PFAS Toxicology and Metabolism

A special issue of Toxics (ISSN 2305-6304). This special issue belongs to the section "Emerging Contaminants".

Deadline for manuscript submissions: closed (15 December 2023) | Viewed by 31864

Special Issue Editors


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Guest Editor
United States Environmental Protection Agency, Center for Computational Toxicology and Exposure, Durham, NC, USA
Interests: PFAS health effects; biotransformations; lipidomics; metabolomics; bioanalytical chemistry method development

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Guest Editor
United States Environmental Protection Agency, Center for Computational Toxicology and Exposure, Research Triangle Park, Durham, NC, USA
Interests: development, assessment, and integration of in vitro and in silico approaches to predict human exposures that can be applied to ensure protection of human health; toxicokinetics; in vitro-in vivo extrapolation (IVIVE); PFAS; metabolism; population variability; new approach methods

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Guest Editor
Department of Biological Sciences, Clemson University, Clemson, SC, USA
Interests: toxicology; obesity; fatty liver disease; PFAS; P450s; nuclear receptors
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Biological Sciences, Clemson University, Clemson, SC, USA
Interests: flame retardants; PFAS; PAHs; neurotoxicity; nuclear receptors; epigenetics; non-ionising radiations; development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Per- and polyfluoroalkyl substances (PFAS) are seemingly everywhere: in our bodies, homes, clothes, food packaging, drinking water, rivers, soils, and carried across the globe in the atmosphere. Yet, despite their widespread occurrence and detection of a growing number of compounds, we know very little about the risks posed by our own and the environment’s exposure to these long-lived chemicals. Multiple studies have been published on the health effects of the first known PFAS, perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), but there are gaps in the data for other legacy and emerging chemicals in this structurally diverse class. Additionally, since we are likely exposed to multiple PFAS simultaneously, gaining an understanding of the potentially toxic effects of mixtures represents another critical data gap to fill.

This Special Issue of Toxics aims to expand knowledge of the health effects of per- and polyfluoroalkyl substances. We welcome original research, new methodologies and protocols, and reviews that evaluate the exposure, hazard, metabolism, and fate of legacy and emerging PFAS, PFAS mixtures, and resulting effects to humans and other organisms. Research may include in vivo, in vitro, and in silico studies in areas including, but not limited to, PFAS biomonitoring, bioaccumulation, biotransformation, dosimetry, exposure, toxicokinetics, lipidomics, metabolomics, integrated omics, neurotoxicity, endocrine disruption, developmental and reproductive toxicology, and cancer. In vivo dose–response studies that evaluate health effects related to sub-chronic and chronic exposure at environmentally relevant levels are welcome, as are those that employ new approach methodologies (NAMs), such as in vitro screening, microphysiologic systems, adverse outcome pathways, in vitroin vivo extrapolation (IVIVE), computational modeling or other approaches.

Dr. Denise MacMillan
Dr. Barbara Wetmore
Prof. Dr. William S. Baldwin
Dr. Subham Dasgupta
Guest Editors

Manuscript Submission Information

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Keywords

  • PFAS
  • toxicity
  • metabolism
  • toxicokinetics
  • adverse outcomes
  • omics
  • biotransformation
  • biomonitoring
  • new approach methodologies
  • in vitro–in vivo extrapolation

Published Papers (14 papers)

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13 pages, 1725 KiB  
Article
Effects of Temperature and Salinity on Perfluorooctane Sulfonate (PFOS) Toxicity in Larval Estuarine Organisms
by Katy W. Chung, Peter B. Key, Philip Tanabe and Marie E. DeLorenzo
Toxics 2024, 12(4), 267; https://doi.org/10.3390/toxics12040267 - 02 Apr 2024
Viewed by 661
Abstract
Perfluorooctane sulfonate (PFOS) is a persistent contaminant that has been found globally within the environment. Key data gaps exist in the toxicity of PFOS to marine organisms, especially estuarine species that are crucial to the food web: fish, shrimp, and mollusks. This study [...] Read more.
