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Abstract

Since 2000, long-chain perfluoroalkyl acids (PFAAs) and their respective precursors have been replaced by numerous fluorinated alternatives.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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... In animal models, studies have reported that the toxicity of GenX might be even greater than that of PFOA and PFOS. For instance, GenX is hepatotoxic and carcinogenic in rats (Gomis et al., 2018;Caverly Rae et al., 2015), induces toxicity in zebrafish embryos (Gebreab et al., 2020), and disrupts thyroid hormones in animal models (Coperchini et al., 2021). There is also some evidence indicating that GenX affects reproduction (Chambers et al., 2021). ...
... The bioconcentration potential of PFAS grows with increasing molecular chain length (Gomis et al., 2018) and the octanol/water partition coefficient (K ow ), which is estimated to be higher for PFOA than for GenX (Martz et al., 2019;Hopkins et al., 2018). Therefore, PFOA was expected to bioconcentrate more than GenX. ...
... the GenX toxicity potency might be higher than that of PFOA. It is worthy of note that previous studies conducted in rats and fish demonstrated that legacy and alternative PFAS do not differ much in potency when toxicokinetics are examined (Gomis et al., 2018;Satbhai et al., 2022). To further confirm that GenX is more toxic at the reproductive level than PFOA, additional aspects should be taken into account, such as a tissue-specific bioconcentration (i.e., a potentially preferential bioconcentration of GenX or PFOA in a specific tissue). ...
... Article less toxic than PFOA 80 GenX has been shown to be more toxic, potentially being as toxic as PFOS. 64,81 Implications for Further Research. Our research illustrates the value of Eurasian otters as sentinels of bioaccumulating contaminants in the freshwater environment. ...
... 17 Limited toxicological data are available for replacement PFASs especially for apex predators and humans, but studies on rats, mice, and fish have started to demonstrate that a number of compounds have the potential to cause toxic effects. 22,30,81,82 Further research is needed on toxicity as well as their potential to bioaccumulate and biomagnify, and thus, the risk to apex predators and humans. As chemical companies continue to innovate, industry confidentiality and the time needed to develop analytical methods mean research and regulatory risk assessment inevitably lag behind production. ...
... The canonical read-across approach assumes that the chemical's toxicological properties can be inferred from those of a structurally similar chemical (Ball et al., 2016). Structureproperty relationships are used to estimate the bioaccumulation potential of novel and emerging PFAS, as well as their protein binding and elimination rates (Cousins et al., 2020;Cheng and Ng, 2018;Gomis et al., 2018). Structure-property relationships have been reported for human hepatocyte lipid accumulation and gene expression in a study of 19 PFAS (Marques et al., 2022). ...
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Per- and polyfluoroalkyl substances (PFAS) are chemicals with important applications; they are persistent in the environment and may pose human health hazards. Regulatory agencies are con­sidering restrictions and bans of PFAS; however, little data exists for informed decisions. Several prioritization strategies were proposed for evaluation of potential hazards of PFAS. Structure-based grouping could expedite the selection of PFAS for testing; still, the hypothesis that structure-effect relationships exist for PFAS requires confirmation. We tested 26 structurally diverse PFAS from 8 groups using human induced pluripotent stem cell-derived hepatocytes and cardiomyocytes, and tested concentration-response effects on cell function and gene expression. Few phenotypic effects were observed in hepatocytes, but negative chronotropy was observed in cardiomyocytes for 8 PFAS. Substance- and cell type-dependent transcriptomic changes were more prominent but lacked substantial group-specific effects. In hepatocytes, we found upregulation of stress-related and extracellular matrix organization pathways, and down-regulation of fat metabolism. In car­diomyocytes, contractility-related pathways were most affected. We derived phenotypic and transcriptomic points of departure and compared them to predicted PFAS exposures. Conservative estimates for bioactivity and exposure were used to derive a bioactivity-to-exposure ratio (BER) for each PFAS; 23 of 26 PFAS had BER > 1. Overall, these data suggest that structure-based PFAS grouping may not be sufficient to predict their biological effects. Testing of individual PFAS may be needed for scientifically-supported decision-making. Our proposed strategy of using two human cell types and considering phenotypic and transcriptomic effects, combined with dose-response analysis and calculation of BER, may be used for PFAS prioritization. Plain language summaryPer- and polyfluoroalkyl substances (PFAS) are man-made chemicals used in many products. However, most of these substances have not been tested for safety, and concerns exist that they may be harmful to human health and/or the environment. This study aimed to use human cell-based models to investigate if some of the PFAS may exhibit hazardous properties and if similarities among substance groups are observed. Few effects were observed in liver cells, but a decrease in beating frequency was observed in heart cells for some PFAS. Gene expression changes were substance-and cell type-dependent. We did not find convincing structure-based similarities among PFAS; this suggests that testing of individual PFAS may be necessary in the future to inform health decisions. Overall, this study showed that a test strategy of using two human cell types, from liver and heart, may inform PFAS prioritization without a need for testing in animals.
... 33,34 Despite extensive research on fluorinated alternatives aimed at improving this situation, these fluorinated alternatives may become an emerging contaminant. [35][36][37][38] Therefore, environmentally friendly polymeric materials deserve further investigation, even though finding fluorine-free alternatives giving comparable performance is still challenging for now. Similarly, research on environmentally friendly polymeric membrane materials and high performance of prepared membranes is of critical interest and worthy of in-depth exploration. ...
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Ultrafiltration (UF) membranes with excellent dye removal and antibacterial activity are highly desired in dye wastewater treatment, and more importantly environmental protection puts high demands on polymeric membrane materials. In this work, three methacrylate copolymers containing quaternary ammonium salt were synthesized to cast UF membranes. The physicochemical property, structural evolution, dye separation, and antibacterial activity of as‐prepared membranes were systematically investigated. With increased content of the hydrophilic monomer allyl polypropylene glycol (APPG) in the feed, the wettability and positive charge of the resultant membranes were enhanced. Remarkably, the supporting layer of membranes changed from finger‐like pore structure to sponge‐like pore structure by increasing APPG content, and the sponge‐like membranes showed higher retention rates for dyes (99.78% for victoria blue B, 90.49% for methylene blue, and 97.43% for methyl blue) compared with the finger‐like membranes. Besides, the sponge‐like membranes exhibited high rejection for vctoria blue B (>99%) in dye/salt mixture and simultaneously low rejection for salts (<10%), indicating effective selective separation to dye/salt mixture, and also achieved easy regeneration. It was also found that increased hydrophilicity and positive charge endowed membranes with better antibacterial activity. This work will provide an alternative for dye/salt selective separation in dye effluent treatment.
