After the discovery of fluoride as a caries-preventing agent in the mid-twentieth century, fluoridation of community water has become a widespread intervention, sometimes hailed as a mainstay of modern public health. However, this practice results in elevated fluoride intake and has become controversial for two reasons. First, topical fluoride application in the oral cavity appears to be a more direct and appropriate means of preventing caries. Second, systemic fluoride uptake is suspected of causing adverse effects, in particular neurotoxicity during early development. The latter is supported by experimental neurotoxicity findings and toxicokinetic evidence of fluoride passing into the brain.
Dose dependence of prenatal fluoride exposure associations with cognitive performance at school age in three prospective studies
Abstract 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 (β = 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.
County-level associations between drinking water PFAS contamination and COVID-19 mortality in the United States
Epidemiologic and animal studies both support relationships between exposures to per- and polyfluoroalkyl substances (PFAS) and harmful effects on the immune system. Accordingly, PFAS have been identified as potential environmental risk factors for adverse COVID-19 outcomes.
Tap Water Contributions to Plasma Concentrations of Poly- and Perfluoroalkyl Substances (PFAS) in a Nationwide Prospective Cohort of U.S. Women
Abstract Background: Between 2013 and 2015, concentrations of poly- and perfluoroalkyl substances (PFAS) in public drinking water supplies serving at least six million individuals exceeded the level set forth in the health advisory established by the U.S. Environmental Protection Agency. Other than data reported for contaminated sites, no systematic or prospective data exist on the relative source contribution (RSC) of drinking water to human PFAS exposures. Objectives: This study estimates the RSC of tap water to overall PFAS exposure among members of the general U.S. population. Methods: We measured concentrations of 15 PFAS in home tap water samples collected in 1989–1990 from 225 participants in a nationwide prospective cohort of U.S. women: the Nurses’ Health Study (NHS). We used a one-compartment toxicokinetic model to estimate plasma concentrations corresponding to tap water intake of PFAS. We compared modeled results with measured plasma PFAS concentrations among a subset of 110 NHS participants. Results: Tap water perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) were statistically significant predictors of plasma concentrations among individuals who consumed ≥8 cups of tap water per day. Modeled median contributions of tap water to measured plasma concentrations were: PFOA 12% (95% probability interval 11%–14%), PFNA 13% (8.7%–21%), linear perfluorooctanesulfonic acid (nPFOS) 2.2% (2.0%–2.5%), branched perfluorooctanesulfonic acid (brPFOS) 3.0% (2.5%–3.2%), and perfluorohexanesulfonic acid (PFHxS) 34% (29%–39%). In five locations, comparisons of PFASs in community tap water collected in the period 2013–2016 with samples from 1989–1990 indicated increases in quantifiable PFAS and extractable organic fluorine (a proxy for unquantified PFAS). Conclusions: Our results for 1989–1990 compare well with the default RSC of 20% used in risk assessments for legacy PFAS by many agencies. Future evaluation of drinking water exposures should incorporate emerging PFAS. https://doi.org/10.1289/EHP4093
A Benchmark Dose Analysis for Maternal Pregnancy Urine‐Fluoride and IQ in Children
Abstract 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.
TrifluoroaceticAcid (TFA) Exceeds All Other ExtractableOrganofluorine in Drinking Water from Eastern Massachusetts, UnitedStates
Abstract Per- and polyfluoroalkyl substances (PFAS) are present in drinking water consumed by ∼200 million United States (US) residents, but many are not detected by routine monitoring methods. Here, we aimed to better characterize the organofluorine mass budget in US drinking water samples from 19 sites in eastern Massachusetts. Extractable organofluorine (EOF) was detected at 16/17 sites served by community water systems (CWS) using conventional treatment techniques (coagulation, flocculation, clarification, and filtration). At these sites, a suite of 37 targeted PFAS accounted for 6–68% of the EOF and suspect screening identified fluorinated agrochemicals in almost all samples. High EOF concentrations in untreated source waters for two CWS that used granular activated carbon (GAC) and ion-exchange (IX) treatment, were reduced below detection in finished drinking water samples. Our EOF measurements were not selective for trifluoroacetic acid (TFA), so we measured concentrations in triplicate samples at one conventional treatment site and from the IX and GAC sites. At these sites, TFA concentrations were higher than those of EOF and were unaffected by the treatment type. Results of this pilot study show GAC and IX treatment removed virtually all organofluorine in drinking water other than TFA.
