British Journal ofHaernatology. 1989, 72, 119-121

Annotation

BENZENE AND LEUKAEMIA

Data from clinical, epidemiological and experimental studies have given abundant evidence for a relationship between benzene exposure and haemopoietic damage. While the classical effects are described as reversible cytopenias. aplas- tic anaemia or leukaemia, these may not be entirely distinct clinical entities. Aplastic or hypoplastic anaemia associated with genetic stem cell damage may result in a preleukaemic state and the morphological changes of myelodysplasia may be seen. Epidemiological studies show an increased incidence of leukaemia and myeloma in workers exposed to benzene. The mechanism of haemopoietic damage is unknown. Exposed subjects may show non-specific chromosome changes and, at a later time, clonal karyotype abnormalities. These changes are accompanied by pathological stem cell function and abnormalities in haemopoietic proliferation.

Clinical effects Aplastic anaemia due to benzene toxicity was first described at the end of the last century (Santesson, 189 7) and some 30 years later recognition of the characteristic picture of throm- bocytopenia, neutropenia and anaemia, often followed by death from bleeding, led to attempts to reduce exposure and substitute less toxic alternatives for industrial use (McCord, 1932; Hamilton, 1928). Hamilton (1928) noted that 32% of workers exposed to benzene developed leucopenia and that this could occur even when the concentration was as low as 100 ppm. The first report of leukaemia occurring in a worker exposed to benzene was published by DeLore & Borgamano (1928).

Since that time there have been numerous reports from many countries of cytopenias. aplasia and leukaemia asso- ciated with benzene exposure and these have been recently reviewed by Alderson (1986), the U.S. Department of Labour (1987) and Aksoy (1988). Despite the many well-docu- mented descriptions of severe bone marrow damage and leukaemia, the effects of low level exposure to benzene remain uncertain. Episodic exposure may result in transient blood changes with no apparent residual effects, and minimal haematological abnormalities may be difficult to differentiate from unrelated pathological states such as infection, haema- tinic deficiency or excess alcohol intake. Although removal of a haematologically affected subject from a benzene-contain- ing environment may result in the disappearance of peri- pheral blood abnormalities, the effect on the long-term risk of leukaemia is not known. Patients with refractory anaemia or leukaemia following benzene exposure may have clonal chromosome abnormalities in their bone marrow similar to those seen in other types of chemically induced leukaemia, Correspondence: Professor A. Jacobs, Department of Haematology. University of Wales College of Medicine, Heath Park, Cardiff CF4 4xw.

commonly deletions of chromosomes 5 and/or 7 (Heim & Mittelman, 1986). Even in the absence of such specific karyotype abnormalities there appears to be an increased incidence of aneuploidy and chromosome aberrations such as gaps, breaks .and dicentric forms in haematologically normal workers exposed to benzene concentrations of 5-2 5 ppm when compared to normal controls (Tough & Court- Brown, 1965; Forni et al, 1971; Picciani. 1979). Although the data is not entirely consistent (Tough et al, 1970). this suggests that genetic damage to haemopoietic cells may occur in the absence of any overt haematological signs and if an analogy can be drawn with other chemically induced leukaemias and preleukaemic states, particularly those fol- lowing cytotoxic therapy, a latent period of up to 10 or more years may elapse before the clinical emergence of an aberrant haemopoietic clone.

Epidemiological evidence Amongst the many reports of leukaemia in patients pre- viously exposed to benzene are those of Aksoy et a1 (1974) who found 26 with acute leukaemia or preleukaemia amongst 28 500 shoe workers in Istanbul, Vigliani (1976) who described 66 patients with haematological abnormali- ties in Milan, 11 of whom developed leukaemia, and Decoufle et al (1983) who found one case of chronic lymphocytic leukaemia. two of acute leukaemia and one of multiple myeloma amongst 259 workers in a U.S. chemical plant. Aksoy & Erdem (1 9 78) followed 44 pancytopenic patients for periods between 2 and 1 7 years and observed that six developed leukaemia; there were 14 deaths from pancyto- penia and one from preleukaemia.

In a number of studies an attempt has been made to compare the incidence of haematological malignancy in exposed workers with a control population. Infante et a1 (1 9 77) found a 5-fold risk of all leukaemias and a 1 0-fold risk ofmyeloid and monocytic leukaemia in U.S. workers, exposed during 1940-49. Vianna & Polan (1979) found a significant excess of deaths from lymphoma in New York State workers exposed to benzene. Rushton & Alderson (198 1) studied deaths amongst oil refinery workers in the U.K.. and although there was no excess of deaths from leukaemia compared to national rates, there was an increased risk for those workers with medium or high exposure compared to those with low exposure. Wong (1987a, b) showed an excess mortality of exposed compared to non-exposed U.S. workers for lymphoma and leukaemia and related this to the cumula- tive dose. Yin et a1 (1987a) found 2676 cases of benzene poisoning amongst 528 729 exposed workers in China, aplastic anaemia in shoemakers being 5.8 times as common than in the general population. In a related study the leukaemia mortality was 14/100 000 in benzene factories