... In response to the continued need for chemicals with similar properties to these compounds, new PFAS have been developed and produced, including supposedly less-harmful shorter-chain analogues (Guo et al., 2019). Nonetheless, when evaluating toxicokinetics, the toxic potency seems similar between fluorinated alternatives and their predecessors (Gomis et al., 2018;Chappell et al., 2020). ...
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Background: Per- and polyfluoroalkyl substances (PFAS) are a class of widely used anthropogenic chemicals. Concerns regarding their persistence and potential adverse effects have led to multiple secondary research publications. Here, we aim to assess the resulting evidence base in the systematic secondary literature by examining research gaps, evaluating the quality of reviews, and exploring interdisciplinary connections. Methods: This study employed a systematic evidence-mapping approach to assess the secondary literature on the biological, environmental, and medical aspects of exposure to 35 fluorinated compounds. The inclusion criteria encompassed systematic reviews published in peer-reviewed journals, pre-prints, and theses. Comprehensive searches across electronic databases and grey literature identified relevant reviews. Data extraction and synthesis involved mapping literature content and narrative descriptions. We employed a modified version of the AMSTAR2 checklist to evaluate the methodological rigour of the reviews. A bibliometric data analysis uncovered patterns and trends in the academic literature. A research protocol for this study was previously pre-registered (osf.io/2tpn8) and published (Vendl et al., Environment International 158 (2022) 106973). The database is freely accessible through the interactive and user-friendly web application of this systematic evidence map at https://hi -this-is-lorenzo.shinyapps.io/PFAS_SEM_Shiny_App/. Results: Our map includes a total of 175 systematic reviews. Over the years, there has been a steady increase in the annual number of publications, with a notable surge in 2021. Most reviews focused on human exposure, whereas environmental and animal-related reviews were fewer and often lacked a rigorous systematic approach to literature search and screening. Review outcomes were predominantly associated with human health, particularly with reproductive and children’s developmental health. Animal reviews primarily focused on studies conducted in controlled laboratory settings, and wildlife reviews were characterised by an over-representation of birds and fish species. Recent reviews increasingly incorporated quantitative synthesis methodologies. The methodological strengths of the reviews included detailed descriptions of study selection processes and disclosure of potential conflicts of interest. However, weaknesses were observed in the critical lack of detail in reporting methods. A bibliometric analysis revealed that the most productive authors collaborate within their own country, leading to limited and clustered international collaborations. Conclusions: In this overview of the available systematic secondary literature, we map literature content, assess reviews’ methodological quality, highlight data gaps, and draw research network clusters. We aim to facilitate literature reviews, guide future research initiatives, and enhance opportunities for cross-country collaboration. Furthermore, we discuss how this systematic evidence map and its publicly available database benefit scientists, regulatory agencies, and other stakeholders by providing access to current systematic secondary literature on PFAS exposure.
... As very persistent and bioaccumulative chemicals they were listed in the Stockholm Convention on Persistent Organic Pollutants (POPs). Their negative impact on living organisms has been proved with their hepatotoxicity, immunotoxicity, neurotoxicity and causing of reproductive and developmental disorders (6,20). Food and water as well as dust ingestion are the main sources of PFASs for humans (8,9,15,16). ...
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Introduction This study focuses on perfluoroalkyl substance (PFAS) content in chickens’ eggs and the livers of farm animals. Material and Methods Chickens’ eggs (n = 25) and the livers of cows (n = 10), chickens (n = 7) and horses (n = 3) were collected from various regions of Poland. Samples were analysed using the isotope dilution technique with liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Results The mean lower bound (LB) sum of four PFAS (∑4 PFAS) concentrations (perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorohexanesulfonic acid (PFHxS)) were the highest in cows’ livers (0.52 μg/kg) and much lower in chickens’ (0.17 μg/kg) and horses’ livers (0.13 μg/kg) and chickens’ eggs (0.096 μg/kg). The ratio of ∑4 PFASs to the limits set by Commission Regulation (EU) 2023/915 was <7% for liver and <6% for eggs. Linear PFOS was the compound with the highest detection frequency (8% in eggs and 48% in all livers). In cows’ livers it was detected in 80% of samples. The estimated exposure to LB ∑4 PFASs via consumption of liver tissue from farm animals (assuming 50 g and 100 g portions) was <52% of the tolerable weekly intake (TWI) for children and <17% of the TWI for adults. Dietary intake via the average portion of three eggs led to low exposure of <15% for children and <5% for adults. Conclusion Neither eggs nor the livers of chickens or horses as analysed in this study are significant sources of PFASs, while cows’ livers might contribute significantly to a child’s overall dietary intake. Further investigation of PFOS in farm animal livers should be conducted.
... [12][13][14] However, the improvement of the surface hydrophobicity of the adhesive film by modifying monomers with polysiloxane is limited, and it is necessary to further improve the hydrophobicity of the adhesive film by combining fluorinated substances with polysiloxane. Due to the bioaccumulation toxicity of long-chain perfluoroalkyl groups (such as PFOS and PFOA), 15,16 this experiment innovatively selected methyltrifluoropropylcyclotrisiloxane (DF 3 ), octamethylcyclotetrasiloxane (D 4 ), tetramethyltetravinylcyclotetrasiloxane (D v 4 ), and the capping agent hexamethyldisiloxane (MM) to prepare fluorinated vinyl polysiloxane through acid catalyzed bulk ring opening reaction. Then, the fluorinated vinyl polysiloxane modified polyacrylates were prepared by miniemulsion polymerizations to increase the compatibility between the fluorinated polysiloxane modified monomer and polyacrylates. ...
