{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T05:07:51Z","timestamp":1778562471582,"version":"3.51.4"},"reference-count":107,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T00:00:00Z","timestamp":1750464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Office of Research and Development, USEPA"},{"name":"Environmental Protection Agency and the Department of Energy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>High-resolution accurate mass non-targeted analysis (NTA) is a useful discovery tool for metabolite characterization of in vivo dosing studies since it enables detection of both predicted and unexpected biotransformation products. We used NTA to investigate biotransformation of perfluorohexanesulfonamide (PFHxSA) in plasma and liver from male and female Sprague Dawley rats after a 5-day repeat exposure study. PFHxSA is an emerging per- and polyfluoroalkyl substance (PFAS) with unknown toxicity and a potentially reactive headgroup. NTA revealed the presence of predicted in vivo biotransformation products (BP) such as perfluorohexane sulfonic acid (PFHxS) and perfluorohexanesulfinic acid (PFHxSi). PFHxSi also has unknown toxicity and has not, to our knowledge, been previously reported as a PFHxSA BP in mammals. Multiple perfluoroalkyl ether sulfonamides, associated BPs, and novel PFAS were also detected in rat plasma and liver. We observed sex-specific distributions of the dosed compound and BPs, suggesting different toxicokinetics and biological responses. The presence of a complex mixture of predicted and unexpected PFAS in plasma and liver not only mimics the complexity of environmental exposure but also highlights the need for toxicity testing with mixtures and a more complete assessment of dosing solution purity.<\/jats:p>","DOI":"10.3390\/toxics13070523","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T07:42:34Z","timestamp":1750664554000},"page":"523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Non-Targeted Analysis (NTA) of Plasma and Liver from Sprague Dawley Rats Exposed to Perfluorohexanesulfonamide (PFHxSA), a Precursor to Perfluorohexane Sulfonic Acid (PFHxS)"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8424-6651","authenticated-orcid":false,"given":"Denise K.","family":"MacMillan","sequence":"first","affiliation":[{"name":"Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency (USEPA), Durham, NC 27709, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4014-8002","authenticated-orcid":false,"given":"Jackson G.","family":"Bounds","sequence":"additional","affiliation":[{"name":"Oak Ridge Associated Universities (ORAU), Oak Ridge, TN 37830, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William A.","family":"Willis","sequence":"additional","affiliation":[{"name":"Oak Ridge Associated Universities (ORAU), Oak Ridge, TN 37830, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark J.","family":"Strynar","sequence":"additional","affiliation":[{"name":"Center for Environmental Measurement and Modeling, Office of Research and Development, U.S. Environmental Protection Agency (USEPA), Durham, NC 27709, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6878-5348","authenticated-orcid":false,"given":"Barbara A.","family":"Wetmore","sequence":"additional","affiliation":[{"name":"Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency (USEPA), Durham, NC 27709, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6089-104X","authenticated-orcid":false,"given":"Richard J.","family":"Liberatore","sequence":"additional","affiliation":[{"name":"Center for Environmental Measurement and Modeling, Office of Research and Development, U.S. Environmental Protection Agency (USEPA), Durham, NC 27709, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1780-4916","authenticated-orcid":false,"given":"James P.","family":"McCord","sequence":"additional","affiliation":[{"name":"Center for Environmental Measurement and Modeling, Office of Research and Development, U.S. Environmental Protection Agency (USEPA), Durham, NC 27709, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1258-4894","authenticated-orcid":false,"given":"Michael J.","family":"Devito","sequence":"additional","affiliation":[{"name":"Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency (USEPA), Durham, NC 27709, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109332","DOI":"10.1016\/j.envint.2025.109332","article-title":"A paradigm shift in environmental monitoring\u2014The time for non-targeted analysis (NTA) is now","volume":"197","author":"Strynar","year":"2025","journal-title":"Environ. Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s00216-022-04434-4","article-title":"Exploring chemical space in non-targeted analysis: A proposed ChemSpace tool","volume":"415","author":"Black","year":"2023","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1021\/ar500432k","article-title":"The Chemical Space Project","volume":"48","author":"Reymond","year":"2015","journal-title":"Acc. Chem. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11622","DOI":"10.1021\/acs.est.5b01215","article-title":"Identification of novel perfluoroalkyl ether carboxylic acids (PFECAs) and sulfonic acids (PFESAs) in natural waters using accurate mass time-of-flight mass spectrometry (TOFMS)","volume":"49","author":"Strynar","year":"2015","journal-title":"Environ. Sci. Tech."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1021\/acs.estlett.0c00640","article-title":"Emerging Chlorinated Polyfluorinated Polyether Compounds Impacting the Waters of Southwestern New Jersey Identified by Use of Nontargeted Analysis","volume":"7","author":"McCord","year":"2020","journal-title":"Environ. Sci. Technol. Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eabg9065","DOI":"10.1126\/science.abg9065","article-title":"Per- and polyfluoroalkyl substances in the environment","volume":"375","author":"Evich","year":"2022","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"143645","DOI":"10.1016\/j.chemosphere.2024.143645","article-title":"Non-targeted analysis reveals hundreds of per- and polyfluoroalkyl substances (PFAS) in UK freshwater in the vicinity of a fluorochemical plant","volume":"367","author":"Megson","year":"2024","journal-title":"Chemosphere"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"136159","DOI":"10.1016\/j.chemosphere.2022.136159","article-title":"A rapid assessment bioaccumulation screening (RABS) study design for emerging per-and polyfluoroalkyl substances in mice exposed to industrially impacted surface water","volume":"308","author":"Bangma","year":"2022","journal-title":"Chemosphere"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2686","DOI":"10.1021\/acs.est.4c08037","article-title":"Emerging Per- and Polyfluoroalkyl Substances in Tap Water from the American Healthy Homes Survey II","volume":"59","author":"Boettger","year":"2025","journal-title":"Environ. Sci. Technol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/s41370-023-00574-6","article-title":"Non-targeted analysis (NTA) and suspect screening analysis (SSA): A review of examining the chemical exposome","volume":"33","author":"Manz","year":"2023","journal-title":"J. Expo. Sci. Environ. Epidemiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.scitotenv.2018.09.214","article-title":"Isomer-specific biotransformation of perfluoroalkyl sulfonamide compounds in aerobic soil","volume":"651","author":"Liu","year":"2019","journal-title":"Sci. Tot. Environ."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Whitehead, H., Buckley, T., Sobus, J., Bangma, J., MacMillan, D., Williams, A., Janesch, G., Coombs, J., Newman, E., and Dahlmeier, A. (2025). Non-Targeted Analysis of Surface and Groundwaters Impacted by Historic PFAS Waste Sites. Environ. Sci. Technol. Accept.","DOI":"10.1021\/acs.est.5c03243"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Whitehead, H.D., Buckley, T.J., Sobus, J.R., Bangma, J., MacMillan, D.K., Ferland, T.M., Chao, A., Williams, A.J., Janesch, G., and Cofield, K. (2025). The ENTAiLS Toolkit: An Integrated Workflow to Perform Non-Targeted Analysis of Per- and Polyfluoroalkyl Substances. Anal. Bioanal. Chem.","DOI":"10.1007\/s00216-025-05921-0"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/ieam.4346","article-title":"Significance of Perfluoroalkyl Substances (PFAS) in Food Packagin","volume":"17","author":"Curtzwiler","year":"2021","journal-title":"Integr. Environ. Assess. Manag."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Seltenrich, N. (2020). PFAS in Food Packaging: A Hot, Greasy Exposure. Environ. Health Perspect., 128.","DOI":"10.1289\/EHP6335"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"14594","DOI":"10.1021\/acs.est.2c02660","article-title":"Targeted and Suspect Screening of Per- and Polyfluoroalkyl Substances in Cosmetics and Personal Care Products","volume":"56","author":"Harris","year":"2022","journal-title":"Environ. Sci. Technol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"97006","DOI":"10.1289\/EHP6470","article-title":"Chemical Characterization of a Legacy Aqueous Film-Forming Foam Sample and Developmental Toxicity in Zebrafish (Danio rerio)","volume":"128","author":"Annunziato","year":"2020","journal-title":"Environ. Health Perspect."