Genotoxicity

Although a number of gene mutation assays have shown benzene to be weakly or non-mutagenic (Dean, 1985; Goldstein, 1989; Parke, 1989), this is contradicted by studies in exposed workers. These have shown chromosome aberrations, mostly breaks, gaps and sister chromatid exchanges (SCE), in benzene exposed workers (e.g., Tough and Court Brown, 1965; Forni et al., 1971a, 1971b; Funes-Cravioto et al., 1977; Yardley-Jones et al., 1990; Karacic et al., 1995; Tunca and Egeli, 1996). There appears to be no correlation between the duration of exposure and the frequency of chromosome changes (Forni et al., 1971a; Tunca and Egeli, 1996; Seiji et al., 1990). Genotoxicity has also been demonstrated in in vitro and in vivo animal studies (reviewed in Snyder, 1987; Ludewig et al., 1989).

A higher mutation frequency has been observed in benzene-exposed workers using a test to identify stem cell or precursor erythroid cell mutations expressed in peripheral erythrocytes (Rothman et al., 1995; 1996b; Smith, 1996b). The mutation frequency was related to cumulative benzene exposure rather than current exposure (Rothman et al., 1995).

Benzene has been reported to cause chromosome specific aneuploidy, the loss or gain of whole chromosomes. Numerical changes in C-group chromosomes 6-12 and X have been observed in the blood and bone marrow of individuals with benzene induced myelogenous leukaemia, myelodysplastic syndrome (preleukaemia) and pancytopenia (Smith, 1996b). Aneuploidy of chromosome 9 has been reported in workers exposed to benzene concentrations >31 ppm, but not in those with exposure to lower concentrations. Aneuploidy correlated with the air concentration of benzene, the urinary concentration of phenol and decreased lymphocyte count in exposed workers (Zhang et al., 1996).

A significantly increased incidence of hyperdiploidy (a gain in chromosome number) of both chromosomes 8 and 21 was observed in the lymphocytes of benzene-exposed workers. The effect was mainly in the form of trisomy (3 copies of the chromosome). There was also an increase in translocations. In workers exposed to >31 ppm benzene there was a 15-fold increase in translocations between chromosome 8 and 21 compared to controls. In this study chromosome aberrations correlated with current (previous 6-12 months) exposure, not to cumulative life-time exposure (Smith et al., 1998). Changes in chromosomes 8 and 21 are common in patients with acute myeloid leukaemia. In addition, cytogenic abnormalities with loss of all or part of chromosomes 5 and 7 are found in patients with myelogenous leukaemia after antineoplastic therapy or benzene/solvent exposure (Irons and Stillman, 1996b).

Follow-up of workers after they had suffered severe benzene haematotoxicity demonstrated that increased chromosome-type aberrations (with normal blood counts) were still present even 30 years after they had recovered from benzene toxicity. This study also investigated 31 subjects with a history of benzene toxicity and 31 controls. There were eleven deaths in the exposed group including five deaths from cancer. The deceased subjects had had significantly higher rates of chromosome-type aberrations than those still living, and those that had died from cancer had the highest rates of chromosome-type aberrations in the last cytogenetic examination before the diagnosis of cancer or their death (Forni, 1996).

Several studies have shown slight or no genotoxic effects in workers exposed to low concentrations of benzene (Watanabe et al., 1980; Sarto et al., 1984; Jablonicka et al., 1987; Yardley-Jones et al., 1988b; Seiji et al., 1990). There was no increase in sister chromatid exchanges (SCEs) in peripheral lymphocytes in workers exposed to a maximum of 40 ppm of benzene for 1-20 years (Watanabe et al., 1980). Similarly there was no significant increase in SCE in workers exposed to benzene at 0.2-12.4 ppm (Sarto et al., 1984). There was no significant increase in SCE in 10 workers exposed to a single acute high exposure to benzene. However, the study was done 3 months after the incident and the number of workers was small (Clare et al., 1984).

In vitro studies on human lymphocytes exposed to various benzene concentrations found no increase in SCEs or the number of chromosome aberrations (Gerner-Smidt and Friedrich, 1978).

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