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Polyacrylate materials are widely used in textile adhesives, functional finishing agents, architectural coatings, and other fields. In order to improve their hydrophobicity and flexibility, a novel fluorinated polysiloxane was prepared by acid catalyzed bulk ring opening reaction with octamethylcyclotetrasiloxane (D4), tetramethyltetravinylcyclotetrasiloxane (D4v), and methyltrifluoropropylcyclotrisiloxane (D3F), and its structure was characterized. Then, as a modified monomer, the fluorinated polysiloxane modified polyacrylates was prepared by miniemulsion polymerization. The effects of fluorinated polysiloxane monomers with different vinyl content and molecular weight on the properties of emulsion, film structure and film hydrophobicity were studied. The results showed that when using fluorinated polysiloxane monomer with Mn = 6235, vinyl content of 0.33 mmol/g, and fluorine content of 7.40 mmol/g for modification, the water contact angle on the surface of the adhesive film reached 100.4°, and the water absorption rate was 8.1%, resulting in the best effect. Used for textile printing, the color fastness to dry and wet friction after fabric printing could reach level 4, and the hand feel was soft.
... As a result, PFAS can remain intact in the environment for years, if not decades, earning them the moniker "forever chemicals" [48]. The stability that makes PFAS valuable in industrial applications also makes their degradation in the environment exceptionally challenging [49]. Traditional environmental remediation techniques are often ineffective at breaking down PFAS, leading to the need for specialized, often costly, treatment methods. ...
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This review examines the extensive use and environmental consequences of Per- and Polyfluoroalkyl Substances (PFAS) on a global scale, specifically emphasizing their potential impact in Nigeria. Recognized for their resistance to water and oil, PFAS are under increased scrutiny for their persistent nature and possible ecotoxicological risks. Here, we consolidate existing knowledge on the ecological and human health effects of PFAS in Nigeria, focusing on their neurological effects and the risks they pose to immune system health. We seek to balance the advantages of PFAS with their potential ecological and health hazards, thereby enhancing understanding of PFAS management in Nigeria and advocating for more effective policy interventions and the creation of safer alternatives. The review concludes with several recommendations: strengthening regulatory frameworks, intensifying research into the ecological and health impacts of PFAS, developing new methodologies and longitudinal studies, fostering collaborative efforts for PFAS management, and promoting public awareness and education to support sustainable environmental practices and healthier communities in Nigeria.
... In recent years, longchain "legacy" PFAS substances have been replaced with shorter chain PFAS substances (Calafat, et al., 2007;Brase et al., 2021). These emerging PFAS remain an area of active research due to their unknown environmental and human health concerns (Gomis, 2018;Wang, 2015). Thus, PFAS are present in the environment as ubiquitous mixtures of legacy and emerging pollutants of unknown toxicity. ...
... We compared concentrations among tissues within individuals to quantify tissue-specific exposure and examine toxic potency and bioaccumulation (Gomis et al., 2018). We assessed equal variance between bird tissues from contaminated sites using paired t-tests and F-tests (sampling was adequate for parametric approaches). ...
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Per- and polyfluoroalkyl substances (PFAS) in the environment pose persistent and complex threats to human and wildlife health. Around the world, PFAS point sources such as military bases expose thousands of populations of wildlife and game species, with potentially far-reaching implications for population and ecosystem health. But few studies shed light on the extent to which PFAS permeate food webs, particularly ecologically and taxonomically diverse communities of primary and secondary consumers. Here we conducted >2000 assays to measure tissue-concentrations of 17 PFAS in 23 species of mammals and migratory birds at Holloman Air Force Base (AFB), New Mexico, USA, where wastewater catchment lakes form biodiverse oases. PFAS concentrations were among the highest reported in animal tissues, and high levels have persisted for at least three decades. Twenty of 23 species sampled at Holloman AFB were heavily contaminated, representing middle trophic levels and wetland to desert microhabitats, implicating pathways for PFAS uptake: ingestion of surface water, sediments, and soil; foraging on aquatic invertebrates and plants; and preying upon birds or mammals. The hazardous long carbon-chain form, perfluorooctanosulfonic acid (PFOS), was most abundant, with liver concentrations averaging >10,000 ng/g wet weight (ww) in birds and mammals, respectively, and reaching as high 97,000 ng/g ww in a 1994 specimen. Perfluorohexanesulfonic acid (PFHxS) averaged thousands of ng/g ww in the livers of aquatic birds and littoral-zone house mice, but one order of magnitude lower in the livers of upland desert rodent species. Piscivores and upland desert songbirds were relatively uncontaminated. At control sites, PFAS levels were strikingly lower on average and different in composition. In sum, legacy PFAS at this desert oasis have permeated local aquatic and terrestrial food webs across decades, severely contaminating populations of resident and migrant animals, and exposing people via game meat consumption and outdoor recreation.
... The high durability and water solubility of PFAS cause aquatic environmental persistence [2]. PFAS is released into the environment through industrial discharges, landfills, and consumer products [3]. PFAS exposure, specifically to perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), has been associated with cancer, immunotoxicity, liver damage, and neurodevelopmental effects [4]. ...
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Per- and poly-fluoroalkyl substances (PFAS) are concerning contaminants due to their ubiquity, persistence, and toxicity. Conventional PFAS water treatments such as granular activated carbon are limited by low adsorption rates and capacities. Carbon-based nano-adsorbents with enhanced surface areas address these limitations but are hindered by their high cost and toxicity. Cellulose nanocrystals (CNC) are promising PFAS adsorbents due to sustainable sourcing, large surface areas, and amenable surface properties. In this study, CNC was synthesized from the agro-food waste, apple pomace (APCNC), and coated with Moringa oleifera cationic protein (MOCP) aqueous extract to produce MOCP/APCNC for the removal of perfluorooctanoic acid (PFOA) from water. APCNC and MOCP/APCNC were manufactured, characterized, and utilized in PFOA batch adsorption kinetics and equilibrium trials. APCNC was successfully produced from apple pomace (AP) and determined through characterization and comparison to commercial CNC (CCNC). APCNC and MOCP/APCNC exhibited rapid PFOA adsorption, approaching equilibrium within 15 min. MOCP coatings inverted the MOCP/CNC surface charge to cationic (−15.07 to 7.38 mV) and enhanced the PFOA adsorption rate (2.65 × 10−3 to 5.05 × 10−3 g/mg/s), capacity (47.1 to 61.1 mg/g), and robustness across varied water qualities. The sustainable sourcing of APCNC combined with a green surface coating to produce MOCP/CNC provides a highly promising environmentally friendly approach to PFAS remediation.
