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Plasma Protein Binding of 109 Per- and Polyfluoroalkyl Substances (PFAS): Using Category-Based New Approach Methods to Inform PFAS Toxicokinetics
Citation:
Wetmore, B., M. Smeltz, A. Kreutz, M. Henderson, AND M. Clifton. Plasma Protein Binding of 109 Per- and Polyfluoroalkyl Substances (PFAS): Using Category-Based New Approach Methods to Inform PFAS Toxicokinetics. SETAC, Pittsburgh, PA, November 13 - 17, 2022. https://doi.org/10.23645/epacomptox.21528567
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Description:
New approach methodologies (NAMs) that utilize in vitro high-throughput screening data and in silico approaches to inform chemical safety assessment rely on in vitro toxicokinetic (TK) data to enable translation of bioactive in vitro assay concentrations to exposure metrics reflective of administered equivalent doses. With 1,220 per- and polyfluoroalkyl substances (PFAS) listed on the U.S. Toxic Substances Control Act (TSCA) inventory and growing concern over their widespread presence and persistence in the environment, the utility of NAMs to predict the potential exposures and toxicokinetics across these data-poor yet structurally diverse compounds is now being evaluated. To address the deficiency in TK data, 143 PFAS stocks, selected to span a wide range of functional groups and physico-chemical properties and after passing a quality control assessment, were evaluated for in vitro human plasma protein binding (PPB) using ultra high-performance liquid chromatography (UPLC) or gas chromatography (GC) coupled with tandem mass spectrometry (MS/MS). PPB was measured in 10-donor mixed sex pools of human adult plasma using ultracentrifugation, a membrane-less approach that separates plasma aqueous fraction from other plasma constituents by centrifugation at 850,000xg for 4 hours. Fraction unbound (fu) values were successfully measured for 109 PFAS: 65 by UPLC-MS/MS and 44 GC-MS/MS. Median, 25th and 75th percentile fu values for the 109 were 0.0230, 0.0039, and 0.1003, respectively, with the lowest fu (0.0001) recorded for pentadecafluorooctanoyl chloride (C8ClF15O). Trend analyses across a range of properties indicated associations between increasing chain length and lower fu (i.e., higher binding) and low van der Waals volumes with higher fu. Evaluations using ToxPrint ChemoTypes for grouping indicate lower binding for PFAS comprised of alcohol, aliphatic amine, and amino-carbonyl groups compared against PFAS carboxylic acids and sulfonic acids. Binding comparisons across other groupings and the entire tested PFAS space are also presented. With high PPB associated with bioaccumulation across all species, these findings demonstrate potential utility of a NAM read-across approach to estimate PFAS human and ecological risk for the broader data-poor PFAS domain. The views expressed in this abstract are those of the authors and do not necessarily represent the views or policies of the US EPA.
URLs/Downloads:
DOI: Plasma Protein Binding of 109 Per- and Polyfluoroalkyl Substances (PFAS): Using Category-Based New Approach Methods to Inform PFAS Toxicokinetics
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