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Background: Exposures to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), environmentally persistent chemicals detectable in the blood of most Americans, have been associated with several health outcomes. To offer insight into their possible biologic effects, we evaluated the metabolomic correlates of circulating PFOS and PFOA among 3,647 participants in eight nested case-control serum metabolomic profiling studies from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial., Methods: Metabolomic profiling was conducted by Metabolon Inc., using ultra high-performance liquid chromatography/tandem accurate mass spectrometry. We conducted study-specific multivariable linear regression analyses estimating the associations of metabolite levels with levels of PFOS or PFOA. For metabolites measured in at least 3 of 8 nested case-control studies, random effects meta-analysis was used to summarize study-specific results (1,038 metabolites in PFOS analyses and 1,100 in PFOA analyses)., Results: The meta-analysis identified 51 and 38 metabolites associated with PFOS and PFOA, respectively, at a Bonferroni-corrected significance level (4.8x10 -5 and 4.6x10 -5 , respectively). For both PFOS and PFOA, the most common types of associated metabolites were lipids (sphingolipids, fatty acid metabolites) and xenobiotics (xanthine metabolites, chemicals). Positive associations were commonly observed with lipid metabolites sphingomyelin (d18:1/18:0) (P = 2.0x10 -10 and 2.0x10 -8 , respectively), 3-carboxy-4-methyl-5-pentyl-2-furanpropionate (P = 2.7x10 -15 , 1.1x10 -17 ), and lignoceroylcarnitine (C24) (P = 2.6x10 -8 , 6.2x10 -6 ). The strongest positive associations were observed for chemicals 3,5-dichloro-2,6-dihydroxybenzoic acid (P = 3.0x10 -112 and 6.8x10 -13 , respectively) and 3-bromo-5-chloro-2,6-dihydroxybenzoic acid (P = 1.6x10 -14 , 2.3x10 -6 ). Other metabolites positively associated with PFOS included D-glucose (carbohydrate), carotene diol (vitamin A metabolism), and L-alpha-aminobutyric acid (glutathione metabolism), while uric acid (purine metabolite) was positively associated with PFOA. PFOS associations were consistent even after adjusting for PFOA as a covariate, while PFOA associations were greatly attenuated with PFOS adjustment., Conclusions: In this large metabolomic study, we observed robust positive associations with PFOS for several molecules. Further investigation of these metabolites may offer insight into PFOS-related biologic effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Aminosilane materials, with their low cost and ease of modification, have exhibited great potential for the adsorption of perfluorinated compounds (PFCs) from water. However, this kind of material may be facing two drawbacks during its application: low resistance to hydrolysis and difficulties in separation from the water matrix. This work proposed a strategy of grafting N-(2-aminoethyl) aminopropyltrimethoxysilane (AE-APTMS) on the surface of magnetic γ-Fe 2 O 3 nanoparticles by full utilization of the sorption sites provided by the aminosilane and the magnetism by γ-Fe 2 O 3 . The FTIR and XRD results verified the formation of the magnetic AE-APTMS nanocomposite. The core-shell nanocomposite showed a superparamagnetic property and an isoelectric point at pH = 8.2. Particularly, compared to the aminopropyltriethoxysilane (APTES) nanocomposite, the AE-APTMS nanocomposite exhibited improved hydrolytic stability with 60% less loss of the amine groups during the 48 h adsorption process, as the longer alkyl chain hindered the aminosilane detachment. The AE-APTMS nanocomposite exhibited a rapid adsorption with the removal efficiency of 78% for perfluorooctane sulfonate (PFOS) and 65% for perfluorooctanoate (PFOA) due to the electrostatic interaction and hydrophobic interaction. The regeneration and reuse of the magnetic AE-APTMS nanocomposite were conveniently realized with the removal efficiency higher than 70% for both PFOS and PFOA even after 15 adsorption-desorption cycles. The stable magnetic aminosilane nanocomposite with the ease of separation may provide a new strategy to achieve the economical and effective removal of typical PFCs from water., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Among many short-term, subchronic, and chronic toxicology studies with ammonium perfluorooctanoate (PFOA), the gastrointestinal tract has not been identified as a target organ for PFOA-related toxicity in laboratory animals where the corresponding serum PFOA concentrations typically approach several orders of magnitude higher than the general human population. These lack of gastrointestinal tract-related findings were in direct contrast to an epidemiological observation where a positive trend was observed for ulcerative colitis, an idiopathic chronic inflammatory condition of the gut, in a Mid-Ohio River community whose drinking water contained higher levels of PFOA. This study was conducted to perform a histological reevaluation of large intestine sections in laboratory animals from 2 long-term toxicological studies: one was with Sprague Dawley rats that received ammonium PFOA in their diet for 2 years and the other one was with cynomolgus macaques that received daily capsules of ammonium PFOA for 6 months. In both studies, there was a lack of histological evidence of treatment-related inflammatory lesions that was suggestive of the occurrence of ulcerative colitis in these laboratory animals even under the most rigorous treatment schedules. These findings do not offer support for the biological plausibility of the epidemiological associations reported.

