Occurrence of Major Perfluorinated Alkylate Substances in Human Blood and Target Organs.

Human exposure to perfluorinated alkylate substances (PFASs) is usually assessed from the concentrations in serum or plasma, assuming one-compartment toxicokinetics. To characterize body distributions of major PFASs, we obtained and extracted tissue samples from 19 forensic autopsies of healthy adult subjects who had died suddenly and were not known to have elevated levels of PFAS exposure. As target organs of toxicological importance, we selected the liver, kidneys, lungs, spleen, and brain, as well as whole blood. Samples weighing about 0.1 g were analyzed by liquid chromatography coupled to triple mass spectrometers. Minor variations in PFAS concentrations were found between the kidney cortex and medulla and between lung lobes. Organ concentrations of perfluorooctanoic sulfonate (PFOS) and perfluorononanoate (PFNA) correlated well with blood concentrations, while perfluorooctanoate (PFOA) and perfluorohexanoic sulfonate (PFHxS) showed more variable associations. Likewise, the liver concentrations correlated well with those of other organs. Calculations of relative distributions were carried out to assess the interdependence of organ retentions. Equilibrium model predictions largely explained the observed PFAS distributions, except for the brain. Although the samples were small and affected by a possible lack of homogeneity, these findings support the use of blood-PFAS concentrations as a measure of PFAS exposure, with the liver possibly acting as the main organ of retention.

Early-life exposure to perfluoroalkyl substances and serum antibody concentrations towards common childhood vaccines in 18-month-old children in the Odense Child Cohort.

Exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with reduced antibody response to childhood vaccinations. Previous studies have mostly focused on antibodies against diphtheria or tetanus, while fewer studies have assessed antibodies toward attenuated viruses, such as measles, mumps or rubella (MMR). Therefore, we set out to determine associations between prenatal and early postnatal PFAS exposure and vaccine-specific Immunoglobulin G (IgG) in the background-exposed Odense Child Cohort. Blood samples were drawn in pregnancy at gestation weeks 8-16 and from the offspring at age 18 months. In the maternal serum samples we quantified perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA). In the offspring serum samples we quantified the same five PFAS compounds and IgG towards diphtheria, tetanus and MMR. A total of 880 and 841 children were included in the analyses of diphtheria and tetanus or MMR, respectively. Multiple linear regression models were used for estimation of difference in virus-specific IgG per doubling of PFAS concentrations. Maternal PFAS concentrations were non-significantly inversely associated with most vaccine-specific antibody concentrations. Likewise, child PFAS concentrations were associated with non-significant reductions of antibodies towards tetanus and MMR. A significant reduction in the percent difference in mumps antibody concentration per doubling of child PFNA (-9.2% (95% confidence interval: -17.4;-0.2)), PFHxS (-8.3% (-15.0;-1.0) and PFOS (-7.9% (-14.8;-0.4) was found. These findings are of public health concern, as inadequate response towards childhood vaccines may represent a more general immune dysfunction.

Dose dependence of prenatal fluoride exposure associations with cognitive performance at school age in three prospective studies.

BACKGROUND: Fluoride may be a developmental neurotoxicant at elevated exposures. We merged new data from a prospective Odense Child Cohort (OCC) with results from two previous birth cohort studies from Mexico and Canada to characterize the dose-effect relationship in greater detail. METHODS: The OCC contributed 837 mother-child pairs to the total of >1500. We measured creatinine-adjusted urine-fluoride concentrations in maternal urine samples obtained during late pregnancy. Child IQ was determined at age 7 years using an abbreviated version of the Wechsler Intelligence Scales for Children. Findings from the three cohorts were used to calculate the joint benchmark concentration (BMC) and the lower confidence limit (BMCL) after adjustment for covariables. RESULTS: In the OCC, urine-fluoride concentrations varied between 0.08 and 3.04 mg/l (median 0.52 mg/l) but were not significantly associated with full-scale IQ at age 7 years (ß = 0.08; 95% confidence interval -1.14 to 1.30 for a doubling in exposure). No difference was apparent between boys and girls. In the OCC, the BMC was 0.92 mg/l, with a BMCL of 0.30 mg/l. The joint analysis of all three cohorts showed a statistically significant association between urine-fluoride and IQ, with a BMC of 0.45 mg/l (BMCL, 0.28 mg/l), slightly higher than the BMC previously reported for the two North American cohorts alone. CONCLUSIONS: As the BMCL reflects an approximate threshold for developmental neurotoxicity, the results suggest that pregnant women and children may need protection against fluoride toxicity.

