Citation:

Kreutz, A., M. Clifton, W. Henderson, M. Smeltz, M. Phillips, J. Wambaugh, AND B. Wetmore. Category-Based Toxicokinetic Evaluations of Data-Poor Per- and Polyfluoroalkyl Substances (PFAS) using Gas Chromatography Coupled with Mass Spectrometry. Toxics. MDPI, Basel, Switzerland, 11(5):463, (2023). https://doi.org/10.3390/toxics11050463

Impact/Purpose:

Per- and polyfluoroalkyl substances (PFAS) represent a large chemical class lacking toxicity, toxicokinetic, and exposure information. Widely recognized as persistent and bioaccumulative, PFAS for which data are available are very highly bound to plasma proteins, with in vivo studies reporting preferential accumulation in the plasma and liver. In vitro measures of plasma protein binding, a useful metric to efficiently estimate bioaccumulation and a key parameter in toxicokinetic models, are limited to only a few of the widely studied perfluoroalkyl acids (e.g., PFOA, PFNA).   This study provides in vitro plasma protein binding data for 71 PFAS, selected to encompass a diverse range of structures and functional groupings. Evaluations across the different PFAS groupings has provided useful information regarding binding trends. Also, plasma protein binding is an important parameter in toxicokinetic modeling, used to translate in vitro bioactive concentrations to an administered equivalent dose. These data will be used to support the evaluation of PFAS using New Approach Methods (NAMs).

Description:

Concern over per- and polyfluoroalkyl substances (PFAS) has increased as more is learned about their environmental presence, persistence, and bioaccumulative potential. The limited monitoring, toxicokinetic (TK), and toxicologic data available are inadequate to inform risk across this diverse domain. Here, 73 PFAS were selected for in vitro TK evaluation to expand knowledge across lesser-studied PFAS alcohols, amides, and acrylates. Targeted methods developed using gas chromatography-tandem mass spectrometry (GC-MS/MS) were used to measure human plasma protein binding and hepatocyte clearance. Forty-three PFAS were successfully evaluated in plasma, with fraction unbound (fup) values ranging from 0.004 to 1. With a median fup of 0.09 (i.e., 91% bound), these PFAS are highly bound but exhibit 10-fold lower binding than legacy perfluoroalkyl acids recently evaluated. Thirty PFAS evaluated in the hepatocyte clearance assay showed abiotic loss, with many exceeding 60% loss within 60 min. Metabolic clearance was noted for 11 of the 13 that were successfully evaluated, with rates up to 49.9 μL/(min × million cells). The chemical transformation simulator revealed potential (bio)transformation products to consider. This effort provides critical information to evaluate PFAS for which volatility, metabolism, and other routes of transformation are likely to modulate their environmental fates.

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