Associations between polyfluoroalkyl substance and organophosphate flame retardant exposures and telomere length in a cohort of women firefighters and office workers in San Francisco.

BACKGROUND: Environmental chemical exposures can affect telomere length, which in turn has been associated with adverse health outcomes including cancer. Firefighters are occupationally exposed to many hazardous chemicals and have higher rates of certain cancers. As a potential biomarker of effect, we assessed associations between chemical exposures and telomere length in women firefighters and office workers from San Francisco, CA. METHODS: We measured serum concentrations of polyfluoroalkyl substances (PFAS), urinary metabolites of flame retardants, including organophosphate flame retardants (OPFRs), and telomere length in peripheral blood leukocytes in women firefighters (N = 84) and office workers (N = 79) who participated in the 2014-15 Women Workers Biomonitoring Collaborative. Multiple linear regression models were used to assess associations between chemical exposures and telomere length. RESULTS: Regression results revealed significant positive associations between perfluorooctanoic acid (PFOA) and telomere length and perfluorooctanesulfonic acid (PFOS) and telomere length among the whole cohort. Models stratified by occupation showed stronger and more significant associations among firefighters as compared to office workers. Among firefighters in models adjusted for age, we found positive associations between telomere length and log-transformed PFOA (ß (95%CI) = 0.57(0.12, 1.02)), PFOS (0.44 (0.05, 0.83)), and perfluorodecanoic acid (PFDA) (0.43 (0.02, 0.84)). Modeling PFAS as categories of exposure showed significant associations between perfluorononanoic acid (PFNA) and telomere length among firefighters. Significant associations between OPFR metabolites and telomere length were seen for bis (1,3-dichloro-2-propyl) phosphate (BDCPP) and telomere length among office workers (0.21(0.03, 0.40)) and bis (2-chloroethyl) phosphate (BCEP) and telomere length among firefighters (- 0.14(- 0.28, - 0.01)). For OPFRs, the difference in the direction of effect by occupational group may be due to the disparate detection frequencies and concentrations of exposure between the two groups and/or potential unmeasured confounding. CONCLUSION: Our findings suggest positive associations between PFAS and telomere length in women workers, with larger effects seen among firefighters as compared to office workers. The OPFR metabolites BDCPP and BCEP are also associated with telomere length in firefighters and office workers. Associations between chemical exposures and telomere length reported here and by others suggest mechanisms by which these chemicals may affect carcinogenesis and other adverse health outcomes.

Life-course Exposure to Perfluoroalkyl Substances in Relation to Markers of Glucose Homeostasis in Early Adulthood.

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, ß (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 substance excretion: Effects of organic anion-inhibiting and resin-binding drugs in a community setting.

BACKGROUND: Longer serum half-lives of perfluoroalkyl substances (PFAS) in humans compared to other species has been attributed to differences in the activity of organic anion transporters (OAT). METHODS: Among 56,175 adult participants in the community-based C8 Health Project, 23 subjects were taking the uricosuric OAT-inhibitor probenecid, and 36 subjects were taking the bile acid sequestrant cholestyramine. In regression models of log transformed serum PFAS, medication effects were estimated in terms of mean ratios, adjusting for age, gender, BMI, estimated glomerular filtration rate (eGFR) and water-district of residence. RESULTS: Probenecid was associated with modest, but not statistically significant increases in serum PFAS concentrations. In contrast, cholestyramine significantly lowered serum PFAS concentrations, notably for perfluorooctane sulfonic acid (PFOS). CONCLUSIONS: The effectiveness of cholestyramine in a community setting supports the importance of gastrointestinal physiology for PFAS excretion kinetics, especially for PFOS. We did not find clear evidence that probenecid, an inhibitor of OAT, affects PFAS clearance.

Plasma Concentrations of Per- and Polyfluoroalkyl Substances and Body Composition From Mid-Childhood to Early Adolescence.

