Summit Toxicology, Orange, Ohio 44022, USA.
Crit Rev Toxicol. 2010 Oct;40 Suppl 1:74-92. doi: 10.3109/10408444.2010.507183.
1,3-Butadiene (BD) is a multisite carcinogen in laboratory rodents following lifetime exposure, with greater potency in the mouse than the rat, and is associated with an increase in leukemia mortality in highly exposed workers. Species differences in the formation of reactive metabolites underlie observed species differences in sensitivity to the carcinogenic effects of BD. The modes of action (MOAs) for human leukemia and rodent tumors are both likely related to mutagenic potencies of one or more of these metabolites. However, differences in the nature of genotoxic lesions associated with human leukemia and rodent tumors, along with their implications for risk assessment, require that they be discussed separately. The MOAs for BD are assessed in this review using the modified Hill criteria and human relevance framework. Key events in MOAs for human and rodent cancers are identified, along with important species differences and sources of nonlinearity for each event that can affect extrapolations made from high- to low-dose exposures. Because occupational exposures to BD have also included co-exposures to styrene and dimethyldithiocarbamide (DMDTC), potential interactions with BD carcinogenicity are also discussed. The MOAs for BD carcinogenesis will be used to guide key decisions made in the quantitative cancer dose-response assessment.
1,3-丁二烯（BD）是一种在实验室啮齿动物中具有多部位致癌性的物质，在老鼠中的致癌作用强于大鼠，并且与高度暴露的工人中白血病死亡率的增加有关。在形成反应性代谢物方面的物种差异是导致观察到 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肿瘤的作用机制（MOAs）都可能与这些代谢物中的一种或多种的致突变能力有关。然而，与人类白血病和啮齿动物肿瘤相关的遗传毒性损伤的性质存在差异，以及它们对风险评估的影响，需要分别讨论。本综述使用改良的希尔标准和人类相关性框架评估 BD 的 MOAs。确定了人类和啮齿动物癌症 MOAs 的关键事件，以及每个事件的重要物种差异和非线性来源，这些差异和非线性来源可能会影响从高剂量暴露到低剂量暴露的推断。因为职业暴露于 BD 还包括对苯乙烯和二甲基二硫代氨基甲酸盐（DMDTC）的共同暴露，因此还讨论了它们与 BD 致癌性的潜在相互作用。BD 致癌作用的 MOAs 将用于指导定量癌症剂量-反应评估中的关键决策。