Perfluorooctane sulfonate (PFOS) is a persistent contaminant that has been found globally within the environment. Key data gaps exist in the toxicity of PFOS to marine organisms, especially estuarine species that are crucial to the food web: fish, shrimp, and mollusks. This study developed toxicity thresholds for larval estuarine species, including grass shrimp (Palaemon pugio), sheepshead minnows (Cyprinodon variegatus), mysids (Americamysis bahia), and Eastern mud snails (Tritia obsoleta). Multiple abiotic stressors (salinity and temperature) were included as variables in testing the toxicity of PFOS. Acute 96 h toxicity testing under standard test conditions of 25 °C and 20 ppt seawater yielded LC50 values of 0.919 mg/L for C. variegatus, 1.375 mg/L for A. bahia, 1.559 mg/L for T. obsoleta, and 2.011 mg/L for P. pugio. The effects of increased temperature (32 °C) and decreased salinity (10 ppt) varied with test species. PFOS toxicity for the sheepshead minnows increased with temperature but was not altered by decreased salinity. For grass shrimp and mud snails, PFOS toxicity was greater under lower salinity. The combination of higher temperature and lower salinity was observed to lower the toxicity thresholds for all species. These data demonstrate that expanding toxicity testing to include a wider range of parameters will improve the environmental risk assessment of chemical contaminants, especially for species inhabiting dynamic estuarine ecosystems. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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15 pages, 3168 KiB  
Article
Species-Specific Unbound Fraction Differences in Highly Bound PFAS: A Comparative Study across Human, Rat, and Mouse Plasma and Albumin
by Sangwoo Ryu, Woodrow Burchett, Sam Zhang, Seyed Mohamad Sadegh Modaresi, Juliana Agudelo Areiza, Emily Kaye, Fabian Christoph Fischer and Angela L. Slitt
Toxics 2024, 12(4), 253; https://doi.org/10.3390/toxics12040253 - 29 Mar 2024
Viewed by 641
Abstract
Per- and polyfluoroalkyl substances (PFAS) are a diverse group of fluorinated compounds which have yet to undergo comprehensive investigation regarding potential adverse health effects and bioaccumulative properties. With long half-lives and accumulative properties, PFAS have been linked to several toxic effects in both [...] Read more.
Per- and polyfluoroalkyl substances (PFAS) are a diverse group of fluorinated compounds which have yet to undergo comprehensive investigation regarding potential adverse health effects and bioaccumulative properties. With long half-lives and accumulative properties, PFAS have been linked to several toxic effects in both non-clinical species such as rat and mouse as well as human. Although biological impacts and specific protein binding of PFAS have been examined, there is no study focusing on the species-specific fraction unbound (fu) in plasma and related toxicokinetics. Herein, a presaturation equilibrium dialysis method was used to measure and validate the binding of 14 individual PFAS with carbon chains containing 4 to 12 perfluorinated carbon atoms and several functional head-groups to albumin and plasma of mouse (C57BL/6 and CD-1), rat, and human. Equivalence testing between each species-matrix combination showed positive correlation between rat and human when comparing fu in plasma and binding to albumin. Similar trends in binding were also observed for mouse plasma and albumin. Relatively high Spearman correlations for all combinations indicate high concordance of PFAS binding regardless of matrix. Physiochemical properties of PFAS such as molecular weight, chain length, and lipophilicity were found to have important roles in plasma protein binding of PFAS. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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23 pages, 2499 KiB  
Article
Per- and Polyfluoroalkyl Substances: Impacts on Morphology, Behavior and Lipid Levels in Zebrafish Embryos
by Janice Albers, John Mylroie, Ashley Kimble, Catherine Steward, Kacy Chapman, Mitchell Wilbanks, Edward Perkins and Natàlia Garcia-Reyero
Toxics 2024, 12(3), 192; https://doi.org/10.3390/toxics12030192 - 29 Feb 2024
Viewed by 1112
Abstract
The presence of per- and polyfluoroalkyl substances (PFASs) in aquatic environments is often persistent and widespread. Understanding the potential adverse effects from this group of chemicals on aquatic communities allows for better hazard characterization. This study examines impacts on zebrafish (Danio rerio [...] Read more.