Background: Perfluorooctanoate (PFOA) has been used extensively in the manufacture of both commercial and household products. PFOA serum concentrations have been associated with adverse health effects, including lower body mass in children and infants., Objective: To determine if there is an association between serum PFOA concentration and body mass, serum insulin and lipid profile in exposed young girls., Methods: We conducted a cross-sectional study of PFAS environmental biomarkers and insulin resistance in 6 to 8 year-old girls from Greater Cincinnati (n=353). In 2004-2006, blood samples were obtained to measure polyfluoroalkyl substances (PFAS), fasting insulin, glucose and lipids. Clinical exams included anthropometric measurements and pubertal maturation staging. Linear regression and mediation analyses, specifically structural equation modeling (SEM), were used to determine the strength and direction of the relationships between PFAS, pubertal maturation status, body mass index (BMI), cholesterol and insulin resistance., Results: The median PFOA (7.7ng/ml) was twice the National Health and Nutrition Examination Survey (2005-2006). Only PFOA, a PFAS sub-species, showed statistically significant relationships with the outcomes. In regression models, PFOA was associated with decreased BMI and waist-to-height ratio (p=0.0008; p=0.0343), HDL-cholesterol (p=0.0046) and had a borderline inverse association with the HOMA Index of insulin resistance (p=0.0864). In SEM, PFOA retained an inverse relationship with BMI (p<0.0001) but the relationships with HOMA and HDL-cholesterol were no longer statistically significant. Pubertal initiation (Tanner breast or pubic stage 2 or greater) and BMI were associated with increased HOMA Index (p<0.0001)., Conclusions: These findings suggest PFOA exposure in young girls affects both BMI and ultimately insulin resistance. In mediation analysis with puberty in the model, the direct effects of PFOA on insulin resistance and were reduced., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Exposure to perfluoroalkyl substances (PFAS) is associated with a range of adverse health effects. However, it remains unclear whether PFAS at environmentally relevant exposure levels are related to diabetes and metabolite concentrations in adults. Using cross-sectional data from 7904 adults (age≥20years) in the 2003-2012 National Health and Nutrition Examination Survey (NHANES), we examined the association of PFAS with the prevalence of diabetes and metabolite concentrations. A multivariate logistic regression was applied to investigate the associations of diabetes prevalence with serum perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorononanoate (PFNA) levels. A multivariate generalised linear regression was further performed to investigate the associations between PFAS exposure and some metabolites. We identified a strong positive association between serum PFOA and diabetes prevalence in men with an adjusted model (OR: 2.66, 95% CI: 1.63-4.35; P for trend=0.001). No significant association between serum PFOA and diabetes prevalence was observed in women (OR: 1.47, 95% CI: 0.88-2.46; P for trend=0.737). Furthermore, diabetes was not related to PFOS, PFHxS and PFNA, regardless of gender. In the gender-stratified generalised linear models, men and women with the highest PFOA levels demonstrated a 1.43% (95% CI: 0.62%-2.34%) and a 1.07% (95% CI: 0.27%-1.97%) greater increase in serum total cholesterol (P for trend=0.006 and 0.001) compared to those with the lowest PFOA levels. There were no significant associations between serum PFOA and other metabolites. These results provide epidemiological evidence that environment-related levels of serum PFOA may be positively associated with the prevalence of diabetes in men and with total cholesterol in adults. Further clinical and animal studies are urgently needed to elucidate putative causal relationships and shed light on the potential mode of action involved., (Copyright © 2017. Published by Elsevier B.V.)

