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Per- and polyfluoroalkyl substances (PFAS) are widely used persistent synthetic chemicals that have been linked to adverse health effects. While the behavior of PFAS has been evaluated in the environment, our understanding of reaction products in mammalian systems is limited. This study identified biological PFAS transformation products and generated mass spectral libraries to facilitate an automated search and identification. The biological transformation products of 27 PFAS, spanning 5 chemical subclasses (alcohols, sulfonamides, carboxylic acids, ethers, and esters), were evaluated following enzymatic reaction with mouse liver S9 fractions. Four major pathways were identified by liquid chromatography-high-resolution mass spectrometry: glucuronidation, sulfation, dealkylation, and oxidation. Class-based fragmentation rules and associated PFAS transformation product libraries were generated and integrated into an automated nontargeted PFAS data analysis software (FluoroMatch). Fragmentation was additionally predicted for the potential transformation products of more than 2,500 PFAS in the EPA CompTox Chemicals Dashboard PFASSTRUCTv4. Generated mass spectral libraries were validated by applying FluoroMatch to a data set of urine from aqueous film-forming foam (AFFF)-dosed mice. Toxicity predictions showed identified PFAS transformation products to be potential developmental and mutagenic toxicants. This research enables more comprehensive PFAS characterization in biological systems, which will improve the assessment of exposures and evaluation of the associated health impacts.

Determining health risks associated with per-/polyfluoroalkyl substances (PFASs) is a highly complex problem requiring massive efforts for scientists, risk assessors, and regulators. Among the most poorly understood pressing questions is the relative importance of pre-PFAAs, which are PFASs that degrade to highly persistent perfluoroalkyl acids. How many of the vast number of existing pre-PFAAs are relevant for direct human exposure, and what are the predominant exposure pathways? What evidence of direct exposure to pre-PFAAs is provided by human biomonitoring studies? How important are pre-PFAAs and their biotransformation products for human health risk assessment? This article outlines recent progress and recommendations toward widening the lens on human PFAS exposure to include the pre-PFAA subclass.

Perfluoroalkyl sulfonamides (FASAs) and other FASA‐based per‐ and polyfluoroalkyl substances (PFASs) can transform into recalcitrant perfluoroalkyl sulfonates in vivo. We conducted high‐resolution mass spectrometry suspect screening of urine and tissues (kidney and liver) from mice dosed with an electrochemically fluorinated aqueous film‐forming foam (AFFF) to better understand the biological fate of AFFF‐associated precursors. The B6C3F1 mice were dosed at five levels (0, 0.05, 0.5, 1, and 5 mg kg−1 day−1) based on perfluorooctane sulfonate and perfluorooctanoate content of the AFFF mixture. Dosing continued for 10 days followed by a 6‐day depuration. Total oxidizable precursor assay of the AFFF suggested significant contributions from precursors with three to six perfluorinated carbons. We identified C4 to C6 FASAs and N‐glucuronidated FASAs (FASA‐N‐glus) excreted in urine collected throughout dosing and depuration. Based on normalized relative abundance, FASA‐N‐glus accounted for up to 33% of the total excreted FASAs in mouse urine, highlighting the importance of phase II metabolic conjugation as a route of excretion. High‐resolution mass spectrometry screening of liver and kidney tissue revealed accumulation of longer‐chain (C7 and C8) FASAs not detected in urine. Chain‐length–dependent conjugation of FASAs was also observed by incubating FASAs with mouse liver S9 fractions. Shorter‐chain (C4) FASAs conjugated to a much greater extent over a 120‐min incubation than longer‐chain (C8) FASAs. Overall, this study highlights the significance of N‐glucuronidation as an excretion mechanism for short‐chain FASAs and suggests that monitoring urine for FASA‐N‐glus could contribute to a better understanding of PFAS exposure, as FASAs and their conjugates are often overlooked by traditional biomonitoring studies. Environ Toxicol Chem 2024;43:2274–2284. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

This article discusses the transformation of environmental contaminants and the importance of understanding the reaction mechanisms, identifying novel products, and assessing the environmental implications. It highlights the challenges posed by synthetic substances released into the environment and the potential for these chemicals to transform into unknown products that may be more toxic or persistent than the parent compound. The article emphasizes the need for appropriate analytical techniques to detect and identify these transformation products. Several studies are highlighted that employ innovative analytical techniques to uncover the formation, occurrence, and environmental implications of transformation products in various contexts. The research presented in this series contributes to our understanding of emerging and novel organic contaminants and provides insights for improving environmental risk assessment. [Extracted from the article]