HUMAN SENSITIVITY TO GENOTOXIC EFFECTS OF BUTADIENE

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1,3-Butadiene is a major industrial chemical which has been shown to be a multipotent carcinogen in mice and rats at concentrations down to 6.25 ppm. While occupational exposure levels are being reduced in response to these findings, it will be many years before the adequacy of current exposure levels for protecting worker health can be judged using traditional epidemiological methods. It is possible to evaluate the biological significance of exposure to genotoxic chemicals at the time of exposure by measuring levels of genetic damage in exposed populations and appropriate control groups. We have conducted a preliminary study to evaluate the mutagenic and biochemical effects of occupational exposure to butadiene in a production facility. eight workers from areas where exposures average 3.5 ppm, five workers from areas where exposures averaged 0.03 ppm and six volunteers not employed in the petrochemical industry were evaluated for the frequency of lymphocytes containing mutations at the hprt gene. The highest exposed group had average mutant frequencies about three-fold greater than either the low, or non-exposed groups (p<0.05). In a collaborative study of the same population, the highest exposed group was found to excrete an n-acetyl cysteinyl conjugate of butadiene at significantly higher concentrations than either of the control groups (p<0.03). The correlation between mutant frequency and metabolite concentration was high (R=0.85). We propose to extend and confirm these studies to determine whether current occupational exposures to butadiene result in genetic damage. A population of 15 exposed and 15 less-exposed workers from a butadiene production facility and 15 subjects not employed in the petrochemical industry will be evaluated for genetic damage in lymphocytes using the following endpoints: 1) hprt mutation assay, 2) structural chromosome aberration analysis, 3) evaluation of fidelity of DNA repair and 4) determination of the concentration of a butadiene specific metabolite (1,2-dihydroxy-4-(N- acetylcysteinyl-)S-butane) in the urine. A longitudinal study design will be used in which subjects will be evaluated five times at six month intervals. Repeated sampling will be used to establish the patterns of effects of exposure on these endpoints, to evaluate the effects of changes in exposure, and to increase the statistical power of the study. In the last year of study, two additional populations in polybutadiene, and butadiene-styrene rubber manufacturing plants will also be evaluated. This study will determine the sensitivity of humans to low level butadiene exposure and provide information which will be significant in determining appropriate occupational exposure limits.