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Since 2000, long-chain perfluoroalkyl acids (PFAAs) and their respective precursors have been replaced by numerous fluorinated alternatives. The main rationale for this industrial transition was that these alternatives were considered less bioaccumulative and toxic than their predecessors. In this study, we evaluated to what extent differences in toxicological effect thresholds for PFAAs and fluorinated alternatives, expressed as administered dose, were confounded by differences in their distribution and elimination kinetics. A dynamic one-compartment toxicokinetic (TK) model for male rats was constructed and evaluated using test data from toxicity studies for perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorobutane sulfonic acid (PFBS), perfluorooctanoic acid (PFOA), perfluoroctanesulfonic acid (PFOS) and ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (GenX). Dose-response curves of liver enlargement from sub-chronic oral toxicity studies in male rats were converted to internal dose in serum and in liver to examine the toxicity ranking of PFAAs and fluorinated alternatives. Converting administered doses into equivalent serum and liver concentrations reduced the variability in the dose-response curves for PFBA, PFHxA, PFOA and GenX. The toxicity ranking using modeled serum (GenX > PFOA > PFHxA > PFBA) and liver (GenX > PFOA ≈ PFHxA ≈ PFBA) concentrations indicated that some fluorinated alternatives have similar or higher toxic potency than their predecessors when correcting for differences in toxicokinetics. For PFOS and perfluorobutane sulfonic acid (PFBS) the conversion from administered dose to serum concentration equivalents did not change the toxicity ranking. In conclusion, hazard assessment based on internal exposure allows evaluation of toxic potency and bioaccumulation potential independent of kinetics and should be considered when comparing fluorinated alternatives with their predecessors.
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... The ratio at which PFAS distribute between body compartments varies with the type PFAS and animal species. 44 As the length of the carbon chain grows, the protein-binding properties and level of resorption of PFAS in the body increase while elimination of the chemical from the body decreases. 43,44 PFAS are eliminated via the urine or feces, but depending on the specific chemical, sex, and animal species, elimination rates and half-lives differ. ...
... 44 As the length of the carbon chain grows, the protein-binding properties and level of resorption of PFAS in the body increase while elimination of the chemical from the body decreases. 43,44 PFAS are eliminated via the urine or feces, but depending on the specific chemical, sex, and animal species, elimination rates and half-lives differ. 37,44 For example, the half-life of PFOS in mice ranges from days to weeks, while in pigs it is almost 2 years (634 days). ...
... 43,44 PFAS are eliminated via the urine or feces, but depending on the specific chemical, sex, and animal species, elimination rates and half-lives differ. 37,44 For example, the half-life of PFOS in mice ranges from days to weeks, while in pigs it is almost 2 years (634 days). 45 For PFOA, the half-life could be as short as 2 hours in mice, while in pigs the half-life of the same compound was 236 days. ...
Per- and polyfluoroalkyl substances (PFAS) are man-made chemicals that are colorless, odorless, and oil and water repellent. Their widespread use in manufacturing and industrial processes has resulted in environmental contamination found across the world. Exposure to PFAS can lead to a variety of adverse human health outcomes such as increased cholesterol, liver damage, immune suppression, and disruption of endocrine and reproductive systems. Exposure to this family of chemicals is considered a significant public health threat. Though nearly every human and animal around the world has been exposed, most of what is known regarding health effects and toxicological processes of PFAS in animals stems from human epidemiological and laboratory animal studies. Discoveries of PFAS contamination on dairy farms and concerns for companion animals have increased interest in PFAS research related to our veterinary patients. In the limited studies published to date, PFAS has been demonstrated in serum, liver, kidneys, and milk of production animals and has been linked to changes in liver enzymes, cholesterol levels, and thyroid hormones in dogs and cats. This is further addressed in the companion Currents in One Health by Brake et al, AJVR, April 2023. There is a gap in understanding the routes of exposure, absorption of PFAS, and adverse health effects among our veterinary patients. The purpose of this review is to summarize the current literature on PFAS in animals and discuss the implications for our veterinary patients.
... That is, kinetics determining the internal dose after (external) intake differ between PFAS, and therefore potencies based on external doses will not be the same as potencies based on internal doses. For example, based on external doses HFPO-DA has been shown to be less potent than PFOA in the male rat when looking at relative liver weight increase 77,79 but was regarded to be more potent when these external concentrations were converted to blood serum concentrations. 79 Considering the fact that HFPO-DA shows a lower degree of accumulation in male rats in comparison with PFOA, 80,81 the differences in external potency between HFPO-DA and PFOA may at least partly be explained by differences in toxicokinetics. ...
... For example, based on external doses HFPO-DA has been shown to be less potent than PFOA in the male rat when looking at relative liver weight increase 77,79 but was regarded to be more potent when these external concentrations were converted to blood serum concentrations. 79 Considering the fact that HFPO-DA shows a lower degree of accumulation in male rats in comparison with PFOA, 80,81 the differences in external potency between HFPO-DA and PFOA may at least partly be explained by differences in toxicokinetics. This topic will be further addressed in the "Discussion" section. ...
... The public literature was screened for toxicokinetic data and models for the 16 PFAS included in the toxicity database, using search engine Google Scholar as well as screening the literature cited in several scientific reports and publications. 44,45,79 For 10 PFAS [PFBA, 68 PFHxA, 81 PFOA, 81 PFNA, 101 PFDA, 81 perfluorododecanoic acid (PFDoDA), 73 PFBS, 102 PFHxS, 102 PFOS, 102 HFPO-DA 80 ], sufficient model parameter values were obtained from single-dose experiments. In most studies, multiple doses and exposure routes were tested. ...
In human biomonitoring, blood is often used as a matrix to measure exposure to per- and polyfluoroalkyl substances (PFAS). Because the toxicokinetics of a substance (determining the steady-state blood concentration) may affect the toxic potency, the difference in toxicokinetics among PFAS has to be accounted for when blood concentrations are used in mixture risk assessment.
This research focuses on deriving relative potency factors (RPFs) at the blood serum level. These RPFs can be applied to PFAS concentrations in human blood, thereby facilitating mixture risk assessment with primary input from human biomonitoring studies.
Toxicokinetic models are generated for 10 PFAS to estimate the internal exposure in the male rat at the blood serum level over time. By applying dose-response modeling, these internal exposures are used to derive quantitative internal RPFs based on liver effects.
Internal RPFs were successfully obtained for nine PFAS. Perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoDA), perfluorooctane sulfonic acid (PFOS), and hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX) were found to be more potent than perfluorooctanoic acid (PFOA) at the blood serum level in terms of relative liver weight increase, whereas perfluorobutane sulfonic acid (PFBS) and perfluorohexane sulfonic acid (PFHxS) were found to be less potent. The practical implementation of these internal RPFs is illustrated using the National Health and Nutrition Examination Survey (NHANES) biomonitoring data of 2017-2018.
It is recommended to assess the health risk resulting from exposure to PFAS as combined, aggregate exposure to the extent feasible. https://doi.org/10.1289/EHP10009.
... and other products; however, this production process results in a substantial amount of chemical waste . The Chemours corporation has been producing GenX commercially since 2009 for the production of Teflon at a site in Fayetteville, North Carolina, and had been dumping its GenX-laden waste in the Cape Fear River, thus contaminating the source of drinking water for 1.5 million people . ...
... A very high dose of the chemical caused the animals to die , . Humans may experience similar negative reactions to GenX, as rodents share close resemblance to humans in their genetic, biological, and behavioral characteristics . ...
Guided by Entman’s Framing theory, this content analytic study explores the journalistic framing of the Cape Fear River contamination in North Carolina, USA. Chemours, a spin-off company of DuPont was responsible for the release of a hazardous chemical known as GenX into the river, which caused the contamination. The study involved an inductive analysis of 359 news reports about the issue. The results indicated that 78.83% of the articles framed the problems, 72.7% framed the causes, 60.17% framed the effects, and 55.71% framed the potential solutions. Five principal problem frames (i.e., river contamination, Chemours’s involvement, scientific uncertainty about GenX, governmental inaction, and the inability of the water treatment plants to filter GenX), four cause frames (i.e., Chemours’s malfeasance, wastewater spillage from Chemours’s facility, politics, and a lack of regulatory standards for GenX), six effect frames (i.e., the revocation of Chemours’s permit, legal action against Chemours, health effects of GenX, stakeholders’ demands for answers, scammers targeting stakeholders, and the potential declaration of Cape Fear River as a swampland), and five solution frames (i.e., stopping the wastewater discharge, securing grants to deal with the issue, using alternative techniques to filter GenX, advancing bills to prevent further corporate contamination, and using alternate sources for drinking water) were identified. By looking at all the four frames together, the current study adds to the framing literature, and can be used in the future to determine how the analyzed news media frames contributed to the formation of public opinion regarding the issue.
... The RPFs for cytotoxicity and ROS generation have been calculated to compare those with RPFs originating from existing in vivo data (Table 4). A previous study on rat's liver weight after PFAS exposure found that the toxic potency of PFASs is similarly linked to the chain-length after correcting for estimated serum levels (Gomis et al., 2018). Bil et al. (2021) have furthermore modeled RPF for a wide range of PFAS' hepatotoxic effects in rats. ...
... As such, the present study allowed for a better understanding of the PFAS structure-activity relationship and observed similar behavior for PFAS up to eight carbons in vitro. However, it also uncovers the limitations of the current in vitro approach as the toxic potential of 6:2 FTOH, PFNA, and PFDA were lower than the in vivo results (Gomis et al., 2018;Bil et al., 2021). ...
Per- and polyfluoroalkyl substances (PFAS) are a family of man-made chemicals with currently over 4'700 compounds identified. While toxicological data are available for some of the legacy PFAS, such as PFOA and PFOS, a knowledge gap remains concerning both emerging and legacy PFAS' toxicity due to the diversity of the PFAS. Therefore, a better understanding of the PFAS structure-activity relationship may prove helpful.
The present study investigated a potential structure-activity relationship between PFAS and hepatotoxicity. As such, the effects of thirteen PFAS with varying carbon chain-length and functional head-groups (in a concentration range of 0-800 µM) on the cell viability of HepG2 cells and intracellular reactive oxygen species formation have been tested using the MTT and DCFH assay, respectively. The exposure times were either 3 or 24 h. In addition, intracellular PFAS levels were determined in HepG2 after 24 h exposure.
The present study demonstrated that the cytotoxicity of PFAS is dependent on their chain-length as cell viability decreased with increasing chain-length at both exposure times. Calculated Relative Potency Factors (RPF), based on the TC50 values, were used for a tentative ranking of PFAS regarding their hepatotoxicity: PFNA ˃ PFDA ˃ PFOS ≥ PFOA ˃ PFHxS ˃ PFBS ˃˃ PFHpA = PFHxA = PFBA = PFPrA = 6:2 FTOH = 4:2 = FTOH = 3:1 FTOH. Similar results were observed regarding intracellular reactive oxygen species generation at both exposure times, with a tentative ranking of: PFNA ˃ PFOS ˃ PFOA ≥ PFDA ˃ PFHxS ˃ PFBS ˃ PFBA ˃ PFHpA ≥ PFHxA ˃ PFPrA ˃ 6:2 FTOH = 4:2 FTOH = 3:1 FTOH. Moreover, a concentration-dependent reactive oxygen species generation has been observed for all PFSAs and PFCAs, but not for the FTOHs.
In conclusion, the carbon chain-length and functional head-group of a PFAS determine their in vitro toxicity for the two toxicological endpoints assessed in the present study. Moreover, no effects were observed for the tested FTOHs. As such, the present study established a potential structure-activity relationship that opens the possibility of developing a predictive model to help with the risk assessment of PFAS in the future.
... For example, hexafluoropropylene oxide dimer acid (HFPO-DA, or trade name of "GenX"), which serves as a replacement for ammonium perfluorooctanoate (the ammonium salt of PFOA), has been detected in high concentrations in the Cape Fear River that supplies drinking water to>200,000 residents in North Carolina [4,8,17]. Previous studies show that these perfluorinated homologues present similar toxic effects as legacy long-chain PFAS . For instance, GenX is toxic to liver cells and can irritate the eyes and skin . ...
... Previous studies show that these perfluorinated homologues present similar toxic effects as legacy long-chain PFAS . For instance, GenX is toxic to liver cells and can irritate the eyes and skin . Because of their proven abundance in water, PFEA and other emerging homologues pose a significant challenge for water purification processes. ...
Although nanofiltration (NF) has been widely reported for removing long-chain per- and polyfluoroalkyl substances (PFAS) from water, little is known about the correlations between removal efficacy and PFAS/membrane characteristics, especially for emerging PFAS with shorter polyfluoroalkyl chain or containing fluoroether moieties. A systematic study of treatment of structurally diverse PFAS by NF can help predict the behavior of more unknown compounds during NF process. In this study, we conducted filtration experiments with five commercial NF membranes. Results show that seven legacy PFAS, three emerging perfluoroalkyl ether acids (PFEA) and two fluorotelomer sulfonates (FTS) can be removed simultaneously during the NF process, with rejection ranging from 66.0% to > 99.9%. The removal efficiency of five membranes decreased successively as DK > NF90 > XN45 > NF270 > DL. Rejection of FTS and PFEA by DK membranes were 88.3% to 97.1% and 81.7% to > 99.9%, respectively. Correlation analysis revealed that PFAS molecular structure and membrane characteristics significantly affect PFAS rejection. PFAS molecular weight (MW) and hydrophobicity (logKow) and membrane intrinsic structural characteristics (e.g., molecular weight cut-off (MWCO), water permeability, and salt selectivity) are among the most significant parameters impacting PFAS removal. The findings imply that both steric hindrance and hydrophobic interactions contribute to PFAS rejection. Moreover, the mass of PFAS adsorbed on the membrane was positively correlated with their molecular parameters (i.e., MW and logKow) and weakly correlated with membrane properties, suggesting that the adsorption and rejection of PFAS have similar driving forces. This study provides critical insights into the application of NF for emerging PFAS removal for both the scientific community and private industry, concerning water purification processes and remediation of thousands of PFAS-impacted sites.
