Accumulation of perfluoroalkyl substances in human tissues
TL;DR: The accumulation of different PFASs in samples of various human tissues from the same subjects is reported for the very first time and may be of high importance for the validation of physiologically based pharmacokinetic models, which are being developed for humans.
About: This article is published in Environment International.The article was published on 2013-09-01 and is currently open access. It has received 360 citations till now.
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TL;DR: The goals of the present review are to assess the state of the science regarding toxicological effects of PFAS and to develop strategies for advancing knowledge on the health effects of this large family of chemicals.
Abstract: Reports of environmental and human health impacts of per- and polyfluoroalkyl substances (PFAS) have greatly increased in the peer-reviewed literature. The goals of the present review are to assess the state of the science regarding toxicological effects of PFAS and to develop strategies for advancing knowledge on the health effects of this large family of chemicals. Currently, much of the toxicity data available for PFAS are for a handful of chemicals, primarily legacy PFAS such as perfluorooctanoic acid and perfluorooctane sulfonate. Epidemiological studies have revealed associations between exposure to specific PFAS and a variety of health effects, including altered immune and thyroid function, liver disease, lipid and insulin dysregulation, kidney disease, adverse reproductive and developmental outcomes, and cancer. Concordance with experimental animal data exists for many of these effects. However, information on modes of action and adverse outcome pathways must be expanded, and profound differences in PFAS toxicokinetic properties must be considered in understanding differences in responses between the sexes and among species and life stages. With many health effects noted for a relatively few example compounds and hundreds of other PFAS in commerce lacking toxicity data, more contemporary and high-throughput approaches such as read-across, molecular dynamics, and protein modeling are proposed to accelerate the development of toxicity information on emerging and legacy PFAS, individually and as mixtures. In addition, an appropriate degree of precaution, given what is already known from the PFAS examples noted, may be needed to protect human health. Environ Toxicol Chem 2021;40:606-630. © 2020 SETAC.
489 citations
Cites background from "Accumulation of perfluoroalkyl subs..."
...…receptor alpha (PPARα)– dependent or –independent and present across species (Maestri et al. 2006; Cui et al. 2009; Wan et al. 2012; Huang et al. 2013; Perez et al. 2013; Filgo et al. 2015; Xu et al. 2016, 2020a; Yao et al. 2016; Zhang L et al. 2016b; Hui et al. 2017; Li et al. 2017a; Guillette…...
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TL;DR: The CONTAM Panel concluded that parts of the European population exceed this tolerable weekly intake (TWI) of 4.4 ng/kg bw per week, which is of concern, and protects against other potential adverse effects observed in humans.
Abstract: The European Commission asked EFSA for a scientific evaluation on the risks to human health related to the presence of perfluoroalkyl substances (PFASs) in food. Based on several similar effects in animals, toxicokinetics and observed concentrations in human blood, the CONTAM Panel decided to perform the assessment for the sum of four PFASs: PFOA, PFNA, PFHxS and PFOS. These made up half of the lower bound (LB) exposure to those PFASs with available occurrence data, the remaining contribution being primarily from PFASs with short half‐lives. Equal potencies were assumed for the four PFASs included in the assessment. The mean LB exposure in adolescents and adult age groups ranged from 3 to 22, the 95th percentile from 9 to 70 ng/kg body weight (bw) per week. Toddlers and ‘other children’ showed a twofold higher exposure. Upper bound exposure was 4‐ to 49‐fold higher than LB levels, but the latter were considered more reliable. ‘Fish meat’, ‘Fruit and fruit products’ and ‘Eggs and egg products’ contributed most to the exposure. Based on available studies in animals and humans, effects on the immune system were considered the most critical for the risk assessment. From a human study, a lowest BMDL 10 of 17.5 ng/mL for the sum of the four PFASs in serum was identified for 1‐year‐old children. Using PBPK modelling, this serum level of 17.5 ng/mL in children was estimated to correspond to long‐term maternal exposure of 0.63 ng/kg bw per day. Since accumulation over time is important, a tolerable weekly intake (TWI) of 4.4 ng/kg bw per week was established. This TWI also protects against other potential adverse effects observed in humans. Based on the estimated LB exposure, but also reported serum levels, the CONTAM Panel concluded that parts of the European population exceed this TWI, which is of concern.
