Summit Toxicology, Orange, Ohio 44022, USA.
Crit Rev Toxicol. 2010 Oct;40 Suppl 1:1-11. doi: 10.3109/10408444.2010.507181.
1,3-Butadiene (BD) is a multisite carcinogen in laboratory rodents following lifetime exposure, with mice demonstrating greater sensitivity than rats. In epidemiology studies of men in the styrene-butadiene rubber industry, leukemia mortality is associated with butadiene exposure, and this association is most pronounced for high-intensity BD exposures. Metabolism is an important determinant of BD carcinogenicity. BD is metabolized to several electrophilic intermediates, including epoxybutene (EB), diepoxybutane (DEB), and epoxybutane diol (EBD), which differ considerably in their genotoxic potency (DEB >> EB > EBD). Important species differences exist with respect to the formation of reactive metabolites and their subsequent detoxification, which underlie observed species differences in sensitivity to the carcinogenic effects of BD. The modes of action for human leukemia and for the observed solid tumors in rodents are both likely related to the genotoxic potencies for one or more of these metabolites. A number of factors related to metabolism can also contribute to nonlinearity in the dose-response relationship, including enzyme induction and inhibition, depletion of tissue glutathione, and saturation of oxidative metabolism. A quantitative risk assessment of BD needs to reflect these species differences and sources of nonlinearity if it is to reflect the current understanding of the disposition of BD.
1,3-丁二烯（BD）是一种多部位致癌物质，在实验室啮齿动物中，终身暴露于这种物质后会引发癌症，其中小鼠比大鼠更敏感。在苯乙烯-丁二烯橡胶工业中男性的流行病学研究中，白血病死亡率与丁二烯暴露有关，而高强度 BD 暴露的关联最为明显。代谢是 BD 致癌性的一个重要决定因素。BD 可代谢为几种亲电中间体，包括环氧丁烯（EB）、双环氧丁烷（DEB）和环氧丁烷二醇（EBD），它们在遗传毒性强度上有很大差异（DEB >> EB > EBD）。在形成反应性代谢物及其随后的解毒方面，存在重要的物种差异，这是观察到 BD 致癌作用敏感性的物种差异的基础。人类白血病和啮齿动物中观察到的实体肿瘤的作用模式都可能与这些代谢物之一或多种的遗传毒性强度有关。与代谢有关的许多因素也会导致剂量-反应关系的非线性，包括酶的诱导和抑制、组织谷胱甘肽的耗竭以及氧化代谢的饱和。如果要反映当前对 BD 处置的理解，BD 的定量风险评估需要反映这些物种差异和非线性来源。