Understanding sorption of PFOA on soil particles is crucial to evaluate its environmental risk. Here, sorption of PFOA onto ten agricultural soils was examined. The influence of soil physico-chemical properties on PFOA sorption was investigated. The sorption rate of PFOA followed a pseudo-second-order kinetics. Isotherm data of PFOA sorption was fitted with both Freundlich and linear models and the latter fitted better. The sorption-desorption of PFOA onto ten soil samples depended on soil organic carbon content and composition of soil minerals. The sorption and desorption isotherms of PFOA on ten soils were linear, except for the sorption of PFOA onto a few soils, which was described by the Freundlich equation with the parameter N >1. The main sorption mechanism of PFOA was hydrophobic interaction between the perfluorinated carbon chain and the organic matter of soil, as evidenced by the correlation between the solid-liquid distribution coefficient and the fraction of soil organic carbon. The sorption of PFOA in soils was highly irreversible., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Many epidemiology studies have investigated associations of perfluorooctanoate (PFOA) exposures with a variety of adverse health outcomes for participants in the C8 Health Project. The exposure concentrations (i.e., air and groundwater) used in these studies were determined primarily based on participant's residential locations. However, for residential addresses that could not be geocoded to the street level, the exposure concentrations were assigned based on population-weighted ZIP code centroid, which may result in exposure mischaracterization. The aim of this current study is to evaluate the potential impact of mischaracterized exposure concentrations due to geocoding uncertainty on the predicted serum PFOA concentrations and the epidemiological association between PFOA exposure and preeclampsia. For both workplace addresses and incompletely geocoded residential addresses, we used Monte Carlo (MC) simulation to assign alternate geographic locations within the reported ZIP code (instead of population-weighted ZIP code centroids) and the corresponding exposure concentrations. We found that mischaracterization of residential exposure due to population-weighted ZIP code centroid assignment had no significant impact on the serum PFOA concentration predictions and the epidemiological association of PFOA exposure with preeclampsia. In contrast, the uncertainty in workplace exposure moderately impacted the rank exposure among the participants. We observed a 41% increase in the average adjusted odds ratio of preeclampsia occurrence that may be due to differing proportions of cases (64.3%) and controls (54.5%) with workplace address geocodes during pregnancy. This finding suggests that differential exposure mischaracterization can be reduced by obtaining accurate exposure information such as street addresses and tap water consumption, for both workplaces and residences. The analysis we present is one approach for estimating the potential impacts of positional errors in a geocoding-based exposure assessment on exposure estimates and epidemiological study results., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The consumption of lactic acid bacteria capable of binding or degrading food-borne carcinogens may reduce human exposure to these deleterious compounds. In this study, 25 Lactobacillus strains isolated from human, plant, or dairy environments were investigated for their potential probiotic capacity against perfluorooctanoate (PFOA) toxicity. The PFOA binding, tolerance ability, and acid and bile salt tolerance were investigated and assessed by principal component analysis. Additionally, the effect of different pH levels and binding times was assessed. These strains exhibited different degrees of PFOA binding; the strain with the highest PFOA binding capability was Lactobacillus plantarum CCFM738, which bound to 49.40 ± 1.5 % of available PFOA. This strain also exhibited relatively good cellular antioxidative properties, acid and bile salt tolerance, and adhesion to Caco-2 cells. This study suggests that L. plantarum CCFM738 could be used as a potential probiotic in food applications against PFOA toxicity.

We recently utilized a suite of environmental fate and transport models and an integrated exposure and pharmacokinetic model to estimate individual perfluorooctanoate (PFOA) serum concentrations, and also assessed the association of those concentrations with preeclampsia for participants in the C8 Health Project (a cross-sectional study of over 69,000 people who were environmentally exposed to PFOA near a major U.S. fluoropolymer production facility located in West Virginia). However, the exposure estimates from this integrated model relied on default values for key independent exposure parameters including water ingestion rates, the serum PFOA half-life, and the volume of distribution for PFOA. The aim of the present study is to assess the impact of inter-individual variability and epistemic uncertainty in these parameters on the exposure estimates and subsequently, the epidemiological association between PFOA exposure and preeclampsia. We used Monte Carlo simulation to propagate inter-individual variability/epistemic uncertainty in the exposure assessment and reanalyzed the epidemiological association. Inter-individual variability in these parameters mildly impacted the serum PFOA concentration predictions (the lowest mean rank correlation between the estimated serum concentrations in our study and the original predicted serum concentrations was 0.95) and there was a negligible impact on the epidemiological association with preeclampsia (no change in the mean adjusted odds ratio (AOR) and the contribution of exposure uncertainty to the total uncertainty including sampling variability was 7%). However, when epistemic uncertainty was added along with the inter-individual variability, serum PFOA concentration predictions and their association with preeclampsia were moderately impacted (the mean AOR of preeclampsia occurrence was reduced from 1.12 to 1.09, and the contribution of exposure uncertainty to the total uncertainty was increased up to 33%). In conclusion, our study shows that the change of the rank exposure among the study participants due to variability and epistemic uncertainty in the independent exposure parameters was large enough to cause a 25% bias towards the null. This suggests that the true AOR of the association between PFOA and preeclampsia in this population might be higher than the originally reported AOR and has more uncertainty than indicated by the originally reported confidence interval., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Previous studies on the exposure to perfluoroalkyl acids (PFAAs) and female fertility have provided conflicting results. We aimed to investigate the association between several PFAAs and time to pregnancy among nulliparous women., Methods: From 2008 to 2013, we included 1372 women from the Aarhus Birth Cohort, Aarhus University Hospital, Denmark, who provided data on time to pregnancy and a blood sample before 20 gestational weeks. We measured the levels of 16 PFAAs in maternal serum and report data for seven compounds with quantifiable values in at least 50% of samples. Fecundability ratios according to PFAA levels (quartiles or continuous levels) were estimated by discrete-time survival analyses, adjusted for potential confounders. We further investigated the association between PFAAs and infertility (time to pregnancy>12 months or infertility treatment prior to the studied pregnancy) by multivariable logistic regression., Results: Median levels of perfluorooctane sulfonate and perfluorooctanoate were 8.3 and 2.0 ng/mL. Overall, no obvious associations were found between any PFAAs and fecundability or infertility. Adjusted fecundability ratios (95% confidence intervals) were 1.09 (0.92-1.29) for perfluorooctane sulfonate and 1.10 (0.93-1.30) for perfluorooctanoate (highest versus lowest quartile)., Conclusions: We found no evidence of an association between present serum levels of PFAAs and longer time to pregnancy or infertility in nulliparous women. This study further adds to the sparse knowledge on PFAAs besides perfluorooctane sulfonate and perfluorooctanoate., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The distribution and fate of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) were investigated in the water and sediment of Bohai Bay, China, during 2011-2013. A total of 360 water samples and 60 sediment samples were collected from 20 locations. The median concentrations of PFOS and PFOA were 4.8 and 12.15 ng/L in the water, and 2.65 and 0.62 ng/g-dry in the sediment, respectively. Significant enrichment were observed for PFOS and PFOA in water of sea surface microlayer. The concentrations of these two compounds showed an apparent gradient from nearshore to offshore stations. The correlation analysis and the distribution tendencies indicated that freshwater inflowing to the bay was the main source of PFOS and PFOA. The salinity of seawater and the total organic carbon (TOC) content of sediment heavily affected the spatial distribution and the partitioning of PFOS and PFOA in the sediment-water system., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