CONTEXT: Per- and polyfluoroalkyl substances (PFAS) may alter body composition by lowering anabolic hormones and increasing inflammation, but data are limited, particularly in adolescence when body composition is rapidly changing. OBJECTIVE: To evaluate associations of PFAS plasma concentrations in childhood with change in body composition through early adolescence. METHODS: A total of 537 children in the Boston-area Project Viva cohort participated in this study. We used multivariable linear regression and Bayesian kernel machine regression (BKMR) to examine associations of plasma concentrations of 6 PFAS, quantified by mass spectrometry, in mid-childhood (mean age, 7.9 years; 2007-2010) with change in body composition measured by dual-energy x-ray absorptiometry from mid-childhood to early adolescence (mean age, 13.1 years). RESULTS: In single-PFAS linear regression models, children with higher concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorodecanoate (PFDA), and perfluorohexane sulfonate (PFHxS) had less accrual of lean mass (eg, -0.33 [95% CI: -0.52, -0.13] kg/m2 per doubling of PFOA). Children with higher PFOS and PFHxS had less accrual of total and truncal fat mass (eg, -0.32 [95% CI: -0.54, -0.11] kg/m2 total fat mass per doubling of PFOS), particularly subcutaneous fat mass (eg, -17.26 [95% CI -32.25, -2.27] g/m2 per doubling of PFOS). Children with higher PFDA and perfluorononanoate (PFNA) had greater accrual of visceral fat mass (eg, 0.44 [95% CI: 0.13, 0.75] g/m2 per doubling of PFDA). Results from BKMR mixture models were consistent with linear regression analyses. CONCLUSION: Early life exposure to some but not all PFAS may be associated with adverse changes in body composition.

Polyfluoroalkyl chemicals and the risk of kidney stones in US adults: A population-based study.

The potential nephrotoxicity of polyfluoroalkyl chemicals (PFCs) have received extensive attention. However, the relationship between PFCs and the risk of kidney stones remain unclear. This study aimed to examine the level of PFCs in the US population and its relationship with the risk of kidney stones. We investigated the serum levels of six PFCs in 8453 adult participants (≥20 years) from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016, including perfluorodecanoic acid (PFDE), perfluorohexane sulfonic acid (PFHS), 2-(N-methyl-perfluorooctane sulfonamido) acetate (MPAH), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUA), and perfluorododecanoic acid (PFDO). Logistic regression model was used to evaluate the correlation between PFCs and kidney stones. Of the 8453 participants, 787 self-reported a history of kidney stones. After adjusting for gender, age, race, education, marital status, body mass index (BMI), hypertension, diabetes and estimated glomerular filtration rate (eGFR), we found that total PFCs and PFHS were positively correlated with the risk of kidney stones. Compared with the lowest tertile, the odds ratios with 95% confidence intervals (CI) with increasing tertiles were 1.30 (95% CI,1.08-1.59, p = 0.007) and 1.25 (95 CI%,1.00-1.52, p = 0.024) for total PFCs and 1.24 (95 CI%,1.03-1.51, p = 0.032), and 1.35 (95 CI,1.10-1.68, p = 0.005) for PFHS. Our study shows that total PFCs and PFHS were associated with an increased risk of kidney stones.

Perfluoroalkyl acids, hyperuricemia and gout in adults: Analyses of NHANES 2009-2014.

BACKGROUND: Previous studies have reported a positive association of perfluoralkyl acids (PFAAs), including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), with hyperuricemia. The objective of the study is to investigate whether there is an association between concurrent serum levels of several PFAAs and gout, serum uric acid (SUA) or hyperuricemia in the U.S. adult population as represented by the National Health and Nutrition Examination Survey (NHANES) 2009-2014 sample (n = 4917). The PFAAs investigated include PFOA, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorohexane sulfonic acid (PFHxS) and PFOS. METHODS: This cross-sectional study used multivariate logistic regressions to analyze the association of single PFAAs with hyperuricemia and self-reported gout; the association with SUA was analyzed by multivariate linear regression. Analyses were adjusted for race/ethnicity, age, sex, education, alcohol consumption, smoking, serum cotinine, BMI, diabetes, hypertension, chronic kidney disease, and SUA (for gout only). RESULTS: Higher quartile values of serum PFOA and PFHxS were associated with increased odds of self-reported gout. There was a positive association of SUA with increased levels of PFOA, PFNA, PFOS, PFHxS and PFDA. Higher quartile values of PFOA, PFNA, and PFHxS were associated with higher odds of hyperuricemia. CONCLUSIONS: In this population-based cross-sectional analysis, we found an association between selected PFAAs and self-reported gout. We also confirmed previous reports of an association between several PFAAs and hyperuricemia. Our study suggests that exposure to PFAAs may be a risk factor for hyperuricemia and gout.