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1021\/acs.est.9b05440","article-title":"Characterization of the Chemical Contents of Fluorinated and Fluorine-Free Firefighting Foams Using a Novel Workflow Combining Nontarget Screening and Total Fluorine Analysis","volume":"54","author":"Dubocq","year":"2020","journal-title":"Environ. Sci. Technol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"178240","DOI":"10.1016\/j.scitotenv.2024.178240","article-title":"A systematic review for non-targeted analysis of per- and polyfluoroalkyl substances (PFAS)","volume":"960","author":"Megson","year":"2025","journal-title":"Sci. Tot. Environ."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1021\/acs.estlett.0c00798","article-title":"Reconstructing the Composition of Per- and Polyfluoroalkyl Substances in Contemporary Aqueous Film-Forming Foams","volume":"8","author":"Ruyle","year":"2021","journal-title":"Environ. Sci. Technol. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"153711","DOI":"10.1016\/j.scitotenv.2022.153711","article-title":"Microbial biotransformation of aqueous film-forming foam derived polyfluoroalkyl substances","volume":"824","author":"Choi","year":"2022","journal-title":"Sci. Tot. Environ."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Renyer, A., Ravindra, K., Wetmore, B.A., Ford, J.L., DeVito, M., Hughes, M.F., Wehmas, L.C., and MacMillan, D.K. (2023). Dose Response, Dosimetric, and Metabolic Evaluations of Replacement PFAS Perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) Acid (HFPO-TeA). Toxics, 11.","DOI":"10.3390\/toxics11120951"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"132095","DOI":"10.1016\/j.jhazmat.2023.132095","article-title":"Established and emerging organophosphate esters (OPEs) and the expansion of an environmental contamination issue: A review and future directions","volume":"459","author":"Ye","year":"2023","journal-title":"J. Haz. Mater."},{"key":"ref_24","unstructured":"Chang, D., Cowden, J., Davidson-Fritz, S., Dean, J., Devito, M., Everett, L., Harrill, A., Hester, S., Hughes, M., and Lambert, J. (2025, June 16). Scientific Studies Supporting Development of Transcriptomic Points of Departure for EPA Transcriptomic Assessment Products (ETAPs). Available online: https:\/\/epa.figshare.com\/articles\/online_resource\/Scientific_Studies_Supporting_Development_of_Transcriptomic_Points_of_Departure_for_EPA_Transcriptomic_Assessment_Products_ETAPs_\/25365550."},{"key":"ref_25","unstructured":"Brennan, A., Chang, D., Cowden, J., Davidson-Fritz, S., Dean, J., Devito, M., Ford, J., Everett, L., Harrill, A., and Hester, S. (2025, June 16). Standard Methods for Development of EPA Transcriptomic Assessment Products (ETAPs). Available online: https:\/\/epa.figshare.com\/articles\/online_resource\/Standard_Methods_for_Development_of_EPA_Transcriptomic_Assessment_Products_ETAPs_\/25365496\/1."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14501","DOI":"10.1289\/EHP4555","article-title":"A Chemical Category-Based Prioritization Approach for Selecting 75 Per- and Polyfluoroalkyl Substances (PFAS) for Tiered Toxicity and Toxicokinetic Testing","volume":"127","author":"Patlewicz","year":"2019","journal-title":"Environ. Health Perspect."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100250","DOI":"10.1016\/j.comtox.2022.100250","article-title":"Towards reproducible structure-based chemical categories for PFAS to inform and evaluate toxicity and toxicokinetic testing","volume":"24","author":"Patlewicz","year":"2022","journal-title":"Comput. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"100258","DOI":"10.1016\/j.comtox.2022.100258","article-title":"Towards systematic read-across using Generalised Read-Across (GenRA)","volume":"25","author":"Patlewicz","year":"2023","journal-title":"Comput. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Mutlu, E., Wehmas, L.C., Harrill, A.H., DeVito, M.J., Thomas, R.S., Hughes, M.F., MacMillan, D.K., Brennan, A.A., Bounds, J.G., and Weitekemp, C.A. (Toxicology, 2025). Transcriptomic dose response of PFAS chemicals 3:3 fluorotelomer carboxylic acid, 7:3 fluorotelomer alcohol, and perfluorohexanesulfonamide, Toxicology, Submitted.","DOI":"10.1016\/j.tox.2025.154223"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1039\/D0EM00291G","article-title":"An overview of the uses of per- and polyfluoroalkyl substances (PFAS)","volume":"22","author":"Scheringer","year":"2020","journal-title":"Environ. Sci. Process. Impacts"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8139","DOI":"10.1021\/acs.est.1c00522","article-title":"Unsaturated PFOS and Other PFASs in Human Serum and Drinking Water from an AFFF-Impacted Community","volume":"55","author":"McDonough","year":"2021","journal-title":"Environ. Sci. Technol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"119739","DOI":"10.1016\/j.envpol.2022.119739","article-title":"Bioaccumulation and trophic magnification of emerging and legacy per- and polyfluoroalkyl substances (PFAS) in a St. Lawrence River food web","volume":"309","author":"Munoz","year":"2022","journal-title":"Environ. Pollut."},{"key":"ref_33","unstructured":"(2023, May 01). All POPs Listed in the Stockholm Convention. Available online: http:\/\/chm.pops.int\/TheConvention\/ThePOPs\/AllPOPs\/tabid\/2509\/Default.aspx."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"163103","DOI":"10.1016\/j.scitotenv.2023.163103","article-title":"PFAS in fish from AFFF-impacted environments: Analytical method development and field application at a Canadian international civilian airport","volume":"879","author":"Carrizo","year":"2023","journal-title":"Sci. Tot. Environ."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kolanczyk, R.C., Saley, M.R., Serrano, J.A., Daley, S.M., and Tapper, M.A. (2023). PFAS Biotransformation Pathways: A Species Comparison Study. Toxics, 11.","DOI":"10.3390\/toxics11010074"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1021\/acs.est.4c07750","article-title":"Expanding PFAS Identification with Transformation Product Libraries: Nontargeted Analysis Reveals Biotransformation Products in Mice","volume":"59","author":"Liu","year":"2025","journal-title":"Environ. Sci. Technol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1021\/tx500470f","article-title":"Transformation Pathways of Isomeric Perfluorooctanesulfonate Precursors Catalyzed by the Active Species of P450 Enzymes: In Silico Investigation","volume":"28","author":"Fu","year":"2015","journal-title":"Chem. Res. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1897\/08-239.1","article-title":"Disposition of perfluorinated acid isomers in Sprague-Dawley rats; part 1: Single dose","volume":"28","author":"Benskin","year":"2009","journal-title":"Environ. Toxicol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"129240","DOI":"10.1016\/j.jhazmat.2022.129240","article-title":"Assessment of perfluorohexane sulfonic acid (PFHxS)-related compounds degradation potential: Computational and experimental approaches","volume":"436","author":"Zhong","year":"2022","journal-title":"J. Haz. Mater."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"007174","DOI":"10.1289\/EHP7169","article-title":"A Roadmap to the Structure-Related Metabolism Pathways of Per- and Polyfluoroalkyl Substances in the Early Life Stages of Zebrafish (Danio rerio)","volume":"129","author":"Han","year":"2021","journal-title":"Environ. Health Perspect."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1021\/es034550j","article-title":"Biotransformation of N-ethyl perfluorooctanesulfonamide by rainbow trout (Onchorhynchus mykiss) liver microsomes","volume":"38","author":"Tomy","year":"2004","journal-title":"Environ. Sci. Technol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1021\/tx034222x","article-title":"Biotransformation of N-ethyl-N-(2-hydroxyethyl)perfluorooetanesulfonamide by rat liver microsomes, cytosol, and slices and by expressed rat and human cytochromes P450","volume":"17","author":"Xu","year":"2004","journal-title":"Chem. Res. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1124\/dmd.106.009399","article-title":"N-glucuronidation of perfluorooctanesulfonamide by human, rat, dog, and monkey liver microsomes and by expressed rat and human UDP-glucuronosyltransferases","volume":"34","author":"Xu","year":"2006","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3196","DOI":"10.1021\/es204028v","article-title":"Isomer-specific biotransformation of perfluorooctane sulfonamide in Sprague-Dawley rats","volume":"46","author":"Ross","year":"2012","journal-title":"Environemental Sci. Technol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.chemosphere.2014.04.022","article-title":"Comparative hepatic in vitro depletion and metabolite formation of major perfluorooctane sulfonate precursors in arctic polar bear, beluga whale and ringed seal","volume":"112","author":"Letcher","year":"2014","journal-title":"Chemosphere"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"124619","DOI":"10.1016\/j.chemosphere.2019.124619","article-title":"Contributions of enzymes and gut microbes to biotransformation of perfluorooctane sulfonamide in earthworms (Eisneia fetida)","volume":"238","author":"Zhao","year":"2020","journal-title":"Chemosphere"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.ecoenv.2018.06.048","article-title":"Biotransformation and responses of antioxidant enzymes in hydroponically cultured soybean and pumpkin exposed to perfluorooctane sulfonamide (FOSA)","volume":"161","author":"Zhao","year":"2018","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.envpol.2019.06.020","article-title":"Fate of 6:2 fluorotelomer sulfonic acid in pumpkin (Cucurbita maxima L.) based on hydroponic culture: Uptake, translocation and biotransformation","volume":"252","author":"Zhao","year":"2019","journal-title":"Environ. Pollut."},{"key":"ref_49","unstructured":"Lange, C.C. (2025, June 16). Biodegradation Study Report: The Aerobic Biodegradation of N-EtFOSE Alcohol by the Microbial Activity Present in Municipal Wastewater Treatment Sludge. Available online: https:\/\/static.ewg.org\/reports\/2003\/pfcs\/226-1030a078.pdf."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1021\/es702866c","article-title":"Aerobic Biotransformation and Fate of N-Ethyl Perfluorooctane Sulfonamidoethanol (N-EtFOSE) in Activated Sludge","volume":"42","author":"Rhoads","year":"2008","journal-title":"Environ. Sci. Technol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1016\/j.chemosphere.2014.09.059","article-title":"Production of PFOS from aerobic soil biotransformation of two perfluoroalkyl sulfonamide derivatives","volume":"119","author":"Avendano","year":"2015","journal-title":"Chemosphere"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1002\/etc.5926","article-title":"Bioconcentration of Per- and Polyfluoroalkyl Substances and Precursors in Fathead Minnow Tissues Environmentally Exposed to Aqueous Film-Forming Foam\u2013Contaminated Waters","volume":"43","author":"Hill","year":"2024","journal-title":"Environ. Toxicol. Chem."},{"key":"ref_53","first-page":"1352","article-title":"Atmospheric Oxidation of PFAS by Hydroxyl Radical: A Density Functional Theory Study","volume":"1","author":"Dooley","year":"2024","journal-title":"Environ. Sci. Technol. Air"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1021\/tx500371a","article-title":"Mechanism of the N-hydroxylation of primary and secondary amines by cytochrome P450","volume":"28","author":"Seger","year":"2015","journal-title":"Chem. Res. Toxicol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5368","DOI":"10.1021\/acs.est.3c00071","article-title":"Emerging Metabolic Profiles of Sulfonamide Antibiotics by Cytochromes P450: A Computational\u2013Experimental Synergy Study on Emerging Pollutants","volume":"57","author":"Zhang","year":"2023","journal-title":"Environ. Sci. Technol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cld.2016.08.001","article-title":"Drug metabolism in the liver","volume":"21","author":"Almazroo","year":"2017","journal-title":"Clin. Liver Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"556","DOI":"10.2174\/1389200218666170316093301","article-title":"Drug Metabolism in Preclinical Drug Development: A Survey of the Discovery Process, Toxicology, and Computational Tools","volume":"18","author":"Issa","year":"2017","journal-title":"Curr. Drug Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"104452","DOI":"10.1016\/j.yrtph.2019.104452","article-title":"Derivation of a chronic reference dose for perfluorohexane sulfonate (PFHxS) for reproductive toxicity in mice","volume":"108","author":"Ali","year":"2019","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1002\/etc.5939","article-title":"N-glucuronidation and Excretion of Perfluoroalkyl Sulfonamides in Mice Following Ingestion of Aqueous Film-Forming Foam","volume":"43","author":"Dukes","year":"2024","journal-title":"Environ. Toxicol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1021\/acs.estlett.4c00143","article-title":"Bioaccumulation of Perfluoroalkyl Sulfonamides (FASA)","volume":"11","author":"Pickard","year":"2024","journal-title":"Environ. Sci. Technol. Lett."