... China [5]. Such emerging alternatives are considered less toxic and bioaccmulative than PFOA and PFOS, but some exhibit similar or more toxic potency [6]. For example, hexafluoropropylene oxide trimer acid (HFPO-TA) exhibits a higher bioaccumulation potential and more serious hepatotoxicity than PFOA [7]. ...
Article
This research developed and optimized innovative, cost-effective methods to quantify extractable total per- and polyfluoroalkyl substances (PFAS) in water, overcoming limitations of existing techniques by integrating persulfate preoxidation with subsequent solid phase extraction (SPE), followed by chemical defluorination using sodium biphenyl (SBP assay) or ion-pair formation with methylene blue (MB assay). Persulfate preoxidation improved selectivity by oxidizing interfering organofluorines and anionic surfactants, while SPE concentrated PFAS and removed impurities such as inorganic fluoride. Both the SBP and MB assays exhibited high responses across various PFAS structures, except for some (ultra)short-chain PFAS. The refined assays, including SPE, achieved limits of detection of 0.016 μgF/L for SBP and 0.2 μgF/L for MB assay, with robust recoveries across various PFAS compounds in synthetic water matrices. Analyses of PFAS-contaminated real waters using the SBP assay revealed extractable total PFAS concentrations of 5.1 μgF/L in industrial wastewater and 0.30 μgF/L in river water, matching those by combustion ion chromatography (CIC), a current benchmark method. The MB assay, however, showed concentrations 1.9–3.1 times higher than the SBP and CIC assays. The extractable total PFAS concentrations in the real waters exceeded the sum of individual PFAS quantified by LC–MS, underscoring the necessity of identifying unknown PFAS.
Article
Hypothesis: Understanding the intricate molecular-level details of toxic per- and polyfluoroalkyl substances (PFAS) partitioning to the air–water interface holds paramount importance in evaluating their fate and transport, as well as for finding safer alternatives for various applications, including aqueous film forming foams (AFFF). The behavior of these substances at interfaces strongly depends on molecular architecture, chemistry, and concentration, which define molecular packing, self-assembly, interfacial diffusion, and the surface tension. Simulations: Modeling of three PFAS surfactants, namely, long-tail (perfluorooctanoate (PFOA)) and short-tail (perfluorobutanoate (PFBA) and 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy) propanoate (GenX)) have been conducted using atomistic molecular dynamics (MD) simulations. A systematic comparison between these representative PFAS of different size and structure along with different concentrations reveals factors influencing their association behavior, mechanism of surface tension reduction, and interfacial mobility as a function of surface coverage. Findings: Shorter-chain PFAS surfactants (GenX or PFBA) require lower surface coverage compared to longer chain (PFOA) PFAS to achieve the same decrease in surface tension. However, a higher concentration of GenX and PFBA is necessary in the bulk aqueous solution to achieve the same surface coverage as PFOA, due to their higher solubility in water. The PFAS molecular orientation and mobility at the interface are found to be vastly influenced by the length and architecture of the hydrophobic fluorocarbon tail. A significant ordering of the water dipole moment near the anionic headgroup is apparent at high surface concentration. A direct correlation is established between the PFAS interfacial properties and PFAS-PFAS, PFAS-counterion, and PFAS-water interactions.
Article
In this study, we focused on the fluorous affinity acting among fluorine compounds, and then developed a new separation medium and evaluated their performance. We prepared the stationary phases for a column using silica gel‐modified alkyl fluoride and investigated the characteristics of fluorous affinity by comparing them with a typical stationary phase, which does not contain fluorine, using high‐performance liquid chromatography (HPLC). In HPLC measurements, we confirmed that while all non‐fluorine compounds were not retained, retention of fluorine compounds increased as the number of fluorine increased with the stationary phase. It also revealed that the strength of fluorous affinity changes depending on the types of the organic solvent; the more polar the solvent, the stronger the effect. Additionally, the stationary phase was employed to compare the efficiency of our column with that of a commercially available column, Fluofix‐II. The retention selectivity was almost the same, but the absolute retention strength was slightly higher on our column, indicating that the column is available for practical use.
Article
Background: Dioxin-like chemicals are a group of ubiquitous environmental toxicants that received intense attention in the last two decades of the 20th century. Through extensive mechanistic research and validation, the global community has agreed upon a regulatory strategy for these chemicals that centers on their common additive activation of a single receptor. Applying these regulations has led to decreased exposure in most populations studied. As dioxin-like chemicals moved out of the limelight, research and media attention has turned to other concerning contaminants, including per- and polyfluoroalkyl substances (PFAS). During the 20th century, PFAS were also being quietly emitted into the environment, but only in the last 20 years have we realized the serious threat they pose to health. There is active debate about how to appropriately classify and regulate the thousands of known PFAS and finding a solution for these "forever chemicals" is of the utmost urgency. Objectives: Here, we compare important features of dioxin-like chemicals and PFAS, including the history, mechanism of action, and effective upstream regulatory strategies, with the objective of gleaning insight from the past to improve strategies for addressing PFAS. Discussion: The differences between these two chemical classes means that regulatory strategies for dioxin-like chemicals will not be appropriate for PFAS. PFAS exert toxicity by both receptor-based and nonreceptor-based mechanisms, which complicates mixtures evaluation and stymies efforts to develop inexpensive assays that accurately capture toxicity. Furthermore, dioxin-like chemicals were unwanted byproducts, but PFAS are useful and valuable, which has led to intense resistance against efforts to restrict their production. Nonetheless, useful lessons can be drawn from dioxin-like chemicals and applied to PFAS, including eliminating nonessential production of new PFAS and proactive investment in environmental remediation to address their extraordinarily long environmental persistence. https://doi.org/10.1289/EHP14449.