Sociodemographic Factors Are Associated with the Abundance of PFAS Sources and Detection in U.S. Community Water Systems
Abstract. Drinking water contaminated by per- and polyfluoroalkyl substances (PFAS) is a widespread public health concern, and exposure–response relationsh
Understanding Mechanisms of PFAS Absorption, Distribution, and Elimination Using a Physiologically Based Toxicokinetic Model
Abstract. Exposures to some per- and polyfluoroalkyl substances (PFAS), including perfluoroalkyl acids (PFAA), have been associated with diverse adverse he
A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects
Here, we review present understanding of sources and trends in human exposure to poly- and perfluoroalkyl substances (PFASs) and epidemiologic evidence for impacts on cancer, immune function, metabolic outcomes, and neurodevelopment. More than 4000 PFASs have been manufactured by humans and hundreds have been detected in environmental samples. Direct exposures due to use in products can be quickly phased out by shifts in chemical production but exposures driven by PFAS accumulation in the ocean and marine food chains and contamination of groundwater persist over long timescales. Serum concentrations of legacy PFASs in humans are declining globally but total exposures to newer PFASs and precursor compounds have not been well characterized. Human exposures to legacy PFASs from seafood and drinking water are stable or increasing in many regions, suggesting observed declines reflect phase-outs in legacy PFAS use in consumer products. Many regions globally are continuing to discover PFAS contaminated sites from aqueous film forming foam (AFFF) use, particularly next to airports and military bases. Exposures from food packaging and indoor environments are uncertain due to a rapidly changing chemical landscape where legacy PFASs have been replaced by diverse precursors and custom molecules that are difficult to detect. Multiple studies find significant associations between PFAS exposure and adverse immune outcomes in children. Dyslipidemia is the strongest metabolic outcome associated with PFAS exposure. Evidence for cancer is limited to manufacturing locations with extremely high exposures and insufficient data are available to characterize impacts of PFAS exposures on neurodevelopment. Preliminary evidence suggests significant health effects associated with exposures to emerging PFASs. Lessons learned from legacy PFASs indicate that limited data should not be used as a justification to delay risk mitigation actions for replacement PFASs.
Safety of Safety Evaluation of Pesticides: developmental neurotoxicity of chlorpyrifos and chlorpyrifos-methyl
Authorization of pesticides for market release requires toxicity testing on animals, typically performed by test laboratories on contract with the pesticide producer. The latter provides the results and summary to the regulatory authorities. For the commonly used pesticide chlorpyrifos, an industry-funded toxicity study concludes that no selective effects on neurodevelopment occur even at high exposures. In contrast, the evidence from independent studies points to adverse effects of current exposures on cognitive development in children. We reviewed the industry-funded developmental neurotoxicity test data on chlorpyrifos and the related substance chlorpyrifos-methyl. We noted treatment-related changes in a brain dimension measure for chlorpyrifos at all dose levels tested, although not been reported in the original test summary. We further found issues which inappropriately decrease the ability of the studies to reveal true effects, including a dosage regimen that resulted in too low exposure of the nursing pups for chlorpyrifos and possibly for chlorpyrifos-methyl, and a failure to detect any neurobehavioral effects of lead nitrate used as positive control in the chlorpyrifos study. Our observations thus suggest that conclusions in test reports submitted by the producer may be misleading. This discrepancy affects the ability of regulatory authorities to perform a valid and safe evaluation of these pesticides. The difference between raw data and conclusions in the test reports indicates a potential existence of bias that would require regulatory attention and possible resolution.
