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1,3-Butadiene (BD) is a major commodity chemical used in the manufacture of synthetic rubber and various plastics and has been shown to be a potent animal carcinogen and a probable human carcinogen. The bioactivation of BD to reactive epoxides, and the balance between activation and detoxication of these reactive metabolites, is thought to play a critical role in the genotoxic and carcinogenic effects of BD. The detoxication of reactive BD metabolites involves enzymatic conjugation with glutathione by glutathione  S -transferases (GSTs) and by hydrolysis, a reaction mediated by microsomal epoxide hydrolase (mEH). Since polymorphisms in genes of xenobiotic-metabolizing enzymes such as mEH may influence individual susceptibility to adverse health effects from BD exposure, we tested the hypothesis that the  mEH  Tyr113His polymorphism increases sensitivity to the genotoxic effects of BD in exposed workers. We used the autoradiographic  hprt  mutant lymphocyte assay as a biomarker of effect to identify genotoxicity associated with BD exposure in 49 workers from two styrene/butadiene polymer plants in Southeast Texas. Exposure to BD was assessed by collecting breathing zone air samples using passive badge dosimeters for three full 12 h work shifts 25, 20 and 14 days before blood was collected for genotyping and for the  hprt  assay. We genotyped the study participants for the Tyr113His polymorphism in the mEH gene and also for deletion polymorphisms in the glutathione  S -transferase genes,  GSTM1  and  GSTT1 , as potential biomarkers of susceptibility to BD. Our data indicate that the majority of the study subjects (67%) were exposed to very low levels of BD of &lt;150 parts per billion (p.p.b.) time-weighted average (TWA). In some workers, however, we found levels of BD exposures that exceeded a TWA of 2000 p.p.b. Our data indicate a significant ( P  &lt; 0.05) 2-fold increase in frequencies of  hprt  variant (mutant) lymphocytes ( Vf ) in workers exposed to &gt;150 p.p.b. BD, compared with workers exposed to &lt;150 p.p.b. There was no significant effect from individual  GSTM1 ,  GSTT1  or  mEH  genotypes in workers exposed to &lt;150 p.p.b. BD. In workers exposed to &gt;150 p.p.b., individuals with at least one polymorphic  mEH  His allele (His/His or His/Tyr genotypes) had a significant ( P  &lt; 0.001) 3-fold increase in  Vf  (mean Vf×10 –6  ± SE = 13.25 ± 1.78) compared with individuals with the Tyr/Tyr genotype (mean  Vf ×10 –6  ± SE = 4.02 ± 0.72). There was no significant effect from individual  GSTM1  or  GSTT1  polymorphisms, but combined polymorphism analysis showed that the genetic damage was highest in individuals who had at least one  mEH  His allele and either the  GSTM1  and/or  GSTT1  null genotypes ( hprt Vf  = 14.19 ± 2.30 ×10 –6 ). In contrast, this response was not observed in individuals exposed to levels of BD &lt; 150 p.p.b. These results indicate that polymorphisms in the  mEH  gene may play a significant role in human sensitivity to the genotoxic effects of BD exposure, and that the  hprt  mutant lymphocyte assay can serve as a sensitive biomarker of genotoxicity for monitoring occupational exposure to BD in industrial settings. Additional investigations in larger populations of workers are needed to confirm our results and to characterize the possible role of additional  mEH  polymorphisms in the induction of genetic damage associated with occupational exposure to butadiene.

Human sensitivity to 1,3-butadiene: role of microsomal epoxide hydrolase polymorphisms