Association Between Prenatal and Early Postnatal Exposure to Perfluoroalkyl Substances and IQ Score in 7-Year-Old Children From the Odense Child Cohort.

Perfluoroalkyl substances (PFAS) are persistent chemicals capable of crossing the placenta and passing into breast milk. Evidence suggests that PFAS exposure may affect brain development. We investigated whether prenatal or early postnatal PFAS exposure was associated with intelligence quotient (IQ) scores in schoolchildren from the Odense Child Cohort (Denmark, 2010-2020). We assessed concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) in maternal serum collected during the first trimester of pregnancy and in child serum at age 18 months. At 7 years of age, children completed an abbreviated version of the Wechsler Intelligence Scale for Children, Fifth Edition, from which Full Scale Intelligence Quotient (FSIQ) and Verbal Comprehension Index scores were estimated. In multiple linear regression analyses conducted among 967 mother-child pairs, a doubling in maternal PFOS and PFNA concentrations was associated with a lower FSIQ score, while no significant associations were observed for PFOA, PFHxS, or PFDA. PFAS concentrations at age 18 months and duration of breastfeeding were strongly correlated, and even in structural equation models it was not possible to differentiate between the opposite effects of PFAS exposure and duration of breastfeeding on FSIQ. PFAS exposure is ubiquitous; therefore, an association with even a small reduction in IQ is of public health concern.

Estimated exposure to perfluoroalkyl substances during infancy and serum-adipokine concentrations in later childhood.

BACKGROUND: Perfluoroalkyl substances (PFASs) are transferred through human milk and may cause elevated exposure during infancy. Given the lack of early postnatal blood samples, PFAS concentrations can be estimated to serve as predictors of subsequent metabolic toxicity. METHODS: A total of 298 children from a prospective birth cohort were followed up through to age 9 years. Serum-PFAS was measured at birth and 18 months of age, while exposures during infancy were estimated by structural equations. Adiponectin, resistin, leptin, and the leptin receptor were measured in serum at age 9. Adjusted regression coefficients for estimated serum-PFAS concentrations were calculated, with additional consideration of the duration of breastfeeding and potential effect modification by sex. RESULTS: A doubling in estimated serum-PFAS concentrations, particularly at ages 6 and 12 months, was associated with a loss of about 10-15% in age 9 resistin concentrations, while other associations were much weaker. Sex dependence of the associations was not observed, and neither did the duration of breastfeeding affect outcomes at age 9. CONCLUSION: Lowered serum-resistin concentrations at age 9 years were most strongly associated with early postnatal PFAS exposures. These findings suggest that infancy may represent a vulnerable time window for some aspects of metabolic programming that may be affected by PFAS exposure. IMPACT: Serum-PFAS concentrations during infancy can be estimated in the absence of blood samples. Adipokine concentrations were measured at age 9 years as metabolic biomarkers. Resistin was significantly lower in children with elevated PFAS exposures in infancy. The findings suggest that early postnatal PFAS exposures may affect subsequent metabolic health. Assessment of infancy vulnerability to PFAS can be explored using estimated serum-PFAS concentrations.

Paired Liver:Plasma PFAS Concentration Ratios from Adolescents in the Teen-LABS Study and Derivation of Empirical and Mass Balance Models to Predict and Explain Liver PFAS Accumulation.

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity; however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentration ratios were perfectly explained (r2 > 0.99) in a multilinear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this study, the liver:plasma concentration ratio of perfluoroheptanoic acid (PFHpA) was considerably higher than the liver:plasma concentration ratio of other PFAS congeners. Comparing the MLR model with an equilibrium mass balance model (MBM) suggested that complex kinetic transport processes are driving the unexpectedly high liver:plasma concentration ratio of PFHpA. Intratissue MBM modeling pointed to membrane lipids as the tissue constituents that drive the liver accumulation of long-chain, hydrophobic PFAS, whereas albumin binding of hydrophobic PFAS dominated PFAS distribution in plasma. The liver:plasma concentration data set, empirical MLR model, and mechanistic MBM modeling allow the prediction of liver from plasma concentrations measured in human cohort studies. Our study demonstrates that combining biomonitoring data with mechanistic modeling can identify underlying mechanisms of internal distribution and specific target organ toxicity of PFAS in humans.

