PBPK Modelling for Environmental Chemicals: Linking to In Vitro Data

摘要

The field of toxicology is currently undergoing a global paradigm shift to use of in vitro approaches for assessing the risks of chemicals and drugs, yielding results more rapidly and more mechanistically based than current approaches relying primarily on live animal testing. However, the use of in vitro data in risk assessment entails a number of new challenges associated with translating the in vitro data on bioactive concentrations into estimates of safe in vivo exposures. When used within a Mode of Action / Adverse Outcome Pathway framework, physiologically based pharmacokinetic (PBPK) models provide an effective tool for conducting quantitative in vitro to in vivo extrapolation (IVIVE). Their physiological structure facilitates the incorporation of in silico- and in vitro-derived chemical-specific parameters in order to predict in vivo absorption, distribution, metabolism and excretion. In particular, the combination of in silico and in vitro parameter estimation with PBPK modeling can be used to predict the in vivo exposure conditions that would produce chemical concentrations in the target tissue equivalent to the concentrations at which effects were observed with in vitro assays of tissue/organ toxicity. They can also support the identification of potentially susceptible populations associated with age-dependent pharmacokinetics or metabolic polymorphisms. This presentation will describe the key elements of IVIVE and the critical issues that must be addressed to move forward. Two examples of PBPK-based IVIVE will be described: the use of in vitro assays and PBPK modeling to estimate a margin of exposure for endocrine active compounds and the use of in vitro metabolism data and PBPK modeling to evaluate early life sensitivity to pesticides.