357 citations
TL;DR: For PFOS, the increase in serum total cholesterol in adults, and the decrease in antibody response at vaccination in children were identified as the critical effects and the CONTAM Panel established a tolerable weekly intake (TWI) of 13 ng/kg body weight (bw) per week for PFOS and 6 ng/ kg bw for PFOA.
Abstract: Acknowledgements: The Panel wishes to thank the hearing experts: Tony Fletcher, Philippe Adam Grandjean and Marco Zeilmaker, and EFSA staff members: Davide Arcella for the support provided to this scientific output. The Panel acknowledges all European Competent Authorities that provided occurrence data on perfluoroalkylated substances in food, and supported the data collection for the Comprehensive European Food Consumption Database. The Panel would also like to thank the following authors and co‐authors for providing additional data in relation to their respective studies: Esben Budtz‐Jorgensen, Jerry Campbell, Jessie A Gleason, Berit Granum, Mette Sorenson, Kyle Steenland and Kristina W Whitworth.
316 citations
North Carolina State University1, National Institutes of Health2, East Carolina University3, Residence Inn by Marriott4, University of North Texas Health Science Center5, Natural Resources Defense Council6, European Environment Agency7, Indiana University8, Harvard University9, ETH Zurich10, University of California, Berkeley11
TL;DR: Options for how governments and industry can apply the class-based approach to PFAS are presented, emphasizing the importance of eliminating non-essential uses of PFAS, and further developing safer alternatives and methods to remove existing PFAS from the environment.
Abstract: This commentary presents a scientific basis for managing as one chemical class the thousands of chemicals known as PFAS (per- and polyfluoroalkyl substances). The class includes perfluoroalkyl acids, perfluoroalkylether acids, and their precursors; fluoropolymers and perfluoropolyethers; and other PFAS. The basis for the class approach is presented in relation to their physicochemical, environmental, and toxicological properties. Specifically, the high persistence, accumulation potential, and/or hazards (known and potential) of PFAS studied to date warrant treating all PFAS as a single class. Examples are provided of how some PFAS are being regulated and how some businesses are avoiding all PFAS in their products and purchasing decisions. We conclude with options for how governments and industry can apply the class-based approach, emphasizing the importance of eliminating non-essential uses of PFAS, and further developing safer alternatives and methods to remove existing PFAS from the environment.
224 citations
TL;DR: The ability of states to develop their own guideline levels and standards provides diverse risk assessment approaches as models for other state and federal regulators, while a sufficiently protective, scientifically sound, and enforceable federal standard would provide more consistent protection.
Abstract: This paper was originally published under a standard licence. This has now been amended to a CC BY licence in the PDF and HTML.
201 citations
References
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TL;DR: An overview of the recent advances in the toxicology and mode of action for PFAAs, and of the monitoring data now available for the environment, wildlife, and humans is provided.
2,175 citations
"Accumulation of perfluoroalkyl subs..." refers background in this paper
...Thus, PFHxA showed the highest concentrations in brain and liver, while PFBA presented the maximummedian levels in kidney and lung, with PFOA as the predominant compound in bone....
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...The application of this approach to the analysis of 99 samples of five different tissues from 20 subjects demonstrated, for the very first time, the accumulation of certain short chain compounds, such as PFBA and PFHxA, in human tissues....
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...Lung samples also presented positive loadings for most acidic compounds with a pair number of carbon chain (PFBA, PFHxA, PFOA, PFDoA), as well as some of the sulphonates (PFOS, PFDS) and FOEA....
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...In brain, acidic compounds with a pair number of carbon chain (PFBA and PFHxA) and sulphonates (PFBS, PFOS and PFDS) were the predominant compounds....
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...PFBA was also the predominant compound in all kidney samples, whose median concentration was 263 ng/g. PFDoDA and PFDA were also detected in kidney samples, but at much lower concentrations (median: 91.4 and 90.2 ng/g, respectively)....
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TL;DR: Humans appear to have a long half-life of serum elimination of PFOS, PFHS, and PFOA, which may be due, in part, to a saturable renal resorption process.