Article
Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are widespread groundwater contaminants and are present in over 7000 drinking water wells near a North Carolina (NC) PFAS plant (Chemours). To understand options available to affected residents, we used new and previously existing water quality data to investigate deeper aquifers as alternate drinking water supplies and compared the regulatory responses near Chemours and three other PFAS production facilities with nearby contaminated wells. Data from >100 wells show that GenX concentrations decrease with increasing depth through the four aquifers in the study area: surficial, Black Creek, Upper Cape Fear, and bedrock. This illustrates the extent of vertical PFAS penetration through the aquifer sequence following roughly 40 years of atmospheric emissions. Detailed data on 143 water quality parameters in nine deep wells (two Upper Cape Fear, seven bedrock) revealed only eight exceedances of drinking water standards (one each for arsenic, perfluorooctanoic acid [PFOA], iron, chloride, and gross alpha, and three for manganese) and nine exceedances of health advisories (all for sodium). Regulatory responses to PFAS contamination of wells in four states included mention of deeper wells as an alternate water source only for nonresidential users in NC and residential users in Vermont. The bedrock aquifer is currently used by some residents and may be a viable alternative to shallower groundwater, though arsenic treatment may be beneficial at some deep wells and long‐term sustainability of the aquifer should be evaluated. Practitioner Points GenX concentrations decreased with increasing depth in four aquifers near a PFAS plant. A few exceedances of drinking water standards and health advisories were found in deep bedrock wells. New bedrock wells could be part of the response to PFAS issues in shallower wells. In the long term, deep bedrock wells might be a less expensive option for some residents.
Article
The increasing interfacial impacts of polystyrene nanoplastics (PS) and per- and polyfluoroalkyl substances (PFAS) complex aquatic environments are becoming more evident, drawing attention to the potential risks to aquatic animal health and human seafood safety. This study aims to investigate the relative impacts following exposure (7 days) of Crassostrea hongkongensis oysters to the traditional PFAS congener, perfluorooctanoic acid (PFOA) at 50 μg/L, and its novel alternative, hexafluoropropylene oxide dimer acid (HFPO-DA), also known as GenX at 50 μg/L, in conjunction with fluorescent polystyrene nanoplastics (PS, 80 nm) at 1 mg/L. The research focuses on assessing the effects of combined exposure on oxidative stress responses and gut microbiota in the C. hongkongensis. Comparing the final results of PS + GenX (PG) and PS + PFOA (PF) groups, we observed bioaccumulation of PS in both groups, with the former causing more pronounced histopathological damage to the gills and intestines. Furthermore, the content of antioxidant enzymes induced by PG was higher than that of PF, including Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Reductase (GR) and Glutathione Peroxidase (GSH). Additionally, in both PG and PF groups, the expression levels of several immune-related genes were significantly upregulated, including tnfα, cat, stat, tlr-4, sod, and β-gbp, with no significant difference between these two groups (p > 0.05). Combined exposure induced significant changes in the gut microbiota of C. hongkongensis at its genus level, with a significant increase in Legionella and a notable decrease in Endozoicomonas and Lactococcus caused by PG. These shifts led to beneficial bacteria declining and pathogenic microbes increasing. Consequently, the microbial community structure might be disrupted. In summary, our findings contribute to a deeper understanding of the comparative toxicities of marine bivalves under combined exposure of traditional and alternative PFAS.
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Due to their significant environmental impact, there has been a gradual restriction of the production and utilization of legacy per- and polyfluoroalkyl substances (PFAS), leading to continuous development and adoption of novel alternatives. To effectively identify the potential environmental risks from crop consumption, the levels of 25 PFAS, including fourteen perfluoroalkyl acids (PFAAs), two precursor substances and nine novel alternatives, in agricultural soils and edible parts of various crops around a fluoride industrial park (FIP) in Changshu city, China, were measured. The concentration of ΣPFAS in the edible parts of all crops ranged from 11.64 to 299.5 ng/g, with perfluorobutanoic acid (PFBA) being the dominant compound, accounting for an average of 71% of ΣPFAS. The precursor substance, N-methylperfluoro-octanesulfonamidoacetic acid (N-MeFOSAA), was detected in all crop samples. Different types of crops showed distinguishing accumulation profiles for the PFAS. Solanaceae and leafy vegetables showed higher levels of PFAS contamination, with the highest ΣPFAS concentrations reaching 190.91 and 175.29 ng/g, respectively. The highest ΣAlternative was detected in leafy vegetables at 15.21 ng/g. The levels of human exposure to PFAS through crop consumption for various aged groups were also evaluated. The maximum exposure to PFOA for urban toddlers reached 109.8% of the standard value set by the European Food Safety Authority (EFSA). In addition, short-chained PFAAs and novel alternatives may pose potential risks to human health via crop consumption.
Article
Background: The TGx-DDI biomarker identifies transcripts specifically induced by primary DNA damage. Profiling similarity of TGx-DDI signatures can allow clustering compounds by genotoxic mechanism. This transcriptomics-based approach complements conventional toxicology testing by enhancing mechanistic resolution. Methods: Unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding (tSNE) were utilized to assess similarity of publicly-available per- and polyfluoroalkyl substances (PFAS) and ToxCast chemicals based on TGx-DDI modulation. TempO-seq transcriptomic data after highest chemical concentrations were analyzed. Results: Clustering discriminated between genotoxic and non-genotoxic compounds while drawing similarity among chemicals with shared mechanisms. PFAS largely clustered distinctly from classical mutagens. However, dynamic range across PFAS types and durations indicated variable potential for DNA damage. tSNE visualization reinforced phenotypic groupings, with genotoxins clustering separately from non-DNA damaging agents. Discussion: Unsupervised learning approaches applied to TGx-DDI profiles effectively categorizes chemical genotoxicity potential, aiding elucidation of biological response pathways. This transcriptomics-based strategy gives further insight into the role and effect of individual TGx-DDI biomarker genes and complements existing assays by enhancing mechanistic resolution. Overall, TGx-DDI biomarker profiling holds promise for predictive safety screening.
