The importance of metabolite identification in quantitative risk estimation.

In the search to define the mechanisms by which xenobiotics produce their toxic effects in biological systems, the importance of metabolism data is clear. Although the detection of electrophilic metabolites and reactive intermediates may challenge our analytical technology, the toxic responses manifested by these agents are often obvious. The identification of toxicologically significant minor metabolites may exceed the state of the art in analytical methodology. New advances in technology may provide the needed answers. As we begin to face the significance of activation reactions, particularly in the area of carcinogenesis, it becomes apparent that metabolism to electrophiles that react covalently with DNA, is not the only mechanism by which the tumorigenic response is produced. The production of tumors by nongenotoxic (epigenetic) means is also important. Exposure to high and sustained levels of exposure to a xenobiotic that leads to a perturbation in metabolic, endocrine or physiologic pathways or tissue injury may also produce tumors. Only through investigations which include definitive metabolite identification and quantitation can the mechanism by which these agents exert their toxicity be identified. The ramification of dose response relationships for genotoxic and nongenotoxic carcinogens will be presented to demonstrate the impact of metabolite identification in quantitative risk estimation.