Himmelstein M W, Turner M J, Asgharian B, Bond J A
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Carcinogenesis. 1994 Aug;15(8):1479-86. doi: 10.1093/carcin/15.8.1479.
1,3-Butadiene (BD), an important commodity chemical used in the production of synthetic rubber, is carcinogenic in B6C3F1 mice and Sprague-Dawley rats, raising concern for potential carcinogenicity in humans. Mice are more sensitive than rats to the carcinogenic effects of BD. Metabolic 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 by epoxide hydrolase. Species differences in metabolic activation and detoxication most likely contribute to the difference in carcinogenic potency of BD by modulating the circulating blood levels of the epoxides. This study measured the in vivo concentrations of BD, BMO and BDE in the blood of male Sprague-Dawley rats and B6C3F1 mice during and following 6 h nose-only exposure to inhaled BD at 62.5, 625 or 1250 p.p.m. BD. Blood samples for BD and BMO (> or = 3 samples/time point) were collected at 2, 3, 4 and 6 h of exposure. Blood samples for BDE were collected at 3 and 6 h of exposure. After exposure, blood 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 using a vial headspace equilibration technique. BD epoxides were extracted into methylene chloride and quantified by gas chromatography-mass spectrometry. The concentration of BD in blood was not directly proportional to the inhaled concentration of BD, suggesting that the uptake of 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 BD. Steady-state blood concentrations of BD were 2.4, 37 and 58 microM in mice and 1.3, 18 and 37 microM in rats exposed to 62.5, 625 and 1250 p.p.m. BD respectively. Both species formed BMO from BD. In mice the respective steady-state BMO concentrations in blood were 0.6, 3.7 and 8.6 microM, compared to BMO blood concentrations in rats of 0.07, 0.94 and 1.3 microM. Mice, but not rats, had quantifiable levels of BDE in the blood. The peak concentrations of BDE in the blood of mice at 6 h were 0.65, 1.9 and 2.5 microM.(ABSTRACT TRUNCATED AT 400 WORDS)
1,3 - 丁二烯（BD）是一种用于生产合成橡胶的重要化工原料，对B6C3F1小鼠和斯普拉格 - 道利大鼠具有致癌性，这引发了人们对其对人类潜在致癌性的担忧。小鼠对BD的致癌作用比大鼠更敏感。BD经代谢活化形成假定的DNA反应性代谢产物丁二烯单环氧化物（BMO）和丁二烯双环氧化物（BDE），这一过程由细胞色素P450介导。环氧化物的解毒通过谷胱甘肽S - 转移酶催化与谷胱甘肽结合以及环氧化物水解酶水解来实现。代谢活化和解毒的种属差异很可能通过调节环氧化物的循环血液水平导致BD致癌效力的差异。本研究测定了雄性斯普拉格 - 道利大鼠和B6C3F1小鼠在仅经鼻吸入浓度为62.5、625或1250 ppm BD的6小时期间及之后血液中BD、BMO和BDE的体内浓度。在暴露的2、3、4和6小时采集用于检测BD和BMO（每个时间点≥3个样本）的血样。在暴露的3和6小时采集用于检测BDE的血样。暴露后，在暴露后30分钟内每隔2 - 10分钟采集用于检测BD、BMO和BDE的血样。BD通过使用小瓶顶空平衡技术的气相色谱法定量。BD环氧化物被萃取到二氯甲烷中并通过气相色谱 - 质谱法定量。血液中BD的浓度与吸入的BD浓度不成正比，这表明在最高吸入浓度下BD的摄取是饱和的。在大鼠和小鼠中，BD和BMO的血液水平在暴露的2、3、4和6小时达到稳态，并且在停止暴露于BD后迅速下降。暴露于62.5、625和1,250 ppm BD的小鼠血液中BD的稳态浓度分别为2.4、37和58微摩尔，大鼠分别为1.3、18和37微摩尔。两种动物均由BD形成BMO。小鼠血液中BMO的稳态浓度分别为0.6、3.7和8.6微摩尔，而大鼠血液中BMO的浓度为0.07、0.94和1.3微摩尔。小鼠血液中有可量化水平的BDE，而大鼠没有。小鼠血液中BDE在6小时的峰值浓度分别为0.65、1.9和2.5微摩尔。（摘要截短至4**00字）