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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.
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Long-chain perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkane sulfonic acids (PFSAs) are persistent, bioaccumulative, and toxic contaminants that are globally present in the environment, wildlife and humans. Phase-out actions and use restrictions to reduce the environmental release of long-chain PFCAs, PFSAs and their precursors have been taken since 2000. In particular, long-chain poly- and perfluoroalkyl substances (PFASs) are being replaced with shorter-chain homologues or other fluorinated or non-fluorinated alternatives. A key question is: are these alternatives, particularly the structurally similar fluorinated alternatives, less hazardous to humans and the environment than the substances they replace? Several fluorinated alternatives including perfluoroether carboxylic acids (PFECAs) and perfluoroether sulfonic acids (PFESAs) have been recently identified. However, the scarcity of experimental data prevents hazard and risk assessments for these substances. In this study, we use state-of-the-art in silico tools to estimate key properties of these newly identified fluorinated alternatives. [i] COSMOtherm and SPARC are used to estimate physicochemical properties. The US EPA EPISuite software package is used to predict degradation half-lives in air, water and soil. [ii] In combination with estimated chemical properties, a fugacity-based multimedia mass-balance unit-world model - the OECD Overall Persistence (POV) and Long-Range Transport Potential (LRTP) Screening Tool - is used to assess the likely environmental fate of these alternatives. Even though the fluorinated alternatives contain some structural differences, their physicochemical properties are not significantly different from those of their predecessors. Furthermore, most of the alternatives are estimated to be similarly persistent and mobile in the environment as the long-chain PFASs. The models therefore predict that the fluorinated alternatives will become globally distributed in the environment similar to their predecessors. Although such in silico methods are coupled with uncertainties, this preliminary assessment provides enough cause for concern to warrant experimental work to better determine the properties of these fluorinated alternatives. Copyright © 2014 Elsevier B.V. All rights reserved.
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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.
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Perfluorinated compounds such as the perfluoroalkyl acids (PFAAs) and their derivatives are important man-made chemicals that have wide consumer and industrial applications. They are relatively contemporary chemicals, being in use only since the 1950s and until recently have been considered as biologically inactive. However, during the past decade, their global distribution, environmental persistence, presence in humans and wildlife, and adverse health effects in laboratory animals have come to light, generating scientific, regulatory, and public interest on an international scale. This chapter will provide a brief overview of recent advances in understanding environmental and human exposure, toxicology, and modes of action for this class of compounds in animal models, as well as a summary of epidemiological findings to date.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
It has been hypothesized that human renal apical membrane transporters play a key role in human renal reabsorption of perfluorooctanoate (PFO), which contributes to the long half-life of PFO in humans. In the present study, PFO uptake kinetics of human organic anion-transporting polypeptide (OATP) 1A2, organic anion transporter (OAT) 4, and urate transporter 1 (URAT1) in stably transfected cell lines was investigated. OAT4 and URAT1, but not OATP1A2, were shown to mediate saturable PFO cellular uptake. OAT4-mediated PFO uptake was stimulated by a low extracellular pH, which was evidenced as a lower Michaelis constant (K(m)) at pH 6 (172.3 ± 45.9μM) than that at pH 7.4 (310.3 ± 30.2μM). URAT1-mediated PFO uptake was greatly enhanced by an outward Cl(-) gradient, and its K(m) value was determined to be 64.1 ± 30.5μM in the absence of extracellular Cl(-). The inhibition of OATP1A2- or OAT4-mediated estrone-3-sulfate uptake or URAT1-mediated urate uptake has been compared for linear perfluorocarboxylates (PFCs) with carbon chain lengths from 4 to 12. A clear chain length-dependent inhibition was observed, suggesting that PFCs in general are substrates of OAT4 and URAT1 but with different levels of affinities to the transporters depending on their chain length. Our results suggest that OAT4 and URAT1 are key transporters in renal reabsorption of PFCs in humans and, as a result, may contribute significantly to the long half-life of PFO in humans.
Article
S-111-S-WB, a mixture of perfluoro fatty acid ammonium salts (C(6)-C(13)), was administered orally to Crl:CD (SD)IGS-BR rats. Higher hepatic beta-oxidation and liver weights with hepatocellular hypertrophy were present at the 0.125 and 0.6 mg/kg/d dosage. The 0.6 mg/kg/d males developed hepatocellular degeneration and necrosis. Lower serum protein and higher bilirubin and BUN were seen in the 0.6 mg/kg/d males and lower globulin and higher alkaline phosphatase in the 0.125 mg/kg/d males and 0.6 mg/kg/d animals. After 2 weeks, serum concentrations of pentadecafluorooctanoic acid (C(8)), heptadecafluorononanoic acid (C(9)), perfluoroundecanoic acid (C(11)), and perfluorotridecanoic acid (C(13)) were constant for at least 8 hours. After 90 days, only C(9) in the 0.025 mg/kg/d females had reached steady state. Serum C(8) and C(9) concentrations in the males were 10-fold higher than in the females, whereas C(11) and C(13) were similar for both genders. The main elimination was via the urine for C(8) (males) and C(9) (females), and via the feces for C(11) and C(13). The no-observed-effect level (NOEL) was 0.025 mg/kg/d for the males and 0.125 mg/kg/d for the females.
