BD, an important industrial chemical with widespread human exposure, was long thought to be a low-level and non-cumulative toxin. However, inhalation studies demonstrate that BD is a potent, multi-site carcinogen in B6C3F1 mice while only a weak carcinogen in S-D rats. Human epidemiological studies consistently linked excess mortality from lymphatic and hematopoietic cancers with occupational BD exposure. All three species metabolize BD to reactive expoxides. The pronounced species difference in BD-induced carcinogenesis is hypothesized to be the result of quantitative differences in bioactivation and deactivation of reactive BD epoxides. This hypothesis suggests the appropriate animal model for human BD risk assessments is the S-D rat. However, other researchers report information that either contradicts or is inadequately explained by the reactive epoxide hypothesis. These investigators suggest the appropriate animal model for human BD risk assessments are B6C3F1 mice. Presently BD is identified as a highly toxic air pollutant by the EPA and as a 2A carcinogen by the IARC. Many researchers question the association between occupational BD exposure and cancer while others support this contention. To investigate these questions and determine which animal model best represents human BD metabolism, we will conduct 14C-BD mass balance experiments in all three species using precision-cut liver slices. We will correlate epoxide bioactivation and/or deactivation with hepatic genotoxic endpoints, and lastly, we will investigate the role stereochemical differences in BD metabolism, and/or entantiomeric differences in hepatic toxicity may play in species differences in BD-induced carcinogenesis. Correlations will be made between in vitro animal and human data and in vivo data.
