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Perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA), which are classified as perfluoroalkyl and polyfluoroalkyl substances (PFASs), have been widely used in industrial applications as a surface protectant. PFASs have been detected in wildlife and in humans around the globe. The purposes of this study are to develop and validate a physiologically based pharmacokinetic (PBPK) model for detecting PFNA and PFDA in male and female rats, and to apply the model to a human health risk assessment regarding the sex difference. A PBPK model of PFNA and PFDA was established based on an in vivo study in male and female rats. Analytes in biological samples (plasma, nine tissues, urine, and feces) were determined by ultra-liquid chromatography coupled tandem mass spectrometry (UPLC–MS/MS) method. PFNA and PFDA showed a gender differences in the elimination half-life and volume of distribution. The tissue–plasma partition coefficients were the highest in the liver in both male and female rats. The predicted rat plasma and urine concentrations simulated and fitted were in good agreement with the observed values. The PBPK models of PFNA and PFDA in male and female rats were then extrapolated to a human PBPK model based on human physiological parameters. The external doses were calculated at 3.35 ng/kg/day (male) and 17.0 ng/kg/day (female) for PFNA and 0.530 ng/kg/day (male) and 0.661 ng/kg/day (female) for PFDA. Human risk assessment was estimated using Korean biomonitoring values considering the gender differences. This study provides valuable insight into human health risk assessment regarding PFNA and PFDA exposure.

Historical application of wastewater treatment sludge (biosolids) has introduced per- and polyfluoroalkyl substances (PFAS) into agricultural systems and led to contamination of crops and livestock. Previous work validated a dynamic exposure and population toxicokinetic (DE_PopTK) modeling approach for estimating perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS) concentrations in cattle tissues at sites primarily dominated by water contamination. This work expands the efforts to validate the DE_PopTK model at a self-contained beef farm in Maine with PFAS exposures from feed grown on site where soil is contaminated from historical biosolids applications. The model is also extended to estimate perfluorodecanoic acid (PFDA) exposure and tissue levels. Farm-specific data were obtained to consider farm management practices, spatial variation of PFAS in soil, animal growth, and seasonal and annual variability in estimating daily exposures based on water, feed, and soil intake. A dynamic exposure pattern was observed as cattle accumulated PFAS while consuming feed grown on contaminated land and eliminated it while grazing on non-contaminated pastures. Model-estimated PFOS and PFDA levels in serum and muscle were in good agreement with biomonitoring data collected at the farm over a four-year period to reflect periods of accumulation and depuration, with the percentage error ranging from 16% to 73% when comparing modeled and measured data. Our findings demonstrated that understanding farm exposures and collecting site-specific data were integral to model performance. The model was applied to simulate management strategies and complement economic analyses to demonstrate that, with modifications to management practices, it is feasible for the farm to achieve lower PFOS and PFDA levels in beef and maintain economic viability despite elevated PFAS soil levels.

Per- and polyfluoroalkyl substances (PFASs) are common industrial and consumer product chemicals with widespread human exposures that have been linked to adverse health effects. PFASs are commonly detected in foods and food-contact materials (FCMs), including fast food packaging and microwave popcorn bags. Our goal was to investigate associations between serum PFASs and consumption of restaurant food and popcorn in a representative sample of Americans. We analyzed 2003-2014 serum PFAS and dietary recall data from the National Health and Nutrition Examination Survey (NHANES). We used multivariable linear regressions to investigate relationships between consumption of fast food, restaurant food, food eaten at home, and microwave popcorn and serum levels of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorohexanesulfonic acid (PFHxS), and perfluorooctanesulfonic acid (PFOS). Calories of food eaten at home in the past 24 h had significant inverse associations with serum levels of all five PFASs; these associations were stronger in women. Consumption of meals from fast food/pizza restaurants and other restaurants was generally associated with higher serum PFAS concentrations, based on 24-h and 7-d recall, with limited statistical significance. Consumption of popcorn was associated with significantly higher serum levels of PFOA, PFNA, PFDA, and PFOS, based on 24-h and 12-month recall, up to a 63% (95% CI: 34, 99) increase in PFDA among those who ate popcorn daily over the last 12 months. Associations between serum PFAS and popcorn consumption may be a consequence of PFAS migration from microwave popcorn bags. Inverse associations between serum PFAS and food eaten at home-primarily from grocery stores-is consistent with less contact between home-prepared food and FCMs, some of which contain PFASs. The potential for FCMs to contribute to PFAS exposure, coupled with concerns about toxicity and persistence, support the use of alternatives to PFASs in FCMs. https://doi.org/10.1289/EHP4092.

Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals associated with risk of adverse birth outcomes. Results of previous studies have been inconsistent. Associations between PFAS and birth outcomes may be affected by psychosocial stress. We estimated risk of adverse birth outcomes in relation to prenatal PFAS concentrations and evaluate whether maternal stress modifies those relationships. We included 3,339 participants from 11 prospective prenatal cohorts in the Environmental influences on the Child Health Outcomes (ECHO) program to estimate the associations of five PFAS and birth outcomes. We stratified by perceived stress scale scores to examine effect modification and used Bayesian Weighted Sums to estimate mixtures of PFAS. We observed reduced birth size with increased concentrations of all PFAS. For a 1-unit higher log-normalized exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), we observed lower birthweight-for-gestational-age z-scores of [95% confidence interval (CI): , ], (95% CI: , ), (95% CI: , ), (95% CI: , 0.06), and (95% CI: , ), respectively. We observed a lower odds ratio (OR) for large-for-gestational-age: (95% CI: 0.38, 0.83), (95% CI: 0.35, 0.77). For a 1-unit increase in log-normalized concentration of summed PFAS, we observed a lower birthweight-for-gestational-age z-score [ ; 95% highest posterior density (HPD): , ] and decreased odds of large-for-gestational-age ( ; 95% HPD: 0.29, 0.82). Perfluorodecanoic acid (PFDA) explained the highest percentage (40%) of the summed effect in both models. Associations were not modified by maternal perceived stress. Our large, multi-cohort study of PFAS and adverse birth outcomes found a negative association between prenatal PFAS and birthweight-for-gestational-age, and the associations were not different in groups with high vs. low perceived stress. This study can help inform policy to reduce exposures in the environment and humans. https://doi.org/10.1289/EHP10723.

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.

Perfluoroalkyl substances (PFAS) are a group of widely used persistent chemicals with suspected immunotoxic effects. The present study aimed to examine the association between infant PFAS exposure and antibody responses to measles vaccination as well as morbidity in a low-income country. In a randomized controlled trial, children from Guinea-Bissau, West Africa, were followed from inclusion (4-7 months of age) through 2 years of age. Half the children received two measles vaccinations (at inclusion and at 9 months of age), and the other half received only one (at 9 months of age). In a subset of 237 children, six PFAS were quantified in serum at inclusion, and measles antibody concentrations were assessed at inclusion and at approximately 9 months and 2 years of age. At inclusion and at the 9-month visit, mothers were interviewed about infant morbidity. All but one child had detectable serum concentrations of all six PFAS, although levels were lower than seen elsewhere. A doubling in perfluorooctane sulfonic acid (PFOS) and perfluorodecanoic acid (PFDA) were associated with 21% (95% CI: 2, 37%) and 25% (95% CI: 1, 43%), respectively, lower measles antibody concentrations at the 9-month visit among the children who had received a measles vaccine at inclusion. Elevated serum PFAS concentrations were also associated with reduced prevaccination measles antibody concentrations and increased morbidity. The present study documents that PFAS exposure has reached West Africa and that infants show PFAS-associated increases in morbidity and decreases in measles-specific antibody concentrations before and after vaccination. These findings support the evidence on PFAS immunotoxicity at comparatively low serum concentrations. https://doi.org/10.1289/EHP6517.

Additional occurrence data are needed to better understand human exposure to per- and poly-fluoroalkyl substances (PFAS) from commercially available foods in the United States. The Food and Drug Administration’s (FDA) Total Diet Study (TDS) collects foods that are both nationally and regionally distributed. In 2018, 172 processed foods were collected from grocery stores around Lenexa, KS, as part of the TDS national collection. A previously developed method for the analysis of PFAS in foods as part of the TDS regional collection was modified and optimized for these samples. This method was single lab validated using 5 different matrices and method detection limits were calculated. During the analysis of these samples, challenges arose with method blanks and further investigation into statistical methods to distinguish between blank and sample concentrations were done. The confirmation of two short chain PFAS, perfluorobutanoic acid (PFBA) and perfluoropentanoic acid (PFPeA), was not possible using triple quadrupole mass spectrometry and a confirmation method was developed using high-resolution mass spectrometry. This technique was also used to investigate potential detections and interferents that fell within the retention time criteria for positive detections. In the national collection, positive detections of perfluorooctanesulfonic acid (PFOS) and perfluorononanoic acid (PFNA) were found in frozen fish sticks/patties, PFOS and perfluorodecanoic acid (PFDA) in canned tuna, and PFOS in protein powder. Concentrations were all below 150 ppt, and no other detects were confirmed above the method detection limits in any other foods.