... In rat and human thyroid cell lines, GenX is shown to be more toxic than PFOA (Zhang et al., 2021). Acute toxicity, genotoxicity, and developmental toxicity have also been reported (Gordon, 2011;Gomis et al., 2018). The current study sought to complement rodent models by assessing the effects of PFAS exposure on a novel laboratory animal model, Monodelphis domestica. ...
Introduction: Perfluoroalkyl and poly-fluoroalkyl substances (PFASs) are widely used in industrial and consumer products. Due to their environmental persistence and bioaccumulation, PFASs can be found in the blood of humans and wild animals all over the world. Various fluorinated alternatives such as GenX have been developed to replace the long-chain PFASs, but there is limited information about their potential toxicity. Methods:The current study developed blood culture protocols to assess the response to toxic compounds in the marsupial, Monodelphis domestica. After whole-blood culture conditions were tested and optimized, changes in gene expression in response to PFOA and GenX treatment were assessed. Results: More than 10,000 genes were expressed in the blood transcriptomes with and without treatment. Both PFOA and GenX treatment led to significant changes in the whole blood culture transcriptomes. A total of 578 and 148 differentially expressed genes (DEGs) were detected in the PFOA and GenX treatment groups, 32 of which overlapped. Pathway enrichment analysis revealed that DEGs involved in developmental processes were upregulated after PFOA exposure, while those enriched for metabolic and immune system processes were downregulated. GenX exposure upregulated genes associated with fatty acid transport pathways and inflammatory processes, which is consistent with previous studies using rodent models. Discussion: To our knowledge, this study is the first to investigate the effect of PFASs in a marsupial model. The findings provide supportive evidence for significant transcriptomic alterations, suggesting that this mammalian model may provide a mechanism for exploring the potential toxicity of PFOA and GenX.
... The broadening global market demand has prompted the development of various fluorinated substituents instead of PFOA and PFOS, which contain shorter-chain PFAAs and novel fluorinated alternatives such as hexafluoropropylene oxide dimer acid (HFPO-DA, with the trade name of GenX), hexafluoropropylene oxide trimer acid (HFPO-TA), 6:2 chlorinated polyfluorinated ether sulfonate (6:2Cl-PFESA) and 6:2 fluorotelomer sulfonate (6:2 FTS) Xiao, 2017). However, adverse ecological and human health outcomes of these substitutes have also gradually emerged (Gomis et al., 2018;Ma et al., 2021). PFAAsrelated chemicals and their alternatives are collectively designated as per-and polyfluoroalkyl substances (PFASs) (Buck et al., 2011). ...
Perfluoroalkyl acids (PFAAs) are contaminants of global concern, and the inadvertent consumption of PFAA-contaminated crops may pose a threat to public health. Therefore, systematically studying their source tracing, bioaccumulation prediction and risk assessments in crops is an urgent priority. This study investigated the source apportionment and transport of PFAAs and novel fluorinated alternatives (collectively as per- and polyfluoroalkyl substances, PFASs) from factories to agricultural fields in a fluorochemical industrial region of China. Furthermore, bioaccumulation specificities and prediction of these chemicals in different vegetables were explored, followed by a comprehensive risk assessment from agricultural fields to dinner plates which considered precursor degradation. A positive matrix factorization model revealed that approximately 70 % of PFASs in agricultural soils were derived from fluorochemical manufacturing and metal processing. Alarming levels of ∑PFASs ranged 8.28–84.3 ng/g in soils and 163–7176 ng/g in vegetables. PFAS with short carbon chain or carboxylic acid group as well as branched isomers exhibited higher environmental transport potentials and bioaccumulation factors (BAFs) across a range of vegetables. The BAFs of different isomers of perfluorooctanoic acid (PFOA) decreased as the perfluoromethyl group moved further from the acid functional group. Hexafluoropropylene oxide dimer acid (GenX) showed relatively low BAFs, probably related to its ether bond with a high affinity to soil. Vegetables with fewer Casparian strips (e.g., carrot and radish), or more protein, possessed larger BAFs of PFASs. A bioaccumulation equation integrating critical parameters of PFASs, vegetables and soils, was built and corroborated with a good contamination prediction. After a total oxidizable precursors (TOP) assay, incremental perfluoroalkyl carboxylic acids (PFCAs) were massively found (325–5940 ng/g) in edible vegetable parts. Besides, precursor degradation and volatilization loss of PFASs was firstly confirmed during vegetable cooking. A risk assessment based on the TOP assay was developed to assist the protection of vegetable consumers.
... Moreover, most of them focused on perfluorooctanesulfonic acid (PFOS), very few on PFCAs and a single one investigated an emerging alternative to legacy compounds: F-53B. Yet, due to their increasing production by manufacturers, emerging PFAS detection is rising in recent years in the environment and biota Gebbink et al. 2017;Awad et al. 2020), and some of them have recently been found to be at least as toxic as legacy PFAS (Gomis et al. 2018). Among these compounds, 7:3 fluorotelomer carboxylic acid (7:3 FTCA) is of particular interest as it has been recently increasingly discovered in humans and numerous marine invertebrate, mammal, fish and bird species worldwide (Powley et al. 2008;Peng et al. 2010;Guruge et al. 2011;Loi et al. 2011;Nyberg et al. 2018;Meng et al. 2021). ...
The developmental period is a very sensitive phase since it sees the synthesis and maturation of all organs and functions of the future organism. Therefore, any disruption experienced early in life may have substantial subsequent consequences. In the context of the considerable impact of Human activities on wildlife, seabirds are particularly at risk since they are exposed to numerous threats, including fisheries interactions, habitat destruction, or environmental pollution. Among them, the later is maybe the most insidious, since it can also be transferred to the progeny via maternal transfer in eggs, and cause adverse effects as early as during the development. The 20th century saw the emergence of numerous synthetic substances. Among them, the per- and polyfluoroalkyl substances (PFAS) are found in seabird eggs, but little is known about their effects. In this thesis, I aimed at investigating the maternal transfer of PFAS in an Arctic seabird, the black-legged kittiwake (Rissa tridactyla). I also examined the eventual consequences of legacy and emerging PFAS exposure for the embryo in this species and in the yellow-legged gull (Larus michahellis). I found relatively high concentrations of legacy PFAS in eggs as well as some emerging compounds including 7:3 FTCA or PFEcHS. PFAS physicochemical characteristics influenced their transfer efficiency. My results also suggested that females PFAS might affect their transfer of maternal hormones in eggs, which may ultimately affect offspring at short and long term. Finally, I found no indications that PFAS deposited in eggs may affect the developing embryo on biomarkers of ageing (telomere length) or metabolism. I therefore suggested that both studied population should be relatively safe at least at the PFAS concentrations measured in their eggs. Nonetheless, additional studies would be needed to assess how PFAS may affect the endocrine maternal transfer and its consequences for the embryo.
... Several studies showed that recalculation of external intake dose to internal serum concentrations in rats and zebrafish embryos reduced the difference in potency considerably.  For interpretation of results from human biomonitoring studies, which commonly present the concentration of PFAS in the human serum or plasma, it is therefore important to use internal RPFs in mixture risk calculations. ...
Relative potency factors (RPFs) for per- and polyfluoroalkyl substances (PFAS) have previously been derived based on liver effects in rodents for the purpose of performing mixture risk assessment with primary input from biomonitoring studies. However, in 2020 EFSA established a tolerable weekly intake for four PFAS assuming equal toxic potency for immune suppressive effects in humans. In this study we explored the possibility of deriving RPFs for immune suppressive effects using available data in rodents and humans. Lymphoid organ weights, differential blood cell counts, and clinical chemistry from 28-day studies in male rats from the National Toxicology Program (NTP) were combined with modeled serum PFAS concentrations to derive internal RPFs by applying dose-response modelling. Identified functional studies used diverse protocols and were not suitable for derivation of RPFs but were used to support immunotoxicity of PFAS in a qualitative manner. Furthermore, a novel approach was used to estimate internal RPFs based on epidemiological data by dose-response curve fitting optimization, looking at serum antibody concentrations and key cell populations from the National Health and Nutrition Examination Survey (NHANES). Internal RPFs were successfully derived for PFAS based on rat thymus weight, spleen weight, and globulin concentration. The available dose-response information for blood cell counts did not show a significant trend. Immunotoxic potency in serum was determined in the order PFDA > PFNA > PFHxA > PFOS > PFBS > PFOA > PFHxS. The epidemiological data showed inverse associations for the sum of PFOA, PFNA, PFHxS, and PFOS with serum antibody concentrations to mumps and rubella, but the data did not allow for deduction of reliable internal RPF estimates. The internal RPFs for PFAS based on decreased rat lymphoid organ weights are similar to those previously established for increased rat liver weight, strengthening the confidence in the overall applicability of these RPFs.
... HFPO-DA is widely used in organic fluorine industry as a substitute of PFOA (Conley et al. 2021;Ke et al. 2020). HFPO-DA shows greater toxicity, acidity, and solubility than its predecessor (Gomis et al. 2018;Mullin et al. 2019). HFPO is more prone to be biodegraded, because the bond energy of C-O bond is lower than that of C-F bond, which is easier to be broken in chemical reaction (Wang et al. 2022a, b). ...
Poly- and perfluoroalkyl substances (PFASs) are toxic persistent organic pollutants and bioaccumulative chemicals, which affect the environment and ecology. PFASs in the wastewater treatment plant (WWTP) and receiving river downstream were investigated. Fourteen out of eighteen PFASs were detected, ranging from 197 to 0.14 ng L−1. The main pollutants were 2,3,3,3-tetrafluoro-2-(1,1,2,2,3,3,3-heptafluoro-propoxy) propanoic acid (HFPO-DA), perfluorooctane sulfonate (PFOS), and perfluorooctanoic acid (PFOA). The concentration of HFPO-DA (181 ng L−1) was the highest in influent, which indicated the use and emission of PFASs in the sewage collection region of WWTP changed from legacy to emerging ones. However, PFOS from catering wastewater as the main source was dominant PFASs in the reclaimed water. Biological treatment could be effective in the removal of PFASs, especially for HFPO-DA. HFPO-DA could directly bind to cytochrome P450 and bring potential ecotoxicity to the surrounding environment, and the ecological risk of degradation products should be under consideration. Coagulation might result in PFASs release from sludge. More attention should be paid to sewage treatment process decision of WWTP for the control of PFASs.
... GenX is a relatively new/emerging PFAS, and little research has been carried out on its bioaccumulation potential in organisms. This should be addressed in future studies given these chemicals are expected to accumulate in ecosystems over a period of time [11,47]. ...
Per and polyfluoroalkyl substances (PFAS) are of concern to environmental regulators due to their widespread occurrence, persistence and reported toxicity. However, little data exist on the effects of PFAS at environmentally relevant concentrations. The development of molecular markers for PFAS exposure would therefore be useful to better understand the environmental risks of these compounds. In this study, we assessed if such markers could be developed using Gas Chromatography–Mass Spectrometry-based metabolomics. We exposed the freshwater amphipod Austrochiltonia subtenuis to a range of environmentally relevant concentrations of perfluoro-octane sulfonic acid (PFOS), hexafluoropropylene oxide dimer acid (GenX) and perfluorohexanesulphonic acid (PFHxS) for 7 days at five concentrations. A metabolic response was detected in all concentrations and treatments even though the survival rates only differed significantly at the highest exposure levels. The metabolic response differed between compounds but all three PFAS induced changes in the levels of amino acids, fatty acids, and cholesterol, in line with the literature. PFOS was found to bioaccumulate. Both GenX and PFHxS were eliminated from the amphipods, but PFHxS was eliminated at a slower rate than GenX. This information improves our understanding of the sublethal effects of PFAS as well as their environmental fate and behaviour.
... However, with its increasing applications in electroplating (Poulsen et al., 2011), the production of fire-fighting foams (Yang et al., 2014), and the transformation of 6:2 FTS precursors (Yang et al., 2022) (such as fluorotelomer thioether amido sulfonate (FtTAoS) (Harding-Marjanovic et al., 2015)), 6:2 FTS has been globally detected in a variety of environmental matrices. The compound has been detected in groundwater (Backe and Day, 2013) (220 μg/L), river water (Qu et al., 2020) (100-800 ng/L), and even in human serum and blood (Lu et al., 2017), posing potential environmental risks and threatening human health by causing kidney and liver diseases (Gomis et al., 2018). ...
6:2 Fluorotelomer sulfonic acid (6:2 FTS) has been identified as an alternative to perfluorooctane sulfonic acid but has been proven to cause potential threats to humans and the environment. In this study, boron nitride (BN) photocatalysis was explored for 6:2 FTS degradation with 100% removal (kobs=1.8 h⁻¹) and desulfurization rate of 100% as well as the defluorination rate of 57.3%. The superior performance of BN was primarily related to oxygen dopants defects (O-dopants). In addition, O-dopants contribution was confirmed by ball-milled BN (B-BN), which introduced more O-dopants and exhibited an increased 6:2 FTS degradation rate of 2.88 h⁻¹. The decomposition of 6:2 FTS was attributed to holes (h⁺), hydroxyl radicals (•OH), and superoxide (•O2-) and proceeded via two pathways, the hydrogen abstraction from ethyl carbons by •OH and the C-S bond activation by h⁺ and •OH. To the best of our knowledge, this is the first study demonstrating that h⁺, •OH, and •O2⁻ played significant roles in the heterogeneous photocatalytic degradation of 6:2 FTS.
... Within the broad category of PFASs, long-chain PFASs ( ≥ 6 perfluorinated carbons) have attracted global attention . In particular, perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) are the most widely studied due to their frequency of detection in the environment ( Gomis et al., 2018 ). The perfluoroalkyl moieties (CnF2n + 1-) in PFASs are highly persistent in natural conditions. ...