Prenatal perfluoroalkyl substances and newborn anogenital distance in a Canadian cohort.

Exposure to the man-made chemicals perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and perfluorohexanesulfonate (PFHxS) is widespread. These perfluoroalkyl substances (PFASs) have been associated with androgenic endocrine-disrupting properties; however, the evidence is equivocal and few human studies have examined the association between prenatal exposure to PFASs and markers of androgenic endocrine disruption such as changes in anogenital distance (AGD). In the MIREC cohort, PFOA, PFOS and PFHxS were analyzed in first trimester maternal plasma. AGD was measured in 205 male and 196 female newborns. The change in estimate procedure was used to identify confounders by sex and AGD in multiple linear regression models. Geometric mean plasma concentrations (95% CI) for PFOA, PFOS and PFHxS were 1.71 (1.61, 1.81), 4.40 (4.18, 4.64) and 1.15 (1.06, 1.25) µg/L, respectively. A one-unit increase in natural log transformed PFOA was associated with a 1.36 mm (95% CI 0.30, 2.41) increase in anoscrotal distance, adjusting for household income, active smoking status during pregnancy and gestational age. However, when examined by quartiles, a non-monotonic pattern was observed with wide confidence intervals. No consistent patterns were observed between maternal PFAS concentrations and female AGDs. This study found no clear evidence that maternal plasma concentrations of PFOS, PFOA or PFHxS were associated with shorter infant anogenital distance in males or any change in AGD in females. Whether the positive association observed between longer anoscrotal distance and PFOA is real or would have any long-lasting effect on the reproductive health of males is unknown and needs to be investigated further.

Association between perfluoroalkyl acids and the prevalence of hypertension among US adults.

The nonlinear associations of serum perfluoroalkyl acids (PFAAs) with hypertension and blood pressure have not been addressed. Cross-sectional data from 6967 adults (age ≥ 20 years) from the 2003-2012 National Health and Nutrition Examination Survey (NHANES) were analyzed. Hypertension was defined as an average systolic blood pressure above 140 mmHg, an average diastolic blood pressure above 90 mmHg or self-reported use of prescribed medicine for diagnosed hypertension. After multivariable adjustment, compared with the lowest tertile, the odds ratios (ORs) with 95% confidence intervals (CIs) of hypertension for the highest tertile of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) were 1.32 (1.13, 1.54), 1.14 (0.97, 1.34), 1.16 (0.99, 1.36) and 1.18 (1.01, 1.37), respectively. PFOA and PFNA displayed a J-shaped relationship with the prevalence of hypertension. Furthermore, threshold effect analysis showed that the inflection point of PFOA was 1.80 ng/ml. Each 10-fold change in PFOA exhibited a 44% decrease (OR 0.56, 95%CI (0.32, 0.99)) in the odds of hypertension on the left side of the inflection point, and an 85% increase (OR 1.85, 95%CI (1.34, 2.54)) on the right side of the inflection point. Threshold effect analysis also indicated that the inflection point of PFNA was 0.53 ng/ml. Each 10-fold change in PFNA exhibited a 60% decrease (OR 0.40, 95%CI (0.18, 0.85)) in the odds of hypertension on the left side of the inflection point, and an 85% increase (OR 1.64, 95%CI (1.25, 2.14)) on the right side of the inflection point. These cross-sectional data showed a J-shaped association between perfluoroalkyl acids and hypertension.

Associations between perfluoroalkyl substances and serum lipids in a Swedish adult population with contaminated drinking water.