While selected perfluoroalkyl acids/substances (PFAAs) like perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) have been detected and measured in laboratory, a method to estimate the total concentration of PFAAs (∑PFAA) in serum has not been developed. Because of the health concerns associated with PFAAs and because of the inability of every laboratory to measure every PFAA as well as because of the non-availability of sensitive enough equipment to be able to detect very small amounts of certain PFAAs, it is of interest to know ∑PFAA. We used data from the National Health and Nutrition Examination Survey for the years 2005-2012 to develop regression models to estimate ∑PFAA by using the levels of PFOA and PFOS only. While data for 2005-2008 were used to develop regression models, data for 2009-2012 were used to evaluate the accuracy of the developed models. Over 63% of observed values for evaluation data were found to be within 10% of the predicted values. The model so developed can be used with just the knowledge of the age, gender, and concentrations of PFOA and PFOS. While the data used to develop the model were generated in U.S., the model can be used to estimate ∑PFAA for data collected in North America and Europe and probably elsewhere in the world., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

High-dose exposure of mice to perfluorooctanoate (PFOA) induces both hepatotoxicity and immunotoxicity. Here, we characterized the effects of 10-day dietary treatment with PFOA (0.002-0.02%, w/w) on the liver and complement system of male C57BL/6 mice. At all four doses, this compound caused hepatomegaly and reduced the serum level of triglycerides (an indicator for activation of the peroxisome proliferator-activated receptor-alpha (PPARα)). At the highest dose (0.02%, w/w), this hepatomegaly was associated with the hepatic injury, as reflected in increased activity of alanine aminotranferase (ALAT) in the serum, severe hepatocyte hypertrophy and hepatocellular necrosis. PFOA-induced hepatic injury was associated with in vivo activation of the complement system as indicated by (i) significant attenuation of the serum activities of both the classical and alternative pathways; (ii) a marked reduction in the serum level of the complement factor C3; and (iii) deposition of the complement factor C3 fragment (C3a) in the hepatic parenchyma. PFOA did not activate the alternative pathway of complement in vitro. At doses lower than 0.02%, PFOA induced hepatocyte hypertrophy without causing liver injury or activating complement. These results reveal substantial involvement of activation of complement in the pathogenesis of PFOA-induced hepatotoxicity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are persistent organic pollutants in the environment and their occurrence causes toxicological effects on humans. We examined different conventional coagulant treatments such as alum, ferric chloride and polyaluminium chloride in removing these compounds. These were then compared with a natural coagulant (Moringa oleifera). We also investigated the powdered-activated carbon (PAC) and granular-activated carbon (GAC) for removing these compounds. At an initial dose of 5 mg/L, polyaluminium chloride led to a higher reduction of PFOS/PFOA compared with alum which in turn was higher than ferric. The removal efficiency increased with the increase in coagulant dose and decrease in pH. M. oleifera was very effective in reducing PFOS and PFOA than conventional coagulants, with a reduction efficiencies of 65% and 72%, respectively, at a dose of 30 mg/L. Both PAC and GAC were very effective in reducing these compounds than coagulations. PAC led to a higher reduction in PFOS and PFOA than GAC due to its greater surface area and shorter internal diffusion distances. The addition of PAC (10 min contact time) with coagulation (at 5 mg/L dosage) significantly increased the removal efficiency, and the maximum removal efficiency was for M. oleifera with 98% and 94% for PFOS and PFOA, respectively. The reduction efficiency of PFOS/PFOA was reduced with the increase in dissolved organic concentration due to the adsorption competition between organic molecules and PFOS/PFOA.

Background: Exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) is ubiquitous in most regions of the world. The most commonly studied PFASs are perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). Animal studies indicate that maternal PFAS exposure is associated with reduced fetal growth. However, the results of human studies are inconsistent., Objectives: To summarize the evidence of an association between exposure to PFASs, particularly PFOS and PFOA, and human fetal growth., Methods: Systematic literature searches were performed in MEDLINE and EMBASE. We included original studies on pregnant women with measurements of PFOA or PFOS in maternal blood during pregnancy or the umbilical cord and associations with birth weight or related outcomes according to the PFAS level. Citations and references from the included articles were investigated to locate more relevant articles. Study characteristics and results were extracted to structured tables. The completeness of reporting as well as the risk of bias and confounding were assessed., Results: Fourteen studies were eligible. In utero PFOA exposure was associated with decreased measures of continuous birth weight in all studies, even though the magnitude of the association differed and many results were statistically insignificant. PFOS exposure and birth weight were associated in some studies, while others found no association., Conclusions: Higher PFOS and PFOA concentrations were associated with decreased average birth weight in most studies, but only some results were statistically significant. The impact on public health is unclear, but the global exposure to PFASs warrants further investigation.