The widespread use of perfluoroalkyl and polyfluoroalkyl substances (PFASs) globally has led to increased pol- lution in the environment and has subsequently posed health risks. Perfluorooctanoic acid (PFOA), perfluorooc- tanesulfonic acid (PFOS), and perfluorooctanesulfonamide (PFOSA) has been reported to induce immunotoxicity, endocrine toxicity, and developmental toxicity. However, the associated mechanisms and induction of cardiotox- icity following PFASs exposure remains poorly understood. Here, we explored the cardiac toxicity and associated mechanism in zebrafish embryos after exposure to PFOA, PFOS, and PFOSA at 1 and 10 𝜇g/L by RNA sequencing, morphological and physiological assessment, and behavioral alterations. Ingenuity Pathway Analysis (IPA) was used to predict disease and functions following exposure and predicted that the cardiac system was significantly affected by these three PFASs. The upregulation of miR-16–5p was predicted to act as an upstream regulator and involved in PFAS-induced pericardial edema. Cardiac output, an abnormal cardiac morphology, and atrial natriuretic peptide content were significantly altered following PFASs exposure. Furthermore, behavioral-level alterations were seen following exposure to PFASs. Our results indicated that PFASs could induce cardiotoxicity in zebrafish during early life stage development, the toxicity of PFOA and PFOSA may induce a more severe response relative to PFOS at relatively high concentrations according to the PCA analysis of all the tested data.
... Recent evidence using animal models suggests that some of these alternative PFAS can be equally hazardous. 16 As the biological disposition and risk of these compounds are also influenced by the route of exposure, determining the relative significance of human exposure pathways (e.g., drinking water, food, consumer materials, indoor dust, air, and breast milk) for PFOA, PFOS, other PFCAs and PFSAs, and other PFAS is critically important. 17−19 One potential source of PFAS exposure is through application of cosmetics and personal care products. ...
Per- and polyfluoroalkyl substances (PFAS) are anthropogenic chemicals reported in cosmetics and personal care products as ingredients, possible impurities in the raw material manufacturing process, or degradation products. The purpose of this study was to further delineate contributions of these varying PFAS sources to these products. Thirty-eight cosmetics and personal care products were selected and analyzed for polyfluoroalkyl phosphates (PAPs), perfluoroalkyl carboxylic acids (PFCAs), fluorotelomer sulfonic acids (FTSAs), and perfluoroalkyl sulfonic acids (PFSAs) using targeted liquid chromatography tandem mass spectrometry (LC-MS/MS). A subset of products was also subjected to suspect screening using LC-high resolution mass spectrometry (HRMS) for >200 compounds. Results of LC-MS/MS and LC-HRMS indicated a predominant and ubiquitous presence of PAPs (detection frequency 99.7%, mean and median ΣPAPs 1 080 000 and 299 ng/g). Total median PFCA and PFSA concentrations were 3 and 38 times lower, respectively. There were significant correlations (Spearman's correlation coefficients = 0.60-0.81, p < 0.05) between 6:2 PAPs and their biotransformation products. Low levels of other PFAS classes were detected, including those previously measured in wastewater and human blood (e.g., hydrido-PFCAs), and five compounds associated with aqueous film-forming foams. Overall, these data highlight that cosmetics and personal care products can contain a breadth of PFAS at extremely high levels, leading to human and environmental exposure.
... 33,34 Major health effects of long-chain PFASs are associated with their low elimination rates and high accumulation levels in the blood and in vital organs. 35 Indeed, the average half-life values for serum elimination of legacy PFASs, such as PFOA and PFOS, in environmentally exposed human populations are estimated to be in the order of 1−5 years, depending on the type of compound. 36,37 Such long persistence and accumulation of long-chain PFASs in circulation have been ascribed to their ability to bind human serum albumin (hSA), the most abundant protein in plasma with a maximum circulatory halflife of 19 days in humans. ...
The current trend dealing with the production of per- and polyfluoroalkyl substances (PFASs) involves the shifting toward branched short-chain fluorinated compounds known as new-generation PFASs. A key aspect to be clarified, to address the adverse health effects associated with the exposure to PFASs, is their binding mode to human serum albumin (hSA), the most abundant protein in plasma. In this study, we investigated the interaction between hSA and two representative branched short-chain PFASs, namely, HPFO-DA and C6O4. In-solution studies revealed that both compounds bind hSA with affinities and stoichiometries lower than that of the legacy long-chain perfluoroalkyl compound PFOA. Competition experiments using hSA-binding drugs with known site-selectivity revealed that both HPFO-DA and C6O4 bound to pockets located in subdomain IIIA. The crystal structure of hSA in complex with HPFO-DA unveiled the presence of two binding sites. The characterization and direct comparison of hSA interactions with new-generation PFASs may be key elements for the understanding of the toxicological impact of these compounds.
... Legacy PFASs featuring with long-chain perfluoroalkyl carboxylic acids (PFCAs) (≥7 perfluorinated carbons) and perfluoroalkanesulfonic acids (PFSAs) (≥6 perfluorinated carbons) have been focused on their ubiquitous distributions worldwide (Houde et al., 2011(Houde et al., , 2006, since the widespread presence of perfluorooctane sulfonate (PFOS) in wildlife and even human blood were firstly discovered twenty years ago (Giesy and Kannan, 2001;Hansen et al., 2001). Additional research further revealed the potential toxicities of long-chain PFASs associated with reproductive and developmental deficits, hepatotoxicity, neurotoxicity, and immunotoxicity (DeWitt et al., 2012;Gomis et al., 2018). As a result, PFOS, its salts and precursor, perfluorooctane sulfonyl fluoride (PFOSF), were added into Annex B of the Stockholm Convention on Persistent Organic Pollutants (POPs) in 2009, calling for restricted uses globally (UNEP, 2009). ...
The levels of legacy per- and polyfluoroalkyl substances (PFASs) have been growing in the environmental matrices and blood of residents living around the fluorochemical industrial park (FIP) in Fuxin of China over the past decade. Although some recent studies have reported occurrence of novel PFAS alternatives in biotic and abiotic matrices near fluorochemical facilities worldwide, little is known about novel PFAS congeners in maternal sera, umbilical cord sera, and placentas from the female residents close to the FIP and their related health risks. In this study, 50 paired samples of maternal and cord serum as well as placenta were derived from Fuxin pregnant women at delivery, and 21 target analytes of legacy PFASs in all the samples were analyzed via high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS), revealing that PFBS, PFBA, and PFOA were the dominant PFAS contaminants observed in the whole samples. Based upon the suspect screening through high-resolution mass spectrometry (HRMS), 49 novel PFASs assigned to 11 classes were further identified in the Fuxin samples, of which, 20 novel congeners in 4 classes were reported in human blood and placentas for the first time. Moreover, the coefficients for mother-placenta transfer (Rm/p), placenta-newborn transfer (Rp/n), and mother-newborn transfer (Rm/n) of legacy PFASs could be calculated with median values of 1.7, 1.1, and 2.0, respectively, and Rm/p, Rp/n, and Rm/n for each novel PFAS identified were also estimated with the median values of 0.9, 1.2, and 0.8 individually. Accordingly, novel PFASs contributed 90% of all the legacy and novel PFASs in maternal sera and even occupied 96% of the whole PFASs in both placentas and cord sera. In addition, significant associations were determined among the neonate birth outcomes and serum concentrations of thyroid hormone, sex hormone, and glucocorticoid, together with the levels of certain legacy and novel PFASs in cord sera.
... These and other 'short-chain' PFAS have been previously touted to be safer based on having fewer carbons in their carbon-fluorine chains (indicated in the molecular formulas in Table 1). Recent research indicates that short chain PFAS may be just as harmful as long chain PFAS (Brendel et al. 2018;Conley et al. 2021;Gomis et al. 2018). This systematic evidence map contains the literature base to conduct systematic reviews to address these types of questions. ...
●PFAS (per-and polyfluoroalkyl substances) are a large class of synthetic chemicals widely used in consumer products and industrial processes. The scientific literature on PFAS has increased dramatically in the last decade. Many stakeholders, including regulators, scientists, non-governmental organizations, and concerned individuals could benefit from an efficient way to access the health and toxicological literature related to PFAS.
●To create a systematic evidence map of the available peer-reviewed health or toxicological research for 29 PFAS.
●A protocol for conducting this systematic evidence map was initially published on Zenodo (Pelch et al. 2019c), then peer reviewed and published in Environment International (Pelch et al. 2019d). PubMed database was searched through January 25, 2021. Studies were screened for inclusion and exclusion according to the Populations, Exposures, Comparators, and Outcomes (PECO) statement. Inclusion criteria were intentionally broad and included any human, animal, and/or in vitro study that investigated exposure to one of the 29 PFAS of interest and a human health or toxicological effect. Selected study details were extracted from included studies as described in the protocol. Study appraisal was not conducted. The included studies and extracted meta-data are freely available in the online, interactive systematic evidence map at https://pfastoxdatabase.org.
●Over 15,000 studies were retrieved from the PubMed literature searches. After manual screening, 1,067 studies were identified and included as investigating the health or toxicological effect of one or more PFAS of interest. There were 505 human, 385 animal, and 220 in vitro studies. Summary tables of the extracted data and overall observations are included in this report.
●The PFAS-Tox Database is a useful tool for searching, filtering, and identifying peer reviewed research on the health and toxicological effects of the included PFAS. In this summary of the evidence map we provide examples of data gaps and clusters revealed by the database, with the goal of helping direct future research efforts, facilitate systematic reviews (e.g. on immune effects, mixtures of PFAS, or effects of short chain PFAS), inform regulatory risk assessments, and improve opportunities for cross-disciplinary coordination. We also discuss how this tool supports scientists, regulatory agencies, and other individuals by increasing awareness and access to current evidence regarding the health effects associated with PFAS exposure.
... Despite industry has rapidly replaced PFOS and PFOA with shorter chain length PFASs and new chemicals due to these regulatory interventions, these chemicals are difficult to detect by using standard methods . Emerging evidence from animal experiments suggests some of these alternative PFASs can be equally hazardous (Gomis et al., 2018). Currently, most studies focus only on PFASs in rivers and water plants, and limited work has been done on PFASs in reservoirs. ...
In order to clarify the pollution characteristics and human health risks of PFASs pollutants in typical drinking water sources in Zhejiang Province, this study relies on ultra -performance liquid chromatography-mass spectrometry (UPLC-MS/MS) technology to analyze the pollution of 26 PFASs in 7 reservoirs in Zhejiang Province. The detected concentrations of PFASs were evaluated to further assess the human health risks. Total PFASs concentrations in the seven reservoirs ranged from 1.30 ng L−1–24.90 ng L−1. Among the 26 PFASs pollutants analyzed, PFOA and PFBA were the main PFASs pollutants, the detected concentrations of PFOA and PFBS ranging from 0.50 ng L−1–13.70 ng L−1 and 0 ng L−1–1.70 ng L−1, respectively. Then we evaluated 15 PFASs and calculated the results of the HQ value of the reproductive toxicity and hepatotoxicity of the total PFASs in this study ranged from 2.30 × 10–8 to 1.16 × 10–4 and 9 × 10–8 to 5.24 × 10–4 respectively, which were both lower than 0.01, indicating that there is no significant risk to the human body.
... Information on internal exposures to PFAS (i.e., plasma or serum concentrations) is required for an extrapolation of the effects seen in animals and their relevance to humans due to significant interspecies differences in toxicokinetics of PFAS (Pizzurro et al. 2019). Results of studies giving applied doses (in mg/kg/day) as only dose metric cannot be readily extrapolated to humans (Chou and Lin 2019, 2020) and thus do not permit a comparison of NOAELs/ LOAELs with present human exposures (ATSDR 2021; Gomis et al. 2018). When internal exposures are considered, a comparison of NOAECs/LOAECs in animals with human blood levels is possible. ...
Per- and polyfluoroalkyl substances (PFAS) have been widely used and represent a class of environmental persistent chemicals. An association of a reduction of vaccination efficacy with PFAS serum levels in humans was used by the European Food Safety Authority as a key effect for PFAS risk assessment. The data support for using this association is reviewed by a critical analysis of the respective human epidemiology and the available animal studies on the immunomodulation of PFAS. Based on an analysis of the available human epidemiology, the overall level of evidence regarding associations between PFAS serum levels and reduced antibody response remains weak. Absence of an association between an increase in clinical infections and PFAS serum levels and the limited understanding of the importance of antibody levels as an isolated data point further support this conclusion. Animal toxicity studies with PFAS focusing on immunomodulation also provide only limited support for immunomodulation as an important endpoint in PFAS toxicity. While immunomodulation is observed after PFAS administration, generally at blood concentrations several orders of magnitude above those seen in environmentally exposed humans, the relevance of these observation is hampered by the high doses required to influence immune endpoints, the limited number of endpoints assessed, and inconsistent results. The limitations of the current database on associations of human PFAS exposures outlined here indicate that more evidence is required to select immunomodulation as a critical endpoint for human PFAS risk assessment.
... While GenX was thought to be a "sustainable replacement" for PFOA, some recent studies have raised growing concerns about its potential adverse effects. Gomis et al. (2018) reported that GenX showed higher toxicity for male rats than PFOA. Wang et al. (2017) observed that exposure to HFPO-DA (1 mg/kg body weight) induced more extensive hepatomegaly for mice than PFOA. ...