Gene-environment interactions in the associations of PFAS exposure with insulin sensitivity and beta-cell function in a Faroese cohort followed from birth to adulthood.

BACKGROUND: Exposure to perfluoroalkyl substances (PFAS) has been associated with changes in insulin sensitivity and pancreatic beta-cell function in humans. Genetic predisposition to diabetes may modify these associations; however, this hypothesis has not been yet studied. OBJECTIVES: To evaluate genetic heterogeneity as a modifier in the PFAS association with insulin sensitivity and pancreatic beta-cell function, using a targeted gene-environment (GxE) approach. METHODS: We studied 85 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes, in 665 Faroese adults born in 1986-1987. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were measured in cord whole blood at birth and in participants' serum from age 28 years. We calculated the Matsuda-insulin sensitivity index (ISI) and the insulinogenic index (IGI) based on a 2 h-oral glucose tolerance test performed at age 28. Effect modification was evaluated in linear regression models adjusted for cross-product terms (PFAS*SNP) and important covariates. RESULTS: Prenatal and adult PFOS exposures were significantly associated with decreased insulin sensitivity and increased beta-cell function. PFOA associations were in the same direction but attenuated compared to PFOS. A total of 58 SNPs were associated with at least one PFAS exposure variable and/or Matsuda-ISI or IGI in the Faroese population and were subsequently tested as modifiers in the PFAS-clinical outcome associations. Eighteen SNPs showed interaction p-values (PGxE) < 0.05 in at least one PFAS-clinical outcome association, five of which passed False Discovery Rate (FDR) correction (PGxE-FDR<0.20). SNPs for which we found stronger evidence for GxE interactions included ABCA1 rs3890182, FTO rs9939609, FTO rs3751812, PPARG rs170036314 and SLC12A3 rs2289116 and were more clearly shown to modify the PFAS associations with insulin sensitivity, rather than with beta-cell function. DISCUSSION: Findings from this study suggest that PFAS-associated changes in insulin sensitivity could vary between individuals as a result of genetic predisposition and warrant replication in independent larger populations.

Predictors of serum- per- and polyfluoroalkyl substance (PFAS) concentrations among infants in Guinea-Bissau, West Africa.

BACKGROUND: Knowledge about PFAS exposure in Africa is limited. We have previously detected six types of PFAS in the serum of infants from Guinea-Bissau, West Africa. The aim of this study was to identify predictors of the infant serum-PFAS concentrations. METHODS: This cross-sectional study was based on a subset of data from a randomized controlled trial of early measles vaccination performed in 2012-2015 in three rural regions of Guinea-Bissau. Blood samples were obtained from 237 children aged 4-to-7 months, and six types of PFAS were quantified in serum. Location of residence was recorded, and information about predictors related to socioeconomic status as well as maternal and child characteristics were obtained through structured interviews with the mothers through routine surveillance. Associations between potential predictors and infant serum-PFAS concentrations were examined in linear regression models while adjusting for potential confounding and mediating factors as identified in a directed acyclic graph. RESULTS: Infants from the Cacheu region had the lowest concentrations of perfluorooctanoic acid (PFOA), while infants from the Oio region had the lowest concentrations of all other PFAS. Compared to infants from Oio, infant serum-perfluorooctane sulfonic acid (PFOS) concentrations were 94.1% (95% CI: 52.4, 147.1%) and 81.9% (95% CI: 45.7, 127.1%) higher in Cacheu and Biombo, respectively. Higher maternal age and lower parity were associated with slightly higher child-serum perfluorohexane sulfonic acid (PFHxS) concentrations, while infants with higher socioeconomic status and infants breastfed without supplementary solid foods at inclusion had higher average concentrations of most PFAS, although the confidence intervals were wide and overlapped zero. DISCUSSION: Location of residence was the most important determinant of serum-PFAS concentrations among Guinea-Bissau infants, indicating a potential role of diet as affected by the global spread of PFAS, but future studies should explore reasons for the regional differences in PFAS exposure.