Previous studies suggested that perfluorooctanoate (PFOA) could activate the estrogen receptor (ER). The present study examined the hypothesis that PFOA can activate ER using an in vivo uterotrophic assay in CD-1 mice and an in vitro reporter assay. Pre-pubertal female CD-1 mice fed an estrogen-free diet from postnatal day (PND)14 through weaning on PND18 were administered 0, 0.005, 0.01, 0.02, 0.05, 0.1, or 1mg/kg PFOA or 17β-estradiol (E2, 0.5mg/kg) from PND18-20. In contrast to E2, PFOA caused no changes in the relative uterine weight, the expression of ER target genes, or the morphology of the uterus/cervix and/or vagina on PND21. Treatment of a stable human cell line containing an ER-dependent luciferase reporter construct with a broad concentration range of PFOA caused no change in ER-dependent luciferase activity; whereas E2 caused a marked increase of ER-dependent luciferase activity. These data indicate that PFOA does not activate mouse or human ER., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Rainbow trout (Oncorhynchus mykiss) confined to respirometer-metabolism chambers were dosed with perfluorooctanoate (PFOA) by intra-arterial (i.a.) injection and sampled to obtain concentration time-course data for plasma, urine, and expired water. The data were then analyzed by compartmental modeling to estimate rates of renal and branchial clearance. Averaged across all animals, the renal clearance rate (1.35mL/h/kg) was more than ten times greater than the branchial clearance rate (0.12mL/h/kg). The average whole-body elimination half-life was 12.6d, which is somewhat longer than values obtained in previous studies with smaller trout. The tissue distribution of PFOA was assessed by collecting tissues at the end of chambered exposures and in a separate tissue time-course experiment. From the time-course study it appeared that an internal steady-state was established within 24h of i.a. injection. Consistent with previous studies, the rank order of PFOA concentration in tissues at steady state was: plasma>liver>kidney>muscle. In a second set of chambered experiments, fish were exposed to PFOA in water to determine the rate of branchial uptake. Branchial uptake rates were too low to assess directly by measuring PFOA concentrations in inspired and expired water. Uptake rate constants (mean 0.19L/d/kg; 0.1% uptake efficiency) were therefore estimated by compartmental modeling using plasma concentration time-course data and model parameters derived from the elimination experiments. It is clear from this effort that elimination of PFOA by trout occurs primarily via the renal route. This finding is consistent with numerous studies of mammals and suggests that trout possess membrane transporters that facilitate the movement of PFOA from plasma to urine., (Published by Elsevier B.V.)

We examined whether perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS) had obesogenic effects and if they increased spontaneous intestinal tumorigenesis in the mouse model C57BL/6J-Min/+ (multiple intestinal neoplasia) after in utero exposure. The dams were exposed to PFOA or PFOS (0.01, 0.1 or 3.0mg/kg bw/day) by po gavage on GD1-17. The Min/+ and wild-type offspring were terminated at week 11 for examination of intestinal tumorigenesis or at week 20 for obesogenic effect, respectively. Body weights of the dams and pups were recorded throughout life. Food intake was determined at week 6 and 10. Blood glucose (non-fasted) was measured at week 6 and 11. No obesogenic effect of PFOA or PFOS was observed up to 20 weeks of age. PFOA or PFOS did not increase the incidence or number of tumors in the small intestine or colon of the Min/+ mice or affect their location along the intestines. Feed intake was not affected. There were some indications of toxicity of PFOA, but not of PFOS. There was lower survival of pups after 3.0mg/kg PFOA, lower body weight in pups after 3.0 and possibly 0.1mg/kg PFOA, and increased relative liver weight after 0.01 and possibly 0.1mg/kg PFOA. Plasma glucose was lower after 0.01 and 0.1mg/kg PFOA. In conclusion, exposure to PFOA and PFOS in utero with the doses used did not have obesogenic effect on either Min/+ or wild-type mice, at least not up to 11 or 20 weeks of age, nor increased intestinal tumorigenesis in Min/+ mice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Supported by several epidemiological studies and a large number of animal studies, certain polyfluorinated alkyl acids are believed to be immunotoxic, affecting particularly humoral immunity. Our aim was to investigate the relationship between the antibody response following vaccination with an inactivated trivalent influenza vaccine and circulating levels of perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS). The study population consisted of 411 adults living in the mid-Ohio region of Ohio and West Virginia where public drinking water had been inadvertently contaminated with PFOA. They participated in a larger cross-sectional study in 2005/2006 and were followed up in 2010, by which time serum levels of PFOA had been substantially reduced but were still well above those found in the general population. Hemagglutination inhibition tests were conducted on serum samples collected preinfluenza vaccination and 21 ± 3 days postvaccination in 2010. Serum samples were also analyzed for PFOA and PFOS concentrations (median: 31.5 and 9.2 ng/ml, respectively). Questionnaires were conducted regarding the occurrence and frequency of recent (during the last 12 months) respiratory infections. Our findings indicated that elevated PFOA serum concentrations are associated with reduced antibody titer rise, particularly to A/H3N2 influenza virus, and an increased risk of not attaining the antibody threshold considered to offer long-term protection. Although the direct relationship between weakened antibody response and clinical risk of influenza is not clear, we did not find evidence for an association between self-reported colds or influenza and PFOA levels nor between PFOS serum concentrations and any of the endpoints examined.

