Elevated somatic cell mutant frequencies and altered DNA repair responses in nonsmoking workers exposed to...

Epidemiological evidence indicates that 1,3-butadiene is a human carcinogen; however, the epidemiological studies reflect past levels of exposures in the work place, which in all likelihood were higher than present-day levels. Studies of the metabolism of butadiene suggest that there may be qualitative differences among species in this respect. The question therefore arises as to the mutagenic and carcinogenic effects of butadiene in humans. The biomonitoring study reported here was designed to determine whether current exposure to this chemical in the work place is sufficient to induce mutations and/or to alter DNA repair functions, and to determine further whether levels of urinary metabolites correlate with the effects of exposure to butadiene. Nonsmoking workers in a butadiene production plant, who were exposed to levels of 1-3 ppm butadiene, were evaluated for hprt mutant frequencies, cytogenetic effects, including a challenge test to detect DNA repair deficiencies, and formation of protein adducts. We report here the results of the initial study on hprt mutant frequencies and of the challenge assay and the correlation between the results of these assays and levels of butadiene metabolite in the urine. A single metabolite of butadiene, 1,2-dihydroxy-4-(N-acetylcysteinyl-S)butane, was detected in the urine of all subjects. The concentration of the metabolite in the highly exposed group of workers was significantly higher than that in the group exposed to low concentrations or that in outside control groups. The correlation between the level of the metabolite in urine and the frequency of hprt mutants was r = 0.85 (p < 0.0003). Initial observations from a newly developed cytogenetic assay intended to measure altered DNA repair capability (the challenge assay) indicate a statistically significant increase in the high-exposure group relative to the low-exposure group (p < 0.01). This study thus reinforces and extends the results of the epidemiological studies and indicates that present exposure levels may not be sufficiently low to protect workers. It also provides evidence that levels of the urinary metabolite that was considered to be indicative of insensitivity correlate with the frequencies of somatic mutations and exposure to butadiene.