BACKGROUND: Exposures to perfluoroalkyl substances (PFAS) have shown positive associations with serum lipids in previous studies. While many studies on lipids investigated associations with perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), there are only a few studies regarding other PFAS, such as perfluorohexane sulfonic acid (PFHxS). The purpose of the current study is to investigate if associations with serum lipids were present, not only for serum PFOS and PFOA, but also for PFHxS, and if the associations with PFAS remained also in a comparison based only on residency in areas with contrasting exposure to PFAS. METHODS: 1945 adults aged 20-60 were included from Ronneby, Sweden, a municipality where one out of two waterworks had been heavily contaminated from aqueous fire-fighting foams, and from a nearby control area. The exposure was categorized based on either been living in areas with contrasting PFAS exposure or based on the actual serum PFAS measurements. Regression analyses of serum lipids were fitted against serum PFAS levels, percentile groups, smooth splines and between exposed and reference areas, adjusting for age, sex and BMI. RESULTS: Drinking water contamination caused high serum levels of PFOS (median 157 ng/ml) and PFHxS (median 136 ng/ml) and PFOA (median 8.6 ng/ml). These serum PFAS levels in the exposed groups were 5 to 100-fold higher than in the controls. In this population with mixed PFAS exposure, predominantly PFOS and PFHxS, PFAS exposure were positively associated with serum lipids. This was observed both when quantifying exposure as contrast between exposed and controls, and in terms of serum PFAS. Due to high correlations between each PFAS, we cannot separate them. CONCLUSIONS: In conclusion, the present study provides further evidence of a causal association between PFAS and serum lipids, especially for PFHxS.

Serum Levels of Perfluoroalkyl Substances (PFAS) in Adolescents and Young Adults Exposed to Contaminated Drinking Water in the Veneto Region, Italy: A Cross-Sectional Study Based on a Health Surveillance Program.

BACKGROUND: In spring 2013, groundwater of a vast area of the Veneto Region (northeastern Italy) was found to be contaminated by perfluoroalkyl substances (PFAS) from a PFAS manufacturing plant active since the late 1960s. Residents were exposed to high concentrations of PFAS, particularly perfluorooctanoic acid (PFOA), through drinking water until autumn 2013. A publicly funded health surveillance program is under way to aid in the prevention, early diagnosis, and treatment of chronic disorders possibly associated with PFAS exposure. OBJECTIVES: The objectives of this paper are: a) to describe the organization of the health surveillance program, b) to report serum PFAS concentrations in adolescents and young adults, and c) to identify predictors of serum PFAS concentrations in the studied population. METHODS: The health surveillance program offered to residents of municipalities supplied by contaminated waterworks includes a structured interview, routine blood and urine tests, and measurement of 12 PFAS in serum by high-performance liquid chromatography-tandem mass spectrometry. We studied 18,345 participants born between 1978 and 2002, 14-39 years of age at recruitment. Multivariable linear regression was used to identify sociodemographic, lifestyle, dietary, and reproductive predictors of serum PFAS concentrations. RESULTS: The PFAS with the highest serum concentrations were PFOA [median 44.4 ng/mL, interquartile range (IQR) 19.3-84.9], perfluorohexanesulfonic acid (PFHxS) (median 3.9 ng/mL, IQR 1.9-7.4), and perfluorooctanesulfonic acid (PFOS) (median 3.9 ng/mL, IQR 2.6-5.8). The major predictors of serum levels were gender, municipality, duration of residence in the affected area, and number of deliveries. Overall, the regression models explained 37%, 23%, and 43% of the variance of PFOA, PFOS, and PFHxS, respectively. CONCLUSIONS: Serum PFOA concentrations were high relative to concentrations in populations with background residential exposures only. Interindividual variation of serum PFAS levels was partially explained by the considered predictors. https://doi.org/10.1289/EHP5337.

Associations of Perfluoroalkyl substances with blood lipids and Apolipoproteins in lipoprotein subspecies: the POUNDS-lost study.