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5107","DOI":"10.1021\/acs.est.2c07185","article-title":"Systematic Evidence Mapping of Potential Exposure Pathways for Per- and Polyfluoroalkyl Substances Based on Measured Occurrence in Multiple Media","volume":"57","author":"Holder","year":"2023","journal-title":"Environ. Sci. Technol."},{"key":"ref_62","unstructured":"(2011). Guide for the Care and Use of Laboratory Animals: Eighth Edition, National Research Council."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Kilkenny, C., Browne, W.J., Cuthill, I.C., Emerson, M., and Altman, D.G. (2010). Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000412"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., and Dirnagl, U. (2020). The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000410"},{"key":"ref_65","unstructured":"(2020). Guidelines for the Euthanasia of Animals, American Veterinary Medical Association (AVMA)."},{"key":"ref_66","unstructured":"Bounds, J.G., Renyer, A., Brennan, A.A., Ford, J.L., Ravindra, K., Wetmore, B.A., Devito, M., Hughes, M.F., Wehmas, L.C., and MacMillan, D.K. (Toxics, 2025). Evaluations of Thyroid Effects, Dosimetry, and Metabolism following Perfluorohexanesulfonamide Exposure in Sprague Dawley Rats, Toxics, To Be Submitted."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1038\/nmeth.2702","article-title":"Mapping differential interactomes by affinity purification coupled with data-independent mass spectrometry acquisition","volume":"10","author":"Lambert","year":"2013","journal-title":"Nat. Methods"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"11742","DOI":"10.1021\/ac503144p","article-title":"Liquid Chromatography, in Combination with a Quadrupole Time-of-Flight Instrument (LC QTOF), with Sequential Window Acquisition of All Theoretical Fragment-Ion Spectra (SWATH) Acquisition: Systematic Studies on Its Use for Screenings in Clinical and Forensic Toxicology and Comparison with Information-Dependent Acquisition (IDA)","volume":"86","author":"Roemmelt","year":"2014","journal-title":"Anal. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"13870","DOI":"10.1021\/acs.analchem.1c02621","article-title":"Nontargeted Analysis Study Reporting Tool: A Framework to Improve Research Transparency and Reproducibility","volume":"93","author":"Peter","year":"2021","journal-title":"Anal. Chem."},{"key":"ref_70","unstructured":"USEPA (2022, June 13). Chemical Transformation Simulator, Available online: https:\/\/qed.epa.gov\/cts\/."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13321-018-0324-5","article-title":"BioTransformer: A comprehensive computational tool for small molecule metabolism prediction and metabolite identification","volume":"11","author":"Fiamoncini","year":"2019","journal-title":"J. Cheminform."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1039\/D1EM00445J","article-title":"Development of a PFAS reaction library: Identifying plausible transformation pathways in environmental and biological systems","volume":"24","author":"Weber","year":"2022","journal-title":"Env. Sci. Process Impacts"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Wolf, S., Schmidt, S., M\u00fcller-Hannemann, M., and Neumann, S. (2010). In silico fragmentation for computer assisted identification of metabolite mass spectra. BMC Bioinform., 11.","DOI":"10.1186\/1471-2105-11-148"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13321-016-0115-9","article-title":"MetFrag relaunched: Incorporating strategies beyond in silico fragmentation","volume":"8","author":"Ruttkies","year":"2016","journal-title":"J. Cheminform."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Ruttkies, C., Neumann, S., and Posch, S. (2019). Improving MetFrag with statistical learning of fragment annotations. BMC Bioinform., 20.","DOI":"10.1186\/s12859-019-2954-7"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/s41587-023-01690-2","article-title":"Integrative analysis of multimodal mass spectrometry data in MZmine 3","volume":"41","author":"Schmid","year":"2023","journal-title":"Nat. Biotechnol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2597","DOI":"10.1038\/s41596-024-00996-y","article-title":"Reproducible mass spectrometry data processing and compound annotation in MZmine 3","volume":"19","author":"Heuckeroth","year":"2024","journal-title":"Nat. Protoc."