Interspecies metabolism of heterocyclic aromatic amines and the uncertainties in extrapolation of animal toxicity data for human risk assessment

Heterocyclic aromatic amines (HAAs) are potent bacterial mutagens that are formed in cooked meats, tobacco smoke condensate, and diesel exhaust. Many HAAs are carcinogenic in experimental animal models. Because of their wide-spread occurrence in the diet and environment, HAAs may contribute to some common types of human cancers. The extrapolation of animal toxicity data on HAAs to assess human health risk has many uncertainties, which can lead to tenuous risk assessment estimates. Perhaps the most critical and variable parameters in interspecies extrapolation are the effects of dose, species differences in catalytic activities of xenobiotic metabolism enzymes (XMEs), human XME polymorphisms that lead to interindividual differences in carcinogen metabolism, and dietary constituents that may either augment or diminish the carcinogenic potency of these genotoxins. The impact of these parameters on the metabolism and toxicological properties of HAAs and uncertainties in extrapolation of animal toxicity data for human risk assessment are presented in this article.