BACKGROUND: The associations of perfluoroalkyl substance (PFAS) exposure with blood lipids and lipoproteins are inconsistent, and existing studies did not account for metabolic heterogeneity of lipoprotein subspecies. This study aimed to examine the associations between plasma PFAS concentrations and lipoprotein and apolipoprotein subspecies. METHODS: The study included 326 men and women from the 2-year Prevention of Obesity Using Novel Dietary Strategies (POUNDS) Lost randomized trial. Five PFASs, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), were measured in plasma at baseline. For lipoprotein and apolipoprotein subspecies, total plasma was fractionated first by apolipoprotein (apo) C-III content and then by density. Each subfraction was then measured for apoB, apoC-III, and apoE concentrations, as well as triglyceride and cholesterol contents, both at baseline and at 2 years. RESULTS: For lipids and apolipoproteins in total plasma at baseline, elevated plasma PFAS concentrations were significantly associated with higher apoB and apoC-III concentrations, but not with total cholesterol or triglycerides. After multivariate adjustment of lifestyle factors, lipid-lowering medication use, and dietary intervention groups, PFAS concentrations were primarily associated with lipids or apolipoprotein concentrations in intermediate-to-low density lipoprotein (IDL + LDL) and high-density lipoprotein (HDL) that contain apoC-III. Comparing the highest and lowest tertiles of PFOA, the least-square means (SE) (mg/dl) were 4.16 (0.4) vs 3.47 (0.4) for apoB (P trend = 0.04), 2.03 (0.2) vs 1.66 (0.2) for apoC-III (P trend = 0.04), and 8.4 (0.8) vs 6.8 (0.8) for triglycerides (P trend = 0.03) in IDL + LDL fraction that contains apoC-III. For HDL that contains apoC-III, comparing the highest and lowest tertiles of PFOA, the least-square means (SE) (mg/dl) of apoC-III were 11.9 (0.7) vs 10.4 (0.7) (P trend = 0.01). In addition, elevated PFNA and PFDA concentrations were also significantly associated with higher concentrations of apoE in HDL that contains apoC-III (P trend< 0.01). Similar patterns of associations were demonstrated between baseline PFAS concentrations and lipoprotein subspecies measured at 2 years. Baseline PFAS levels were not associated with changes in lipoprotein subspecies during the intervention. CONCLUSIONS: Our results suggest that plasma PFAS concentrations are primarily associated with blood lipids and apolipoproteins in subspecies of IDL, LDL, and HDL that contain apoC-III, which are associated with elevated cardiovascular risk in epidemiological studies. Future studies of PFAS-associated cardiovascular risk should focus on lipid subfractions.

Perfluorinated substances in the Flemish population (Belgium): Levels and determinants of variability in exposure.

Because of their dirt-, water- and oil-repelling properties, per- and polyfluoroalkyl substances (PFASs) are frequently used in a broad variety of consumer products. They have been detected in human samples worldwide. In Flanders, Belgium, the Flemish Environment and Health Studies (FLEHS) measured the levels of five PFAS biomarkers in four different age groups of the Flemish population and identified determinants of variability in exposure. Cord plasma or peripheric serum samples and questionnaire data were available for 220 mother-newborn pairs (2008-2009), 269 mother-newborn pairs (2013-2014), 199 adolescents (14-15 years old, 2010), 201 adults (20-40 years old, 2008-2009) and 205 adults (50-65 years old, 2014). Measured levels of perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) in Flanders are in the middle or low range compared to concentrations reported in other Western countries. Levels of perfluorobutanesulfonic acid (PFBS) were below the quantification limit in 98%-100% of the samples. Despite decreasing levels in time for PFOS and PFOA, 77% of the adults (2014) had serum levels exceeding HBM-I values of 5 µg/L for PFOS and 2 µg/L for PFOA. Beside age, sex, fish consumption, parity and breastfeeding, the multiple regression models identified additionally consumption of offal and locally grown food, and use of cosmetics as possible exposures and menstruation as a possible route of elimination. Better knowledge on determinants of exposure is essential to lower PFASs exposure.

The Association Between Perfluoroalkyl Substances and Lipids in Cord Blood.