Article
Polyfluoroalkyl chemicals (PFCs) have been used worldwide for more than 50 years in a wide variety of industrial and consumer products. Limited data exist on human exposure to PFCs in the Southern Hemisphere. Human blood serum collected in southeast Queensland, Australia, in 2006−2007 from 2420 donors was pooled according to age (cord blood, 0−0.5, 0.6−1, 1.1−1.5, 1.6−2, 2.1−2.5, 2.6−3, 3.1−3.5, 3.6−4, 4.1−6, 6.1−9, 9.1−12, 12.1−15, 16−30, 31−45, 46−60, and >60 years) and gender and was analyzed for eight PFCs. Across all pools, perfluorooctane sulfonate (PFOS) was detected at the highest mean concentration (15.2 ng/mL) followed by perfluorooctanoate (PFOA, 6.4 ng/mL), perfluorohexane sulfonate (PFHxS, 3.1 ng/mL), perfluorononanoate (PFNA, 0.8 ng/mL), 2-(N-methyl-perfluorooctance sulfonamide) acetate (Me-PFOSA-AcOH, 0.66 ng/mL), and perfluorodecanoate (PFDeA, 0.29 ng/mL). Perfluorooctane sulfonamide was detected in only 24% of the pools, and 2-(N-ethylperfluorooctane sulfonamide) acetate was detected in only one. PFOS concentrations were significantly higher in pools from adult males than from adult females (p = 0.002); no gender differences were apparent in the pools from children (<12 years old). The highest mean concentrations of PFOA, PFHxS, PFNA, PFDeA, and Me-PFOSA-AcOH were found in children <15 years, while PFOS was highest in adults >60 years. Investigation into the sources and exposure pathways in Australia, in particular for children, is necessary as well as continued biomonitoring to determine the potential effects on human concentrations as a result of changes in the PFC manufacturing practices, including the cessation of production of several PFCs.
Article
Perfluorinated compounds (PFCs), a class of synthetic surfactants that are widely used, have become global environmental contaminants because of their high persistence and bioaccumulation. An increasing number of studies have described the pharmacokinetics of PFCs following in vivo exposure, however, few papers have focused on the excretion of these compounds during a period of consecutive exposure. In this study, the excretions of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) in male Sprague-Dawley rats gavaged consecutively for 28 days were investigated and compared. The faster elimination rate in urine compared to feces indicated that urinary excretion is the primary clearance route in rats for either PFOA or PFOS. During the first 24 h after administration of PFOA (5 and 20 mg/kg body weight/day), about 24.7-29.6% of the oral dose was excreted through urine and feces, while for PFOS, the excretion amounts were only 2.6-2.8% of the total gavaged doses (5 and 20 mg/kg body weight/day). The excretion rates of both PFCs increased with increasing exposure doses. The higher elimination rate of PFOA through excretion indicated its lower accumulation in rats, thus inducing possible lower toxicities compared to PFOS.
Article
The toxicokinetics of perfluorohexanoic acid (PFHxA) and nonafluoro-1-butanesulfonic acid (PFBS) were evaluated in Sprague-Dawley rats and cynomolgus monkeys. Systemic exposure to PFHxA was lower than for PFBS following single equivalent intravenous or oral (rat only) doses. Serum clearance was more rapid for PFHxA than for PFBS. In rats, exposure to PFHxA and PFBS was up to 8-fold (intravenous) and 4-fold (oral) higher for males than females and serum clearance of PFHxA and PFBS was more rapid in females than males; however, there was no appreciable difference in the extent or rate of urinary elimination between compounds or genders. There were no apparent differences between genders in the serum half-life for PFHxA following 26 days of repeated oral dosing in rats; exposure decreased upon repeated dosing.
Article
Possible toxic effects of perfluorohexanoic acid (PFHxA) were evaluated when administered orally by gavage to rats at levels up to 200mg/kg/day for 90 days. Lower body weight gains were noted in the 10, 50 and 200mg/kg/day group males (not dose-responsive) throughout dosing. Other changes included lower red blood cell parameters, higher reticulocyte counts and lower globulin in the 200mg/kg/day group males and females, higher liver enzymes in males at 50 and 200mg/kg/day, lower total protein and higher albumin/globulin ratio, and lower cholesterol, calcium in males at 200mg/kg/day. Minimal centrilobular hepatocellular hypertrophy was present in 200mg/kg/day group males and correlated with higher liver weights and slightly higher peroxisome beta oxidation activity at the end of the dosing period. Based on liver histopathology and liver weight changes, the no-observed-adverse-effect level (NOAEL) for oral administration was 50mg/kg/day for males and 200mg/kg/day for females.
Article
Materials derived from perfluorobutanesulfonyl fluoride (PBSF, C(4)F(9)SO(2)F) have been introduced as replacements for eight-carbon homolog products that were manufactured from perfluorooctanesulfonyl fluoride (POSF, C(8)F(17)SO(2)F). Perfluorobutanesulfonate (PFBS, C(4)F(9)SO(3)(-)) is a surfactant and potential degradation product of PBSF-derived materials. The purpose of this series of studies was to evaluate the pharmacokinetics of PFBS in rats, monkeys, and humans, thereby providing critical information for human health risk assessment. Studies included: (1) intravenous (i.v.) elimination studies in rats and monkeys; (2) oral uptake and elimination studies in rats; and (3) human serum PFBS elimination in a group of workers with occupational exposure to potassium PFBS (K(+)PFBS). PFBS concentrations were determined in serum (all species), liver (rats), urine (all species), and feces (rats). In rats, the mean terminal serum PFBS elimination half-lives, after i.v. administration of 30mg/kg PFBS, were: males 4.51+/-2.22h (standard error) and females 3.96+/-0.21h. In monkeys, the mean terminal serum PFBS elimination half-lives, after i.v. administration of 10mg/kg PFBS, were: males 95.2+/-27.1h and females 83.2+/-41.9h. Although terminal serum half-lives in male and female rats were similar, without statistical significance, clearance (CL) was significantly greater in female rats (469+/-40mL/h) than male rats (119+/-34mL/h) with the area under the curve (AUC) significantly larger in male rats (294+/-77microg.h/mL) than female rats (65+/-5microg.h/mL). These differences were not observed in male and female monkeys. Volume of distribution estimates suggested distribution was primarily extracellular in both rats and monkeys, regardless of sex, and urine appeared to be a major route of elimination. Among 6 human subjects (5 male, 1 female) followed up to 180 days, the geometric mean serum elimination half-life for PFBS was 25.8 days (95% confidence interval 16.6-40.2). Urine was observed to be a pathway of elimination in the human. Although species-specific differences exist, these findings demonstrate that PFBS is eliminated at a greater rate from human serum than the higher chain homologs of perfluorooctanesulfonate (PFOS) and perfluorohexanesulfonate (PFHxS). Thus, compared to PFOS and PFHxS, PFBS has a much lower potential for accumulation in human serum after repeated occupational, non-occupational (e.g., consumer), or environmental exposures.
