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Applications for fluoropolymers and PFOA include surface coatings for stain, oil, and water resistance on household products, carpets, textiles, and food packaging; personal care products; seals; coatings for cables and wires; and construction materials. Since the previous classification of PFOA (as “possibly carcinogenic to humans”, Group 2B) by the IARC Monographs in 2014,2 many new studies have investigated the association between exposure to PFOA and cancer in experimental animals and humans, as well as mechanistic endpoints relevant to the key characteristics of carcinogens. [...]PFOA induces oxidative stress, modulates receptor-mediated effects (via PPARα, CAR/PXR, and PPARγ), and alters cell proliferation, cell death, and nutrient and energy supply in human primary cells and experimental systems. For testicular cancer, additional evidence was a positive association in an ecological analysis conducted by the Working Group of available data on orchiectomies from the Veneto region of Italy, and a US study finding no associations.9 For all other cancers, the evidence was “inadequate”, as there were only sporadic positive findings.

Emerging evidence suggests that perfluoroalkyl substances (PFASs) are endocrine disruptors and may contribute to the etiology of type 2 diabetes (T2D), but this hypothesis needs to be clarified in prospective human studies. Our objective was to examine the associations between PFAS exposures and subsequent incidence of T2D in the Nurses' Health Study II (NHSII). In addition, we aimed to evaluate potential demographic and lifestyle determinants of plasma PFAS concentrations. A prospective nested case-control study of T2D was conducted among participants who were free of diabetes, cardiovascular disease, and cancer in 1995-2000 [(mean±SD): 45.3±4.4 y) of age]. We identified and ascertained 793 incident T2D cases through 2011 (mean±SD) years of follow-up: 6.7±3.7 y). Each case was individually matched to a control (on age, month and fasting status at sample collection, and menopausal status and hormone replacement therapy). Plasma concentrations of five major PFASs, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonate, perfluorononanoic acid, and perfluorodecanoic acid were measured. Odds ratios (ORs) of T2D by PFAS tertiles were estimated by conditional logistic regression. Shorter breastfeeding duration and higher intake of certain foods, such as seafood and popcorn, were significantly associated with higher plasma concentrations of PFASs among controls. After multivariate adjustment for T2D risk factors, including body mass index, family history, physical activity, and other covariates, higher plasma concentrations of PFOS and PFOA were associated with an elevated risk of T2D. Comparing extreme tertiles of PFOS or PFOA, ORs were 1.62 (95% CI: 1.09, 2.41; =0.02) and 1.54 (95% CI: 1.04, 2.28; =0.03), respectively. Other PFASs were not clearly associated with T2D risk. Background exposures to PFASs in the late 1990s were associated with higher T2D risk during the following years in a prospective case-control study of women from the NHSII. These findings support a potential diabetogenic effect of PFAS exposures. https://doi.org/10.1289/EHP2619.

Perfluorinated and polyfluorinated alkyl substances (PFAS), more than 4700 in number, are a group of widely used man-made chemicals that accumulate in living things and the environment over time. They are known as “forever chemicals” because they are extremely persistent in our environment and body. Because PFAS have been widely used for many decades, their presence is evident globally, and their persistence and potential toxicity create concern for animals, humans and environmental health. They can have multiple adverse health effects, such as liver damage, thyroid disease, obesity, fertility problems, and cancer. The most significant source of living exposure to PFAS is dietary intake (food and water), but given massive industrial and domestic use, these substances are now punctually present not only domestically but also in the outdoor environment. For example, livestock and wildlife can be exposed to PFAS through contaminated water, soil, substrate, air, or food. In this review, we have analyzed and exposed the characteristics of PFAS and their various uses and reported data on their presence in the environment, from industrialized to less populated areas. In several areas of the planet, even in areas far from large population centers, the presence of PFAS was confirmed, both in marine and terrestrial animals (organisms). Among the most common PFAS identified are undoubtedly perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA), two of the most widely used and, to date, among the most studied in terms of toxicokinetics and toxicodynamics. The objective of this review is to provide insights into the toxic potential of PFAS, their exposure, and related mechanisms.

In this perspective, we evaluate key and emerging epidemiological and toxicological data concerning immunotoxicity of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) and seek to reconcile conflicting conclusions from two reviews published in 2016. We summarize ways that immunosuppression and immunoenhancement are defined and explain how specific outcomes are used to evaluate immunotoxicity in humans and experimental animals. We observe that different approaches to defining immunotoxicological outcomes, particularly those that do not produce clinical disease, may lead to different conclusions from epidemiological and toxicological studies. The fundamental point that we make is that aspects of epidemiological studies considered as limitations can be minimized when data from toxicological studies support epidemiological findings. Taken together, we find that results of epidemiological studies, supported by findings from toxicological studies, provide strong evidence that humans exposed to PFOA and PFOS are at risk for immunosuppression.