INTRODUCTION: Perfluoroalkyl substances (PFAS) were among various persistent organic pollutants suspected to have been released during the collapse of the World Trade Center (WTC) on 9/11/2001. Evidence suggests that PFAS may have cardiometabolic effects, including alterations in lipid profiles. This study evaluated the association between cord blood PFAS and lipids in a population prenatally exposed to the WTC disaster. STUDY POPULATION: 222 pregnant women in the Columbia University WTC birth cohort enrolled between December 13, 2001 and June 26, 2002 at hospitals located near the WTC site: Beth Israel, St. Vincent's, and New York University Downtown. METHODS: We evaluated the association between 5 cord blood PFAS-perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorodecane sulfonate (PFDS)-and cord blood lipids (total lipids, total cholesterol, triglycerides). RESULTS: Median (interquartile range [IQR]) concentrations of PFAS were 6.32 (4.58-8.57), 2.46 (1.77-3.24), 0.38 (0.25-0.74), 0.66 (0.48-0.95) and 0.11 (0.09-0.16) ng/mL for PFOS, PFOA, PFNA, PFHxS, and PFDS, respectively. Median (IQR) for lipids were 59.0 (51.5-68.5) mg/dL for total cholesterol, 196.5 (170.5-221.2) mg/dL for total lipids and 33.1 (24.2-43.9) mg/dL for triglycerides. In fully adjusted models, several PFAS were associated with higher lipid levels, including evidence of a strong linear trend between triglycerides and both PFOA and PFHxS. CONCLUSIONS: Findings support previous evidence of an association between PFAS exposure and altered lipid profiles and add novel information on this relationship in cord blood, as well as for an understudied PFAS, PFDS (J Clin Endocrinol Metab XX: 0-0, 2019).

In utero exposure to poly- and perfluoroalkyl substances (PFASs) and subsequent breast cancer.

We tested the hypothesis that maternal perinatal serum levels of poly and perfluoroalkyl substances (PFASs) predict risk for breast cancer in daughters in a 54-year follow-up of 9300 daughters born 1959-1967 in the Child Health and Development Studies pregnancy cohort. Total cholesterol and PFASs were measured in archived maternal perinatal serum for 102 daughter breast cancer cases diagnosed by age 52, and 310 controls matched on birth year and blood draw trimester. High maternal N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA), a precursor of perfluorooctane sulfonic acid (PFOS), in combination with high maternal total cholesterol predicted a 3.6-fold increased risk of breast cancer (pinteraction<0.05). Conversely, maternal PFOS was associated with decreased daughters' breast cancer risk. Predictions were robust to alternative modeling and independent of other maternal factors. Future generations continue to be exposed to ubiquitous, persistent PFASs. These findings are relevant to breast cancer prevention if confirmed experimentally and where possible, in additional epidemiology studies of internal doses of PFASs and other chemical mixtures especially during vulnerable windows in early life.

Children's exposure to perfluoroalkyl acids - a modelling approach.

Adults are mainly exposed to per- and polyfluoroalkyl substances (PFASs) via ingestion of food, inhalation of air and ingestion of dust, whereas for children the exposure to PFASs is largely unknown. This study aimed to reconstruct the serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS) in children after infancy up to 10.5 years of age and to test if dietary intake is the major exposure pathway for children to PFOA, PFOS and PFHxS after infancy. For this work, a dataset from a Finnish child cohort study was available, which comprised serum concentrations of the studied perfluoroalkyl acids (PFAAs) and PFAS concentration measurements in dust and air samples from the children's bedrooms. The calculated PFAA intakes were used in a pharmacokinetic model to reconstruct the PFAA serum concentrations from 1 to 10.5 years of age. The calculated PFOA and PFOS intakes were close to current regulatory intake thresholds and diet was the major exposure medium for the 10.5 year-olds. The one-compartment PK model reconstructed median PFOA and PFOS serum concentrations well compared to corresponding measured median serum concentrations, while the modelled PFHxS serum concentrations showed a constant underestimation. The results imply that children's exposure to PFOA and PFOS after breastfeeding and with increasing age resembles the exposure of adults. Further, the children in the Finnish cohort experienced a rather constant exposure to PFOA and PFOS between 1 and 10.5 years of age. The PFHxS exposure sources and respective pharmacokinetic parameter estimations need further investigation.

Sex differences in the association between perfluoroalkyl acids and liver function in US adolescents: Analyses of NHANES 2013-2016.