The presence of per- and polyfluoroalkyl substances (PFASs) in aquatic environments is often persistent and widespread. Understanding the potential adverse effects from this group of chemicals on aquatic communities allows for better hazard characterization. This study examines impacts on zebrafish (Danio rerio) embryo physiology, behavior, and lipid levels from exposure to perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), and heptadecafluorooctanesulfonic acid (PFOS). Embryos were exposed to lethal and sublethal levels of each chemical and monitored for alterations in physiological malformations, mortality, lipid levels, and behavior (only PFOA and PFHxS). The predicted 50% lethal concentrations for 120 hpf embryos were 528.6 ppm PFOA, 14.28 ppm PFHxS, and 2.14 ppm PFOS. Spine curvature and the inability of the 120 hpf embryos to maintain a dorsal-up orientation was significantly increased at 10.2 ppm PFHxS and 1.9 ppm PFOS exposure. All measured 120 hpf embryo behaviors were significantly altered starting at the lowest levels tested, 188 ppm PFOA and 6.4 ppm PFHxS. Lipid levels decreased at the highest PFAS levels tested (375 PFOA ppm, 14.4 PFHxS ppm, 2.42 ppm PFOS). In general, the PFAS chemicals, at the levels examined in this study, increased morphological deformities, embryo activity, and startle response time, as well as decreased lipid levels in 120 hpf zebrafish embryos. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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25 pages, 6402 KiB  
Article
Increased Perfluorooctanesulfonate (PFOS) Toxicity and Accumulation Is Associated with Perturbed Prostaglandin Metabolism and Increased Organic Anion Transport Protein (OATP) Expression
by Lanie A. Williams, Matthew C. Hamilton, Matthew L. Edin, Fred B. Lih, Jazmine A. Eccles-Miller, Nishanth Tharayil, Elizabeth Leonard and William S. Baldwin
Toxics 2024, 12(2), 106; https://doi.org/10.3390/toxics12020106 - 26 Jan 2024
Viewed by 1264
Abstract
Perfluorooctanesulfonate (PFOS) is a widespread environmental pollutant with a long half-life and clearly negative outcomes on metabolic diseases such as fatty liver disease and diabetes. Male and female Cyp2b-null and humanized CYP2B6-transgenic (hCYP2B6-Tg) mice were treated with 0, 1, or 10 mg/kg/day PFOS [...] Read more.
Perfluorooctanesulfonate (PFOS) is a widespread environmental pollutant with a long half-life and clearly negative outcomes on metabolic diseases such as fatty liver disease and diabetes. Male and female Cyp2b-null and humanized CYP2B6-transgenic (hCYP2B6-Tg) mice were treated with 0, 1, or 10 mg/kg/day PFOS for 21 days, and surprisingly it was found that PFOS was retained at greater concentrations in the serum and liver of hCYP2B6-Tg mice than those of Cyp2b-null mice, with greater differences in the females. Thus, Cyp2b-null and hCYP2B6-Tg mice provide new models for investigating individual mechanisms for PFOS bioaccumulation and toxicity. Overt toxicity was greater in hCYP2B6-Tg mice (especially females) as measured by mortality; however, steatosis occurred more readily in Cyp2b-null mice despite the lower PFOS liver concentrations. Targeted lipidomics and transcriptomics from PFOS-treated Cyp2b-null and hCYP2B6-Tg mouse livers were performed and compared to PFOS retention and serum markers of toxicity using PCA. Several oxylipins, including prostaglandins, thromboxanes, and docosahexaenoic acid metabolites, are associated or inversely associated with PFOS toxicity. Both lipidomics and transcriptomics indicate PFOS toxicity is associated with PPAR activity in all models. GO terms associated with reduced steatosis were sexually dimorphic with lipid metabolism and transport increased in females and circadian rhythm associated genes increased in males. However, we cannot rule out that steatosis was initially protective from PFOS toxicity. Moreover, several transporters are associated with increased retention, probably due to increased uptake. The strongest associations are the organic anion transport proteins (Oatp1a4-6) genes and a long-chain fatty acid transport protein (fatp1), enriched in female hCYP2B6-Tg mice. PFOS uptake was also reduced in cultured murine hepatocytes by OATP inhibitors. The role of OATP1A6 and FATP1 in PFOS transport has not been tested. In summary, Cyp2b-null and hCYP2B6-Tg mice provided unique models for estimating the importance of novel mechanisms in PFOS retention and toxicity. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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15 pages, 1990 KiB  
Article
Mixture Effects of Per- and Polyfluoroalkyl Substances on Embryonic and Larval Sheepshead Minnows (Cyprinodon variegatus)
by Philip Tanabe, Peter B. Key, Katy W. Chung, Emily C. Pisarski, Jessica L. Reiner, Alix E. Rodowa, Jason T. Magnuson and Marie E. DeLorenzo
Toxics 2024, 12(1), 91; https://doi.org/10.3390/toxics12010091 - 20 Jan 2024
Cited by 1 | Viewed by 1247
Abstract
Per- and polyfluoroalkyl substances (PFAS) are ubiquitous and persistent environmental contaminants originating from many everyday products. Perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are two PFAS that are commonly found at high concentrations in aquatic environments. Both chemicals have previously been shown [...] Read more.
Per- and polyfluoroalkyl substances (PFAS) are ubiquitous and persistent environmental contaminants originating from many everyday products. Perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are two PFAS that are commonly found at high concentrations in aquatic environments. Both chemicals have previously been shown to be toxic to fish, as well as having complex and largely uncharacterized mixture effects. However, limited information is available on marine and estuarine species. In this study, embryonic and larval sheepshead minnows (Cyprinodon variegatus) were exposed to several PFAS mixtures to assess lethal and sublethal effects. PFOS alone was acutely toxic to larvae, with a 96 h LC50 of 1.97 mg/L (1.64–2.16). PFOS + PFOA resulted in a larval LC50 of 3.10 (2.62–3.79) mg/L, suggesting an antagonistic effect. These observations were supported by significant reductions in malondialdehyde (105% ± 3.25) and increases in reduced glutathione concentrations (43.8% ± 1.78) in PFOS + PFOA exposures compared to PFOS-only treatments, indicating reduced oxidative stress. While PFOA reduced PFOS-induced mortality (97.0% ± 3.03), perfluorohexanoic acid (PFHxA) and perfluorobutanoic acid (PFBA) did not. PFOS alone did not affect expression of peroxisome proliferator-activated receptor alpha (pparα) but significantly upregulated apolipoprotein A4 (apoa4) (112.4% ± 17.8), a downstream product of pparα, while none of the other individually tested PFAS affected apoa4 expression. These findings suggest that there are antagonistic interactions between PFOA and PFOS that may reduce mixture toxicity in larval sheepshead minnows through reduced oxidative stress. Elucidating mechanisms of toxicity and interactions between PFAS will aid environmental regulation and management of these ubiquitous pollutants. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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19 pages, 13001 KiB  
Article
Toxicity Assessment of Mixed Exposure of Nine Perfluoroalkyl Substances at Concentrations Relevant to Daily Intake
by Kazuki Takeda, Taki Saito, Sakura Sasaki, Akifumi Eguchi, Makoto Sugiyama, Saeka Eto, Kio Suzuki and Ryo Kamata
Toxics 2024, 12(1), 52; https://doi.org/10.3390/toxics12010052 - 10 Jan 2024
Viewed by 1704
Abstract
Per- and poly-fluoroalkyl substances (PFAS) exhibit high persistence in the environment and accumulate within the human body, warranting a thorough assessment of their toxicity. In this study, we exposed mice (male C57BL/6J mice aged 8 weeks) to a composite of nine PFAS, encompassing [...] Read more.
