PHYSIOLOGICAL PHARMACOKINETICS AND CANCER RISK ASSESSMENT

There has been considerable progress in recent years in developing phy siological models for the pharmacokinetics of toxic chemicals and in t he application of these models in cancer risk assessment. Physiologica l pharmacokinetic models consist of a number of individual compartment s, based on the anatomy and physiology of the mammalian organism of in terest, and include specific parameters for metabolism, tissue binding , and tissue reactivity. Because of the correspondence between these c ompartments and specific tissues or groups of tissues, these models ar e particularly useful for predicting the doses of biologically active forms of toxic chemicals at target tissues under a wide variety of exp osure conditions and in different animal species, including humans. Du e to their explicit characterization of the biological processes gover ning pharmacokinetic behaviour, these models permit more accurate pred ictions of the dose of active metabolites reaching target tissues in e xposed humans and hence of potential cancer risk. In addition, physiol ogical models also permit a more direct evaluation of the impact of pa rameter uncertainty and inter-individual variability in cancer risk as sessment. In this article, we review recent developments in physiologi c pharmacokinetic modeling for selected chemicals and the application of these models in carcinogenic risk assessment. We examine the use of these models in integrating diverse information on pharmacokinetics a nd pharmacodynamics and discuss challenges in extending these pharmaco kinetic models to reflect more accurately the biological events involv ed in the induction of cancer by different chemicals.