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

Vinyl chloride (VC) is a trans-species carcinogen, producing tumors in a va riety of tissues, from both inhalation and oral exposures, across a number of species. In particular, exposure to VC has been associated with a rare t umor, liver angiosarcoma, in a large number of studies in mice, rats, and h umans. The mode of action for the carcinogenicity of VC appears to be a rel atively straightforward example of DNA adduct formation by a reactive metab olite, Leading to mutation, mistranscription, and neoplasia. The objective of the present analysis was to investigate the comparative potency of a cla ssic genotoxic carcinogen across species, by performing a quantitative comp arison of the carcinogenic potency of VC using data from inhalation and ora l rodent bioassays as well as from human epidemiological studies. A physiol ogically-based pharmacokinetic (PBPK) model for VC was developed to support the target tissue dosimetry for the cancer risk assessment. Unlike previou s models, the initial metabolism of VC was described as occurring via two s aturable pathways, one representing low capacity-high affinity oxidation by CYP2E1 and the other (in the rodent) representing higher capacity-lower af finity oxidation by other isozymes of P450, producing in both cases chloroe thylene oxide (CEO) and chloroacetaldehyde (CAA) as intermediate reactive p roducts. Depletion of glutathione by reaction with CEO and CAA was also des cribed. Animal-based risk estimates for human inhalation exposure to VC usi ng total metabolism estimates from the PBPK model were consistent with risk estimates based on human epidemiological data, and were lower than those c urrently used in environmental decision-making by a factor of 80. (C) 2001 Elsevier Science B.V. All rights reserved.