Per- and poly-fluoroalkyl substances (PFAS) exhibit high persistence in the environment and accumulate within the human body, warranting a thorough assessment of their toxicity. In this study, we exposed mice (male C57BL/6J mice aged 8 weeks) to a composite of nine PFAS, encompassing both long-chain PFAS (e.g., perfluorooctanoic acid and perfluorooctanesulfonic acid) and short-chain PFAS (e.g., perfluorobutanoic acid and perfluorobutanesulfonic acid). The exposure concentrations of PFAS were equivalent to the estimated daily human intake in the composition reported (1 µg/L (sum of the nine compounds), representing the maximum reported exposure concentration). Histological examination revealed hepatocyte vacuolization and irregular hepatocyte cord arrangement, indicating that exposure to low levels of the PFAS mixture causes morphological changes in liver tissues. Transcriptome analysis revealed that PFAS exposure mainly altered a group of genes related to metabolism and chemical carcinogenesis. Machine learning analysis of the liver metabolome showed a typical concentration-independent alteration upon PFAS exposure, with the annotation of substances such as glutathione and 5-aminovaleric acid. This study demonstrates that daily exposure to PFAS leads to morphological changes in liver tissues and alters the expression of metabolism- and cancer-related genes as well as phospholipid metabolism. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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24 pages, 2670 KiB  
Article
Dose Response, Dosimetric, and Metabolic Evaluations of Replacement PFAS Perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) Acid (HFPO-TeA)
by Aero Renyer, Krishna Ravindra, Barbara A. Wetmore, Jermaine L. Ford, Michael DeVito, Michael F. Hughes, Leah C. Wehmas and Denise K. MacMillan
Toxics 2023, 11(12), 951; https://doi.org/10.3390/toxics11120951 - 22 Nov 2023
Viewed by 1421
Abstract
Few studies are available on the environmental and toxicological effects of perfluoroalkyl ether carboxylic acids (PFECAs), such as GenX, which are replacing legacy PFAS in manufacturing processes. To collect initial data on the toxicity and toxicokinetics of a longer-chain PFECA, male and female [...] Read more.
Few studies are available on the environmental and toxicological effects of perfluoroalkyl ether carboxylic acids (PFECAs), such as GenX, which are replacing legacy PFAS in manufacturing processes. To collect initial data on the toxicity and toxicokinetics of a longer-chain PFECA, male and female Sprague Dawley rats were exposed to perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) acid (HFPO-TeA) by oral gavage for five days over multiple dose levels (0.3–335.2 mg/kg/day). Clinically, we observed mortality at doses >17 mg/kg/day and body weight changes at doses ≤17 mg/kg/day. For the 17 mg/kg/day dose level, T3 and T4 thyroid hormone concentrations were significantly decreased (p < 0.05) from controls and HFPO-TeA plasma concentrations were significantly different between sexes. Non-targeted analysis of plasma and in vitro hepatocyte assay extractions revealed the presence of another GenX oligomer, perfluoro-(2,5-dimethyl-3,6-dioxanonanoic) acid (HFPO-TA). In vitro to in vivo extrapolation (IVIVE) parameterized with in vitro toxicokinetic data predicted steady-state blood concentrations that were within seven-fold of those observed in the in vivo study, demonstrating reasonable predictivity. The evidence of thyroid hormone dysregulation, sex-based differences in clinical results and dosimetry, and IVIVE predictions presented here suggest that the replacement PFECA HFPO-TeA induces a complex and toxic exposure response in rodents. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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12 pages, 1342 KiB  
Communication
Toxicity of Per- and Polyfluoroalkyl Substances to Nematodes
by Tingting Ma, Xia Pan, Tiantian Wang, Xiuhua Li and Yongming Luo
Toxics 2023, 11(7), 593; https://doi.org/10.3390/toxics11070593 - 07 Jul 2023
Cited by 1 | Viewed by 1269
Abstract
Per- and polyfluoroalkyl substances (PFASs) are a class of compounds that persist in the environment globally. Besides being transported to the soil and sediments, which act as their sinks, PFASs can be transferred to several species of higher organisms directly or via bacteria, [...] Read more.