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120 Annotation

compared to 2jlOO 000 in control factories (Yin et al. 1987b). The average latency of benzene leukaemia was 1 1.4 years. Kinsky et a1 (1 987) followed a cohort of 11 65 Ohio men exposed between 1940 and 1965. The standardized mortality ratio (SMR) for leukaemia was 337 and for myeloma 409. In both cases mortality was related to cumulative exposure with the SMK for leukaemia increasing from 109 at an annual exposure of 1 ppm to 6639 (CI 1334: 19 393 j at an annual exposure of 10 ppm. However, Bond et a1 (1986). in their study of 956 Michigan workers, were unable to find any evidence suggesting a causal association between benzene exposure and any particular cause of death.

Austin ef a1 (1988). in a critical review of the literature, conclude that while the data supports the inference that benzene causes acute myelocytic leukaemia it is too sparse to substantiate this relationship at 1-1 0 ppm benzene. They speculate that 1000 men exposed to 10 ppm benzene for a working life of 3 0 years would suffer about 5 0 excess deaths due to leukaemia.

A number of case-control studies have been carried out in which prior environmental chemical exposure in patients with haematological disease has been compared with that of control populations. Brandt et a1 19 78) showed an excess of patients with acute myeloblastic leukaemia to have had an occupation with exposure to petroleum products. Linet et al (1989) showed no excess exposure to benzene in patients with aplastic leukaemia. but 41% of the patients in this series were less than 20 years old. In our own study ofpatients with myelodysplasia there was a significant association with prior exposure to petrol or diesel compounds (Farrow et al. 1989).

Haematological screening The objectives of carrying out routine blood counts for screening benzene workers have often been confused. The U S . Department of Labour i 1987) have recently suggested the following: (1 ) early detection and reversal of cytopenias and aplasias; ( 2 ) prevention of some leukaemias by reducing the dose to susceptible workers: 13) early recognition and treatment of leukaemia: 14) to obtain evidence of the effectiveness of existing standards for benzene exposure. I t IS

difficult to know how successfully these objectives can be accomplished.

It is recommended that all screening should be carried out by accredited laboratories and the parameters measured should either be compared with values obtained from a control population or related to agreed critical values. Examinations should be carried out annually or following accidental exposure, when three examinations at monthly intervals are indicated. Abnormal blood findings should be confirmed within 2 weeks, the worker removed from expo- sure and referred to a haematologist

Experinwntal data There is abundant evidence of both benzene haemotoxicity and tumorigenesis in animals at inhaled concentrations down to 100 ppm and less. and this has been recently reviewed (Cronkite, 1987: Aksoy, 1988). Both leukaemia and lymphoma may be induced experimentally in addition to non-haemopoietic tumours. and marrow aplasia may also be

observed. In the haemopoietic system all cell elements can be affected and benzene metabolites may cause both biochemi- cal damage and impairment of proliferation at all levels of the stem cell hierarchy. Inhibition or killing of multipotential stem cells (Green et a], 1981a) or committed erythroid or granulocytic progenitors (Green et al, 1981a; Daudu & Geelhoed. 1986) may occur and the end result is a decrease in numbers of lymphoid, myeloid and erythroid cells in both the bone marrow and the blood (Green et al, 1981b). The decrease in radio-iron incorporation into red cells caused by benzene metabolities (Bolcsak & Nerland, 1983) may be the result of impaired proliferation or to a direct effect on haem or globin synthesis (Forte e f al. 1976). Similarly the effect on lymphocytes may be related to impaired protein synthesis (Post et a!, 1985).

It is doubtful whether the consequences of benzene exposure in animals can be directly related to man either with regard to the precise metabolic derangements produced or with respect to dose-effect relationships. However, the sum of evidence available suggests that genetic damage, haemopoie- tic damage and malignant transformation may occur in a variety of species including humans. The similarities between species in this respect are perhaps more striking than the differences. At present we have no precise knowledge of the genetic defects produced by benzene but the effects produced appear similar to those seen in other types of secondary myelodysplasia and leukaemia.

Problerns The major problems that remain unsolved in attempting to understand the leukaemogenic role of benzene include:

1. The nature of the genetic lesions caused by benzene metabolites.

2. The relationship between the amount and type of exposure and irreversible stem cell damage.

3 . The importance of interaction with other mutagens. 4. Whether hereditary susceptibility is of importance in

5. A methodology for the detection of minimal haemopoie- predisposing to the leukaemogenic effect of benzene.

tic damage.

Department of Haematology, ALLAN JACOBS

University of Wales College of Medicine. Cardiff

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