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.

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This paper presents a simulation modeling approach to establish biological exposure indexes (BEIs) from ambient occupational exposure limits (OELs). A physiologically based pharmacokinetic (PB-PK) model was used to describe the disposition of volatile organic chemicals in the human. The model was used to simulate an exposure regimen similar to a typical work schedule. Exposure concentrations were set to equal the ambient OELs of the corresponding chemicals. Chemical concentrations in the expired air and blood and concentrations of metabolites in the urine were estimated with the PB-PK model for this exposure condition. Because the OELs establish the criteria for ambient exposure to chemicals, the concentrations of chemicals or their metabolites in biological media resulting from exposure to the OELs would likewise define acceptable exposure standards. On the basis of this rationale and method, BEIs were developed for 13 common industrial organic chemicals.

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This chapter presents the readers with a primer on the subject of physiologically based pharmacokinetic (PBPK) modelling. It discusses the theory and principles of PBPK modelling, and compares and contrasts it with classical pharmacokinetic modelling. It describes the multiple steps involved in developing PBPK models, and includes a compilation, with complete referencing, of published PBPK models for environmental chemicals that have been developed to date. The many applications of PBPK modelling to address issues in toxicology and health risk assessment are discussed with relevant examples. It concludes with some discussion of the problems and limitations in PBPK modelling, and offers some observations about future directions for this rapidly emerging field.

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