This protocol supports studies of human populations which investigate the toxic hazards of exposure to mutagenic agents using biological markers of exposure and effects to exposure. The primary exposures currently under study are to 1,3-butadiene, a chemical used to make synthetic rubber and other polymers, and cigarette smoking. In addition, studies to improve the methodology are in progress. The primary biological marker in use is an assay for the frequency of mutations at the hprt gene in human lymphocytes. Results are coupled with measurements of exposure by personal monitoring using badge dosimeters (for butadiene) and biological exposure based on measurements of metabolite concentrations in plasma or urine. These studies have demonstrated that in workers exposed to butadiene and in cigarette smokers an increase of about 4 fold in the frequency of hprt mutants compared to control groups. These results demonstrate that exposures to both butadiene and cigarette smoking significantly increase the frequency of mutations. Since mutation is a precursor event in carcinogenesis an increase in mutant frequency indicates an increased cancer risk in these populations. This is not surprising in the case of cigarette smoking, a well documented carcinogenic activity. Recent results of epidemiological studies of butadiene exposed workers have demonstrated a causal link between exposure and an increased incidence of leukemias. Our results are of significance in that they indicate that current occupational exposure levels, although lower than in the past, may still be high enough to pose a cancer risk. We plan to continue these studies with the evaluation of a polybutadiene production facility. In addition, we are developing molecular techniques for the analysis of isolated hprt mutant clones to determine their origin and to determine the structural characteristics of the mutations.
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