1,3-Butadiene: III. Assessing carcinogenic modes of action.

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.