The impact of chemical mixtures on the assumptions of additivity, susceptibility and bioavailability in human health risk assessments

The purpose of this research is to evaluate the default assumptions of additivity, susceptibility and bioavailability in human health risk assessments. In vivo studies were performed to assess the impact of age, strain and gene expression on the interactions of two common environmental carcinogens, benzo[a]pyrene (B[a]P) and 2,3,4,5,6-pentachlorophenol (PCP). Infant and adult 136C3F1 male mice were exposed to 55mg B[ a]P/g body weight alone and in combination with PCP through i.p. injection. Hepatic and lung DNA was analyzed for +/-anti-7,8-diol-9,10-epoxide-B[ a]P-N2-Guanine (BPDE-N2G) DNA adducts using the 32P-postlabeling assay. An antagonistic effect on BPDE-N2G adducts was observed in infant mice exposed to mixtures of B[a]P and PCP compared to mice exposed to B[a ]P alone. Comparatively, PCP potentiated BPDE-N2G formation in adult B6C3F1 mice (p < 0.05) revealing that the influence of PCP on BPDE-N2G DNA adduct formation is age dependent. Additionally, adult p53 wild-type and knockout mice were exposed to the same mixture of B[a]P and PCP. PCP antagonized BPDE-N2G formation in mice expressing functional p53 protein but not in knockout mice, suggesting that the p53 protein and corresponding protective pathways were induced by PCP but not B[a]P. These experiments reveal that PCP acts in both a potentiative and antagonistic manner on BPDE-N2G formation depending on the age, strain and genetic characteristics of the animal model used. The default assumption of 100% bioavailability was investigated in Fischer 344 rats that were exposed to soil containing unaged and aged coal tar (CT) contaminated diets for 17 days. Hepatic and lung DNA was analyzed for non-polar DNA adducts associated with the polycyclic aromatic hydrocarbons (PAHs) present in CT. Results from this study revealed that the presence of contaminants in the soil, but not aging, decreased the bioavailability of the DNA reactive components in CT. Collectively, these studies demonstrate that the default assumptions of additivity between chemicals in a mixture and 100% bioavailability are not accurate for all environmental contaminants.