Benchmark dose calculations for PFAS exposure based on two data sets on immunotoxic effects.

BACKGROUND: Exposure to perfluorinated alkylate substances (PFAS) is associated with harmful effects on human health, including developmental immunotoxicity. This outcome was chosen as the critical effect by the European Food Safety Authority (EFSA), which calculated a new joint reference dose for four PFAS using a Benchmark Dose (BMD) analysis of a study of 1-year old children. However, the U.S. Environmental Protection Agency (EPA) recently proposed much lower exposure limits. METHODS: We explored the BMD methodology for summary and individual data and compared the results with and without grouping for two data sets available. We compared the performance of different dose-response models including a hockey-stick model and a piecewise linear model. We considered different ways of testing the assumption of equal weight-based toxicity of the four PFAS and evaluated more flexible models with exposure indices allowing for differences in toxicity. RESULTS: Results relying on full and decile-based data were in good accordance. However, BMD results for the larger study were lower than observed by EFSA for the smaller study. EFSA derived a lower confidence limit for the BMD of 17.5 ng/mL for the sum of serum-PFAS concentration, while similar calculations in the larger cohort yielded values of about 1.5 ng/mL. As the assumption of equal weight-based toxicity of the four PFAS seems questionable, we confirmed dose-dependencies that allowed potency differences between PFAS. We also found that models linear in the parameters for the BMD analysis showed superior coverage probabilities. In particular, we found the piecewise linear model to be useful for Benchmark analysis. CONCLUSIONS: Both data sets considered could be analyzed on a decile basis without important bias or loss of power. The larger study showed substantially lower BMD results, both for individual PFAS and for joint exposures. Overall, EFSA's proposed tolerable exposure limit appears too high, while the EPA proposal is in better accordance with the results.

Consideration of pathways for immunotoxicity of per- and polyfluoroalkyl substances (PFAS).

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are of public health concern, because of their ubiquitous and extremely persistent occurrence, and depending on their structure, their bio-accumulative, mobile and toxic properties. Human health effects associated with exposure to PFAS include adverse effects on the immune system. In 2020, EFSA (the European Food Safety Authority) defined adverse effects on the immune system as the most critical effect for human health risk assessment, based on reduced antibody responses to childhood vaccines and similar effects observed in experimental animal studies. Likewise, the U.S. EPA (Environmental Protection Agency) considers PFAS-induced immunotoxicity, especially in children, as the critical effect for risk assessment. However, the mechanisms by which antibody concentrations are impacted are not completely understood. Furthermore, other targets of the immune system functions have been reported in the literature. OBJECTIVE: The aim of this review is to explore PFAS-associated immune-related effects. This includes, relevant mechanisms that may underlie the observed effects on the immune system, immunosuppression as well as immunoenhancement, such as i) modulation of cell signalling and nuclear receptors, such as NF-κB and PPARs; ii) alteration of calcium signalling and homoeostasis in immune cells; iii) modulation of immune cell populations; iv) oxidative stress and v) impact on fatty acid metabolism & secondary effects on the immune system. METHODS: A literature research was conducted using three databases (Web of Science, PubMed, and Scopus), which were searched in July 2021 for relevant studies published in the time frame from 2018 to 2021. In total, 487 publications were identified as potentially eligible and following expert-based judgement, articles relevant for mechanisms of PFAS induced immunotoxicity are discussed. CONCLUSIONS: Taken together, we show that there is substantial evidence from both in vitro and in vivo experimental as well as epidemiological studies, supporting that various PFAS, not only PFOA and PFOS, affect multiple aspects of the immune system. Timing of exposure is critical, because the developing immune system is especially vulnerable to toxic insults, resulting in a higher risk of particularly adverse immune effects but also other organs later in life.

Effects of Lifetime Exposures to Environmental Contaminants on the Adult Gut Microbiome.