Per- and polyfluoroalkyl substances (PFASs) are a class of compounds that persist in the environment globally. Besides being transported to the soil and sediments, which act as their sinks, PFASs can be transferred to several species of higher organisms directly or via bacteria, eliciting a wide range of adverse effects. Caenorhabditis elegans has been widely used in toxicological studies and life science research owing to its numerous advantages over traditional vertebrate models; notably, C. elegans has 65% conserved human-disease-associated genes and does not require ethical approvals for experimental use. This review covers a range of topics, from reported accumulation characteristics and lethal concentrations of PFAS in C. elegans to the mechanisms underlying the toxicity of PFAS at different levels, including reproductive, developmental, cellular, neurologic, oxidative, metabolic, immune, and endocrine toxicities. Additionally, the toxicity levels of some PFAS substitutes are summarized. Lastly, we discuss the toxicological mechanisms of these PFAS substitutes and the importance and promising potential of nematodes as in vivo models for life science research, epidemiological studies (obesity, aging, and Alzheimer’s disease research), and toxicological investigations of PFASs and other emerging pollutants compared with other soil animals or model organisms. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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22 pages, 6729 KiB  
Article
Cross-Species Transcriptomics Analysis Highlights Conserved Molecular Responses to Per- and Polyfluoroalkyl Substances
by Livia Beccacece, Filippo Costa, Jennifer Paola Pascali and Federico Manuel Giorgi
Toxics 2023, 11(7), 567; https://doi.org/10.3390/toxics11070567 - 29 Jun 2023
Cited by 3 | Viewed by 3769
Abstract
In recent decades, per- and polyfluoroalkyl substances (PFASs) have garnered widespread public attention due to their persistence in the environment and detrimental effects on the health of living organisms, spurring the generation of several transcriptome-centered investigations to understand the biological basis of their [...] Read more.
In recent decades, per- and polyfluoroalkyl substances (PFASs) have garnered widespread public attention due to their persistence in the environment and detrimental effects on the health of living organisms, spurring the generation of several transcriptome-centered investigations to understand the biological basis of their mechanism. In this study, we collected 2144 publicly available samples from seven distinct animal species to examine the molecular responses to PFAS exposure and to determine if there are conserved responses. Our comparative transcriptional analysis revealed that exposure to PFAS is conserved across different tissues, molecules and species. We identified and reported several genes exhibiting consistent and evolutionarily conserved transcriptional response to PFASs, such as ESR1, HADHA and ID1, as well as several pathways including lipid metabolism, immune response and hormone pathways. This study provides the first evidence that distinct PFAS molecules induce comparable transcriptional changes and affect the same metabolic processes across inter-species borders. Our findings have significant implications for understanding the impact of PFAS exposure on living organisms and the environment. We believe that this study offers a novel perspective on the molecular responses to PFAS exposure and provides a foundation for future research into developing strategies for mitigating the detrimental effects of these substances in the ecosystem. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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19 pages, 2470 KiB  
Article
Category-Based Toxicokinetic Evaluations of Data-Poor Per- and Polyfluoroalkyl Substances (PFAS) using Gas Chromatography Coupled with Mass Spectrometry
by Anna Kreutz, Matthew S. Clifton, W. Matthew Henderson, Marci G. Smeltz, Matthew Phillips, John F. Wambaugh and Barbara A. Wetmore
Toxics 2023, 11(5), 463; https://doi.org/10.3390/toxics11050463 - 16 May 2023
Cited by 2 | Viewed by 2212
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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19 pages, 3988 KiB  
Article
Gut Microbiome-Host Metabolome Homeostasis upon Exposure to PFOS and GenX in Male Mice
by Faizan Rashid, Veronika Dubinkina, Saeed Ahmad, Sergei Maslov and Joseph Maria Kumar Irudayaraj
Toxics 2023, 11(3), 281; https://doi.org/10.3390/toxics11030281 - 19 Mar 2023
Cited by 6 | Viewed by 2616
Abstract
Alterations of the normal gut microbiota can cause various human health concerns. Environmental chemicals are one of the drivers of such disturbances. The aim of our study was to examine the effects of exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS)—specifically, perfluorooctane sulfonate (PFOS) [...] Read more.