GenX, the ammonium salt of hexafluoropropylene oxide dimer acid, has been used as a replacement for perfluorooctanoic acid. Due to its widespread uses, GenX has been detected in waters around the world amid growing concerns about its persistence and adverse health effects. As relevant regulations are rapidly evolving, new technologies are needed to cost-effectively remove and degrade GenX. In this study, we developed an adsorptive photocatalyst by depositing a small amount (3 wt.%) of bismuth (Bi) onto activated-carbon supported titanate nanotubes, Bi/[email protected], and tested the material for adsorption and subsequent solid-phase photodegradation of GenX. Bi/[email protected] at 1 g/L was able to adsorb GenX (100 µg/L, pH 7.0) within 1 h, and then degrade 70.0% and mineralize 42.7% of pre-sorbed GenX under UV (254 nm) in 4 h. The efficient degradation also regenerated the material, allowing for repeated uses without chemical regeneration. Material characterizations revealed that the active components of Bi/[email protected] included activated carbon, anatase, and Bi nanoparticles with a metallic Bi core and an amorphous Bi2O3 shell. Electron paramagnetic resonance spin-trapping, UV-vis diffuse reflectance spectrometry, and photoluminescence analyses indicated the superior photoactivity of Bi/[email protected] was attributed to enhanced light harvesting and generation of charge carriers due to the UV-induced surface plasmon resonance effect, which was enabled by the metallic Bi nanoparticles. •OH radicals and photogenerated holes (h⁺) were responsible for degradation of GenX. Based on the analysis of degradation byproducts and density functional theory calculations, photocatalytic degradation of GenX started with cleavage of the carboxyl group and/or ether group by •OH, h⁺, and/or eaq⁻, and the resulting intermediates were transformed into shorter-chain fluorochemicals following the stepwise defluorination mechanism. Bi/[email protected] holds the potential for more cost-effective degradation of GenX and other per- and polyfluorinated alkyl substances.
... While PFOA and PFOS are no longer being made in the U.S., they continue to be manufactured in other nations, and continued exposures are possible from these sources and from other PFAS [20,21]. Additionally, an overall decrease in blood PFAS levels in the national population in recent years is anticipated, given the decrease in PFAS use and dissemination . ...
Epidemiologic evidence indicates exposure to polyfluoroalkyl substances (PFAS) influences immunosuppression, with diminished vaccination response. The relationship between PFAS blood levels and coronavirus disease 2019 (COVID-19) occurrence by age warrants further examination. This assessment identified blood PFAS exposure levels in discrete populations. Recent PFAS population studies summarizing age and gender results were identified and included. Geographically corresponding COVID-19 incidence data were determined for selected counties in North Carolina (NC) and Ohio (OH), and the state of New Jersey (NJ). Centers for Disease Control and Prevention COVID-19 databases were accessed for national incidence data by age groupings. We assessed associations between blood PFAS concentrations, COVID-19 incidence rates, and key demographic characteristics, within subpopulations. COVID-19 incidence counts and blood PFAS concentration were obtained for each age group, along with estimated U.S. Census total population. A general trend observed is higher PFAS levels in older age groups. Younger age groups contained fewer COVID-19 cases. Global COVID-19 mortality is highest in elderly populations with hospitalization and death greatly increasing from age 50. PFAS exposures occurring early in life may cause deleterious health effects later in life, including decreased antibody response and reduced disease resistance. Highest levels of both PFAS exposure and COVID-19 were found in the oldest populations. While this does not determine causality, such associations should help promote further study.
... Their presence in PM can possibly be explained by the photochemical oxidation of volatile precursors (Ahrens et al., 2010) or by solubilising in a liquid particle droplet. There are numerous reports suggesting that newly introduced substitutes for PFOA and PFOS (and their degradation products) can be as toxic as their predecessors (Gomis et al., 2018). ...
A sensitive analytical method has been developed and validated for the determination of 16 polyfluorinated alkyl substances (PFAS) in fine airborne particulate matter (PM2.5) using on-line solid phase extraction (SPE) coupled with liquid chromatography (LC) – negative electrospray ionisation high resolution mass spectrometry (−) ESI-HRMS. On-line SPE allows simultaneous sample clean-up from interfering matrices and lower limits of detection (LODs) by injecting a large volume of sample into the LC system without compromising chromatographic efficiency and resolution. The method provides LODs in the range 0.08–0.5 pg/mL of sample extract allowing detection of selected PFAS in aerosol particles at low fg/m³ level and showed good tolerance to the considered PM matrix. The validated method was applied for analysis of PFAS in ambient PM2.5 samples collected at two urban locations in Ireland, i.e., Enniscorthy and Dublin. Several PFAS were observed above the detection limit, including perfluorobutyrate (PFBA), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorobutanesulfonic acid (L-PFBS) and perfluorononanoic acid (PFNA), as well as fluorotelomer sulfonates: 4: 2 FTS, 6: 2 FTS and 8: 2 FTS. The results indicate that some toxic PFAS, such as PFOS and PFOA, are still detected in the environment despite being phased out from production and subject to restricted use in the EU and USA for more than two decades. Observation of fluorotelomer sulfonates (4: 2 FTS, 6: 2 FTS and 8: 2 FTS, which are used as alternatives for legacy PFOA and PFOS) in ambient PM2.5 samples raises a concern about their persistence in the atmosphere and impact on human health considering emerging evidence that they could have similar health endpoints as PFOA and PFOS. To our knowledge, this is the first study to identify PFAS in ambient PM2.5 at urban locations in Ireland and also the first study to detect 4:2 and 8:2 fluorotelomer sulfonates in atmospheric aerosol particles.
... Carbon chain length has been proposed to be the most important factor in determining the bioaccumulative nature of PFAS, leading some researchers to suggest that shorter chain alternatives to PFOS and PFOA are inherently safer (Renner, 2006;Olsen et al., 2007;Conder et al., 2008). However, recent evidence suggests that some of the short-chain alternatives may be equally persistent and bioaccumulative as PFOS and PFOA (Wilkinson et al., 2017;Gomis et al., 2018;Ateia et al., 2019). In fact, research conducted by Shi et al. (2018) suggests that one factor associated with increased bioaccumulation in long-chain PFAS, hydrophobicity, may have the opposite effect on bioaccumulative potential in short-chain PFAS. ...
Per- and polyfluoroalkyl substances (PFAS) are a class of structurally diverse synthetic organic chemicals that are chemically stable, resistant to degradation, and persistent in terrestrial and aquatic environments. Widespread use of PFAS in industrial processing and manufacturing over the last 70 years has led to global contamination of built and natural environments. The brain is a lipid rich and highly vascularized organ composed of long-lived neurons and glial cells that are especially vulnerable to the impacts of persistent and lipophilic toxicants. Generally, PFAS partition to protein-rich tissues of the body, primarily the liver and blood, but are also detected in the brains of humans, wildlife, and laboratory animals. Here we review factors impacting the absorption, distribution, and accumulation of PFAS in the brain, and currently available evidence for neurotoxic impacts defined by disruption of neurochemical, neurophysiological, and behavioral endpoints. Emphasis is placed on the neurotoxic potential of exposures during critical periods of development and in sensitive populations, and factors that may exacerbate neurotoxicity of PFAS. While limitations and inconsistencies across studies exist, the available body of evidence suggests that the neurobehavioral impacts of long-chain PFAS exposures during development are more pronounced than impacts resulting from exposure during adulthood. There is a paucity of experimental studies evaluating neurobehavioral and molecular mechanisms of short-chain PFAS, and even greater data gaps in the analysis of neurotoxicity for PFAS outside of the perfluoroalkyl acids. Whereas most experimental studies were focused on acute and subchronic impacts resulting from high dose exposures to a single PFAS congener, more realistic exposures for humans and wildlife are mixtures exposures that are relatively chronic and low dose in nature. Our evaluation of the available human epidemiological, experimental, and wildlife data also indicates heightened accumulation of perfluoroalkyl acids in the brain after environmental exposure, in comparison to the experimental studies. These findings highlight the need for additional experimental analysis of neurodevelopmental impacts of environmentally relevant concentrations and complex mixtures of PFAS.
... Still, there are several limitations, such as rapid clearance frequent dosage leading to immunotoxicity and liver toxicity. Intramuscular delivery is the technique that injects the drug deep into the muscles to provide rapid and uniform drug absorption of the aqueous solution  . IM has a higher onset of action when compared to that of the intravenous drug delivery system. ...
There is significant progress in biomedical sciences to use biomaterials as a potential medium for the delivery of pharmacologically active components to diseased cells. This multidisciplinary approach has established that the therapeutic benefit is not directly proportional to the potency of drugs. It is more related to the mode of drug formulations and routes of administration. Biomaterials play a vital role in the formulations of a wide range of pharmaceutical compounds, including antibodies, peptides, drugs, enzymes, and vaccines. Most of these materials have been engineered to release therapeutics for an extended period to overcome the limitations of conventional therapies. This review has initially discussed a brief history of different biomaterials in drug delivery and the clinical needs of the same. The latter part describes the strategies to use RNA as a therapeutic molecule to stop the synthesis of disease-causing proteins that are generated by the misregulations.
Per- and polyfluoroalkyl substances (PFAS) cause potential threats to biota and are persistent and never-ending substances in the environment. Regulations and ban on legacy PFAS by various global organizations and national level regulatory agencies had shifted the fluorochemical production to emerging PFAS and fluorinated alternatives. Emerging PFAS are mobile and more persistent in aquatic systems, posing potential greater threats to human and environmental health. Emerging PFAS have been found in aquatic animals, rivers, food products, aqueous film-forming foams, sediments, and a variety of other ecological media. This review summarizes the physicochemical properties, sources, occurrence in biota and the environment, and toxicity of the emerging PFAS. Fluorinated and non-fluorinated alternatives for several industrial applications and consumer goods as the replacement of historical PFAS are also discussed in the review. Fluorochemical production plants and wastewater treatment plants are the main sources of emerging PFAS to various environmental matrices. Information and research are scarcely available on the sources, existence, transport, fate, and toxic effects of emerging PFAS to date.
The present study assessed the bioaccumulation potential of per- and polyfluoroalkyl substances (PFAS) in ferns and linked root uptake behaviors to root characteristics and PFAS molecular structure. Tissue and subcellular-level behavioral differences between alternative and legacy PFAS were compared via an electron probe microanalyzer with energy dispersive spectroscopy (EPMA-EDS) and differential centrifugation. Our results show that ferns can accumulate PFAS from water, immobilize them in roots, and store them in harvestable tissue. The PFAS loading in roots was dominated by PFOS; however, a substantial amount of associated PFOS could be rinsed off by methanol. Correlation analyses indicated that root length, surface and project area, surface area per unit length of the root system, and molecular size and hydrophobicity of PFAS were the most significant factors affecting the magnitude of root uptake and upward translocation. EPMA-EDS images together with exposure experiments suggested that long-chain hydrophobic compounds tend to be adsorbed and retained on the root epidermis, while short-chain compounds are absorbed and quickly translocated upward. Our findings demonstrated the feasibility of using ferns in phytostabilization and phytoextraction initiatives of PFAS in the future.
Per- and polyfluoroalkyl substances (PFAS) are a diverse set of commercial chemicals widely detected in humans and the environment. However, only a limited number of PFAS are associated with epidemiological or experimental data for hazard identification. To provide developmental neurotoxicity (DNT) hazard information, the work herein employed DNT new approach methods (NAMs) to generate in vitro screening data for a set of 160 PFAS. The DNT NAMs battery was comprised of the microelectrode array neuronal network formation assay (NFA) and high-content imaging (HCI) assays to evaluate proliferation, apoptosis, and neurite outgrowth. The majority of PFAS (118/160) were inactive or equivocal in the DNT NAMs, leaving 42 active PFAS that decreased measures of neural network connectivity and neurite length. Analytical quality control indicated 43/118 inactive PFAS samples and 10/42 active PFAS samples were degraded; as such, careful interpretation is required as some negatives may have been due to loss of the parent PFAS, and some actives may have resulted from a mixture of parent and/or degradants of PFAS. PFAS containing a perfluorinated carbon (C) chain length ≥8, a high C:fluorine ratio, or a carboxylic acid moiety were more likely to be bioactive in the DNT NAMs. Of the PFAS positives in DNT NAMs, 85% were also active in other EPA ToxCast assays, whereas 79% of PFAS inactives in the DNT NAMs were active in other assays. These data demonstrate that a subset of PFAS perturb neurodevelopmental processes in vitro and suggest focusing future studies of DNT on PFAS with certain structural feature descriptors.
Warming and exposure to emerging global pollutants, such as per- and polyfluoroalkyl substances (PFAS), are significant stressors in the aquatic ecosystem. However, little is known about the warming effect on the bioaccumulation of PFAS in aquatic organisms. In this study, the pelagic organisms Daphnia magna and zebrafish, and the benthic organism Chironomus plumosus were exposed to 13 PFAS in a sediment-water system with a known amount of each PFAS at different temperatures (16, 20, and 24 °C). The results showed that the steady-state body burden (Cb-ss) of PFAS in pelagic organisms increased with increasing temperatures, mainly attributed to increased water concentrations. The uptake rate constant (ku) and elimination rate constant (ke) in pelagic organisms increased with increasing temperature. In contrast, warming did not significantly change or even mitigate Cb-ss of PFAS in the benthic organism Chironomus plumosus, except for PFPeA and PFHpA, which was consistent with declined sediment concentrations. The mitigation could be explained by the decreased bioaccumulation factor due to a more significant percent increase in ke than ku, especially for long-chain PFAS. This study suggests that the warming effect on the PFAS concentration varies among different media, which should be considered for their ecological risk assessment under climate change.
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.
In this study we synthesized a library of 12 novel adsorbent materials that utilize a chemically well-defined silica support for superior removal of PFAS from real groundwater from a contaminated United States Air Force base. The library of sorbents probed the importance of a fluorous, hydrophobic, and electrostatic components in the removal efficacy. The materials were assessed in batch studies with PFOA, PFOS, and PFBA and compared directly to GAC and Ion Exchange resin. Adsorption kinetics with PFOS were best fit to a pseudo-second order model and equilibrium data fit well to a Langmuir isotherm model. The results were also validated externally, and the best performing material removed greater than 90% of 8 PFAS tested and was able to be regenerated up to 5 cycles. The results provide a top performing material that with further testing can be used to clean up environmentally contaminated water and provide support for the theory that a fluorous component when combined with the electrostatic and hydrophobic components, imparts both enhanced PFAS selectivity and functional resilience to the material.