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/978-1-60761-444-9_22","article-title":"Mass Spectrometer Output File Format mzML","volume":"604","author":"Deutsch","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1038\/nbt.2377","article-title":"A cross-platform toolkit for mass spectrometry and proteomics","volume":"30","author":"Chambers","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1007\/s00216-025-05771-w","article-title":"Automated QA\/QC reporting for non-targeted analysis: A demonstration of \u201cINTERPRET NTA\u201d with de facto water reuse data","volume":"417","author":"Sobus","year":"2025","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13321-017-0247-6","article-title":"The CompTox Chemistry Dashboard: A community data resource for environmental chemistry","volume":"9","author":"Williams","year":"2017","journal-title":"J. Chemoinform."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Janesch, G., Carr, E.T., Sivasupramaniam, S., Charest, N., Tkachenko, V., and Williams, A.J. (2025). Applying Chemoinformatics to Develop a Structure Searchable Database of Analytical Methods. JoVE, e68194.","DOI":"10.3791\/68194"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1021\/es5002105","article-title":"Identifying Small Molecules via High Resolution Mass Spectrometry: Communicating Confidence","volume":"48","author":"Schymanski","year":"2014","journal-title":"Environ. Sci. Technol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S0065-2318(08)60326-1","article-title":"The Koenigs-Knorr Reaction","volume":"Volume 34","author":"Igarashi","year":"1977","journal-title":"Advances in Carbohydrate Chemistry and Biochemistr"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"D1516","DOI":"10.1093\/nar\/gkae1059","article-title":"PubChem 2025 update","volume":"53","author":"Kim","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Auerbach, S.S., Ballin, J.D., Blake, J.C., Browning, D.B., Collins, B.J., Cora, M.C., Fernando, R.A., Fostel, J.M., Liu, Y.F., and Luh, J. (2023). Report on the In Vivo Repeat Dose Biological Potency Study of Perfluorohexanesulfonamide (CASRN 41997-13-1) in Sprague Dawley (Hsd:Sprague Dawley\u00ae SD\u00ae) Rats (Gavage Studies). NIEHS Report 10, National Institute of Environmental Health Sciences.","DOI":"10.22427\/NIEHS-10"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0378-4274(01)00466-0","article-title":"Perfluorooctanoate, perflourooctanesulfonate, and N-ethyl perfluorooctanesulfonamido ethanol; peroxisome proliferation and mitochondrial biogenesis","volume":"129","author":"Berthiaume","year":"2002","journal-title":"Toxicol. Lett."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1248\/bpb.19.765","article-title":"Differences in the induction of carboxylesterase RL4 in rat liver microsomes by various perfluorinated fatty acids, metabolically inert derivatives of fatty acids","volume":"19","author":"Derbel","year":"1996","journal-title":"Biol. Pharm. Bull."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Crizer, D.M., Rice, J.R., Smeltz, M.G., Lavrich, K.S., Ravindra, K., Wambaugh, J.F., DeVito, M., and Wetmore, B.A. (2024). In Vitro Hepatic Clearance Evaluations of Per- and Polyfluoroalkyl Substances (PFAS) across Multiple Structural Categories. Toxics, 12.","DOI":"10.3390\/toxics12090672"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"142390","DOI":"10.1016\/j.chemosphere.2024.142390","article-title":"Evaluation of 14 PFAS for permeability and organic anion transporter interactions: Implications for renal clearance in humans","volume":"361","author":"Ryu","year":"2024","journal-title":"Chemosphere"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s00204-022-03428-6","article-title":"Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4)","volume":"97","author":"Louisse","year":"2023","journal-title":"Arch. Toxicol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0009-2797(02)00006-6","article-title":"Sex hormone-regulated renal transport of perfluorooctanoic acid","volume":"139","author":"Kudo","year":"2002","journal-title":"Chem.-Biol. Interact."