents. II't2"13"14 It may therefore be speculated that the chromosome abnormalities in solvent exposed patients may result from genotoxic mechanisms similar to those initiated by exposure to alkylating drugs.

Exposure to solvents may enhance the effect of other leukaemogenic agents. Thus Ishimaru et al. 54 found that the risk of leukaemia was especially high for atomic bomb survivors with a history of occupational exposure to solvents. Similarly, Flodin et al. 9 found that exposure to solvents may increase the risk of ANLL associated with background gamma radiation.

Exposure to benzene will induce a dose- dependent lymphocytopenia in experimental animals. 45 A similar effect of exposure to aromatic solvents may occur in man. The number of circulat- ing T-lymphocytes may be subnormal in workers handling such chemicals and this reduction becomes more pronounced with increasing duration of exposure. 55 These findings may have some bearing on the relation between solvent exposure and development of non-Hodgkin's lymphoma. It has been proposed that a reduction of suppressor T-cell func- tions may facilitate the development of B-cell lymphomas. 56

CONCLUDING REMARKS

Results of several epidemiological studies indicate that exposure to organic solvents is a risk factor for malignancies affecting haematopoietic and lymphatic tissues. Benzene is a well documented carcinogenic agent and there are indications that even very low levels of benzene exposure may be hazardous. Exposure to other solvents may also be risky but further studies are needed to confirm this suspicion.

Solvent exposure may be associated with various haematoiogical malignancies, i.e. acute leukaemia, malignant lymphomas and myeloma. It is also suspected to be a risk factor for myelofibrosis. The mechanisms bringing about the malignant trans-


formation have not been fully elucidated and should be further explored. Genotoxic effects of metabolites of aromatic solvents have been observed but other mechanisms should also be considered.

Although there is increasing evidence that solvent exposure may be associated with the development of haematologicai malignancies, some studies have failed to confirm such a relation. Further epidemi- ologicai studies to estimate the quantitative import- ance of solvent exposure in carcinogenesis are therefore motivated. It is assumed that a systematic and close questioning of patients and controls will give more reliable information on the relation between solvent exposure and haematological malignancies than analyses of data obtained from regis- ters. This implies that clinicians should take an active part in epidemiological studies.

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Leukaemia and lymphoma risks derived from solvents