Physiologically Based Pharmacokinetic Toxicokinetic Modeling In Risk Assessment

Physiologically-based pharmacokinetic (PBPK) modeling has become the tool of choice to develop estimates of target site dosimetries in animals and humans for risk assessment purposes. PBPK model compartments correspond directly to the tissues and organs in the species. The drawbacks of PBPK modeling primarily relate to the time, effort and cost involved in appropriately developing, validating and applying a model. We outline some of the practical issues involved in the appropriate development of a PBPK model. Among the first models to be developed and used for risk assessment were those for volatile organics. These basic models are discussed in this report. For some chemicals, however, simpler models are not enough to adequately describe the data. We discuss some of the issues involved in the development of more complex PBPK models. Issues may include more detailed modeling of metabolic processes and specific organs; changes in physiology due to development, pregnancy or aging (life-stage modeling); and interactions between more than one chemical. It may also be necessary to interface the pharmacokinetic models with models of the interaction of the chemical with the target tissue (pharmacodynamic PD models) in order to provide a more complete description of the overall process. Certain experimental techniques are central to the successful development of PBPK models. These include methods to experimentally determine blood and tissue partition coefficients, metabolic parameters, and exposure kinetics.