Abstract: Perfluorooctanesulfonate [PFOS; CF3(CF2)7SO3−] and its acid salts were derived from perfluorooctanesulfonyl fluoride [POSF; CF3(CF2)7SO2F]. Major product applications were developed using POSF through formation of N-alkylsulfonamides that were used in surfactants, paper and packaging 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 electrochemical fluorination and telomerization. Perfluorooctanoate [PFOA; CF3(CF2)6COO−], 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 metabolized and enter into the enterohepatic circulation (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 studies 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 albumin, 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 monkeys in separate experiments, with no significant 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 during 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 intravenous dose of 14C-PFOS, 30% of the 14C 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 proximal tubule cells have been suggested as an explanation for sex differences in the rat (Kudo et al. 2002) and low elimination rates in humans (Andersen et al. 2006).
The purpose of the present study was to estimate the serum elimination half-life of PFOS, PFHS, and PFOA in humans through the long-term follow-up of retired fluoro-chemical production workers. Although these retirees were no longer occupationally exposed, their serum concentrations were expected to be considerably higher than those of the general population.
1,623 citations
"Accumulation of perfluoroalkyl subs..." refers background in this paper
...The elimination half-life of PFOA in humans was roughly estimated to be 3.5 years, while that of PFOS was approximately 4.8 years (Olsen et al., 2007), according to data from retired workers....
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...8 years (Olsen et al., 2007), according to data from retired workers....
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TL;DR: The utility of these compounds seems to ensure their continued use in one form or another for the foreseeable future, presenting a long-term challenge to scientists, industry leaders, and public health officials worldwide.
Abstract: Interest and concern about polyfluorinated compounds (PFCs), such as perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and an increasing number of other related compounds is growing as more is learned about these ubiquitous anthropogenic substances. Many of these compounds can be toxic, and they are regularly found in the blood of animals and humans worldwide. A great deal of research has been conducted in this area, but a surprising amount remains unknown about their distribution in the environment and how people ultimately become exposed. The utility of these compounds seems to ensure theircontinueduseinoneformoranotherfortheforeseeablefuture,presentingalong-termchallengetoscientists,industryleaders, and public health officials worldwide.
1,149 citations
"Accumulation of perfluoroalkyl subs..." refers background in this paper
...industry undertook voluntary actions to phase out production of perfluorooctane sulfonic acid (PFOS) between 2000 and 2002, and in 2007 the United States Environmental Protection Agency (US EPA) published the Significant New Use Rules (SNURs) to restrict the production of PFOS and related substances (Lindstrom et al., 2011)....
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...…actions to phase out production of perfluorooctane sulfonic acid (PFOS) between 2000 and 2002, and in 2007 the United States Environmental Protection Agency (US EPA) published the Significant New Use Rules (SNURs) to restrict the production of PFOS and related substances (Lindstrom et al., 2011)....
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TL;DR: Perfluorooctane sulfonic acid in serum is in general bound to albumins, and it is unlikely that PFOS would cause displacement of hormones from serum proteins in wildlife.
Abstract: Perfluorooctane sulfonic acid (PFOS) accumulates in the liver and blood of exposed organisms. The potential for these surfactant molecules to interfere with hormone/protein interactions in blood is of concern given the importance of these interactions. The PFOS binding to serum proteins was investigated by assessing its ability to displace a variety of steroid hormones from specific binding proteins in the serum of birds and fishes. Perfluorooctane sulfonic acid had only a weak ability to displace estrogen or testosterone from carp serum steroid binding proteins. Displacement of cortisone in avian sera occurred at relatively low PFOS concentrations. Corticosterone displacement potency increased with chain length, and sulfonic acids were more potent than carboxylic acids. The PFOS concentrations estimated to cause these effects were 320 μM or greater, equivalent to serum concentrations greater than 160 mg/L. Using mass spectrometry and direct in vitro binding assays, PFOS was demonstrated to bind strongly to bovine serum albumin (BSA) in a 1:1 stoichiometric ratio. It appears that PFOS in serum is in general bound to albumins. Concentrations of PFOS required to saturate albumin would be in excess of 50 to 100 mg/L. Based on current environmental concentrations, it is unlikely that PFOS would cause displacement of hormones from serum proteins in wildlife.
558 citations
"Accumulation of perfluoroalkyl subs..." refers background in this paper
...In the human body, the polar hydrophobic nature of fluorinecontaining compounds can lead to increased affinity for proteins (Jones et al., 2003; Luebker et al., 2002; Vanden Heuvel et al., 1992; Weiss et al., 2009)....
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