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John Wambaugh

OpenTox 2022 Virtual Conference  

PBPK and Toxicokinetics Modeling 

A model of toxicokinetics (TK) quantitatively describes the body’s absorption, distribution,  metabolism, and excretion (ADME) of a chemical or substance. (Different terms for this concept  are preferred in different fields, including “toxicokinetics”, “pharmacokinetics”, “biokinetics”,  and simply “kinetics”; here we use “TK”). TK models are used to estimate internal dose following  an external exposure or infer an exposure from a measured chemical concentration in a biological sample. Because TK relates chemical concentrations in the body to external exposures that cause  those concentrations TK plays a key role in quantitative risk assessment; that is, determining the  amount of chemical exposure associated with adverse outcomes. Physiologically based TK  models (PBTK) in particular support chemical risk assessment by explaining ADME data in terms  of key physiological processes, allowing consideration of the relevance of those processes when  extrapolating to new situations. There are thousands of chemicals present in our environment,  and there is a need to rapidly assess potential risk to human health for these chemicals. In vitro high throughput screening (HTS) assays and in silico quantitative structure-activity relationships  (QSARs) are two methods that now provide predictions of potential adversity for thousands of  chemicals, but to interpret these in a risk context the predictions must be extrapolated to an  equivalent in vivo external dose or exposure (in vitro-in vivo extrapolation, or IVIVE). The equivalent external dose can then be compared to estimates of exposure to assess potential risk.  IVIVE for thousands of chemicals requires rapid approaches therefore a high throughput toxicokinetics (HTTK) approach is needed. HTTK methods use generic TK models, including PBTK,  that can be parameterized rapidly for large numbers of chemicals using in vitro measurements  and/or in silico predictions of chemical-specific TK properties like metabolism. TK, PBTK, and  HTTK for IVIVE are all important considerations for next generation risk assessment. This abstract  does not necessarily reflect the official policy of the U.S. Environmental Protection Agency.