Quantitative in vitro to in vivo extrapolation (QIVIVE) and physiologically based modelling of human toxicokinetics for AOP-based risk assessment

摘要

For future risk assessments based on in vitro data it will be necessary to perform quantitative in vitro to in vivo extrapolation (QIVIVE) - translation of the in vitro data on bioactive concentrations into estimates of safe in vivo exposures, or extrapolation of the in vitro concentration-effect relationship to an in vivo dose-response, for regulatory use in safety assessments. QIVIVE approaches with differing degrees of complexity can support different aspects of safety assessment, from prioritization to safe exposure estimation. In particular, physiologically based pharmacokinetic (PBPK) modeling can be used to integrate data collected based on aggregate exposure pathways (AEPs) and adverse outcome pathways (AOPs) to support risk-based decisions. Their physiological structure facilitates the incorporation of in silico- and in vitro-derived chemical-specific parameters in order to predict in vivo kinetic behaviors of the test chemicals. With the use of modern parameterization methods based on in silico and in vitro data, PBPK modeling will provide the quantitative bridge from bioactive concentrations in vitro to equivalent in vivo exposure conditions, using the internal exposure at the target tissue as the linking point. Together with the USEPA, we are currently developing an open source PBPK modelling platform, the Population Lifecourse Exposure-To-Health-Effects Model (PLETHEM) suite, to efficiently describe the exposure to health effect continuum using a suite of PBPK models as the integration point. To support high-throughput PBPK modeling, the platform includes capabilities for rapid parameterization of PBPK models, including a database of physiological parameters, automated IVIVE for in vitro metabolism data, and in silico prediction models for tissue partitioning. This freely available PBPK platform will increase the applicability of PBPK models to support the new safety assessment paradigm.