BackgroundPerfluoroalkyl substances (PFAS) are man-made chemicals with unique properties that are widely distributed in humans and the environment. Recent studies suggest that PFAS are involved in cholesterol metabolism, however, the mechanisms underlying the associations are poorly understood.ObjectiveWe aimed to evaluate associations of plasma PFAS with detailed lipid and lipoprotein subfractions in an adult population of men and women.MethodsWe measured concentrations of cholesterol and triglycerides in lipoprotein subfractions, apolipoprotein subclasses, as well as fatty acid and different phospholipid measures, using serum proton nuclear magnetic resonance (1H-NMR), and four plasma PFAS using liquid chromatography-mass spectrometry (UHPLC-MS/MS). Measurements were available for 493 participants (all aged 50 years, 50% female). Multivariable linear regression was used to estimate the association of four PFAS with 43 different 1H-NMR measures, with adjustment for body mass index (BMI), smoking, education, and physical activity.ResultsWe found that perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), but not perfluorohexanesulfonate (PFHxS), concentrations were consistently positively associated with concentrations of cholesterol in lipoprotein subfractions, apolipoproteins, as well as composite fatty acid- and phospholipid profiles. The most consistent associations were found for the relationship of PFAS with total cholesterol in intermediate-density lipoprotein (IDL), across all low-density lipoprotein (LDL) subfractions and small high-density lipoprotein (HDL). Moreover, we found weak to null evidence for an association of any of the measured 13 triglyceride lipoprotein subfractions with PFAS.ConclusionsOur results suggest that plasma PFAS concentrations are associated with cholesterol in small HDL, IDL and all LDL subfractions, as well as apolipoproteins and composite fatty acid and phospholipid profiles but to a lesser extent with triglycerides in lipoproteins. Our findings draw attention to the need for more detailed measurements of lipids across various lipoprotein subfractions and subclasses in assessing the role of PFAS in lipid metabolism.ImpactBy performing an in-depth characterization of circulating cholesterol and triglycerides in lipoprotein subfractions, apolipoprotein, fatty acid, and phospholipid concentrations, this study has expanded upon the limited literature available on the associations of plasma PFAS concentrations beyond clinical routine laboratory testing for lipids.

It remains unsettled whether prenatal exposure to perfluoroalkyl substances (PFASs) affects human reproductive health through potential endocrine disruption. We aimed to explore the associations between prenatal exposure to several PFASs and various aspects of pubertal development in boys and girls. We studied two samples ([Formula: see text] and 445) from the Puberty Cohort, nested within the Danish National Birth Cohort (DNBC), measuring PFAS in maternal plasma from early gestation. Data on pubertal development were collected biannually from the age of 11 y until full maturation, using web-based questionnaires. Outcomes were age at menarche, voice break, first ejaculation, and Tanner stages 2 to 5 for pubic hair, breast, genital development, and a combined puberty indicator. A regression model for censored data was used to estimate mean difference (months) in age at achieving the pubertal outcomes across tertiles of PFAS concentrations and with a doubling of PFAS concentrations (continuous). For perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), a meta-analysis was used to provide a weighted average of the point estimates from samples 1 and 2. Overall, prenatal exposure to PFOS, perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PDFA) (girls) and PFHxS and PFHpS (boys) was associated with lower mean age at puberty marker onset. PFDA and PFNA exposure was associated with higher mean age at onset of puberty in boys. Nonmonotonic associations in girls (PFOS, PFHpS, PFDA) and boys (PFDA, PFNA) were observed, showing larger mean age differences for the combined puberty indicator in the middle tertile [girls: PFOS: [Formula: see text] mo, 95% confidence interval (CI): [Formula: see text], [Formula: see text]; PFHpS: [Formula: see text] mo, 95% CI: [Formula: see text], 1.85; PFDA: [Formula: see text] mo, 95% CI: [Formula: see text], 1.83; and boys: PFNA: 4.45 mo, 95% CI: [Formula: see text], 10.21; PFDA: 4.59 mo, 95% CI: [Formula: see text], 10.11] than in the highest tertile with the lowest as reference. Our population-based cohort study suggests sex-specific associations of altered pubertal development with prenatal exposure to PFASs. These findings are novel, and replication is needed. https://doi.org/10.1289/EHP3567.

OBJECTIVE:Perfluoroalkyl substances (PFAS) and liver function biomarkers were reexamined for relatively lower serum concentrations of PFAS observed in recent years. METHODS:National Health and Nutrition Examination Survey 2011 to 2014 data were analyzed for obese and nonobese participants for serum perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA) as well as four liver function biomarkers in risk-adjusted analysis. RESULTS:Among obese participants only, alanine aminotransferase (ALT) was positively associated with PFOA (β = 0.07065, P < 0.01), PFHxS (β = 0.051349, P < 0.01), and with PFNA (β = 0.072742, P < 0.01). PFOA (β = 0.07422, P = 0.03) and PFNA (β = 0.077995, P < 0.01) were associated with gamma glutamyl transferase (GGT) in obese participants. CONCLUSIONS:Recent lower levels of PFOA, PFHxS, and PFNA are associated with higher serum liver functions but only among obese participants. The findings are consistent with PFAS animal toxicology concerning steatosis.