Bone mass density following developmental exposures to perfluoroalkyl substances (PFAS): a longitudinal cohort study
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.
Species-Specific Unbound Fraction Differences in Highly Bound PFAS: A Comparative Study across Human, Rat, and Mouse Plasma and Albumin
Per- and polyfluoroalkyl substances (PFAS) are a diverse group of fluorinated compounds which have yet to undergo comprehensive investigation regarding potential adverse health effects and bioaccumulative properties. With long half-lives and accumulative properties, PFAS have been linked to several toxic effects in both non-clinical species such as rat and mouse as well as human. Although biological impacts and specific protein binding of PFAS have been examined, there is no study focusing on the species-specific fraction unbound (fu) in plasma and related toxicokinetics. Herein, a presaturation equilibrium dialysis method was used to measure and validate the binding of 14 individual PFAS with carbon chains containing 4 to 12 perfluorinated carbon atoms and several functional head-groups to albumin and plasma of mouse (C57BL/6 and CD-1), rat, and human. Equivalence testing between each species-matrix combination showed positive correlation between rat and human when comparing fu in plasma and binding to albumin. Similar trends in binding were also observed for mouse plasma and albumin. Relatively high Spearman correlations for all combinations indicate high concordance of PFAS binding regardless of matrix. Physiochemical properties of PFAS such as molecular weight, chain length, and lipophilicity were found to have important roles in plasma protein binding of PFAS.
Serum Perfluoroalkyl Substances, Vaccine Responses, and Morbidity in a Cohort of Guinea-Bissau Children
Guideline levels for PFOA and PFOS in drinking water: the role of scientific uncertainty, risk assessment decisions, and social factors
Communities across the U.S. are discovering drinking water contaminated by perfluoroalkyl and polyfluoroalkyl substances (PFAS) and determining appropriate actions. There are currently no federal PFAS drinking water standards despite widespread drinking water contamination, ubiquitous population-level exposure, and toxicological and epidemiological evidence of adverse health effects. Absent federal PFAS standards, multiple U.S. states have developed their own health-based water guideline levels to guide decisions about contaminated site cleanup and drinking water surveillance and treatment. We examined perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) water guideline levels developed by the U.S. Environmental Protection Agency (EPA) and state agencies to protect people drinking the water, and summarized how and why these levels differ. We referenced documents and tables released in June 2018 by the Interstate Technology and Regulatory Council (ITRC) to identify states that have drinking water and groundwater guideline levels for PFOA and/or PFOS that differ from EPA’s health advisories (HAs). We also gathered assessment documents from state websites and contacted state environmental and health agencies to identify and confirm current guidelines. Seven states have developed their own water guideline levels for PFOA and/or PFOS ranging from 13 to 1000 ng/L, compared to EPA’s HA of 70 ng/L for both compounds individually or combined. We find that the development of PFAS guideline levels via exposure and hazard assessment decisions is influenced by multiple scientific, technical, and social factors, including managing scientific uncertainty, technical decisions and capacity, and social, political, and economic influences from involved stakeholders. Assessments by multiple states and academic scientists suggest that EPA’s HA is not sufficiently protective. The ability of states to develop their own guideline levels and standards provides diverse risk assessment approaches as models for other state and federal regulators, while a sufficiently protective, scientifically sound, and enforceable federal standard would provide more consistent protection.
Unbound Fractions of PFAS in Human and Rodent Tissues: Rat Liver a Suitable Proxy for Evaluating Emerging PFAS?
Abstract. Adverse health effects associated with exposures to perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a concern for public health and are
Benchmark dose calculations for PFAS exposure based on two data sets on immunotoxic effects
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.
Binding of Per- and Polyfluoroalkyl Substances (PFAS) to Serum Proteins: Implications for Toxicokinetics in Humans
Abstract. Per- and polyfluoroalkyl substances (PFAS) are a diverse class of highly persistent anthropogenic chemicals that are detectable in the serum of m