Perfluoroalkyl carboxylic acids (PFCAs) including perfluorooctanoic acid (PFOA) have been widely recognized as persistent environmental contaminants. For accurate quantification of PFCAs, their stability in calibration solutions is important because they are criteria of quantification. To examine stability of PFCAs in methanol, we monitored PFOA and its related compounds around 4 years. Interestingly, perfluorooctanoate was varied randomly, and methyl perfluorooctanoate (MePFOA) and methyl formate were observed when perfluorooctanoate decreased. Moreover, no detection of both methyl esters was in methanol solutions immediately after preparation. In each of prepared methanol solution of perfluorohexanoic, perfluoroheptanoic, and perfluorononanoic acids, their corresponding methyl esters and methyl formate were observed. Furthermore, MePFOA was observed even in the solutions stored around 4 months and thereafter MePFOA increased with increase in methyl formate. Therefore, PFCAs including PFOA should be used immediately after preparation when methanol is used as a solvent., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In order to compare between in vivo toxicity studies, dosimetry is needed to translate study-specific dose regimens into dose metrics such as tissue concentration. These tissue concentrations may then be compared with in vitro bioactivity assays to perhaps identify mechanisms relevant to the lowest observed effect level (LOEL) dose group and the onset of the observed in vivo toxicity. Here, we examine the perfluorinated compounds (PFCs) perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS). We analyzed 9 in vivo toxicity studies for PFOA and 13 in vivo toxicity studies for PFOS. Both PFCs caused multiple effects in various test species, strains, and genders. We used a Bayesian pharmacokinetic (PK) modeling framework to incorporate data from 6 PFOA PK studies and 2 PFOS PK studies (conducted in 3 species) to predict dose metrics for the in vivo LOELs and no observed effect levels (NOELs). We estimated PK parameters for 11 combinations of chemical, species, strain, and gender. Despite divergent study designs and species-specific PK, for a given effect, we found that the predicted dose metrics corresponding to the LOELs (and NOELs where available) occur at similar concentrations. In vitro assay results for PFOA and PFOS from EPA's ToxCast project were then examined. We found that most in vitro bioactivity occurs at concentrations lower than the predicted concentrations for the in vivo LOELs and higher than the predicted concentrations for the in vivo NOELs (where available), for a variety of nonimmunological effects. These results indicate that given sufficient PK data, the in vivo LOELs dose regimens, but not necessarily the effects, could have been predicted from in vitro studies for these 2 PFCs.

Fetal exposure to the perfluoroalkyl acids, perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA), has been associated with lower birth weight and lower weight and body mass index (weight (kg)/height (m)(2)) in early infancy. It is, however, unclear if exposure to prenatal PFOS and PFOA has a lasting influence on growth. We estimated the associations between the maternal plasma level of PFOS or PFOA and the children's body mass index, waist circumference, and risk of overweight at 7 years of age. A total of 1,400 women were randomly selected from the Danish National Birth Cohort among those who provided blood samples early in pregnancy and gave birth to liveborn singletons in 1996-2002. Weight and height information at 7 years was available for 811 children. Multiple linear and logistic regression models were used for analyses. Maternal PFOS and PFOA concentrations were overall inversely but nonsignificantly associated with the children's body mass index, waist circumference, and risk of overweight at 7 years of age. In conclusion, plasma levels of PFOS and PFOA in pregnant women did not seem to have any appreciable influence on their children's anthropometry at this point in childhood.