Abstract Objective To investigate the prospective associations of life-course perfluoroalkyl substances (PFASs) exposure with glucose homeostasis at adulthood. Methods We calculated insulin sensitivity and beta-cell function indices based on 2-h oral glucose tolerance tests at age 28 in 699 Faroese born in 1986–1987. Five major PFASs were measured in cord whole blood and in serum from ages 7, 14, 22, and 28 years. We evaluated the associations with glucose homeostasis measures by PFAS exposures at different ages using multiple informant models fitting generalized estimating equations and by life-course PFAS exposures using structural equation models. Results Associations were stronger for perfluorooctane sulfonate (PFOS) and suggested decreased insulin sensitivity and increased beta-cell function—for example, β (95% CI) for log-insulinogenic index per PFOS doubling = 0.12 (0.02, 0.22) for prenatal exposures, 0.04 (−0.10, 0.19) at age 7, 0.07 (−0.07, 0.21) at age 14, 0.05 (−0.04, 0.15) at age 22, and 0.04 (−0.03, 0.11) at age 28. Associations were consistent across ages (P for age interaction > 0.10 for all PFASs) and sex (P for sex interaction > 0.10 for all PFASs, except perfluorodecanoic acid). The overall life-course PFOS exposure was also associated with altered glucose homeostasis (P = 0.04). Associations for other life-course PFAS exposures were nonsignificant. Conclusions Life-course PFAS exposure is associated with decreased insulin sensitivity and increased pancreatic beta-cell function in young adults.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs), a group of ubiquitous environmental chemicals with properties of endocrine disruption, are often detectable in humans. The current study investigated the association between exposure to PFAS and primary ovarian insufficiency (POI). Levels of plasma PFAS were measured in 120 Chinese women with overt POI and 120 healthy control subjects from 2013 to 2016. Associations between PFAS levels and odds of POI, as well as hormonal profiles, were evaluated using multiple logistic regression and multiple linear regression models. Levels of perfluorooctanate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexanesulfonate (PFHxS) were positively associated with the risks of POI (highest vs. lowest tertile, PFOA: OR, 3.80; 95% CI, 1.92-7.49; PFOS: OR, 2.81; 95% CI, 1.46-5.41; PFHxS: OR, 6.63; 95% CI, 3.22-13.65). In patients with POI, levels of PFOS and PFHxS exposure were positively associated with FSH (PFOS: adjusted β, 0.26; 95% CI, 0.15 to 0.38; PFHxS: adjusted β, 0.16; 95% CI, 0.04 to 0.28) and negatively associated with estradiol (PFOS: adjusted β, -0.30; 95% CI, -0.47 to -0.12; PFHxS: adjusted β, -0.19; 95% CI, -0.37 to -0.02). Exposure to PFOS and PFOA was associated with elevation of prolactin (PFOS: adjusted β, 0.17; 95% CI, 0.06 to 0.29; PFOA: adjusted β, 0.16; 95% CI, 0.01 to 0.30) or with a decrease of free triiodothyronine (PFOS: adjusted β, -0.88; 95% CI, -1.64 to -0.09; PFOA: adjusted β, -0.90; 95% CI, -1.88 to 0.09) and thyroxine (PFOS: adjusted β, -2.99; 95% CI, -4.52 to -1.46; PFOA: adjusted β, -3.42; 95% CI, -5.39 to -1.46). High exposure to PFOA, PFOS, and PFHxS is associated with increased risk of POI in humans.

