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A tiered approach to incorporate exposure and pharmacokinetics considerations in in vitro based safety assessment
Citation:
Tan, C. A tiered approach to incorporate exposure and pharmacokinetics considerations in in vitro based safety assessment. 2018 SOT Annual Meeting and ToxExpo, San Antonio, TX, March 11 - 15, 2018.
Impact/Purpose:
This presentation is part of a continuing education course that will be presented at the Society of Toxicology Annual Meeting in March 2018. Physiologically based pharmacokinetic (PBPK) models have been applied to chemical risk and safety assessments for more than three decades. Currently, extrapolation of animal toxicity findings to humans has been the major application of PBPK models in risk assessment. Under the proposed new toxicity testing paradigm, which relies on data from human-relevant in vitro toxicity assays interpreted through computational approaches, PBPK models have been redefined as a critical translation tool for quantitative in vitro to in vivo extrapolation, The models would link effect concentrations in cell-based assays to equivalent human exposures. PBPK models provide a biologically relevant integration platform to describe the absorption, distribution, metabolism, and excretion of chemicals based on a wide range of in vitro, in silico, and if available, in vivo information. This course will provide an opportunity to revisit the basic principles of PBPK modeling with a special focus on supporting chemical safety assessment under the new toxicity testing paradigm. In addition to describing the basics of model construction, recent advances in model parametrization including in vitro to in vivo extrapolation and in silico prediction will be presented.
Description:
Application of in vitro based safety assessment requires reconciling chemical concentrations sufficient to produce bioactivity in vitro with those that trigger a molecular initiating event at the relevant in vivo target site. To address such need, computational tools such as physiologically based pharmacokinetic (PBPK) modeling and molecular chemistry modeling can be used in a tiered approach to evaluate the potential for chemicals to reach a target site given their likely exposure concentrations, along with comparing chemical concentrations at target sites to in vitro doses at which bioactivities are observed.