Emerging experimental evidence indicates that toxicant-induced alterations in gut microbiota composition and activity may affect host homeostasis. However, data from human studies are scarce; to our knowledge, no previous studies have quantified the association of lifetime exposure to environmental chemicals, across multiple time points, with the composition of the adult gut microbiome. Here we studied 124 individuals born in the Faroe Islands in 1986-1987 who were followed approximately every seven years from birth through age 28 years. Organochlorine compounds, including polychlorinated biphenyls (PCBs) and pesticides, perfluoroalkyl substances (PFAS), and mercury (Hg), were measured in cord blood and longitudinally in participants' blood. At age 28, the gut microbiome was assessed using shotgun metagenomic sequencing. Historical contaminant exposures had little direct effect on the adult gut microbiome, while a small number of fastidious anaerobes were weakly linked to recent PFAS/PFOS exposures at age 28. In this cohort, our findings suggest no lasting effects of early life exposures on adult gut microbial composition, but proximal exposures may contribute to gut microbiome alterations. The methods developed and used for this investigation may help in future identification of small but lasting impacts of environmental toxicant exposure on the gut microbiome.

Early-life exposure to perfluoroalkyl substances in relation to serum adipokines in a longitudinal birth cohort.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) exposure has been linked to metabolic health outcomes such as obesity, and changes in adipokine hormones may be one of the underlying biological mechanisms. We prospectively evaluated the associations between prenatal and early childhood exposures to PFASs and adipokines in children. MATERIAL AND METHODS: PFAS concentrations were measured in serum samples collected at birth, 18 months, and 5 and 9 years, and adiponectin, leptin, leptin receptor, and resistin were measured in serum samples collected at birth and 9 years. We used multivariable linear regression models to estimate the percent change in serum-adipokine concentrations for a doubling in serum-PFAS concentrations. The potential sex-specific effect of PFAS was assessed by including an interaction term between PFAS and sex in each model. Bayesian kernel machine regression (BKMR) was implemented to evaluate the overall effect of PFAS mixtures. RESULTS: Significant associations with leptin, leptin receptor, and resistin at age 9 years were observed for serum-PFAS concentrations at 18 months and 5 and 9 years, whereas associations for PFAS concentrations at birth were mostly null. However, we observed a positive association between serum-PFHxS at birth and leptin receptor at birth. We found limited evidence regarding modification effect of sex on serum-PFAS concentrations. BKMR findings were consistent and suggested some significant effects of the overall PFAS mixtures at 18 months and 5 and 9 years on adipokine concentrations at 9 years. CONCLUSIONS: Given the associations of PFAS exposure with both adipokine hormones and metabolic functions, future studies should include assessment of adipokine hormones when examining PFAS-associated metabolic alterations.

Concentrations of tetanus and diphtheria antibodies in vaccinated Greenlandic children aged 7-12 years exposed to marine pollutants, a cross sectional study.

Previous studies have shown immunotoxic effects of environmental chemicals, and the European Food Safety Authority (EFSA) recently identified a need for more studies on PFAS immunotoxicity in different populations. In the Arctic, populations are exposed to several environmental chemicals through marine diet, and the objective of this study was therefore to examine the association between Greenlandic children's exposure to major environmental chemicals and their concentrations of diphtheria and tetanus vaccine antibodies after vaccination. The study includes cross-sectional data from Greenlandic children aged 7-12 years examined during 2012-2015. A total of 338 children were eligible for the study, and 175 of these had available vaccination records. A parent or guardian participated in a structured interview, and a blood sample from the child was analyzed for specific antibodies against diphtheria and tetanus as well as perfluoroalkyl substances (PFASs), polychlorinated biphenyls (PCBs) and total mercury. Furthermore, for a subgroup, blood samples from pregnancy were available and analyzed for environmental contaminants. The associations between the environmental exposures and antibody concentrations and odds of having antibody concentrations below the protective level were examined in linear and logistic regression models. In crude analyses, elevated concentrations of some of the contaminants were associated with higher concentrations of diphtheria and tetanus antibodies, but the associations were reversed when adjusting for area of residence, and duration of being breastfed and including children with a known vaccination date only. Each 1 ng/mL increase in serum concentrations of perfluorohexane sulfonic acid (PFHxS) and perfluorooctane sulfonic acid (PFOS) was associated with decreases of 78 % (95 % CI: 25-94 %) and 9 % (95 % CI: 2-16 %), respectively, in diphtheria antibody concentrations. Exposure to PCBs and all PFASs was associated with markedly increased odds of having diphtheria antibody concentrations below the protective level. For each 1 ng/mL increase in serum concentrations of PFHxS, PFOS, perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), odds of not having protective levels of diphtheria antibodies were increased 6.44 times (95 % CI: 1.51-27.36), 1.14 times (95 % CI: 1.04-1.26), 1.96 times (95 % CI: 1.07-3.60), and 5.08 times (95 % CI: 1.32-19.51, respectively. No consistent associations were seen between maternal contaminant concentrations and vaccine antibody concentrations. In conclusion, we found that increased exposure to environmental chemicals among children in this Arctic population were associated with a decrease in post-vaccination antibody concentrations and with increased odds of not being protected against diphtheria despite appropriate vaccination. These findings emphasize the risk of environmental chemical exposures also in this Arctic population.