In vivo, in vitro, and epidemiological evidence suggests that perfluoroalkyl substances (PFAS) may alter thyroid function in human health, with negative effects on maternal and fetal development outcomes. However, data on the effects of PFAS on thyroid hormones remain controversial. Here, we conducted a meta-analysis of 13 eligible studies searched from Embase, PubMed, and Web of Science by July 10, 2022, to explore the relationship between maternal exposure to PFAS and thyroid health effects, including thyroid stimulating hormone (TSH), triiodothyronine (TT3), thyroxin (TT4), free T3 (FT3), and free T4 (FT4). The estimated values (β) and the corresponding confidence intervals (95%CI) were extracted for analysis. The tests for heterogeneity, sensitivity and publication bias between studies were performed using Stata 15.0. The combined results showed a positive association between changes in TSH and exposure to perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA), with no significant correlation observed between changes in other thyroid hormones and exposure to PFAS. This difference was attributed to sample size, region, sample type, body mass index (BMI), and gestational week. Our data recommend verifying the relationship between PFAS exposure and thyroid health effects in a large sample population cohort in future studies. In addition, health care should be taken into account in early and mid-pregnancy.
Per- and polyfluoroalkyl substances (PFAS) are a chemical class of highly stable, fluorinated compounds popular for use in a variety of consumer products. PFAS environmental persistence in drinking water contributes to acute exposure in humans and subsequent bioaccumulation of the compounds in the liver and lung tissue. Prenatal PFAS exposure has been associated with lowered birth weight, premature birth, and developmental defects including cranio-facial abnormalities. The cytochrome P450 enzyme CYP3A7 is responsible for facilitating a variety of reactions essential for proper fetal development in humans. In addition to drug metabolism, CYP3A7 is responsible for metabolizing endogenous ligands in the developing human liver, including the steroid precursor dehydroepiandrosterone 3-sulfate (DHEA-S), essential for estriol synthesis during pregnancy, along with the morphogen all-trans-retinoic acid (atRA). Interference with estriol synthesis during pregnancy, as well as atRA clearance, is known to result in similar effects associated with prenatal PFAS exposure including lowered birth weight, premature birth, and developmental defects. We hypothesized that PFAS compounds bind to the CYP3A7 enzyme resulting in its inhibition. We implemented a series of binding studies using spectral characterization of six PFAS compounds (PFOA, PFOS, GenX, PFNA, PFNS, and PFHxS), and evaluated their interactions with recombinant CYP3A7. In addition, we screened PFAS for their ability to inhibit CYP3A7 oxidative activity using dibenzylfluorescein, a fluorescent probe, and DHEA-S, an endogenous substrate of CYP3A7. Our data demonstrate that of the six PFAS tested, PFOA, PFOS, PFNA, and PFHxS bind to and inhibit CYP3A7.
This study investigates an electrochemical approach for the treatment of water polluted with per- and poly-fluoroalkyl substances (PFAS), looking at the impact of different variables, contributions from generated radicals, and degradability of different structures of PFAS. Results obtained from a central composite design (CCD) showed the importance of mass transfer, related to the stirring speed, and the amount of charge passed through the electrodes, related to the current density on decomposition rate of PFOA. The CCD informed optimized operating conditions which we then used to study the impact of solution conditions. Acidic condition, high temperature, and low initial concentration of PFOA accelerated the degradation kinetic, while DO had a negligible effect. The impact of electrolyte concentration depended on the initial concentration of PFOA. At low initial PFOA dosage (0.2 mg L-1), the rate constant increased considerably from 0.079 ± 0.001 to 0.259 ± 0.019 min-1 when sulfate increased from 0.1% to 10%, likely due to the production of SO4•-. However, at higher initial PFOA dosage (20 mg L-1), the rate constant decreased slightly from 0.019 ± 0.001 to 0.015 ± 0.000 min-1, possibly due to the occupation of active anode sites by excess amount of sulfate. SO4•- and •OH played important roles in decomposition and defluorination of PFOA, respectively. PFOA oxidation was initiated by one electron transfer to the anode or SO4•-, undergoing Kolbe decarboxylation where yielded perfluoroalkyl radical followed three reaction pathways with •OH, O2 and/or H2O. PFAS electrooxidation depended on the chemical structures where the decomposition rate constants (min-1) were in the order of 6:2 FTCA (0.031) > PFOA (0.019) > GenX (0.013) > PFBA (0.008). PFBA with a shorter chain length and GenX with -CF3 branching had slower decomposition than PFOA. While presence of C-H bonds makes 6:2 FTCA susceptible to the attack of •OH accelerating its decomposition kinetic. Conducting experiments in mixed solution of all studied PFAS and in natural water showed that the co-presence of PFAS and other water constituents (organic and inorganic matters) had adverse effects on PFAS decomposition efficiency.
Fluoroalkylethers (ether-PFASs), as alternatives to phased-out per- and perfluoroalkyl substances (PFASs), have attracted mounting attention due to their ubiquitous detection in aquatic environment and their similarity to legacy PFASs in terms of persistence and toxicity. In this review, the sources and distribution of ether-PFASs in soil ecosystem as well as their toxic impacts on soil microbial community are summarized. The plant uptake and bioaccumulation potential of ether-PFASs are presented, and a wide range of the influencing factors for their uptake and translocation is discussed. In response to ether-PFASs, the corresponding phytotoxic effects, such as seed germination, plant growth, photosynthesis, oxidative damage, antioxidant enzymes activities, and genotoxicity, are systematically elucidated. Finally, the current knowledge gaps and future research prospective are highlighted. The findings of this review will advance our understanding for the environmental behavior and implications ether-PFASs in soil-plant systems and help explore the strategies for ether-PFASs remediation to minimize their adverse toxicity.
Per- and polyfluoroalkyl substances (PFAS) are globally distributed in the natural environment, and their persistent and bioaccumulative potential illicit public concern. The production of certain PFAS has been halted or controlled by regulation due to their adverse effect on the health of humans and wildlife. However, new PFAS are continuously developed as alternatives to legacy PFAS. Additionally, many precursors are unknown, and their metabolites have not been assessed. To better understand the PFAS profiles in the Lake Ontario (LO) aquatic food web, a quadrupole time-of-flight mass spectrometer (QToF) coupled to ultrahigh-performance liquid chromatography (UPLC) was used to generate high-resolution mass spectra (HRMS) from sample extracts. The HRMS data files were analyzed using an isotopic profile deconvoluted chromatogram (IPDC) algorithm to isolate PFAS profiles in aquatic organisms. Fourteen legacy PFAAs (C5-C14) and 15 known precursors were detected in the LO food web. In addition, over 400 unknown PFAS features that appear to biomagnify in the LO food web were found. Profundal benthic organisms, deepwater sculpin(Myoxocephalus thompsonii), and Mysis were found to have more known precursors than other species in the food web, suggesting that there is a large reservoir of fluorinated substances in the benthic zone.
Large fluoropolymer manufacturing facilities are major known sources of per- and polyfluoroalkyl substances (PFAS), many of which accumulate in groundwater, surface water, crops, wildlife, and people. Prior studies have measured high PFAS concentrations in groundwater, drinking water, soil, as well as dry and wet deposition near fluoropolymer facilities; however, much less is known about near-source PFAS air concentrations. We measured airborne PFAS on PM2.5 filters in close proximity to a major fluoropolymer manufacturing facility (Chemours' Fayetteville Works) located near Fayetteville, North Carolina, USA. Weekly PM2.5 filter samples collected over a six-month field campaign using high-volume air samplers at locations 3.7 km apart, north-northeast and south-southwest of the facility were analyzed for thirty-four targeted ionic PFAS species by liquid chromatography coupled to electrospray ionization tandem mass spectrometry. Twelve emerging and ten legacy PFAS compounds were detected. Thirteen PFAS were found at higher concentrations in these nearfield samples than at regional background sites, suggesting a local source for these compounds. Five emerging and five legacy PFAS compounds had maximum concentrations exceeding 1 pg m-3. PFBA, PFHxA, PFHxDA, PFOS, PMPA, NVHOS, PFO5DoA, and Nafion BP1 contributed the most to the total (legacy + emerging) PFAS concentration (86%). Six PFAS, specifically PFBA, PFOS, PFO5DoA, Nafion BP1, Nafion BP2, and Nafion BP4, provide a consistent representative profile of elevated species across the two sites (with detection frequency >50%). To our knowledge, this is the first study to report both legacy and emerging ionic PFAS in air in close proximity to a U.S. fluoropolymer manufacturing facility.
Perfluoro-2-propoxypropanoic acid (PFPrOPrA), a free acid form of GenX, is a problematic perfluorinated alkyl substance (PFAS). Standard and advanced wastewater treatment methods are unable to effectively degrade PFAS due to its strong and unreactive C-F bonds. TiO2 photocatalytic, radiolytic, and ultrasonic irradiation (USI) methods were applied in an attempt to degrade PFPrOPrA. A bimolecular rate constant for the reaction of eaq− and GenX of (3.09±0.03)×107 M−1·s−1 was measured in a buffered aqueous solution by monitoring the transient signal of the hydrated electron as a function of GenX concentration. Corroborating this relatively slow rate constant, less than 2% GenX degradation was observed after 8 h of continuous Co60 gamma radiolysis under a variety of conditions. TiO2 photocatalysis at 350 nm under alkali conditions showed minimal destruction of GenX without detectable levels of defluorination as measured by the production of fluoride ions. However, upon ultrasonic irradiation at 640 kHz and 396 W in an argon-saturated aqueous solution, greater than 80% of GenX was degraded within 60 min, yielding fluoride ions as the major product. We propose that the ultrasonic-induced degradation of GenX occurs primarily by pyrolysis. Computational methods were used to probe the energetics of the completing degradation pathways and possible pyrolytic products. The results demonstrate ultrasonic-induced pyrolysis is a promising process to mineralize GenX. The process can be accurately monitored and likely extended to mineralize a variety of perfluorinated and polyfluorinated substances.
Climate change affects how the emerging contaminants per- and polyfluoroalkyl substances (PFAS) and microplastics impact human health and the environment. The known and implied effects from PFAS compounds and microplastics are reviewed, followed by an overview of their occurrence, transport, degradation in fresh water and ocean water, and health impacts. PFAS and microplastics releases are increasing as a result of climate change, and the breakdown of microplastics is releasing greenhouse gases, which in turn augments climate change. Strategies are presented for reductions in the release of these emerging contaminants.
Per- and polyfluoroalkyl substances (PFAS) are a class of artificially synthetic organic compounds that are hardly degraded in the natural environment. PFAS have been widely used for many decades, and the persistence and potential toxicity of PFAS are an emerging concern in the world. PFAS exposed via diet can be readily absorbed by the intestine and enter the circulatory system or accumulate directly at intestinal sites, which could interact with the intestine and cause the destruction of intestinal barrier. This review summarizes current relationships between PFAS exposure and intestinal barrier damage with a focus on more recent toxicological studies. Exposure to PFAS could cause inflammation in the gut, destruction of the gut epithelium and tight junction structure, reduction of the mucus layer, and induction of the toxicity of immune cells. PFAS accumulation could also induce microbial disorders and metabolic products changes. In addition, there are limited studies currently, and most available studies converge on the health risk of PFAS exposure for human intestinal disease. Therefore, more efforts are deserved to further understand potential associations between PFAS exposure and intestinal dysfunction and enable better assessment of exposomic toxicology and health risks for humans in the future.
The short-chain per- and polyfluorinated alkyl substances (PFAS), introduced to replace the legacy PFAS compounds, turned out to be as toxic and harmful as their longer-chain predecessors and even harder to sequester from contaminated water sources. In this work, molecular dynamics (MD) simulations are employed to investigate the adsorption mechanism of GenX, a representative compound for short-chain PFAS, on a polycationic hydrogel with various extents of fluorination in its backbone and cross-linkers. Simulations indicate that the presence of fluorinated segments next to cationic groups in the polymer gel structure provides the most efficient environment for GenX adsorption. The combination of electrostatic and hydrophobic interactions offered by the cationic-fluorophilic segments amplifies the binding of GenX molecules compared to polymer segments with nonfluorinated cationic or noncationic fluorinated segments. Moreover, such a gel demonstrates high selectivity toward GenX against its hydrogenated analogue.
This commentary proposes an approach to risk assessment of mixtures of per- and polyfluorinated alkyl substances (PFAS) as EFSA was tasked to derive a tolerable intake for a group of 27 PFAS. The 27 PFAS to be considered contain different functional groups and have widely variable physicochemical (PC) properties and toxicokinetics and thus should not treated as one group based on regulatory guidance for risk assessment of mixtures. The proposed approach to grouping is to split the 27 PFAS into two groups, perfluoroalkyl carboxylates and perfluoroalkyl sulfonates, and apply a relative potency factor approach (as proposed by RIVM) to obtain two separate group TDIs based on liver toxicity in rodents since liver toxicity is a sensitive response of rodents to PFAS. Short chain PFAS and other PFAS structures should not be included in the groups due to their low potency and rapid elimination. This approach is in better agreement with scientific and regulatory guidance for mixture risk assessment.
This research evaluates photocatalytic ozonation for removing 5 PFAS (PFOA/PFHxS/PFBS/6:2 FTS/GenX) from water using a WO3/TiO2 catalyst under UVA-visible radiation. Four catalysts of varying WO3 content (0/1/3/5 wt%) were synthesized by sol-gel and characterized by XRD, TEM, STEM-EDS, HAADF-STEM, adsorption/desorption N2 isotherms, and DRS-UV–vis. 5 wt% WO3/TiO2 was the optimal composition based on physicochemical properties and photocatalytic activity tests with methylene blue. PFAS degradation showed that photocatalytic ozonation inefficiently degraded PFAS with WO3/TiO2 under UVA-visible light after 4 h (ΣPFAS removal 16 %, [range 4 %–26 %]). Photocatalysis had comparable removal to photocatalytic ozonation, photolysis and ozone photolysis showed lower removal, and ozonation had no effect. Microtox analysis showed the initial acute toxicity was no longer detectable after photocatalysis and photocatalytic ozonation treatment. Low PFAS removals under tested conditions require that future work evaluate different catalysts or treatment conditions, while disparities between tested PFAS removals demonstrate the need to evaluate multiple compounds.