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1080\/00498254.2019.1683776","article-title":"Toxicokinetics of perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) in male and female Hsd:Sprague dawley SD rats following intravenous or gavage administration","volume":"50","author":"Dzierlenga","year":"2020","journal-title":"Xenobiotica"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.toxrep.2019.06.016","article-title":"Toxicokinetics of perfluorobutane sulfonate (PFBS), perfluorohexane-1-sulphonic acid (PFHxS), and perfluorooctane sulfonic acid (PFOS) in male and female Hsd:Sprague Dawley SD rats after intravenous and gavage administration","volume":"6","author":"Huang","year":"2019","journal-title":"Toxicol. Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0300-483X(02)00573-5","article-title":"Comparison of the toxicokinetics between perfluorocarboxylic acids with different carbon chain length","volume":"184","author":"Ohmori","year":"2003","journal-title":"Toxicology"},{"key":"ref_96","first-page":"441","article-title":"Comparative pharmacokinetics of perfluorohexanesulfonate (PFHxS) in rats, mice, and monkeys","volume":"13","author":"Chang","year":"2012","journal-title":"Reprod. Toxicol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1016\/j.chemosphere.2004.11.078","article-title":"Synthesis of environmentally relevant fluorinated surfactants\u2014A review","volume":"58","author":"Lehmler","year":"2005","journal-title":"Chemosphere"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.jfluchem.2007.01.013","article-title":"Synthesis and Structure of Environmentally Relevant Perfluorinated Sulfonamides","volume":"128","author":"Lehmler","year":"2007","journal-title":"J. Fluor. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"134347","DOI":"10.1016\/j.tet.2024.134347","article-title":"Synthesis of reference standards for emerging sulfonamide PFAS precursors suspected in aqueous film-forming foams via a benzyl intermediate","volume":"169","author":"Liwara","year":"2025","journal-title":"Tetrahedron"},{"key":"ref_100","unstructured":"Qiu, Z.-M. (2005). Water-and Oil-Repellency Imparting Ester Oligomers Comprising Perfluoroalkyl Moieties. (CN1492854)."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1021\/acs.chemrestox.2c00072","article-title":"Neurotransmission Targets of Per- and Polyfluoroalkyl Substance Neurotoxicity: Mechanisms and Potential Implications for Adverse Neurological Outcomes","volume":"35","author":"Cannon","year":"2022","journal-title":"Chem. Res. Toxicol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"107174","DOI":"10.1016\/j.ntt.2023.107174","article-title":"Sources, occurrence and toxic effects of emerging per- and polyfluoroalkyl substances (PFAS)","volume":"97","author":"Manojkumar","year":"2023","journal-title":"Neurotoxicol. Teratol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"47005","DOI":"10.1289\/EHP5843","article-title":"Evaluation of Developmental Toxicity, Developmental Neurotoxicity, and Tissue Dose in Zebrafish Exposed to GenX and Other PFAS","volume":"128","author":"Gaballah","year":"2020","journal-title":"Environ. Health Perspect."},{"key":"ref_104","first-page":"16774","article-title":"Neurotoxic Effects of Mixtures of Perfluoroalkyl Substances (PFAS) at Environmental and Human Blood Concentrations","volume":"58","author":"Aga","year":"2024","journal-title":"Environ. Sci. Technol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.3390\/jox14040094","article-title":"Impact of Legacy Perfluorooctane Sulfonate (PFOS) and Perfluorooctanoate (PFOA) on GABA Receptor-Mediated Currents in Neuron-Like Neuroblastoma Cells: Insights into Neurotoxic Mechanisms and Health Implications","volume":"14","author":"Lagostena","year":"2024","journal-title":"J. Xenobiot."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1111\/j.1471-4159.2006.03913.x","article-title":"The glutamate\/GABA-glutamine cycle: Aspects of transport, neurotransmitter homeostasis and ammonia transfer","volume":"98","author":"Bak","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1007\/s10811-019-01834-5","article-title":"The role of GAD pathway for regulation of GABA accumulation and C\/N balance in Synechocystis sp. PCC6803","volume":"31","author":"Kanwal","year":"2019","journal-title":"J. Appl. Phycol."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/13\/7\/523\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:56:23Z","timestamp":1760032583000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/13\/7\/523"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,21]]},"references-count":107,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["toxics13070523"],"URL":"https:\/\/doi.org\/10.3390\/toxics13070523","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,21]]}}}