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1,3-Butadiene (BD), a compound used extensively in the rubber industry, is weakly carcinogenic in Sprague-Dawley rats after chronic exposures to concentrations of 1000 and 8000 ppm. Conversely, in B6C3F1 mice, tumors occur after chronic exposures to concentrations as low as 6.25 ppm. Previously, we have shown that tissue concentrations of the mutagenic BD metabolites, butadiene monoepoxide (BDO) and butadiene diepoxide (BDO2), are present in greater concentrations in mice than in rats following acute exposures to low levels (100 ppm or less). This disparity was particularly significant for the diepoxide. We hypothesized that if these epoxides are involved in the carcinogenic response of BD, then they will also be present in rat tissues at relatively high concentrations following exposures to 8000 ppm BD. In the present study, concentrations of the BD epoxides, BDO and BDO2, were determined in blood of female Sprague-Dawley rats following a single 6-h exposure and 10 repeated exposures to a target concentration of 8000 ppm BD. Concentrations of these epoxides were also determined in a number of other tissues, including the primary rat target organ-mammary gland-following 10 repeated exposures. Blood concentrations of BDO were 4030 pmol/g +/- 191 following a 6-h exposure and were 18% lower following the 10-day exposure. Blood concentrations of BDO2, following the 8000 ppm exposures, were very similar to those previously observed after exposures to 62.5 ppm BD (11 +/- 1 and 17 +/- 1 pmol/g following exposures of 6h and 6h/day for 10 days, respectively.) Concentrations of BDO ranged from 740 +/- 110 (femur) to 8990 +/- 1150 (fat) pmol/g tissue. Concentrations of BDO2 were similar among eight tissues analyzed, ranging from 5 +/- 1 (femur) to 17 +/- 3 (heart) pmol/g tissue. Tissue concentrations of butadiene monoepoxide were increased by 17- to 50-fold in tissues from rats exposed by inhalation to 8000 ppm BD as compared to tissues from rats exposed to 62.5 ppm BD. Based on earlier studies at our institute the internal dose of BD increases approximately 14-fold in the 8000 ppm-exposed rats compared to rats exposed to 62.5 ppm BD. Concentrations of butadiene diepoxide in rat tissues following an exposure to 8000 ppm BD were similar to those observed in rat tissues following exposures to 62.5 ppm BD. This study shows that pathways responsible for the accumulation of BDO2 in rats are saturated following low-level BD exposures. This suggests that the primary determinant of BD tumorigenicity in rats is not butadiene diepoxide. The high levels of BDO observed in rat mammary tissue suggest that this metabolite may be a more important determinant of BD carcinogenesis in the rat.

toxicological sciences

Disposition of Butadiene Epoxides in Sprague-Dawley Rats Following Exposures to 8000 ppm 1,3-Butadiene: Comparisons with Tissue Epoxide Concentrations Following Low-Level Exposures