Plasma concentrations of perfluoroalkyl substances and risk of inflammatory bowel diseases in women: A nested case control analysis in the Nurses' Health Study cohorts.

BACKGROUND: Perfluoroalkyl substances (PFASs) are synthetic compounds used in a wide variety of industrial and consumer applications. An association between PFAS exposure and risk of ulcerative colitis (UC) has been reported in a highly exposed population. However, data are limited on risk of inflammatory bowel diseases (IBD) among individuals with background population levels of PFAS exposure. OBJECTIVES: We set out to examine the association between plasma PFAS concentrations and risk of IBD among women in two population-based, prospective cohort studies in which pre-diagnostic blood specimens were available. METHODS: We conducted a nested case-control study in the Nurses' Health Study and Nurses' Health Study II cohorts. We identified 73 participants with incident Crohn's disease (CD) and 80 participants with incident UC who had provided blood samples before diagnosis. Cases were matched 1:2 to IBD-free controls. Plasma concentrations of five major PFASs were measured by liquid chromatography and tandem mass spectrometry. We used conditional logistic models to estimated odds ratios for risk of IBD according to log10-transformed PFAS concentrations, adjusting for potential confounders. RESULTS: In multivariable models, we observed inverse associations between plasma concentrations of three PFASs and risk of CD (all P ≤ 0.012 for a standard deviation increase in log10PFAS). The inverse association with CD was strongest for perfluorodecanoate, where, compared to the lowest tertile, the odds ratio (OR) for the highest tertile was 0.39 (95% confidence interval, 0.17-0.92). No associations were observed between PFAS concentrations and UC risk. DISCUSSION: Our results do not support the hypothesis that elevated PFAS exposure is associated with higher risk of UC. Contrary to expectation, our data suggest that circulating concentrations of some PFASs may be inversely associated with CD development.

Higher free thyroxine associated with PFAS exposure in first trimester. The Odense Child Cohort.

BACKGROUND: Perfluoroalkyl substances (PFAS) are endocrine disrupting chemicals with elimination half-lives ranging from four to eight years. Experimental studies found PFAS able to interfere with thyroid hormone-binding proteins. During the first 20 weeks of gestation (GW), the fetus is reliant on placental transfer of maternal thyroid hormones, mainly free thyroxine (FT4). However, previous studies investigating associations between exposure to PFAS and thyroid hormone status mainly focused on blood samples from late pregnancy or umbilical cord with mixed findings. OBJECTIVES: To investigate associations between serum-PFAS concentrations and thyroid hormone status in early pregnancy as reflected by FT4 and thyroid-stimulating hormone (TSH). METHODS: In the Odense Child Cohort, a single-center study, we measured maternal pregnancy serum concentrations of five PFAS: perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA); and FT4 and TSH in 1048 pregnant women at median GW 12 (25th, 75th percentile: 10, 15). Multivariate linear regression models were performed to estimate associations between PFAS exposure and thyroid hormone status. RESULTS: A doubling in PFOS, PFOA, and PFNA concentrations was associated with an increment in FT4 concentration by 1.85% (95% CI: 0.66%, 3.05%), 1.29% (95% CI: 0.21%, 2.39%), and 1.70% (95% CI: 0.48%, 2.94%), respectively, in adjusted analyses. A statistically significant dose-response relationship was observed across exposure quartiles for PFOS, PFOA, and PFNA in the association with FT4. No association was found between concentrations of PFAS and TSH in adjusted analyses. CONCLUSION: Exposure to PFOS, PFOA, and PFNA was associated with higher FT4 concentrations in women during early pregnancy. The potential clinical implications of these findings remain to be clarified.