Perfluoroalkyl acids (PFAAs) are persistent in the environment, highly bio-accumulative in the body, and likely hepatotoxic in humans. There is evidence of sex-specific physiological responses to PFAA exposure. However, epidemiological studies seldom stratify the analyses by sex. Given the high prevalence of liver disease in general population adolescents, this study was designed to determine whether or not there is association between exposure to PFAAs and biomarkers of liver function in adolescent participants of the 2013-2016 National Health and Nutrition Examination Survey, and whether or not such association is sex-specific. Multivariate linear regressions were performed to examine the association between single PFAAs [perfluorooctane sulfonic acid (PFOS); linear form of perfluorooctanoic acid (PFOA); perfluorohexane sulfonic acid (PFHxS); perfluorononanoic acid (PFNA)], and biomarkers of liver function - gamma glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin. Multivariate logistic regressions were performed to estimate adjusted odd ratios (aOR) of elevated ALT, AST and GGT. The study results show that, in females, there was a positive association of the highest PFOA quartile with increased ALT, AST and GGT, and the highest PFNA quartile with increased ALT and AST. Conversely, in male adolescents there was an association of the highest linear PFOA quartile with decreased ALT, and the highest PFNA quartile with ALT and AST. Females had higher odds of clinically-defined elevated ALT with increased PFOA (aOR = 1.79; 95% CI: 1.05, 3.04) or PFNA (aOR = 2.28; 95% CI: 1.08, 2.28), whereas males had decreased odds of clinically-defined elevated ALT with increased n-PFOA (aOR = 0.43; 95% CI: 0.20, 0.93) or PFNA (aOR = 0.5; 95% CI: 0.28, 0.89). In conclusion, there were sex differences in the association between serum PFAA levels and biomarkers of liver function. These results may provide support for analyzing sex-based adverse effects of PFAAs.

Prenatal exposure to chlorinated polyfluoroalkyl ether sulfonic acids and perfluoroalkyl acids: Potential role of maternal determinants and associations with birth outcomes.

Transplacental exposure to per/polyfluoroalkyl substances (PFASs) may impact fetal growth, but published evidence are still sparse and not in agreement. Moreover, little is known on the occurrence of emerging chlorinated polyfluorinated ether sulfonates (Cl-PFESAs, 6:2 and 8:2) in maternal-neonatal population. This study investigated eleven PFASs by analyzing 98 cord samples from Hangzhou, China. All target compounds can be transported across placenta, with highest median concentrations of 4.07, 1.05 and 0.731 ng/mL for PFOS, PFOA, and 6:2 Cl-PFESA. Older ages and higher pre-pregnancy BMI were associated with higher cord PFASs concentration; being primiparous was also significantly associated. Notably, after adjusting for potential confounders, PFOS was negatively associated with birth weight (ß = -417.3 g, 95% CI: -742.1, -92.4, p = 0.011, per a log10 unit increase in exposure) and ponderal index (ß = -0.005 g/cm3, 95% CI: -0.008, -0.002, p = 0.000). PFOS and PFHxS were also indicated to be associated with small for gestational age birth (SGA) (p <  0.05). Although no evidence of association was observed between Cl-PFESAs and birth outcomes in this study, the bioaccumulative properties and development toxicity of Cl-PFESAs deserve continuous concern.

Early Life Exposures to Perfluoroalkyl Substances in Relation to Adipokine Hormone Levels at Birth and During Childhood.

BACKGROUND: Birth cohort studies have linked exposure to perfluoroalkyl substances (PFASs) with child anthropometry. Metabolic hormone dysregulation needs to be considered as a potential adverse outcome pathway. We examined the associations between PFAS exposures and concentrations of adipokine hormones from birth to adolescence. METHODS: We studied 80 mother-child pairs from a Faroese cohort born in 1997 to 2000. Five PFASs were measured in maternal pregnancy serum and in child serum at ages 5, 7, and 13 years. Leptin, adiponectin, and resistin were analyzed in cord serum and child serum at the same ages. We fitted multivariable-adjusted generalized estimating equations to assess the associations of PFASs at each age with repeated adipokine concentrations at concurrent and subsequent ages. RESULTS: We observed tendencies of inverse associations between PFASs and adipokine hormones specific to particular ages and sex. Significant associations with all adipokines were observed for maternal and child 5-year serum PFAS concentrations, whereas associations for PFASs measured at ages 7 to 13 years were mostly null. The inverse associations with leptin and adiponectin were seen mainly in females, whereas the inverse PFAS associations with resistin levels were seen mainly in males. Estimates for significant associations (P value <0.05) suggested mean decreases in hormone levels (range) by 38% to 89% for leptin, 16% to 70% for adiponectin, and 33% to 62% for resistin for each twofold increase in serum PFAS concentration. CONCLUSIONS: These findings suggest adipokine hormone dysregulation in early life as a potential pathway underlying PFAS-related health outcomes and underscore the need to further account for susceptibility windows and sex-dimorphic effects in future investigations.

