Human Sensitivity to Genotoxic Effects of Butadiene

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DESCRIPTION (provided by applicant): Butadiene (BD) is a gaseous compound used in the manufacture of synthetic rubber and is an environmental contaminant derived from auto exhaust and tobacco smoke. It is a potent rodent carcinogen and probable human carcinogen. At current levels of occupational exposure it will be very difficult to determine the cancer risks related to workplace BD exposure. The broad objective of this project has been to characterize human sensitivity to BD by using biological markers of exposure, markers of the effects of exposure, and markers of susceptibility to exposure in BD-exposed workers. In the previous project period we found that BD exposure is associated with an increase in the concentration of a butadiene-related metabolite in urine, and a dose-related increase in hprt mutation in lymphocytes with an. increased proportion of deletion and frameshift mutations. Also, the frequency of mutations was increased in BD-exposed individuals with a combination of polymorphisms resulting in low activity of microsomal epoxide hydrolase (mEH). The aims of the current proposal are to 1) delineate the influence of microsomal epoxide hydrolase polymorphisms on mutant frequency and on the spectrum of different types of mutations in the HPRT gene in individuals occupationally exposed to BD, 2) characterize, in vitro, the functional significance of mEH polymorphisms in butadiene diepoxide- induced genetic damage, and 3) characterize how the stability of the different allelic forms of mEH proteins contributes to the cellular level of mEH activity. Through these aims we expect to better understand how genetic variation in mEH influences human sensitivity to the genotoxic effects of BD, and better understand the role of variants in biotransformation genes in modifying human susceptibility to toxic chemicals