You are here:
Plasma Protein Binding Evaluations of Per- and Polyfluoroalkyl Substances for Category-Based Toxicokinetic Assessment
Citation:
Smeltz, M., J. Wambaugh, AND B. Wetmore. Plasma Protein Binding Evaluations of Per- and Polyfluoroalkyl Substances for Category-Based Toxicokinetic Assessment. CHEMICAL RESEARCH IN TOXICOLOGY. American Chemical Society, Washington, DC, 36(6):870-871, (2023). https://doi.org/10.1021/acs.chemrestox.3c00003
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:
New approach methodologies (NAMs) that make use of in vitro screening and in silico approaches to inform chemical evaluations rely on in vitro toxicokinetic (TK) data to translate in vitro bioactive concentrations to exposure metrics reflective of administered dose. With 1364 per- and polyfluoroalkyl substances (PFAS) identified as of interest under Section 8 of the U.S. Toxic Substances Control Act (TSCA) and concern over the lack of knowledge regarding environmental persistence, human health, and ecological effects, the utility of NAMs to understand potential toxicities and toxicokinetics across these data-poor compounds is being evaluated. To address the TK data deficiency, 71 PFAS selected to span a wide range of functional groups and physico-chemical properties were evaluated for in vitro human plasma protein binding (PPB) by ultracentrifugation with liquid chromatography-mass spectrometry analysis. For the 67 PFAS successfully evaluated by ultracentrifugation, fraction unbound in plasma (fup) ranged from less than 0.0001 (pentadecafluorooctanoyl chloride) to 0.7302 (tetrafluorosuccinic acid), with over half of the PFAS showing PPB exceeding 99.5% (fup < 0.005). Category-based evaluations revealed that perfluoroalkanoyl chlorides and perfluorinated carboxylates (PFCAs) with 6-10 carbons were the highest bound, with similar median values for alkyl, ether, and polyether PFCAs. Interestingly, binding was lower for the PFCAs with a carbon chain length of ≥11. Lower binding also was noted for fluorotelomer carboxylic acids when compared to their carbon-equivalent perfluoroalkyl acids. Comparisons of the fup value derived using two PPB methods, ultracentrifugation or rapid equilibrium dialysis (RED), revealed RED failure for a subset of PFAS of high mass and/or predicted octanol-water partition coefficients exceeding 4 due to failure to achieve equilibrium. Bayesian modeling was used to provide uncertainty bounds around fup point estimates for incorporation into TK modeling. This PFAS PPB evaluation and grouping exercise across 67 structures greatly expand our current knowledge and will aid in PFAS NAM development.
URLs/Downloads:
DOI: Plasma Protein Binding Evaluations of Per- and Polyfluoroalkyl Substances for Category-Based Toxicokinetic Assessment
https://pubmed.ncbi.nlm.nih.gov/37184865/