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Tox21 Partnership on In Vitro Disposition: Study-design and Potential Impact
Citation:
Paul-Friedman, K. Tox21 Partnership on In Vitro Disposition: Study-design and Potential Impact. Presented at Society of Toxicology Annual Meeting, Baltimore, MD, March 10 - 14, 2019.
Impact/Purpose:
The primary objective of this collaborative Tox21 project is to address the following hypothesis: the physicochemical properties of a given chemical, along with the specific in vitro assay conditions, can be used to predict the difference between ‘nominal’ concentration of a chemical in the medium and ‘true’ medium and cellular concentrations. The in vitro disposition of approximately 200 chemicals is being analytically evaluated, with the goal of developing model predictions of in vitro disposition for the rest of the Tox21 chemical library.
Description:
The use of high-throughput screening (HTS) bioactivity data to inform risk assessments depends on in vitro to in vivo extrapolation (IVIVE) to convert bioactive concentrations in micromolar units to administered dose equivalents (e.g., mg/kg-bw/day). One of the major assumptions of human IVIVE is that chemical partitioning between medium and cells is equivalent to chemical partitioning between blood and tissue in humans. However, in vitro chemical partitioning between media and cells in an in vitro assay is likely dependent on multiple factors, including the amount of serum in the media, the relative binding of the chemical to serum binding proteins, and chemical binding to plastic; all of which have been linked to some extent to chemical log Kow. To date, in vitro partitioning has been evaluated for very few chemicals; thus while mathematical models exist for predicting in vitro disposition, it is unknown how differential chemical partitioning may affect the accuracy of IVIVE predictions made across the Tox21 chemical library. The primary objective of this collaborative Tox21 project is to address the following hypothesis: the physicochemical properties of a given chemical, along with the specific in vitro assay conditions, can be used to predict the difference between ‘nominal’ concentration of a chemical in the medium and ‘true’ medium and cellular concentrations. The in vitro disposition of approximately 200 chemicals is being analytically evaluated, with the goal of developing model predictions of in vitro disposition for the rest of the Tox21 chemical library. Understanding the relationship between chemical structure and assay parameters and medium-to-cell partitioning may enable more accurate extrapolations of in vitro data to in vivo exposures and improve confidence in applications of HTS data to screening level risk assessment applications. This abstract does not necessarily reflect U.S. EPA policy.