Citation:

Smeltz, M., D. Crizer, L. McMillan, E. Korol-Bexell, M. Strynar, AND B. Wetmore. Generating In Vitro Toxicokinetic Data on Per and Polyfluoroalkyl Substances (PFAS) for use in In Vitro-In Vivo Extrapolation (IVIVE) Modeling. SETAC NA Focus Meeting: Environmental Risk Assessment of PFAS, Durham, NC, August 12 - 15, 2019.

Impact/Purpose:

Poster to be presented at the 2019 SETAC Focused Topic Meeting, scheduled for August 2019 in Durham, NC.

Description:

Concern over exposure and potential health effects of per- and polyfluoroalkyl substances (PFAS) continues to increase as more is learned about their environmental persistence and human bioaccumulative potential. With estimates of unique PFAS currently exceeding 4600 structures, the limited toxicologic data currently available across a small subset is inadequate to provide an understanding of the potential exposures, toxicokinetics and toxicities across this diverse domain. New approach methodologies (NAMs) that use in vitro high-throughput screening (HTS) assays to assess potential effects require incorporation of in vitro toxicokinetic data to translate bioactive in vitro assay concentrations out to an administered dose equivalent necessary in chemical risk evaluations. To address this need, experimental in vitro measures of human plasma protein binding and hepatic clearance are being generated across a panel of PFAS for use in in vitro-in vivo extrapolation (IVIVE) models to predict systemic concentrations given a certain external exposure. Plasma protein binding (PPB) measures using ultracentrifugation showed very high binding rates (i.e., >99.5% bound) across over half of the chemicals assessed to date. The lowest percent binding was ~80% for two compounds, perfluorobutanoic acid and 4H-perfluorobutanoic acid. Overall, this trend toward high PPB rates is distinct from the distribution of values previously observed in studies assessing the commercial chemical space covered under Toxic Substances Control Act (TSCA). Hepatic clearance rates are being derived in cryopreserved primary human hepatocytes (mixed-donor pools) in a tiered fashion, using an initial high-throughput screen followed by a more comprehensive time course to quantitate intrinsic clearance (Clint) rates for those PFAS shown to be cleared. Interestingly, only four of the PFAS screened to date were shown to not undergo hepatic clearance. Follow-up time-course assessments are underway, as are efforts to generate additional TK data across a broader range of PFAS. Once the hepatic clearance and PPB data along with renal clearance estimates are incorporated into the IVIVE model, predicted internal concentrations can then be combined with HTS bioactivity data to provide a risk context for a more informed assessment. The views expressed in this abstract are those of the authors and do not necessarily represent the views or policies of the U.S. Environmental Protection Agency.

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