Comparison of cancer risk estimates for vinyl chloride using animal and human data with a PBPK model

Vinyl chloride ŽVC. is a trans-species carcinogen, producing tumors in a variety of tissues, from both inhalation and oral exposures, across a number of species. In particular, exposure to VC has been associated with a rare tumor, liver angiosarcoma, in a large number of studies in mice, rats, and humans. The mode of action for the carcinogenicity of VC appears to be a relatively straightforward example of DNA adduct formation by a reactive metabolite, leading to mutation, mistranscription, and neoplasia. The objective of the present analysis was to investigate the comparative potency of a classic genotoxic carcinogen across species, by performing a quantitative comparison of the carcinogenic potency of VC using data from inhalation and oral rodent bioassays as well as from human epidemiological studies. A physiologically-based pharmacokinetic ŽPBPK. model for VC was developed to support the target tissue dosimetry for the cancer risk assessment. Unlike previous models, the initial metabolism of VC was described as occurring via two saturable pathways, one representing low capacity-high affinity oxidation by CYP2E1 and the other Žin the rodent. representing higher capacity-lower affinity oxidation by other isozymes of P450, producing in both cases chloroethylene oxide ŽCEO. and chloroacetaldehyde ŽCAA. as intermediate reactive products. Depletion of glutathione by reaction with CEO and CAA was also described. Animal-based risk estimates for human inhalation exposure to VC using total metabolism estimates from the PBPK model were consistent with risk estimates based on human epidemiological data, and were lower than those currently used in environmental decision-making by a factor of 80.