Alterations of the normal gut microbiota can cause various human health concerns. Environmental chemicals are one of the drivers of such disturbances. The aim of our study was to examine the effects of exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS)—specifically, perfluorooctane sulfonate (PFOS) and 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy) propanoic acid (GenX)—on the microbiome of the small intestine and colon, as well as on liver metabolism. Male CD-1 mice were exposed to PFOS and GenX in different concentrations and compared to controls. GenX and PFOS were found to have different effects on the bacterial community in both the small intestine and colon based on 16S rRNA profiles. High GenX doses predominantly led to increases in the abundance of Clostridium sensu stricto, Alistipes, and Ruminococcus, while PFOS generally altered Lactobacillus, Limosilactobacillus, Parabacteroides, Staphylococcus, and Ligilactobacillus. These treatments were associated with alterations in several important microbial metabolic pathways in both the small intestine and colon. Untargeted LC-MS/MS metabolomic analysis of the liver, small intestine, and colon yielded a set of compounds significantly altered by PFOS and GenX. In the liver, these metabolites were associated with the important host metabolic pathways implicated in the synthesis of lipids, steroidogenesis, and in the metabolism of amino acids, nitrogen, and bile acids. Collectively, our results suggest that PFOS and GenX exposure can cause major perturbations in the gastrointestinal tract, aggravating microbiome toxicity, hepatotoxicity, and metabolic disorders. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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22 pages, 1720 KiB  
Article
A Machine Learning Model to Estimate Toxicokinetic Half-Lives of Per- and Polyfluoro-Alkyl Substances (PFAS) in Multiple Species
by Daniel E. Dawson, Christopher Lau, Prachi Pradeep, Risa R. Sayre, Richard S. Judson, Rogelio Tornero-Velez and John F. Wambaugh
Toxics 2023, 11(2), 98; https://doi.org/10.3390/toxics11020098 - 20 Jan 2023
Cited by 8 | Viewed by 4988
Abstract
Per- and polyfluoroalkyl substances (PFAS) are a diverse group of man-made chemicals that are commonly found in body tissues. The toxicokinetics of most PFAS are currently uncharacterized, but long half-lives (t½) have been observed in some cases. Knowledge of chemical-specific [...] Read more.
Per- and polyfluoroalkyl substances (PFAS) are a diverse group of man-made chemicals that are commonly found in body tissues. The toxicokinetics of most PFAS are currently uncharacterized, but long half-lives (t½) have been observed in some cases. Knowledge of chemical-specific t½ is necessary for exposure reconstruction and extrapolation from toxicological studies. We used an ensemble machine learning method, random forest, to model the existing in vivo measured t½ across four species (human, monkey, rat, mouse) and eleven PFAS. Mechanistically motivated descriptors were examined, including two types of surrogates for renal transporters: (1) physiological descriptors, including kidney geometry, for renal transporter expression and (2) structural similarity of defluorinated PFAS to endogenous chemicals for transporter affinity. We developed a classification model for t½ (Bin 1: <12 h; Bin 2: <1 week; Bin 3: <2 months; Bin 4: >2 months). The model had an accuracy of 86.1% in contrast to 32.2% for a y-randomized null model. A total of 3890 compounds were within domain of the model, and t½ was predicted using the bin medians: 4.9 h, 2.2 days, 33 days, and 3.3 years. For human t½, 56% of PFAS were classified in Bin 4, 7% were classified in Bin 3, and 37% were classified in Bin 2. This model synthesizes the limited available data to allow tentative extrapolation and prioritization. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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24 pages, 8430 KiB  
Article
PFAS Biotransformation Pathways: A Species Comparison Study
by Richard C. Kolanczyk, Megan R. Saley, Jose A. Serrano, Sara M. Daley and Mark A. Tapper
Toxics 2023, 11(1), 74; https://doi.org/10.3390/toxics11010074 - 12 Jan 2023
Cited by 12 | Viewed by 4200
Abstract
Limited availability of fish metabolic pathways for PFAS may lead to risk assessments with inherent uncertainties based only upon the parent chemical or the assumption that the biodegradation or mammalian metabolism map data will serve as an adequate surrogate. A rapid and transparent [...] Read more.