The research presented in this manuscript involves the preparation and characterization of WO3/TiO2 catalysts used, for the first time, to remove multiple PFAS in water via photocatalytic ozonation. This manuscript supports the development of a catalytic process for the elimination of hard to degrade environmental pollutants, provides new knowledge on aspects of photocatalytic processes, and provides insights on environmental pollution abatement.
While toxicity information is available for selected PFAS, little or no information is available for most, thereby necessitating a resource-effective approach to screen and prioritize those needing further safety assessment. The threshold of toxicological concern (TTC) approach proposes a de minimis exposure value based on chemical structure and toxicology of similar substances. The applicability of the TTC approach to PFAS was tested by incorporating a data set of no-observed-adverse-effect level (NOAEL) values for 27 PFAS into the Munro TTC data set. All substances were assigned into Cramer Class III and the cumulative distribution of the NOAELs evaluated. The TTC value for the PFAS-enriched data set was not statistically different compared to the Munro data set. Derived human exposure level for the PFAS-enriched data set was 1.3 μg/kg/day. Structural chemical profiles showed the PFAS-enriched data set had distinct chemotypes with lack of similarity to substances in the Munro data set using Maximum Common Structures. The incorporation of these 27 PFAS did not significantly change TTC Cramer Class III distribution and expanded the chemical space, supporting the potential use of the TTC approach for PFAS chemicals.
Emerging per- and polyfluoroalkyl substances (PFAS) alternatives are increasingly used in daily life. Although legacy PFAS have been associated with miscarriage in previous studies, it remains unknown whether exposure to emerging and legacy PFAS has any impact on the risk of unexplained recurrent spontaneous abortion (URSA). We conducted a case-control study with 464 URSA cases who had at least 2 unexplained miscarriages and 440 normal controls who had at least one normal livebirth. Concentrations of 21 PFAS in plasma, including three emerging PFAS alternatives, eight linear and branched PFAS isomers, four short-chain PFAS, and six legacy PFAS, were measured by ultra-performance liquid chromatography coupled with a tandem mass spectrometry (UPLC-MS/MS). Multiple logistic regression was applied to evaluate the relationship between PFAS and URSA risk. Perfluorooctanoic acid (PFOA, median: 6.18 ng/mL), perfluorooctane sulfonate (PFOS, median: 4.10 ng/mL), and 6:2 chlorinated perfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA, median: 2.27 ng/mL) were the predominant PFAS in the controls. Exposure to 6:2 Cl-PFESA [adjusted odds ratio (aOR) = 1.18 (95% CI: 1.00, 1.39)] and hexafluoropropylene oxide dimer acid (HFPO-DA) [aOR = 1.35 (95% CI: 1.15, 1.59)] were significantly associated with increased risks of URSA. Women with older age (>30 years old) had a stronger association between PFAS and URSA. Our results suggest that emerging PFAS alternatives may be an important risk factor for URSA.
Various per- and polyfluoroalkyl substances (PFASs) remain undiscovered and unexplored in the environment. The goals of this study were to discover new species of PFASs in effluent and surface waters from a fluorochemical industrial zone, and to assess their concentration, distribution, and temporal trends in the adjacent natural environment. In total, 83 emerging PFASs from 14 classes were identified, 22 of which were reported for the first time. Authentic standards were synthesized for 13 per- and polyfluoroalkyl ether carboxylic acids (PFECAs), thereby greatly expanding the scope of PFAS-targeted monitoring. The newly identified compounds accounted for 27%-95% of the total PFAS concentrations. Of note, a novel diether carboxylic acid, 2-[2-(trifluoromethoxy)hexafluoropropoxy]tetrafluoropropanoic acid (C7 HFPO-TA) was detected at an extremely high concentration in the fluorochemical zone effluent (447 000 ng/L) and at a median concentration in the fluorochemical zone surface water (670 ng/L), with detectable levels also found in the natural environment, that is, Wangyu River (23 ng/L) and Taihu Lake (5.6 ng/L). The distinct geographic distribution of C7 HFPO-TA suggests transport from the industrial point source to Taihu Lake via the Wangyu River. The concentration of C7 HFPO-TA in Taihu Lake, along with that of many other emerging PFASs, continued to grow in three sampling campaigns from 2016 to 2021. Considering the environmental persistence and toxicity of structurally similar PFECAs (e.g., HFPO-DA), studies on C7 HFPO-TA are urgently needed.
Perfluoroalkyl and polyfluoroalkyl substances (PFASs) have raised serious public health concerns because of their potential adverse effects in humans as revealed by toxicological and epidemiological research. However, routine monitoring of PFASs is still challenging due to their trace levels in various environmental and biological matrices. In this study, magnetic composite materials based on iron (II, III) oxide (Fe3O4) with surface functionalization by cucurbit(n)uril (CB(n)) (Fe3O4@CB(n)) (n = 6, 7, 8), were prepared and evaluated as new adsorbents for the magnetic solid-phase extraction of nine PFASs in lake water, tap water and fish muscle samples. The Fe3O4@CB(n) was characterized to examine their surface morphologies, sizes magnetism and thermal stability. Featuring good aqueous solution dispersibility, the macrocyclic structure of Fe3O4@CB(n) was also endowed with strong host-guest interactions, allowing extraction and enrichment capability towards the PFASs in complex matrices. MSPE using Fe3O4@CB(7) combination with ultra-high performance liquid chromatography coupled to Orbitrap high-resolution mass spectrometry, gave satisfactory quantitative analytical performance with low limits of detection of 0.004-0.04 μg L⁻¹ and limits of quantification of 0.005-0.1 μg L⁻¹, linearities ranging from 0.01 to 10 μg L⁻¹ with high coefficients of determination (R² ≥ 0.993), and enrichment factors (15-76) for the nine target PFASs. The method proved to be effective for the enrichment and analysis of trace levels of PFASs in genuine environmental water and fish muscle samples, indicating that Fe3O4@CB(7) has promising applicability as an adsorbent for these contaminants.
The Bohai Sea is one of the most polluted hotspots by per- and Polyfluoroalkyl substances (PFASs) in the world and studies on the vertical distribution of PFASs at different water layers and phase partitioning between water and suspended particulate matter (SPM) were still limited. 23 legacy and emerging PFASs were investigated in seawater and SPM throughout the Bay in this study. The average concentrations of ∑PFASs in seawater were 48.21 ng/L and 52.71 ng/L during the periods of wet and normal water, respectively. In general, the concentrations of ∑PFASs in surface water were higher than that in deep water. Legacy PFASs in seawater were dominated by PFOA and short-chain PFASs, while the emerging alternative HFPO-DA was detected in the whole water layer of the Bohai Bay with an average concentration of 1.09 ng/L. The spatial distribution showed that ∑PFASs were higher nearshore than inside the bay and higher in the south than that in the north of the bay. The average concentration of ∑PFASs in SPM was 9.02 ng/g. Long-chain PFASs and the emerging alternative 6:2 Cl-PFESA accounted for the major contaminants. The partition coefficients log Kd and φspm-w showed a linear positive correlation with carbon chain length. Preliminary risk assessments revealed that the ecological risk of common PFASs in the Bohai Bay was low, while PFOA was at moderate risk. The principal component analysis demonstrated that the production process of traditional fluorochemical factories, fire-fighting and emerging electroplating industries were the main sources of PFASs. This was the first comprehensive survey of emerging PFASs in different water depths and in SPM of the Bohai Bay during different seasons, which provided important scientific data for studying the ecological risks and pollution prevention of PFASs.
Surfactants are molecules that reduce interfacial energy and increase solubility of other pollutants in water. These properties make them suitable for various domestic and industrial applications, soil remediation, pesticide formulation, among others. The increase in their use and the lack of strict regulations regarding their disposal and management is a matter of concern and requires more attention since the release and distribution of these compounds into the environment can modify important water quality parameters. As a result of these changes, different toxicological effects to aquatic organisms are discussed and exposed herein. On this basis, we provide an overview of the classes of surfactants, as well as their occurrence in different aqueous matrices. In addition, existing regulations around the world regarding their concentration limit for different environments are discussed. Current research focuses on the application of conventional treatments, such as biological treatments; notwithstanding, more toxic and bioaccumulative products can be generated. Advanced Oxidation Processes are promising alternatives and have also been widely applied for the removal of surfactants. This study provides, for the first time, an overview of the application of persulfate-based processes for surfactants degradation based on recent literature findings, as well as the various factors related to the activation of the persulfate anions. This review also highlights the challenges and opportunities for future research to overcome the obstacles to the practical application of this process.
Per- and polyfluoroalkyl substances (PFAS) constitute a class of highly stable and extensively manufactured anthropogenic chemicals that have been linked to a variety of adverse health effects in humans and wildlife. These compounds are ubiquitously distributed in the environment and have been measured in aquatic systems globally. However, there are limited data on longitudinal comprehensive assessments of PFAS profiles within sensitive aquatic ecosystems. Surface water samples were collected from the Indian River Lagoon (IRL) and the Atlantic coast within Brevard County (BC), FL in December of 2019 (n = 57) and again from corresponding locations in February of 2021 (n = 40). Samples were analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to determine the occurrence, concentration, and distribution of 92 PFAS. No significant difference in total PFAS concentrations were identified between samples collected in 2019 (87 ng/L) and those collected in 2021 (77 ng/L). However, comparisons of PFAS among four natural sub-regions within Brevard County revealed site- and regional-specific differences. The Banana River exhibited the greatest concentration of total PFAS, followed by the southern Indian River, the northern Indian River, and then the Atlantic coast. Six distinct PFAS profiles were identified with the novel application of multivariate statistical cluster analysis, which may be useful for identifying potential sources of PFAS. Elevated total PFAS and unique compound mixtures identified in the Banana River are most likely a result of industrial discharge and extensive historical use of aqueous film-forming foams (AFFF). The environmental persistence of PFAS threatens key ecosystem services and the ecological homeostasis of the Indian River Lagoon – the most biologically diverse estuary in North America. Brevard County offers a unique model site that may be used to investigate potential exposure and health implications for wildlife and adjacent coastal communities, which could be extrapolated to better understand and manage other critical coastal systems.
Research Perfluorooctanesulfonate [PFOS; CF 3 (CF 2) 7 SO 3 – ] and its acid salts were derived from perfluorooctanesulfonyl fluoride [POSF; CF 3 (CF 2) 7 SO 2 F]. Major product applications were developed using POSF through formation of N-alkylsulfonamides that were used in surfactants, paper and pack-aging treatments, and surface protectants (e.g., carpet, upholstery, textiles). Depending on the specific functional derivitization or polymerization, these POSF-based products may have degraded or metabolized, to an undetermined degree, to PFOS, a stable and persistent end product that has a widespread presence in the general population (Butenhoff et al. 2006) and wildlife (Houde et al. 2006). Salts of perfluorooctanoic acid, in particular ammonium perfluorooctanoate (APFO), have been used as surfactants and processing aids in the production of fluoropolymers and fluoro-elastomers. Industrial production of the salts of perfluorooctanoic acid occur through electro-chemical fluorination and telomerization. Perfluorooctanoate [PFOA; CF 3 (CF 2) 6 COO – ], the dissociated carboxylate anion, has been measured in humans worldwide but generally at lower nanogram per milliliter concentrations than PFOS (Houde et al. 2006). In rats, PFOS and PFOA are not metabo-lized and enter into the enterohepatic circula-tion (Johnson et al. 1984; Kemper 2003; Kuslikis et al. 1992; Vanden Heuvel et al. 1991). Because of the stability of the carbon– fluorine bond and the high electronegativity of perfluorinated alkyl acids, metabolism would not be favored; thus, perfluorohexanesulfonate (PFHS) is also not expected to be metabolized. Based on the determination of volumes of distribution from single-dose intravenous stud-ies in cynomolgus monkeys, the distributions of PFOS, PFHS, and PFOA are primarily extracellular (Butenhoff et al. 2004; Noker and Gorman 2003a, 2003b). Kerstner-Wood et al. (2003) found PFOS, PFHS, and PFOA to be highly bound in rat, monkey, and human plasma over a concentration range of 1–500 µg/mL. When incubated with human plasma protein fractions, all three compounds were highly bound (99.7 to > 99.9%) to albu-min, and showed affinity for β-lipoproteins (95.6, 64.1, and 39.6% for PFOS, PFHS, and PFOA, respectively). Some binding to α-and γ-globulin fractions and minor interactions with transferrin (PFHS and PFOA) were also noted. PFOS and PFOA have been shown to compete for fatty acid binding sites on liver fatty acid binding protein, with PFOS giving the stronger response (Luebker et al. 2002). The elimination rates of PFOS and PFHS have been studied in male and female cynomolgus monkeys after intravenous dosing (Noker and Gorman 2003a, 2003b) and for PFOS after repeated oral dosing (Seacat et al. 2002). Noker and Gorman (2003a, 2003b) reported mean (± SD) terminal elimination half-lives, ranging from 88 to 146 days (132 ± 13 days for males and 110 ± 26 days for females) for PFOS and 49 to 200 days (141 ± 52 days for males and 87 ± 47 days for females) for PFHS, after intravenous dosing of three male and three female cynomolgus mon-keys in separate experiments, with no signifi-cant difference between males and females or between the two compounds. Seacat et al. (2002) reported an approximate terminal elimination half-life of 200 days for PFOS in male and female cynomolgus monkeys dur-ing 1 year immediately following 6 months of daily oral dosing with either 0.15 or 0.75 mg/kg PFOS. Elimination rates in species other than the monkey have been determined for PFOS and PFOA. Within 89 days after a single intra-venous dose of 14 C-PFOS, 30% of the 14 C was excreted in the urine and 12% in the feces of male rats (Johnson et al. 1979). For PFOA, significant interspecies differences have been observed (Hundley et al. 2006; Kudo and Kawashima 2003), and differential expression of organic anion transporters in renal proxi-mal tubule cells have been suggested as an
We view residue-effects relationships as integral in an overall scheme of environmental risk assessment involving fate modeling, bioaccumulation modeling (including bioconcentration, food chain accumulation, and metabolism), and community dynamics, as discussed by Bartell et al. (4). Residue-effects relationships will allow the substantial progress environmental toxicology has made in the past few decades to continue without losing touch with either the large body of exposure-based information or the field-based observations of adverse responses and residue monitoring data. The opportunity to correlate and validate the observations of laboratory toxicologists and field ecologists via residue levels in organisms and population effects (or lack of them), is particularly attractive.