Article
Existing methods used to screen chemical inventories for hazardous substances that may pose risks to humans and the environment are evaluated with a holistic mass balance modeling approach. The model integrates persistence (P), bioaccumulation (B), toxicity (T), and quantity (Q) information for a specific substance to assess chemical exposure, hazard, and risk. P and B are combined in an exposure assessment factor (EAF), P, B, and T in a hazard assessment factor (HAF), and P, B, T, and Q in a risk assessment factor (RAF) providing single values for transparent comparisons of exposure, hazard, and risk for priority setting. This holistic approach is illustrated using 200 Canadian Domestic Substances List(DSL) chemicals and 12 United Nations listed Persistent Organic Pollutants (POPs). Priority setting results are evaluated with those of multiple category-based screening methods employed by Environment Canada and applied elsewhere that use cutoff criteria in multiple categories (P, B, and T) to identify hazardous chemicals for more comprehensive evaluations. Existing methods have categorized the DSL chemicals as either higher priority (requiring further assessment; screened in) or lower priority (requiring no further action at this time; screened out). The priority setting results of the cutoff-based categorization are largely inconsistent with the proposed integrated method, and reasons for these discrepancies are discussed. Many chemicals screened out using existing methods have equivalent or greater risk potential than chemicals screened in. Decisions for screening assessments using binary classification on the basis of cutoff criteria can be flawed, and complementary holistic methods for priority setting evaluations such as the one proposed should be considered.
Article
The elimination, tissue distribution, and metabolism of [1-14C]perfluorooctanoic acid (PFOA) was examined in male and female rats for 28 days after a single ip dose (9.4 mumol/kg, 4 mg/kg). A sex difference in urinary elimination of PFOA-derived 14C was observed. Female rats eliminated PFOA-derived radioactivity rapidly in the urine with 91% of the dose being excreted in the first 24 hr. In the same period, male rats eliminated only 6% of the administered 14C in the urine. The sex-related difference in urinary elimination resulted in the observed difference in the whole-body elimination half-life (t1/2) of PFOA in males (t1/2 = 15 days) and females (t1/2 less than 1 day). Analysis of PFOA-derived 14C in tissues showed that the liver and plasma of male rats and the liver, plasma, and kidney of female rats were the primary tissues of distribution. The relatively high concentration of PFOA in the male liver was further examined using an in situ nonrecirculating liver perfusion technique. It was shown that 11% of the PFOA infused was extracted by the liver in a single pass. The ability of the liver to eliminate PFOA into bile was examined in rats whose renal pedicles were ligated to alleviate sex differences in the urinary excretion of PFOA. In a 6-hr period following IP administration of PFOA, there was no apparent difference in biliary excretion, where both males and females eliminated less than 1% of the PFOA dose via this route. We hypothesized that the sex difference in the persistence of PFOA was due to a more rapid formation of a PFOA-containing lipid (i.e., a PFOA-containing mono-, di-, or triacylglycerol, cholesteryl ester, methyl ester, or phospholipid) in the male rat. Also, the increased urinary elimination of PFOA in females may have been due to increased metabolism to a PFOA-glucuronide or sulfate ester. However, no evidence that PFOA is conjugated to form a persistent hybrid lipid was obtained, nor were polar metabolites of PFOA in urine or bile detected. In addition, daily urinary excretion of fluoride in male and female rats before or after PFOA treatment were similar, suggesting that the parent compound is not defluorinated. Thus, the more rapid elimination of PFOA from female rats is not due to formation of a PFOA metabolite.
Article
The acute toxicities of single ip injections of perfluorooctanoic (PFOA) and perfluorodecanoic (NDFDA) acids were evaluated in male Fischer rats. The LD50/30 day for PFOA was 189 (208-175) mg/kg and for NDFDA was 41 (47-34) mg/kg. All rats treated with lethal doses of PFOA died within the first 5 days; with NDFDA there was delayed lethality, with deaths in the second and third weeks after dosing. Four groups of rats were used for a more detailed study of toxicity and for analysis of fatty acids from liver, testes, and whole blood. One group received a single dose of 100 mg PFOA/kg; a second, a single dose of 2 ml of propylene glycol-water (1:1)/kg (vehicle control); a third, a single dose of 50 mg NDFDA/kg; the fourth was given 2 ml vehicle/kg and pair-fed with the NDFDA group. The first three groups were fed ad libitum. Rats from each group were killed at 2, 4, 8, and 16 days after dosing for fatty acid analysis. Rats dosed with NDFDA lost half their body weight in 16 days and ate virtually no food from Day 7 to Day 14 after dosing. Weight loss was less rapid in pair-fed controls. With PFOA there were transient decreases in food intake and body weight which were reversed by Day 7. Liver weights of PFOA rats were slightly greater than those from vehicle controls. With NDFDA, liver weights were much greater than those from pair-fed controls. In the livers of PFOA rats there were transient increases in oleic and palmitic acids and a decrease in stearic and docosahexaenoic acids. These changes were maximum by Day 2 and nearly resolved by Day 8. With NDFDA, similar changes were observed and arachidonic acid was also greatly decreased. These changes were quantitatively much larger and more persistent. NDFDA has unusually high toxic potency for a perfluorinated hydrocarbon, and some of the toxic effects caused by this acid are remarkably similar to those seen with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The acute toxicity of NDFDA may be due to an ability to interfere with fatty acid metabolism, and studies of its toxicity may be valuable in helping to understand mechanisms of action of TCDD.
Article
Drug exposure in toxicology studies is dependent on input from the drug delivery system and elimination of the drug once absorbed. Although seemingly straightforward, absorption, metabolism, and other factors require a more complex interpretation of plasma concentrations and the resulting area under the plasma concentration versus time curve values at doses free from significant toxicity. Absorption may be saturable due to the intestinal, physiologic processes necessary for drug transfer, or intrinsic drug solubility limits may lead to a plateau in systemic plasma concentrations. Different vehicles or administration of drug with food or in the diet may be investigated