Limited availability of fish metabolic pathways for PFAS may lead to risk assessments with inherent uncertainties based only upon the parent chemical or the assumption that the biodegradation or mammalian metabolism map data will serve as an adequate surrogate. A rapid and transparent process, utilizing a recently created database of systematically collected information for fish, mammals, poultry, plant, earthworm, sediment, sludge, bacteria, and fungus using data evaluation tools in the previously described metabolism pathway software system MetaPath, is presented. The fish metabolism maps for 10 PFAS, heptadecafluorooctyl(tridecafluorohexyl)phosphinic acid (C6/C8 PFPiA), bis(perfluorooctyl)phosphinic acid (C8/C8 PFPiA), 2-[(6-chloro-1,1,2,2,3,3,4,4,5,5,6,6-dodecafluorohexyl)oxy]-1,1,2,2-tetrafluoroethanesulfonic acid (6:2 Cl-PFESA), N-Ethylperfluorooctane-1-sulfonamide (Sulfuramid; N-EtFOSA), N-Ethyl Perfluorooctane Sulfonamido Ethanol phosphate diester (SAmPAP), Perfluorooctanesulfonamide (FOSA), 8:2 Fluorotelomer phosphate diester (8:2 diPAP), 8:2 fluorotelomer alcohol (8:2 FTOH), 10:2 fluorotelomer alcohol (10:2 FTOH), and 6:2 fluorotelomer sulfonamide alkylbetaine (6:2 FTAB), were compared across multiple species and systems. The approach demonstrates how comparisons of metabolic maps across species are aided by considering the sample matrix in which metabolites were quantified for each species, differences in analytical methods used to identify metabolites in each study, and the relative amounts of metabolites quantified. Overall, the pathways appear to be well conserved across species and systems. For PFAS lacking a fish metabolism study, a composite map consisting of all available maps would serve as the best basis for metabolite prediction. This emphasizes the importance and utility of collating metabolism into a searchable database such as that created in this effort. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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Review

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20 pages, 3136 KiB  
Review
A Scoping Assessment of Implemented Toxicokinetic Models of Per- and Polyfluoro-Alkyl Substances, with a Focus on One-Compartment Models
by Alexander East, Daniel E. Dawson, Sydney Brady, Daniel A. Vallero and Rogelio Tornero-Velez
Toxics 2023, 11(2), 163; https://doi.org/10.3390/toxics11020163 - 09 Feb 2023
Cited by 5 | Viewed by 2123
Abstract
Toxicokinetic (TK) models have been used for decades to estimate concentrations of per-and polyfluoroalkyl substances (PFAS) in serum. However, model complexity has varied across studies depending on the application and the state of the science. This scoping effort seeks to systematically map the [...] Read more.
Toxicokinetic (TK) models have been used for decades to estimate concentrations of per-and polyfluoroalkyl substances (PFAS) in serum. However, model complexity has varied across studies depending on the application and the state of the science. This scoping effort seeks to systematically map the current landscape of PFAS TK models by categorizing different trends and similarities across model type, PFAS, and use scenario. A literature review using Web of Science and SWIFT-Review was used to identify TK models used for PFAS. The assessment covered publications from 2005–2020. PFOA, the PFAS for which most models were designed, was included in 69 of the 92 papers, followed by PFOS with 60, PFHxS with 22, and PFNA with 15. Only 4 of the 92 papers did not include analysis of PFOA, PFOS, PFNA, or PFHxS. Within the corpus, 50 papers contained a one-compartment model, 17 two-compartment models were found, and 33 used physiologically based pharmacokinetic (PBTK) models. The scoping assessment suggests that scientific interest has centered around two chemicals—PFOA and PFOS—and most analyses use one-compartment models in human exposure scenarios. Full article
(This article belongs to the Special Issue PFAS Toxicology and Metabolism)
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