Physico-chemical properties and gestational diabetes predict transplacental transfer and partitioning of perfluoroalkyl substances.

BACKGROUND: Per- and polyfluoroalkyl substances (PFASs) are a growing public health concern. Some longer chain PFASs bioaccumulate and many compounds persist in the environment for long time periods. Recent studies have established their ability to pass through placenta, yet data on the transplacental transfer efficiency and partitioning of short and long chain PFASs in blood matrices are limited. OBJECTIVES: To assess predictors of the partitioning of 17 PFAS compounds detected in the maternal serum, umbilical cord serum and whole cord blood samples from matched mother-newborn pairs from two Faroe Islands cohorts. METHODS: We examined 151 mother-newborn pairs from two successive Faroese birth cohorts. Cord:maternal serum (transplacental transfer) and serum:whole cord blood (blood partitioning) ratios were estimated for 17 PFAS compounds. We also examined the relationships of these ratios with maternal, newborns', and physico-chemical properties using multivariable regression analyses. RESULTS: Moderate to high correlations were observed between maternal and cord serum PFAS concentrations (ρ: 0.41 to 0.95), indicating significant transfer of these compounds from the mother to the fetus. Median transplacental transfer ratios were generally below 1, except for perfluorooctane sulfonamide (FOSA), and ranged between 0.36 for perfluorodecanoate (PFDA) and perfluoroundecanoate (PFUnDA) and 1.21 for FOSA. Most PFASs exhibited a preference to the serum component of the blood, except FOSA and perfluoroheptanoate (PFHpA), with blood partitioning ratios ranging from 0.36 for FOSA to 2.75 for PFUnDA. Both the functional groups and carbon chain length of different PFASs were important predictors of transplacental transfer and blood partitioning. We observed a U-shaped relationship between transplacental transfer ratios and carbon chain length for perfluorocarboxylates and perfluorosulfonates. Importantly, gestational diabetes was also a strong predictor of transplacental transfer ratios, with significantly higher transfer in mothers with gestational diabetes. CONCLUSIONS: Our findings provide a better understanding of the transplacental transfer and blood partitioning of a large number of PFAS compounds. Results elucidate the importance of chemical structure for future risk assessments and choice of appropriate blood matrices for measurement of PFAS compounds.

Metabolomics of childhood exposure to perfluoroalkyl substances: a cross-sectional study.

INTRODUCTION: Exposure to perfluoroalkyl substances (PFAS), synthetic and persistent chemicals used in commercial and industrial processes, are associated with cardiometabolic dysfunction and related risk factors including reduced birth weight, excess adiposity, and dyslipidemia. Identifying the metabolic changes induced by PFAS exposure could enhance our understanding of biological pathways underlying PFAS toxicity. OBJECTIVE: To identify metabolic alterations associated with serum concentrations of four PFAS in children using a metabolome-wide association study. METHODS: We performed untargeted metabolomic profiling by liquid chromatography with ultra-high-resolution mass spectrometry, and separately quantified serum concentrations of perfluorooctanoic acid, perfluorooctanesulfonic acid, perfluorononanoic acid, and perfluorohexanesulfonic acid (PFHxS) for 114 8-year old children from Cincinnati, OH. We evaluated associations between each serum PFAS concentration and 16,097 metabolic features using linear regression adjusted for child age, sex, and race with a false discovery rate < 20%. We annotated PFAS-associated metabolites and conducted pathway enrichment analyses. RESULTS: Serum PFAS concentrations were associated with metabolic features annotated primarily as lipids and dietary factors. Biological pathways associated with all four PFAS included arginine, proline, aspartate, asparagine, and butanoate metabolism. CONCLUSIONS: In this cross-sectional study, childhood serum PFAS concentrations were correlated with metabolic pathways related to energy production and catabolism. Future studies should determine whether these pathways mediate associations between PFAS exposure and childhood cardiometabolic health.