Prenatal exposure to perfluoroalkyl substances (PFAS) has been associated with lower birth weight in epidemiologic studies. This association could be attributable to glomerular filtration rate (GFR), which is related to PFAS concentration and birth weight. We used a physiologically based pharmacokinetic (PBPK) model of pregnancy to assess how much of the PFAS-birth weight association observed in epidemiologic studies might be attributable to GFR. We modified a PBPK model to reflect the association of GFR with birth weight (estimated from three studies of GFR and birth weight) and used it to simulate PFAS concentrations in maternal and cord plasma. The model was run 250,000 times, with variation in parameters, to simulate a population. Simulated data were analyzed to evaluate the association between PFAS levels and birth weight due to GFR. We compared simulated estimates with those from a meta-analysis of epidemiologic data. The reduction in birth weight for each 1-ng/mL increase in simulated cord plasma for perfluorooctane sulfonate (PFOS) was 2.72 g (95% CI: -3.40, -2.04), and for perfluorooctanoic acid (PFOA) was 7.13 g (95% CI: -8.46, -5.80); results based on maternal plasma at term were similar. Results were sensitive to variations in PFAS level distributions and the strength of the GFR-birth weight association. In comparison, our meta-analysis of epidemiologic studies suggested that each 1-ng/mL increase in prenatal PFOS and PFOA levels was associated with 5.00 g (95% CI: -21.66, -7.78) and 14.72 g (95% CI: -8.92, -1.09) reductions in birth weight, respectively. Results of our simulations suggest that a substantial proportion of the association between prenatal PFAS and birth weight may be attributable to confounding by GFR and that confounding by GFR may be more important in studies with sample collection later in pregnancy.

Citation: Blum A, Balan SA, Scheringer M, Trier X, Goldenman G, Cousins IT, Diamond M, Fletcher T, Higgins C, Lindeman AE, Peaslee G, de Voogt P, Wang Z, Weber R. 2015. The Madrid statement on poly- and perfluoroalkyl substances (PFASs). Environ Health Perspect 123:A107-A111; http://dx.doi.org/10.1289/ehp.1509934 E-mail: arlenereensciencepolicy.org The views expressed in this statement are solely those of the authors and signatories. The authors declare they have no actual or potential competing financial interests. Published: 1 May 2015

Cardiovascular disease (CVD) poses the leading threats to human health and life, and their occurrence and severity are associated with exposure to environmental pollutants. Per- and polyfluoroalkyl substances (PFAS), a group of widely used industrial chemicals, are characterized by persistence, long-distance migration, bioaccumulation, and toxicity. Some PFAS, particularly perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorohexanesulfonic acid (PFHxS), have been banned, leaving only legacy exposure to the environment and human body, while a number of novel PFAS alternatives have emerged and raised concerns, such as polyfluoroalkyl ether sulfonic and carboxylic acid (PFESA and PFECA) and sodium p-perfluorous nonenoxybenzene sulfonate (OBS). Overall, this review systematically elucidated the adverse cardiovascular (CV) effects of legacy and emerging PFAS, emphasized the dose/concentration-dependent, time-dependent, carbon chain length-dependent, sex-specific, and coexposure effects, and discussed the underlying mechanisms and possible prevention and treatment. Extensive epidemiological and laboratory evidence suggests that accumulated serum levels of legacy PFAS possibly contribute to an increased risk of CVD and its subclinical course, such as cardiac toxicity, vascular disorder, hypertension, and dyslipidemia. The underlying biological mechanisms may include oxidative stress, signaling pathway disturbance, lipid metabolism disturbance, and so on. Various emerging alternatives to PFAS also play increasingly prominent toxic roles in CV outcomes that are milder, similar to, or more severe than legacy PFAS. Future research is recommended to conduct more in-depth CV toxicity assessments of legacy and emerging PFAS and explore more effective surveillance, prevention, and treatment strategies, accordingly.

Per- and polyfluoroalkyl substances (PFASs) are omnipresent in the environment, food chain, and humans. Epidemiological studies have shown a positive association between serum levels of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), and increased serum cholesterol and, in some cases, also triglyceride levels. However, causality has been questioned, as animal studies, as well as a human trial, showed a decrease in serum cholesterol and no effects or a decrease in plasma triglycerides. To obtain more insight into the effects of PFASs on these processes, the present study investigated the effects of PFOA, PFOS, and perfluorononanoic acid (PFNA) on intracellular triglyceride and cholesterol levels in human HepaRG liver cells. DNA microarray analyses were performed to provide insight into underlying mechanisms. All PFASs induced an increase in cellular triglyceride levels, but had no effect on cholesterol levels. Gene set enrichment analysis (GSEA) of the microarray data indicated that gene sets related to cholesterol biosynthesis were repressed by PFOA, PFOS, and PFNA. Other gene sets commonly affected by all PFAS were related to PERK/ATF4 signaling (induced), tRNA amino-acylation (induced), amino acid transport (induced), and glycolysis/gluconeogenesis (repressed). Moreover, numerous target genes of peroxisome proliferator-activated receptor α (PPARα) were found to be upregulated. Altogether, the present study shows that PFOA, PFOS, and PFNA increase triglyceride levels and inhibit cholesterogenic gene expression in HepaRG cells. In addition, the present study indicates that PFASs induce endoplasmic reticulum stress, which may be an important mechanism underlying some of the toxic effects of these chemicals.