COMPARISON OF BLOOD-CONCENTRATIONS OF 1,3-BUTADIENE AND BUTADIENE EPOXIDES IN MICE AND RATS EXPOSED TO 1,3-BUTADIENE BY INHALATION

1,3-Butadiene (BD), an important commodity chemical used in the produc tion of synthetic rubber, is carcinogenic in B6C3F1 mice and Sprague-D awley rats, raising concern for potential carcinogenicity in humans. M ice are more sensitive than rats to the carcinogenic effects of BD. Me tabolic activation of BD to form the putative DNA-reactive metabolites , butadiene monoxide (BMO) and butadiene diepoxide (BDE), is mediated by cytochrome P450. Detoxication of the epoxides occurs by glutathione S-transferase-catalyzed conjugation with glutathione and hydrolysis b y epoxide hydrolase. Species differences in metabolic activation and d etoxication most likely contribute to the difference in carcinogenic p otency of BD by modulating the circulating blood levels of the epoxide s. This study measured the in vivo concentrations of BD, BMO and BDE i n the blood of male Sprague-Dawley rats and B6C3F1 mice during and fol lowing 6 h nose-only exposure to inhaled BD at 62.5, 625 or 1250 p.p.m . BD. Blood samples for BD and BMO (greater than or equal to 3 samples /time point) were collected at 2, 3, 4 and 6 h of exposure. Blood samp les for BDE were collected at 3 and 6 h of exposure. After exposure, b lood samples for BD, BMO and BDE were collected at 2-10 min intervals up to 30 min post-exposure. BD was quantified by gas chromatography us ing a vial headspace equilibration technique. BD epoxides were extract ed into methylene chloride and quantified by gas chromatography-mass s pectrometry. The concentration of BD in blood was not directly proport ional to the inhaled concentration of BD, suggesting that the uptake o f BD was saturable at the highest inhaled concentration. In both rats and mice, BD and BMO blood levels were at steady-state at 2, 3, 4 and 6 h of exposure, and declined rapidly after removal from exposure to B D. Steady-state blood concentrations of BD were 2.4, 37 and 58 mu M in mice and 1.3, 18 and 37 mu M in rats exposed to 62.5, 625 and 1250 p. p.m. BD respectively. Both species formed BMO from BD. In mice the res pective steady-state BMO concentrations in blood concentrations in rat s of 0.07, 0.94 and 1.3 mu M. Mice, but not rats, had quantifiable lev els of BDE in the blood. The peak concentrations of BDE in the blood o f mice at 6 h were 0.65, 1.9 and 2.5 mu M. These data suggest that the greater sensitivity of mice to BD-induced carcinogenicity can be expl ained, in part, by the higher levels of both BMO and BDE in the blood of mice compared to rats.