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are two emerging contaminants that have been detected in all environmental compartments. However, while most of the studies in the literature deal with their presence or removal in wastewater treatment, few of them are devoted to their detection in treated drinking water and fate during drinking water treatment. In this study, analyses of PFOS and PFOA have been carried out in river water samples and in the different stages of a drinking water treatment plant (DWTP) which has recently improved its conventional treatment process by adding ultrafiltration and reverse osmosis in a parallel treatment line. Conventional and advanced treatments have been studied in several pilot plants and in the DWTP, which offers the opportunity to compare both treatments operating simultaneously. From the results obtained, neither preoxidation, sand filtration, nor ozonation, removed both perfluorinated compounds. As advanced treatments, reverse osmosis has proved more effective than reverse electrodialysis to remove PFOA and PFOS in the different configurations of pilot plants assayed. Granular activated carbon with an average elimination efficiency of 64±11% and 45±19% for PFOS and PFOA, respectively and especially reverse osmosis, which was able to remove ≥99% of both compounds, were the sole effective treatment steps. Trace levels of PFOS (3.0-21 ng/L) and PFOA (<4.2-5.5 ng/L) detected in treated drinking water were significantly lowered in comparison to those measured in precedent years. These concentrations represent overall removal efficiencies of 89±22% for PFOA and 86±7% for PFOS., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Perfluoroalkanoates, [e.g., perfluorooctanoate (PFOA)], are known peroxisome proliferators that induce hepatomegaly and hepatocarcinogenesis in rodents, and are classic non-genotoxic carcinogens that inhibit in vitro gap-junctional intercellular communication (GJIC). This inhibition of GJIC is known to be a function of perfluorinated carbon lengths ranging from 7 to 10., Objectives: The aim of this study was to determine if the inhibition of GJIC by PFOA but not perfluoropentanoate (PFPeA) observed in F344 rat liver cells in vitro also occurs in F344 rats in vivo and to determine mechanisms of PFOA dysregulation of GJIC using in vitro assay systems., Methods: We used an incision load/dye transfer technique to assess GJIC in livers of rats exposed to PFOA and PFPeA. We used in vitro assays with inhibitors of cell signaling enzymes and antioxidants known to regulate GJIC to identify which enzymes regulated PFOA-induced inhibition of GJIC., Results: PFOA inhibited GJIC and induced hepatomegaly in rat livers, whereas PFPeA had no effect on either end point. Serum biochemistry of liver enzymes indicated no cytotoxic response to these compounds. In vitro analysis of mitogen-activated protein kinase (MAPK) indicated that PFOA, but not PFPeA, can activate the extracellular receptor kinase (ERK). Inhibition of GJIC, in vitro, by PFOA depended on the activation of both ERK and phosphatidylcholine-specific phospholipase C (PC-PLC) in the dysregulation of GJIC in an oxidative-dependent mechanism., Conclusions: The in vitro analysis of GJIC, an epigenetic marker of tumor promoters, can also predict the in vivo activity of PFOA, which dysregulated GJIC via ERK and PC-PLC.

Background: Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are man-made, ubiquitous, and persistent contaminants in the environment, wildlife, and humans. Although recent studies have shown that these chemicals interfere with fetal growth in humans, the results are inconsistent., Objectives: Our goal was to investigate the correlation between relatively low levels of PFOS and PFOA in maternal serum and birth weight and birth size., Methods: We conducted a hospital-based prospective cohort study between July 2002 and October 2005 in Sapporo, Japan. A total of 428 women and their infants were involved in the study. We obtained characteristics of the mothers and infants from self-administered questionnaire surveys and from medical records. We analyzed maternal serum samples for PFOS and PFOA by liquid chromatography-tandem mass spectrometry (LC/MS/MS)., Results: After adjusting for confounding factors, PFOS levels negatively correlated with birth weight [per log10 unit: beta = -148.8 g; 95% confidence interval (CI), -297.0 to -0.5 g]. In addition, analyses stratified by sex revealed that PFOS levels negatively correlated with birth weight only in female infants (per log10 unit: beta = -269.4 g; 95% CI, -465.7 to -73.0 g). However, we observed no correlation between PFOA levels and birth weight., Conclusion: Our results indicate that in utero exposure to relatively low levels of PFOS was negatively correlated with birth weight.

Background: Recent studies have reported developmental toxicity among rodents dosed with perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA)., Objectives: We examined the relationship between concentrations of PFOS and PFOA in cord serum (surrogates for in utero exposures) and gestational age, birth weight, and birth size in humans., Methods: We conducted a hospital-based cross-sectional epidemiologic study of singleton deliveries in Baltimore, Maryland. Cord serum samples (n = 293) were analyzed for PFOS and PFOA by online solid-phase extraction, coupled with reversed-phase high-performance liquid chromatography-isotope dilution tandem mass spectrometry. Maternal characteristics and anthropometric measures were obtained from medical charts., Results: After adjusting for potential confounders, both PFOS and PFOA were negatively associated with birth weight [per ln-unit: beta = -69 g, 95% confidence interval (CI), -149 to 10 for PFOS; beta = -104 g, 95% CI, -213 to 5 for PFOA], ponderal index (per ln-unit: beta = -0.074 g/cm(3) x 100, 95% CI, -0.123 to -0.025 for PFOS; beta = -0.070 g/cm(3) x 100, 95% CI, -0.138 to -0.001 for PFOA), and head circumference (per ln-unit: beta = -0.32 cm, 95% CI, -0.56 to -0.07 for PFOS; beta = -0.41 cm, 95% CI, -0.76 to -0.07 for PFOA). No associations were observed between either PFOS or PFOA concentrations and newborn length or gestational age. All associations were independent of cord serum lipid concentrations., Conclusions: Despite relatively low cord serum concentrations, we observed small negative associations between both PFOS and PFOA concentrations and birth weight and size. Future studies should attempt to replicate these findings in other populations.