Humans are simultaneously exposed to a multitude of chemicals. Human health risk assessment of chemicals is, however, normally performed on single substances, which may underestimate the total risk, thus bringing a need for reliable methods to assess the risk of combined exposure to multiple chemicals. Per- and polyfluoroalkylated substances (PFASs) is a large group of chemicals that has emerged as global environmental contaminants. In the Swedish population, 17 PFASs have been measured, of which the vast majority lacks human health risk assessment information. The objective of this study was to for the first time perform a cumulative health risk assessment of the 17 PFASs measured in the Swedish population, individually and in combination, using the Hazard Index (HI) approach. Swedish biomonitoring data (blood/serum concentrations of PFASs) were used and two study populations identified: 1) the general population exposed indirectly via the environment and 2) occupationally exposed professional ski waxers. Hazard data used were publicly available toxicity data for hepatotoxicity and reproductive toxicity as well as other more sensitive toxic effects. The results showed that PFASs concentrations were in the low ng/ml serum range in the general population, reaching high ng/ml and low μg/ml serum concentrations in the occupationally exposed. For those congeners lacking toxicity data with regard to hepatotoxicity and reproductive toxicity read-across extrapolations was performed. Other effects at lower dose levels were observed for some well-studied congeners. The risk characterization showed no concern for hepatotoxicity or reproductive toxicity in the general population except in a subpopulation eating PFOS-contaminated fish, illustrating that high local exposure may be of concern. For the occupationally exposed there was concern for hepatotoxicity by PFOA and all congeners in combination as well as for reproductive toxicity by all congeners in combination, thus a need for reduced exposure was identified. Concern for immunotoxicity by PFOS and for disrupted mammary gland development by PFOA was identified in both study populations as well as a need of additional toxicological data for many PFAS congeners with respect to all assessed endpoints.
The primary aim of this article is to provide an overview of perfluoroalkyl and polyfluoroalkyl substances (PFASs) detected in the environment, wildlife, and humans, and recommend clear, specific, and descriptive terminology, names, and acronyms for PFASs. The overarching objective is to unify and harmonize communication on PFASs by offering terminology for use by the global scientific, regulatory, and industrial communities. A particular emphasis is placed on long-chain perfluoroalkyl acids, substances related to the long-chain perfluoroalkyl acids, and substances intended as alternatives to the use of the long-chain perfluoroalkyl acids or their precursors. First, we define PFASs, classify them into various families, and recommend a pragmatic set of common names and acronyms for both the families and their individual members. Terminology related to fluorinated polymers is an important aspect of our classification. Second, we provide a brief description of the 2 main production processes, electrochemical fluorination and telomerization, used for introducing perfluoroalkyl moieties into organic compounds, and we specify the types of byproducts (isomers and homologues) likely to arise in these processes. Third, we show how the principal families of PFASs are interrelated as industrial, environmental, or metabolic precursors or transformation products of one another. We pay particular attention to those PFASs that have the potential to be converted, by abiotic or biotic environmental processes or by human metabolism, into long-chain perfluoroalkyl carboxylic or sulfonic acids, which are currently the focus of regulatory action. The Supplemental Data lists 42 families and subfamilies of PFASs and 268 selected individual compounds, providing recommended names and acronyms, and structural formulas, as well as Chemical Abstracts Service registry numbers.
La simulation est devenue dans la dernière décennie un outil essentiel du traitement statistique de modèles complexes et de la mise en oeuvre de techniques statistiques avancées, comme le bootstrap ou les méthodes d'inférence simulée. Ce livre présente les éléments de base de la simulation de lois de probabilité (génération de variables uniformes et de lois usuelles) et de leur utilisation en Statistique (intégration de Monte Carlo, optimisation stochastique). Après un bref rappel sur les chaînes de Markov, les techniques plus spécifiques de Monte Carlo par chaînes de Markov (MCMC) sont présentées en détail, à la fois du point de vue théorique (validité et convergence) et du point de vue de leur implémentation (accélération, choix de paramètres, limitations). Les algorithmes d'échantillonnage de Gibbs sont ainsi distingués des méthodes générales de Hastings-Metropolis par leur plus grande richesse théorique. Les derniers chapitres contiennent un exposé critique sur l'état de l'art en contrôle de convergence de ces algorithmes et une présentation unifiée des diverses applications des méthodes MCMC aux modèles à données manquantes. De nombreux exemples statistiques illustrent les méthodes présentées dans cet ouvrage destiné aux étudiants de deuxième et troisième cycles universitaires en Mathématiques Appliquées ainsi qu'aux chercheurs et praticiens désirant utiliser les méthodes MCMC. Monte Carlo statistical methods, particularly those based on Markov chains, are now an essential component of the standard set of techniques used by statisticians. This new edition has been revised towards a coherent and flowing coverage of these simulation techniques, with incorporation of the most recent developments in the field. In particular, the introductory coverage of random variable generation has been totally revised, with many concepts being unified through a fundamental theorem of simulation There are five completely new chapters that cover Monte Carlo control, reversible jump, slice sampling, sequential Monte Carlo, and perfect sampling. There is a more in-depth coverage of Gibbs sampling, which is now contained in three consecutive chapters. The development of Gibbs sampling starts with slice sampling and its connection with the fundamental theorem of simulation, and builds up to two-stage Gibbs sampling and its theoretical properties. A third chapter covers the multi-stage Gibbs sampler and its variety of applications. Lastly, chapters from the previous edition have been revised towards easier access, with the examples getting more detailed coverage. This textbook is intended for a second year graduate course, but will also be useful to someone who either wants to apply simulation techniques for the resolution of practical problems or wishes to grasp the fundamental principles behind those methods. The authors do not assume familiarity with Monte Carlo techniques (such as random variable generation), with computer programming, or with any Markov chain theory (the necessary concepts are developed in Chapter 6). A solutions manual, which covers approximately 40% of the problems, is available for instructors who require the book for a course. oui
Perfluorinated carboxylates (PFCAs) are generally stable to metabolic and environmental degradation and have been found at low concentrations in environmental and biological samples. Renal clearance of PFCAs depends on chain length, species, and, in some cases, gender within species. While perfluoroheptanoate (C7) is almost completely eliminated renally in both male and female rats, renal clearance of perfluorooctanoate (C8) and perfluorononanoate (C9) is much higher in female rats. Perfluorodecanoate (C10) mainly accumulates in the liver for both genders. Therefore, we tested whether PFCAs with different chain lengths are substrates of rat renal transporters with gender-specific expression patterns. Inhibition of uptake of model substrates was measured for the basolateral organic anion transporter (Oat)1 and Oat3 and the apical Oat2, organic anion transporting polypeptide (Oatp)1a1, and Urat1 with 10microM PFCAs with chain lengths from 2 to 18 (C2-C18) carbons. Perfluorohexanoate (C6), C7, and C8 inhibited Oat1-mediated p-aminohippurate transport, with C7 being the strongest inhibitor. C8 and C9 were the strongest inhibitors for Oat3-mediated estrone-3-sulfate transport, while Oatp1a1-mediated estradiol-17beta-glucuronide uptake was inhibited by C9, C10, and perflouroundecanoate (C11), with C10 giving the strongest inhibition. No strong inhibitors were found for Oat2 or Urat1. Kinetic analysis was performed for the strongest inhibitors. Oat1 transported C7 and C8 with K(m) values of 50.5 and 43.2microM, respectively. Oat3 transported C8 and C9 with K(m) values of 65.7 and 174.5microM, respectively. Oatp1a1-mediated transport yielded K(m) values of 126.4 (C8), 20.5 (C9), and 28.5microM (C10). These results suggest that Oat1 and Oat3 are involved in renal secretion of C7-C9, while Oatp1a1 can contribute to the reabsorption of C8 through C10, with highest affinities for C9 and C10.
It is argued that chemical substances can be meaningfully ranked or classified according to their persistence (P), bioaccumulation (B), toxicity (T), and potential for long-range transport (LRT) only if these attributes can be shown to be intensive, as distinct from extensive, properties of the substance, i.e., they are independent of quantity of substance. It is shown that P, B, and LRT can be considered intensive or quasi-intensive properties, but toxicity is more problematic. To obtain an intensive metric of toxicity requires selection of one of several possible extensive quantities that define exposure or dose. Ranking of a group of chemicals by toxicity is shown to be very dependent on which quantity is selected. It is suggested that toxicity metrics, such as lethal concentration to 50% of the population (LC50), lethal dose to 50% of the population (LD50), and threshold limit value (TLV) suffer the severe disadvantage of being dependent on the efficiency of delivery of the substance to the site(s) of toxic action in the organism. The use of measured or calculated internal dose is a preferable measure of toxicity since it reduces ambiguities inherent in the other metrics. Also, the primary concern is not the quasi-intensive property of toxicity; rather, it is the risk of toxic effects, an extensive quantity. To adequately assess the risk of toxic effects, both the toxic hazard and the degree of exposure must be characterized. Since exposure cannot be estimated without knowledge of the emission rate of chemicals to the environment, a compelling case can be made that screening to identify priority P, B, T, and LRT substances should be expanded to include quantity released to the environment as an additional factor.
Emissions of perfluoroalkyl acids (PFAAs) have increased in China over the past decade, but human exposure pathways are poorly understood. Here we analyzed 16 PFAAs in commonly consumed food items and calculated body weight normalized dietary intake rates (estimated dietary intake, EDIs) in an area with ongoing PFAA production (Hubei province; n=121) and an urbanized coastal area (Zhejiang province; n=106). Geographical differences in concentrations were primarily observed for perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS) in animal food items and short-chain PFAAs in vegetable food items. The average EDI of ΣPFAAs for adults in Hubei (998 ng kg-1 day-1) was more than two orders of magnitude higher than in Zhejiang (9.03 ng kg-1 day-1). In Hubei province, the average EDI of PFOS for adults (87 ng kg-1 day-1) was close to or exceeded advisory guidelines used in other countries indicating health risks for the population from long-term exposure. Yet, PFOS could only account for about 10% of the EDI of ΣPFAA in the Hubei province, which was dominated by short-chain PFAAs through consumption of vegetables. The large contribution of short-chain PFAAs to the total EDIs in manufacturing areas emphasize the need for improved exposure- and hazard assessment tools of these substances.
Perfluorinated compounds are fully fluorinated anthropogenic substances that have been used in various products, applications, and industrial processes. Due to their persistence and toxic effects, some of them are restricted, and therefore replacement products have been developed. The aim of the study was to quantify the body burden of different perfluorinated substances in two adult populations living close to or about 80km apart from a former perfluorooctanoate (PFOA) production plant who are exposed via drinking water, and in a control population. In this plant, the replacement emulsifier 3H-perfluoro-3-[(3-methoxy-propoxy)propanoic acid] (ADONA) has been used in the production of fluoropolymers since 2008. We quantified 7 perfluorinated compounds and ADONA in a total of 396 plasma samples collected at different time points. With regard to samples collected in 2015 or 2016, the highest 95th percentile levels were 13.5μg/l for perfluorooctane sulfonate (PFOS), 3.0μg/l for perfluorononanoate (PFNA), and 1.5μg/l for perfluorohexane sulfonate (PFHxS). For PFOA, the highest 95th percentile was found at the site close to the facility (85.5μg/l), while in the control region the value was 2.4μg/l. Overall, the concentration of PFOA and PFOS declined over time in all study regions. ADONA was detected only in few samples slightly above the limit of quantification (0.2μg/l). While health risks related to ADONA are unlikely under the present exposure situation, the exposure to PFOA via tap water should be reduced markedly, especially for the population living close to the plant.
The aim of this study was to confirm and investigate the gender differences in pharmacokinetic (PK) characteristics and tissue distribution of 3 perfluoroalkyl and polyfluoroalkyl substances (PFASs) consisted of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS) in both male and female rats. For this study, a simultaneous determination method of the 3 PFASs in rat plasma and tissues was developed and validated using a UPLC-MS/MS system. The PK parameters after a single oral or intravenous administration of the 3 PFASs in both rats were calculated using WinNonlin® software. The mean half-life of the 3 PFASs in female and male rats was in the range of 0.15–0.19 and 1.6–1.8 days for PFOA, 23.5–24.8 and 26.4–28.7 days for PFOS, and 0.9–1.7 and 20.7–26.9 days for PFHxS, respectively. The 3 PFASs were highly distributed in the liver and kidney. These results suggest that there are gender differences in the PKs for PFOA and PFHxS in rats, whereas the PFOS represented no significant gender differences except the Kp value of liver. The validated simultaneous determination method of the 3 PFASs was also within the accepted criteria of the international guidance.
Ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate has been developed as a processing aid used in the manufacture of fluoropolymers. The absorption, distribution, elimination, and distribution (ADME) and kinetic behavior of this substance has been evaluated in rats, mice, and cynomolgus monkeys by oral and intravenous routes of exposure and studied in both plasma and urine. The test substance is rapidly and completely absorbed in both rats and mice and both in vivo and in vitro experiments indicate that it is not metabolized. The test substance is rapidly eliminated exclusively in the urine in both rats and mice, with rats eliminating it more quickly than mice (approximately 5h elimination half-life in rats, 20h half-life in mice). Pharmacokinetic analysis in monkeys, rats, and mice indicate rapid, biphasic elimination characterized by a very fast alpha phase and a slower beta phase. The beta phase does not contribute to potential accumulation after multiple dosing in rats or monkeys. Comparative pharmacokinetics in rats, mice, and monkeys indicates that the rat is more similar to the monkey and is therefore a more appropriate rodent model for pharmacokinetics in primates.