Bone mass density following developmental exposures to perfluoroalkyl substances (PFAS): a longitudinal cohort study.

BACKGROUND: Environmental exposures to industrial chemicals, including perfluoroalkyl substances (PFAS), may play a role in bone development and future risk of osteoporosis. However, as prospective evidence is limited, the role of developmental PFAS exposures in bone density changes in childhood is unclear. The objective of this study was to estimate associations between serum-PFAS concentrations measured in infancy and early childhood and areal bone mineral density (aBMD) measured at age 9 years in a birth cohort of children from the Faroe Islands. METHODS: We prospectively measured concentrations of five PFAS in cord serum and serum collected at 18 months, 5 years and 9 years, and conducted whole-body DXA scans at the 9-year clinical visit. Our study included 366 mother-child pairs with DXA scans and at least one PFAS measurement. We estimated covariate-adjusted associations of individual PFAS concentrations with age-, sex- and height-adjusted aBMD z-scores using multivariable regression models and applied formal mediation analysis to estimate the possible impact of by several measures of body composition. We also evaluated whether associations were modified by child sex. RESULTS: We found PFAS exposures in childhood to be negatively associated with aBMD z-scores, with the strongest association seen for perfluorononanoic acid (PFNA) at age 5 years. A doubling in age-5 PFNA was associated with a 0.15 decrease in aBMD z-score (95% CI: - 0.26, - 0.039). The PFNA-aBMD association was significantly stronger in males than females, although effect modification by sex was not significant for other PFAS exposures. Results from the mediation analysis suggested that any potential associations between aBMD and 18-month PFAS concentrations may be mediated by total body fat and BMI, although most estimated total effects for PFAS exposures at age 18 months were non-significant. PFAS exposures at age 9 were not associated with age-9 aBMD z-scores. CONCLUSIONS: The PFAS-aBMD associations identified in this and previous studies suggest that bone may be a target tissue for PFAS. Pediatric bone density has been demonstrated to strongly track through young adulthood and possibly beyond; therefore, these prospective results may have important public health implications.

Reducing disease and death from Artisanal and Small-Scale Mining (ASM) - the urgent need for responsible mining in the context of growing global demand for minerals and metals for climate change mitigation.

Artisanal and small-scale mining (ASM) takes place under extreme conditions with a lack of occupational health and safety. As the demand for metals is increasing due in part to their extensive use in 'green technologies' for climate change mitigation, the negative environmental and occupational consequences of mining practices are disproportionately felt in low- and middle-income countries. The Collegium Ramazzini statement on ASM presents updated information on its neglected health hazards that include multiple toxic hazards, most notably mercury, lead, cyanide, arsenic, cadmium, and cobalt, as well as physical hazards, most notably airborne dust and noise, and the high risk of infectious diseases. These hazards affect both miners and mining communities as working and living spaces are rarely separated. The impact on children and women is often severe, including hazardous exposures during the child-bearing age and pregnancies, and the risk of child labor. We suggest strategies for the mitigation of these hazards and classify those according to primordial, primary, secondary, and tertiary prevention. Further, we identify knowledge gaps and issue recommendations for international, national, and local governments, metal purchasers, and employers are given. With this statement, the Collegium Ramazzini calls for the extension of efforts to minimize all hazards that confront ASM miners and their families.

Public-health risks from tea drinking: Fluoride exposure.

