Concern over exposure to 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 PFAS estimates ranging to over 10,000, the limited exposure and toxicologic data currently available is inadequate to provide an understanding of the potential exposures, toxicokinetics (TK), and toxicities across this diverse domain. New approach methods (NAMs) use in vitro high-throughput screening (HTS) to assess potential effects and require incorporation of in vitro TK data to translate bioactive in vitro assay concentrations to an administered equivalent dosage (AED) necessary for chemical risk evaluations. To address this need, NAM toxicity and TK data have been generated on over 100 PFAS, selected primarily to facilitate category-based read-across and capture structural diversity. Generally, HTS data characterizing phenotypic profiles, nuclear receptor activation, immunosuppression, and developmental neurotoxicity indicate increased bioactivity for those PFAS with higher carbon number and/or molecular weights exceeding 330 g/mol, with several noting activity for PFAS sulfonamides. While PFAS nuclear receptor targets were identified (e.g., peroxisome proliferator-activated receptors), similar or lower potencies were observed compared to the overall ToxCast chemical library screened to date. TK plasma protein binding (PPB) measures for PFAS showed higher binding than is typical for non-PFAS commercial chemicals, with median fraction unbound in plasma (f_up) values of 0.023 vs. 0.13, respectively. Highest binding was observed for perfluorocarboxylates, perfluoroalkanoyl chlorides, and perfluoropolyether carboxylates. High binding generally increases tissue distribution, reduces renal elimination, and decrease rate of metabolism. Measured human hepatic clearance rates were minimal for most, with metabolism noted primarily for PFAS alcohols, amides, and sulfonamides. Efforts incorporating TK to predict AEDs for HTS data demonstrate that PPB differences drive the range of values derived, with legacy PFAS remaining those with the highest systemic concentrations after exposure. These findings have enabled refinements to a NAM based read-across approach to estimate risk for the broader untested PFAS domain.

Grace Patlewicz

Appearances