Background: The presence of perfluorooctanesulfonate (PFOS), perfluorohexanesulfonate (PFHS), and perfluorooctanoate (PFOA) has been reported in humans and wildlife. Pharmacokinetic differences have been observed in laboratory animals., Objective: The purpose of this observational study was to estimate the elimination half-life of PFOS, PFHS, and PFOA from human serum., Methods: Twenty-six (24 male, 2 female) retired fluorochemical production workers, with no additional occupational exposure, had periodic blood samples collected over 5 years, with serum stored in plastic vials at -80 degrees C. At the end of the study, we used HPLC-mass spectrometry to analyze the samples, with quantification based on the ion ratios for PFOS and PFHS and the internal standard (18)O(2)-PFOS. For PFOA, quantitation was based on the internal standard (13)C(2)-PFOA., Results: THE ARITHMETIC MEAN INITIAL SERUM CONCENTRATIONS WERE AS FOLLOWS: PFOS, 799 ng/mL (range, 145-3,490); PFHS, 290 ng/mL (range, 16-1,295); and PFOA, 691 ng/mL (range, 72-5,100). For each of the 26 subjects, the elimination appeared linear on a semi-log plot of concentration versus time; therefore, we used a first-order model for estimation. The arithmetic and geometric mean half-lives of serum elimination, respectively, were 5.4 years [95% confidence interval (CI), 3.9-6.9] and 4.8 years (95% CI, 4.0-5.8) for PFOS; 8.5 years (95% CI, 6.4-10.6) and 7.3 years (95% CI, 5.8-9.2) for PFHS; and 3.8 years (95% CI, 3.1-4.4) and 3.5 years (95% CI, 3.0-4.1) for PFOA., Conclusions: Based on these data, humans appear to have a long half-life of serum elimination of PFOS, PFHS, and PFOA. Differences in species-specific pharmacokinetics may be due, in part, to a saturable renal resorption process.

Many epidemiology studies have investigated associations of perfluorooctanoate (PFOA) exposures with a variety of adverse health outcomes for participants in the C8 Health Project. The exposure concentrations (i.e., air and groundwater) used in these studies were determined primarily based on participant's residential locations. However, for residential addresses that could not be geocoded to the street level, the exposure concentrations were assigned based on population-weighted ZIP code centroid, which may result in exposure mischaracterization. The aim of this current study is to evaluate the potential impact of mischaracterized exposure concentrations due to geocoding uncertainty on the predicted serum PFOA concentrations and the epidemiological association between PFOA exposure and preeclampsia. For both workplace addresses and incompletely geocoded residential addresses, we used Monte Carlo (MC) simulation to assign alternate geographic locations within the reported ZIP code (instead of population-weighted ZIP code centroids) and the corresponding exposure concentrations. We found that mischaracterization of residential exposure due to population-weighted ZIP code centroid assignment had no significant impact on the serum PFOA concentration predictions and the epidemiological association of PFOA exposure with preeclampsia. In contrast, the uncertainty in workplace exposure moderately impacted the rank exposure among the participants. We observed a 41% increase in the average adjusted odds ratio of preeclampsia occurrence that may be due to differing proportions of cases (64.3%) and controls (54.5%) with workplace address geocodes during pregnancy. This finding suggests that differential exposure mischaracterization can be reduced by obtaining accurate exposure information such as street addresses and tap water consumption, for both workplaces and residences. The analysis we present is one approach for estimating the potential impacts of positional errors in a geocoding-based exposure assessment on exposure estimates and epidemiological study results.

We recently utilized a suite of environmental fate and transport models and an integrated exposure and pharmacokinetic model to estimate individual perfluorooctanoate (PFOA) serum concentrations, and also assessed the association of those concentrations with preeclampsia for participants in the C8 Health Project (a cross-sectional study of over 69,000 people who were environmentally exposed to PFOA near a major U.S. fluoropolymer production facility located in West Virginia). However, the exposure estimates from this integrated model relied on default values for key independent exposure parameters including water ingestion rates, the serum PFOA half-life, and the volume of distribution for PFOA. The aim of the present study is to assess the impact of inter-individual variability and epistemic uncertainty in these parameters on the exposure estimates and subsequently, the epidemiological association between PFOA exposure and preeclampsia. We used Monte Carlo simulation to propagate inter-individual variability/epistemic uncertainty in the exposure assessment and reanalyzed the epidemiological association. Inter-individual variability in these parameters mildly impacted the serum PFOA concentration predictions (the lowest mean rank correlation between the estimated serum concentrations in our study and the original predicted serum concentrations was 0.95) and there was a negligible impact on the epidemiological association with preeclampsia (no change in the mean adjusted odds ratio (AOR) and the contribution of exposure uncertainty to the total uncertainty including sampling variability was 7%). However, when epistemic uncertainty was added along with the inter-individual variability, serum PFOA concentration predictions and their association with preeclampsia were moderately impacted (the mean AOR of preeclampsia occurrence was reduced from 1.12 to 1.09, and the contribution of exposure uncertainty to the total uncertainty was increased up to 33%). In conclusion, our study shows that the change of the rank exposure among the study participants due to variability and epistemic uncertainty in the independent exposure parameters was large enough to cause a 25% bias towards the null. This suggests that the true AOR of the association between PFOA and preeclampsia in this population might be higher than the originally reported AOR and has more uncertainty than indicated by the originally reported confidence interval.