HUMAN SENSITIVITY TO GENOTOXIC EFFECTS OF BUTADIENE

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1,3-Butadiene is a widely used chemical in the manufacture of synthetic rubber and other polymers. It is carcinogenic in laboratory animals and evidence of its carcinogenic effects in man have been greatly strengthened by a recent update of the ongoing evaluation of workers in the rubber industry which showed a significant association between butadiene exposure and leukemia. a more complete understanding of the health risks faced by workers exposed to levels of butadiene in facilities in use today is urgently needed. Furthermore, a large percentage of the general public is exposed daily to low levels of butadiene from auto emissions, cigarette smoke and other sources. We earlier documented that workers exposed to about 1 ppm of butadiene had a significant elevation in the frequency of mutations at the hprt gene in their lymphocytes. The purpose of this project is to evaluate current conditions of occupational exposure to butadiene using biological markers of exposure, effect and susceptibility. During the first cycle of this grant we confirmed our earlier finding of increased hprt mutant lymphocyte frequencies in workers. The research proposed for the renewal of this project will address three knowledge gaps: 1) better defining the relationship between butadiene exposure and biological effects, 2) characterizing the types of mutations induced by butadiene, and 3) the role of activating and detoxifying enzymes in the metabolism and genetic toxicity of butadiene. A previously studied population of workers in a styrene-butadiene polymer plant and a new population in a polybutadiene plant will be evaluated. The specific aims of the project are 1) to more precisely define the relationship between exposure and hprt mutation induction using repeated measurements of air concentration of butadiene and the concentration of a urinary metabolite, 2) to determine the spectrum of hprt mutations in lymphocyte clones, and 3) to characterize the role of metabolism in individual susceptibility to the mutagenic effects of butadiene by determining polymorphic variations activating and detoxifying enzymes CYP 2E1 and GST T1 and M1.