Development and utilization of physiologically based pharmacokinetic models for toxicological applications

Recent advances in physiologically based pharmacokinetic (PB-PK) modeling have introduced novel approaches for evaluating toxicological problems. Because PB-PK models are amenable to extrapolation of tissue dosimetry, they are increasingly being applied to chemical risk assessment. This paper reviews the development of PB-PK modeling for toxicological applications. It briefly compares and contrasts the fundamental differences between conventional compartmental analysis and PB-PK modeling. The theory and principles, data requirements and the methodologies to obtain them, and the steps to construct PB-PK models are described. A comprehensive listing of PB-PK models for environmental chemicals developed to date is referenced. Salient applications of PB-PK modeling to toxicological problems are illustrated with examples. Finally, the uncertainties and limitations in PB-PK modeling are also discussed.