Human sensitivity to 1,3-butadiene: role of microsomal epoxide hydrolase polymorphisms
individuals with at least one polymorphic mEH His Jonathan B.Ward Jr allele (His/His or His/Tyr genotypes) had a significant (P < 0.001) 3-fold increase in Vf (mean Vfϫ10 -6 Ϯ SE ⍧ 13.25 Ϯ 1.78) compared with individuals with the Tyr/Tyr of Texas Medical Branch, Galveston, TX 77555-1110, USA 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
... e was highest in individuals 1,3-Butadiene (BD) is a major commodity chemical used who had at least one mEH His allele and either the GSTM1 in the manufacture of synthetic rubber and various plastics and/or GSTT1 null genotypes (hprt Vf ⍧ 14.19 ⍨ 2.30 and has been shown to be a potent animal carcinogen and ⍥10 -6 ). In contrast, this response was not observed in a probable human carcinogen. The bioactivation of BD individuals exposed to levels of BD < 150 p.p.b. These to reactive epoxides, and the balance between activation results indicate that polymorphisms in the mEH gene may and detoxication of these reactive metabolites, is thought play a significant role in human sensitivity to the genotoxic to play a critical role in the genotoxic and carcinogenic effects of BD exposure, and that the hprt mutant lymphocyte effects of BD. The detoxication of reactive BD metaboassay can serve as a sensitive biomarker of genotoxicity lites involves enzymatic conjugation with glutathione by for monitoring occupational exposure to BD in industrial glutathione S-transferases (GSTs) and by hydrolysis, a settings. Additional investigations in larger populations reaction mediated by microsomal epoxide hydrolase (mEH). of workers are needed to confirm our results and to Since polymorphisms in genes of xenobiotic-metabolizing characterize the possible role of additional mEH polyenzymes such as mEH may influence individual susceptimorphisms in the induction of genetic damage associated bility to adverse health effects from BD exposure, we tested with occupational exposure to butadiene. 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 Introduction identify genotoxicity associated with BD exposure in 49 1,3-Butadiene (BD) is a major commodity chemical used in workers from two styrene/butadiene polymer plants in the manufacture of synthetic rubber and various plastics. Southeast Texas. Exposure to BD was assessed by collecting Global consumption of BD was 6.1 million metric tons in breathing zone air samples using passive badge dosimeters 1995, with consumption expected to rise to more than 7.5 for three full 12 h work shifts 25, 20 and 14 days before million metric tons in the year 2000 (1). BD ranked 36th in blood was collected for genotyping and for the hprt assay. production volume in the United States in 1995 (over 3.6 billion We genotyped the study participants for the Tyr113His pounds), with the United States producing approximately one polymorphism in the mEH gene and also for deletion polymorphisms in the glutathione S-transferase genes, fourth of the world's total industrial butadiene output of more GSTM1 and GSTT1, as potential biomarkers of susceptithan 5 million metric tons per year. It is estimated that at least bility to BD. Our data indicate that the majority of the 65 000 US workers may be exposed annually to BD (2). While study subjects (67%) were exposed to very low levels of BD is mainly an industrial chemical, it is also a common air BD of <150 parts per billion (p.p.b.) time-weighted average contaminant found in auto emissions and cigarette smoke. It (TWA). In some workers, however, we found levels of BD is a component of automotive exhaust and of the vapor phase exposures that exceeded a TWA of 2000 p.p.b. Our data of environmental tobacco smoke (~400 µg/cigarette) (3). Due indicate a significant (P < 0.05) 2-fold increase in frequencies to the potential for serious health effects associated with BD of hprt variant (mutant) lymphocytes (Vf) in workers exposure, it was classified as one of 33 priority air toxics exposed to Ͼ150 p.p.b. BD, compared with workers exposed listed in the EPA's Integrated Urban Air Toxics Strategy (EPA to <150 p.p.b. There was no significant effect from indi-FRL-6157-2 Docket No. A-97-44). vidual GSTM1, GSTT1 or mEH genotypes in workers BD is carcinogenic in rodent bioassays (4), and exposure exposed to <150 p.p.b. BD. In workers exposed to Ͼ150 of mice to BD at 20 parts per million (p.p.m.) for 4 days induced mutations in spleen lymphocytes at the hprt locus (5). In several epidemiological studies, excess mortality from Abbreviations: BD, 1,3-butadiene; DEB, 1,2,3,4-diepoxybutane; EB, 3,4lymphatic and hematopoietic cancer was associated with epoxy-1-butene; EBD, 3,4-epoxy-1,2-butanediol; GM, growth medium; GSTs, glutahione S-transferases; IARC, International Agency for Reseach on Cancer; occupational exposure to BD (6,7). Differences in carcinogenic LI, labeling index; mEH, microsomal epoxide hydrolase; OSHA, Occupational responses between rats and mice, and weaknesses in some of Safety and Health Administration; PEL, permissible exposure limit; SBR, the epidemiological studies, have resulted in controversies styrene-butadiene rubber; SCE, sister chromatid exchanges; SEM, standard regarding the probable carcinogenic risks of BD to humans error of the mean; TG, 6-thioguanine; TWA, tame-weighted average; UTMB, University of Texas Medical Branch.