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Volume 12
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Article

In Vitro Hepatic Clearance Evaluations of Per- and Polyfluoroalkyl Substances (PFAS) across Multiple Structural Categories

by
David M. Crizer
1,
Julie R. Rice
1,
Marci G. Smeltz
2,
Katelyn S. Lavrich
1,†,
Krishna Ravindra
3,
John F. Wambaugh
4,
Michael DeVito
4 and
Barbara A. Wetmore
4,*
1
Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27711, USA
2
Center for Public Health and Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA
3
Oak Ridge Associated Universities, Oak Ridge, TN 37830, USA
4
Center for Computational Toxicology and Exposure, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA
*
Author to whom correspondence should be addressed.
†
Current address: US Environmental Protection Agency, Region 8 Headquarters, 1595 Wynkoop Street, Denver, CO 80202, USA.
Toxics 2024, 12(9), 672; https://doi.org/10.3390/toxics12090672
Submission received: 12 August 2024 / Revised: 6 September 2024 / Accepted: 10 September 2024 / Published: 14 September 2024
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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Abstract

Toxicokinetic (TK) assays and in vitro–in vivo extrapolation (IVIVE) models are New Approach Methods (NAMs) used to translate in vitro points of departure to exposure estimates required to reach equivalent blood concentrations. Per- and polyfluoroalkyl substances (PFAS) are a large chemical class with wide-ranging industrial applications for which only limited toxicity data are available for human health evaluation. To address the lack of TK data, a pooled primary human hepatocyte suspension model was used with targeted liquid chromatography–mass spectrometry to investigate substrate depletion for 54 PFAS. A median value of 4.52 μL/(min x million cells) was observed across those that showed significant clearance, with 35 displaying no substrate depletion. Bayesian modeling propagated uncertainty around clearance values for use in IVIVE models. Structural evaluations showed the fluorotelomer carboxylic acids were the only PFAS carboxylates showing appreciable clearance, and per- and polyfluorosulfonamides were more readily metabolized than other PFAS sulfonates. Biotransformation product prediction, using the chemical transformation simulator, suggested hydrolysis of PFAS sulfonamides to more stable sulfonic acids, which is an important consideration for exposure modeling. This effort greatly expands the PFAS in vitro toxicokinetic dataset, enabling refined TK modeling, in silico tool development, and NAM-based human health evaluations across this important set of emerging contaminants.
Keywords: PFAS; toxicokinetics (TK); hepatic clearance; in vitro–in vivo extrapolation (IVIVE); New Approach Methods (NAMs); metabolism; biotransformation PFAS; toxicokinetics (TK); hepatic clearance; in vitro–in vivo extrapolation (IVIVE); New Approach Methods (NAMs); metabolism; biotransformation

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MDPI and ACS Style

Crizer, D.M.; Rice, J.R.; Smeltz, M.G.; Lavrich, K.S.; Ravindra, K.; Wambaugh, J.F.; DeVito, M.; Wetmore, B.A. In Vitro Hepatic Clearance Evaluations of Per- and Polyfluoroalkyl Substances (PFAS) across Multiple Structural Categories. Toxics 2024, 12, 672. https://doi.org/10.3390/toxics12090672

AMA Style

Crizer DM, Rice JR, Smeltz MG, Lavrich KS, Ravindra K, Wambaugh JF, DeVito M, Wetmore BA. In Vitro Hepatic Clearance Evaluations of Per- and Polyfluoroalkyl Substances (PFAS) across Multiple Structural Categories. Toxics. 2024; 12(9):672. https://doi.org/10.3390/toxics12090672

Chicago/Turabian Style

Crizer, David M., Julie R. Rice, Marci G. Smeltz, Katelyn S. Lavrich, Krishna Ravindra, John F. Wambaugh, Michael DeVito, and Barbara A. Wetmore. 2024. "In Vitro Hepatic Clearance Evaluations of Per- and Polyfluoroalkyl Substances (PFAS) across Multiple Structural Categories" Toxics 12, no. 9: 672. https://doi.org/10.3390/toxics12090672

APA Style

Crizer, D. M., Rice, J. R., Smeltz, M. G., Lavrich, K. S., Ravindra, K., Wambaugh, J. F., DeVito, M., & Wetmore, B. A. (2024). In Vitro Hepatic Clearance Evaluations of Per- and Polyfluoroalkyl Substances (PFAS) across Multiple Structural Categories. Toxics, 12(9), 672. https://doi.org/10.3390/toxics12090672

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