In this chapter, the major human health risk assessment activities that have been undertaken for human exposure to perfluoroalkyls, with emphasis on perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA), have been summarized. Margin of exposure risk assessments, risk assessments based on dietary exposure, and the establishment of regulatory levels for PFOS and PFOA concentration in drinking water are covered in detail. Although a large and robust database exists for PFOS and PFOA that covers multiple health endpoints, data are more limited for other perfluoroalkyls. A brief review of the chemical/physical properties and hazard profiles of PFOS and PFOA in the context of risk assessment and human relevance is given. It becomes apparent that the methods used to assess human health risk from exposure to perfluoroalkyls have been evolving and will likely continue to develop as new information and approaches are introduced. Perhaps the most important direction that risk assessment for perfluoroalkyls has taken has been in the use of internal dose metrics to bridge differences in pharmacokinetic elimination kinetics between species. There is a need to better inform epidemiological investigations with the understanding obtained from toxicological and pharmacokinetic investigations and principals. Translating our understanding from toxicological systems into a human context will improve our collective ability to understand whether environmental exposure to perfluoroalkyls affects human health risk.
The author is employed by the American Chemistry Council and manages the FluoroCouncil, a global organization representing the world’s leading fluorotechnology companies, with a primary focus on fluoropolymers and fluorotelomer-based performance products. The members of the FluoroCouncil are Archroma Management LLC, Arkema France, Asahi Glass Co., Ltd., Daikin Industries, Ltd., DuPont Company, and Solvay Specialty Polymers.
The reproductive toxicity potential of Ammonium Salt of Perfluorinated Hexanoic Acid (PFHxA Ammonium Salt) in pregnant Crl: CD1(ICR) mice was investigated. Twenty females/group were administered the test substance or vehicle once daily from gestation day 6 through 18. Phase 1 doses: 0, 100, 350, and 500 mg/kg/d; phase 2: 0, 7, 35, and 175 mg/kg/d. Parameters evaluated include mortality, viability, body weights, clinical signs, abortions, premature deliveries, pregnancy and fertility, litter observations, maternal behavior, and sexual maturity in the F1 generation. The level of PFHxA Ammonium Salt was measured in the liver of F0 and F1 mice. At doses of 350 and 500 mg/kg/d maternal mortalities, excess salivation and changes in body weight gains occurred. Pup body weights were reduced on postpartum day (PPD) 0 in all the dosage groups, but persisted only in the 350 and 500 mg/kg/d groups. Additional effects at 300 and 500 mg/kg/d included stillbirths, reductions in viability indices, and delays in physical development. Levels of PFHxA Ammonium Salt in the livers of the 100 mg/kg/d dams were all below the lower limit of quantization (0.02 µg/mL); in the 350 mg/kg/d group, 3 of the 8 samples had quantifiable analytical results. In phase 2 no PFHxA Ammonium Salt was found in the liver. Adverse effects occurred only in the 175 mg/kg/d group and consisted of increased stillborn pups, pups dying on PPD 1, and reduced pup weights on PPD 1. Based on these data, the maternal and reproductive no observable adverse effect level of PFHxA Ammonium Salt is 100 mg/kg/d.
Since 2000 there has been an on-going industrial transition to replace long-chain perfluoroalkyl carboxylic acids(PFCAs), perfluoroalkane sulfonic acids (PFSAs) and their precursors. To date, information on these replacements including their chemical identities, however, has not been published or made easily accessible to the public, hampering risk assessment and management of these chemicals. Here we review information on fluorinated alternatives in the public domain. We identify over 20 fluorinated substances that are applied in [i] fluoropolymer manufacture, [ii] surface treatment of textile, leather and carpets, [iii] surface treatment of food contact materials,[iv] metal plating, [v] fire-fighting foams, and [vi] other commercial and consumer products.We summarize current knowledge on their environmental releases, persistence, and exposure of biota and humans. Based on the limited information available, it is unclear whether fluorinated alternatives are safe for humans and the environment.We identify three major data gaps that must be filled to perform meaningful risk assessments and recommend generation of the missing data through cooperation among all stakeholders (industry, regulators, academic scientists and the public).
To investigate toxicity and neoplastic potential from chronic exposure to perfluorooctanesulfonate (PFOS), a two-year toxicity and cancer bioassay was conducted with potassium PFOS (K⁺ PFOS) in male and female Sprague Dawley rats via dietary exposure at nominal K⁺ PFOS concentrations of 0, 0.5, 2, 5, and 20 μg/g (ppm) diet for up to 104 weeks. Additional groups were fed 20 ppm for the first 52 weeks, after which they were fed control diet through study termination (20 ppm Recovery groups). Scheduled interim sacrifices occurred on Weeks 4, 14, and 53, with terminal sacrifice between Weeks 103 and 106. K⁺ PFOS appeared to be well-tolerated, with some reductions in body weight occurring in treated rats relative to controls over certain study periods. Male rats experienced a statistically significant decreased trend in mortality with significantly increased survival to term at the two highest treatment levels. Decreased serum total cholesterol, especially in males, and increased serum urea nitrogen were consistent clinical chemistry observations that were clearly related to treatment. The principal non-neoplastic effect associated with K⁺ PFOS exposure was in livers of males and females and included hepatocellular hypertrophy, with proliferation of endoplasmic reticulum, vacuolation, and increased eosinophilic granulation of the cytoplasm. Statistically significant increases in hepatocellular adenoma were observed in males (p=0.046) and females (p=0.039) of the 20 ppm treatment group, and all of these tumors were observed in rats surviving to terminal sacrifice. The only hepatocellular carcinoma observed was in a 20 ppm dose group female. There were no treatment-related findings for thyroid tissue in rats fed K⁺ PFOS through study termination; however, male rats in the 20 ppm Recovery group had statistically significantly increased thyroid follicular cell adenoma, which was considered spurious. There was no evidence of kidney or bladder effects. In rats, the dietary dose estimated as the lower 95% confidence limit of the benchmark dose for a 10% increase in hepatic tumors was 8 ppm for both sexes. Recent mechanistic studies suggest a PPARα/CAR/PXR-mediated mode of action for the liver tumors observed in the present two-year study.
Sequential 28-day and 90-day oral toxicity studies were performed in male and female rats with ammonium perfluorobutyrate (NH(4)(+)PFBA) at doses up to 150 and 30mg/kg-d, respectively. Ammonium perfluorooctanoate was used as a comparator at a dose of 30mg/kg-d in the 28-day study. Female rats were unaffected by NH(4)(+)PFBA. Effects in males included: increased liver weight, slight to minimal hepatocellular hypertrophy; decreased serum total cholesterol; and reduced serum thyroxin with no change in serum thyrotropin. During recovery, liver weight, histological, and cholesterol effects were resolved. Results of RT-qPCR were consistent with increased transcriptional expression of the xenosensor nuclear receptors PPARα and CAR as well as the thyroid receptor, and decreased expression of Cyp1A1 (Ah receptor-regulated). No observable adverse effect levels (NOAELs) were 6 and >150mg/kg-d for male and female rats in the 28-day study and 6 and >30mg/kg-d in the 90-dat study, respectively.
As an emerging class of environmentally persistent and bioaccumulative contaminants, perfluorinated compounds (PFCs), especially perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), have been ubiquitously found in the environment. Increasing evidence shows that the accumulated levels of PFCs in animals and the human body might cause potential impairment to their health. In the present study, toxicological effects of PFOA and PFOS on male Sprague-Dawley rats were examined after 28 days of subchronic exposure. Abnormal behavior and sharp weight loss were observed in the high-dose PFOS group. Marked hepatomegaly, renal hypertrophy, and orchioncus in treated groups were in accordance with the viscera-somatic indexes of the liver, kidney, and gonad. Histopathological observation showed that relatively serious damage occurred in the liver and lung, mainly including hepatocytic hypertrophy and cytoplasmic vacuolation in the livers and congestion and thickened epithelial walls in the lungs. PFOA concentrations in main target organs were in the order of kidney > liver > lung > (heart, whole blood) > testicle > (spleen, brain), whereas the bioaccumulation order for PFOS was liver > heart > kidney > (whole blood) > lung > (testicle, spleen, brain). The highest concentration of PFOA detected in the kidney exposed to 5 mg/kg/day was 228+/-37 microg/g and PFOS in the liver exposed to 20 mg/kg/day reached the highest level of 648+/-17 microg/g, indicating that the liver, lung, and kidney might serve as the main target organs for PFCs. Furthermore, a dose-dependent accumulation of PFOS in various tissues was found. The accumulation levels of PFOS were universally higher than PFOA, which might explain the relative high toxicity of PFOS. The definite toxicity and high accumulation of the tested PFCs might pose a great threat to biota and human beings due to their widespread application in various fields.
The absorption, tissue distribution, elimination, and metabolism of [1-¹⁴C]-PFHx in rats and mice dosed orally at 2 or 100 mg/kg was evaluated following a single dose or after 14 consecutive doses. Absorption was rapid in rats as evidenced by a short time to maximum concentration (C(max)) of 30 min in male rats and 15 min in female rats at both the 2 and 100mg/kg dose level. The plasma elimination half-life was somewhat longer in males (1.5-1.7 h) than in females (0.5-0.7 h). Absorption in the mouse was also rapid with the maximum plasma concentration occurring between 15 and 30 min after dosing. The maximum concentration was not appreciably different between male and female mice (8 μg equiv./g at 2 mg/kg; ~350 μg equiv./g at 100 mg/kg). The primary route of elimination was via the urine. PFHx was not metabolized in rat or mouse hepatocytes, nor were any metabolites observed after oral dosing in either rodent species. Essentially 100% of the dose was eliminated in urine within 24 h demonstrating that PFHx is readily absorbed and bioavailability approaches 100%, even at a dose as high as 100 mg/kg. The route and extent of elimination was unchanged after 14 days of daily dosing. Tissues were collected at three time points (rat: 0.5, 2, and 24 h; mice: 0.25, 1, and 24 h) after dosing to investigate the tissue clearance kinetics of PFHx following a single dose at 2 or 100 mg/kg. In all tissues except skin, PFHx was not quantifiable 24 h after dosing in both sexes of the two species.
Over the past few years, the "critical body residue" approach for assessing toxicity based on bioaccumulated chemicals has evolved into a more expansive consideration of tissue residues as the dose metric when defining dose-response relationships, evaluating mixtures, developing protective guidelines, and conducting risk assessments. Hence, scientists refer to "tissue residue approach for toxicity assessment" or "tissue residue-effects approach" (TRA) when addressing ecotoxicology issues pertaining to tissue (or internal) concentrations. This introduction provides an overview of a SETAC Pellston Workshop held in 2007 to review the state of the science for using tissue residues as the dose metric in environmental toxicology. The key findings of the workshop are presented, along with recommendations for research to enhance understanding of toxic responses within and between species, and to advance the use of the TRA in assessment and management of chemicals in the environment.
Structure and energies of the binding sites of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) to human serum albumin (HSA) were determined through molecular modeling. The calculations consisted of a compound approach based on docking, followed by molecular dynamics simulations and by the estimation of the free binding energies adopting WHAM-umbrella sampling and semiempirical methodologies. The binding sites so determined are common either to known HSA fatty acids sites or to other HSA sites known to bind to pharmaceutical compounds such as warfarin, thyroxine, indole, and benzodiazepin. Among the PFOA binding sites, five have interaction energies in excess of -6 kcal/mol, which become nine for PFOS. The calculated binding free energy of PFOA to the Trp 214 binding site is the highest among the PFOA complexes, -8.0 kcal/mol, in good agreement with literature experimental data. The PFOS binding site with the highest energy, -8.8 kcal/mol, is located near the Trp 214 binding site, thus partially affecting its activity. The maximum number of ligands that can be bound to HSA is 9 for PFOA and 11 for PFOS. The calculated data were adopted to predict the level of complexation of HSA as a function of the concentration of PFOA and PFOS found in human blood for different levels of exposition. The analysis of the factors contributing to the complex binding energy permitted to outline a set of guidelines for the rational design of alternative fluorinated surfactants with a lower bioaccumulation potential.
Perfluorocarboxylic acids (PFCAs) of chain length greater than seven carbon atoms bioconcentrate in the livers of fish. However, a mechanistic cause for the empirically observed increase in the bioconcentration potential of PFCAs as a function of chain length has yet to be determined. To this end, recombinant rat liver fatty acid-binding protein (L-FABP) was purified, and its interaction with PFCAs was characterized in an aqueous system at pH 7.4. Relative binding affinities of L-FABP with PFCAs of carbon chain lengths of five to nine were established fluorimetrically. The energetics, mechanism, and stoichiometry of the interaction of perfluorooctanoic acid (PFOA) with L-FABP were examined further by isothermal titration calorimetry (ITC) and electrospray ionization combined with tandem mass spectrometry (ESI-MS/MS). Perfluorooctanoic acid was shown to bind to L-FABP with an affinity approximately an order of magnitude less than the natural ligand, oleic acid, and to have at least 3:1 PFOA:L-FABP stoichiometry. Two distinct modes of PFOA binding to L-FABP were observed by ESI-MS/MS analysis; in both cases, PFOA binds solely as the neutral species under typical physiological pH and aqueous concentrations of the anion. A comparison of their chemical and physical properties with other well-studied biologically relevant chemicals showed that accumulation of PFCAs in proteins as the neutral species is predictable. For example, the interaction of PFOA with L-FABP is almost identical to that of the acidic ionizing drugs ketolac, ibuprofen, and warfarin that show specificity to protein partitioning with a magnitude that is proportional to the K(OW) (octanol-water partitioning) of the neutral species. The experimental results suggest that routine pharmacochemical models may be applicable to predicting the protein-based bioaccumulation of long-chain PFCAs.