AIMS: Due to new evidence on fluoride neurotoxicity during early life, this study examined maternal exposure to fluoride through tea consumption in a low-fluoride region and measured fluoride releases from commercially available teas (tea bags and loose teas) to determine the need to limit fluoride exposure. METHODS: Maternal urine fluoride (MUF) concentrations were measured in spot urine samples (N=118) from first-trimester pregnant women and in prepared tea infusions made with deionised water from 33 brand teas and 57 loose-tea products, as determined by the direct method of using a fluoride-selective electrode. RESULTS: The fluoride concentration in the local drinking water supplies ranged from 0.10 to 0.18 mg/L, and the creatinine-adjusted MUF ranged from 0.09 to 1.57 mg/L. Seventeen per cent of the women were daily tea drinkers, and their MUFs were higher than those with no consumption (p=0.002). The fluoride concentration from tea bags ranged from 0.34 to 2.67 mg/L, while loose teas showed 0.72-4.50 mg/L (black), 0.56-1.58 mg/L (oolong), 1.28-1.50 mg/L (green), and 0.33-1.17 mg/L (white tea). CONCLUSIONS: Fluoride exposure among pregnant women increases with tea consumption, with likely risks of developmental neurotoxicity to their children. As the fluoride release from tea varies widely, the fluoride concentration should be indicated on tea packages in order to allow consumers to make informed decisions on minimising their fluoride exposure.

A Benchmark Dose Analysis for Maternal Pregnancy Urine-Fluoride and IQ in Children.

As a guide to establishing a safe exposure level for fluoride exposure in pregnancy, we applied benchmark dose modeling to data from two prospective birth cohort studies. We included mother-child pairs from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort in Mexico and the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort in Canada. Maternal urinary fluoride concentrations (U-F, in mg/L, creatinine-adjusted) were measured in urine samples obtained during pregnancy. Children were assessed for intelligence quotient (IQ) at age 4 (n = 211) and between six and 12 years (n = 287) in the ELEMENT cohort, and three to four years (n = 407) in the MIREC cohort. We calculated covariate-adjusted regression coefficients and their standard errors to assess the association of maternal U-F concentrations with children's IQ measures. Assuming a benchmark response of 1 IQ point, we derived benchmark concentrations (BMCs) and benchmark concentration levels (BMCLs). No deviation from linearity was detected in the dose-response relationships, but boys showed lower BMC values than girls. Using a linear slope for the joint cohort data, the BMC for maternal U-F associated with a 1-point decrease in IQ scores was 0.31 mg/L (BMCL, 0.19 mg/L) for the youngest boys and girls in the two cohorts, and 0.33 mg/L (BMCL, 0.20 mg/L) for the MIREC cohort and the older ELEMENT children. Thus, the joint data show a BMCL in terms of the adjusted U-F concentrations in the pregnant women of approximately 0.2 mg/L. These results can be used to guide decisions on preventing excess fluoride exposure in pregnant women.

PFAS concentration during pregnancy in relation to cardiometabolic health and birth outcomes.

INTRODUCTION: Poly- and perfluoroalkyl substances (PFAS) are persistent organic pollutants with pervasive exposure and suspected associations with metabolic abnormalities and adverse pregnancy outcomes. The goal of the present study was to examine the relationship between serum-PFAS concentrations measured in late pregnancy with relevant outcomes. METHODS: The study sample included 433 pregnant women enrolled in the Vanguard Pilot Study of the National Children's Study. Six PFAS were measured in primarily third trimester serum, as well as fasting insulin, total cholesterol, and triglycerides. The PFAS were examined in quartiles in relation to serum biomarkers, gestational age at birth and birth weight standardized for gestational age using multivariable-adjusted regression models. RESULTS: Over 98% of the study population had detectable concentrations of four of the PFAS, and concentrations varied by race/ethnicity. Total cholesterol was positively associated with PFDA, PFNA, and PFOS, and triglycerides with PFDA, PFNA, PFOS, and PFOA, but PFAS were not associated with fasting insulin in adjusted models. Only PFNA was associated with an increased odds of birth at <37 weeks gestation. PFAS were generally not associated with birth weight, though PFHxS was associated with the first quartile of birth weight among males only. CONCLUSIONS: This study of pregnant U.S. women supports the ubiquitous exposure to PFAS and positive associations between PFAS exposure with serum-lipid concentrations. PFAS were largely unassociated with gestational age at birth and birth weight, though PFNA was associated with preterm birth. The results support the vulnerability to PFAS exposure of pregnancy.