APPLICATIONS OF PHYSIOLOGICAL PHARMACOKINETIC MODELING IN CARCINOGENIC RISK ASSESSMENT

The use of physiologically based pharmacokinetic (PBPK) models has bee n proposed as a means of estimating the dose of the reactive metabolit es of carcinogenic xenobiotics reaching target tissues, thereby afford ing an opportunity to base estimates oi potential cancer risk on tissu e dose rather than external levels of exposure. In this article, we de monstrate how a PBPK model can be constructed by specifying mass-balan ce equations for each physiological compartment included in the model. in general, this leads to a system of nonlinear partial differential equations with which to characterize the compartmental system. These e quations then can be solved numerically to determine the concentration of metabolites in each compartment as functions of time. In the speci al case of a linear pharmacokinetic system, we present simple closed-f orm expressions for the area under the concentration-time curves (AUC) in individual tissue compartments. A general relationship between the AUC in blood and other tissue compartments is also established. These results are of use in identifying those parameters in the models that characterize the integrated tissue dose, and which should therefore b e the primary focus of sensitivity analyses. Applications of PBPK mode ling for purposes of tissue dosimetry are reviewed, including models d eveloped for methylene chloride, ethylene oxide, 1,4-dioxane. 1-nitrop yrene, as well as polychlorinated biphenyls, dioxins, and furans. Spec ial considerations in PBPK modeling related to aging, topical absorpti on, pregnancy, and mixed exposures are discussed. The linkage between pharmacokinetic models used for tissue dosimetry and pharmacodynamic m odels for neoplastic transformation of stem cells in the target tissue is explored.