A cross-disciplinary evaluation of evidence for multipollutant effects on cardiovascular disease.

BACKGROUND: The current single-pollutant approach to regulating ambient air pollutants is effective at protecting public health, but efficiencies may be gained by addressing issues in a multipollutant context since multiple pollutants often have common sources and individuals are exposed to more than one pollutant at a time. OBJECTIVE: We performed a cross-disciplinary review of the effects of multipollutant exposures on cardiovascular effects. METHODS: A broad literature search for references including at least two criteria air pollutants (particulate matter [PM], ozone [O3], oxides of nitrogen, sulfur oxides, carbon monoxide) was conducted. References were culled based on scientific discipline then searched for terms related to cardiovascular disease. Most multipollutant epidemiologic and experimental (i.e., controlled human exposure, animal toxicology) studies examined PM and O3 together. DISCUSSION: Epidemiologic and experimental studies provide some evidence for O3 concentration modifying the effect of PM, although PM did not modify O3 risk estimates. Experimental studies of combined exposure to PM and O3 provided evidence for additivity, synergism, and/or antagonism depending on the specific health endpoint. Evidence for other pollutant pairs was more limited. CONCLUSIONS: Overall, the evidence for multipollutant effects was often heterogeneous, and the limited number of studies inhibited making a conclusion about the nature of the relationship between pollutant combinations and cardiovascular disease.

Research standardization tools: pregnancy measures in the PhenX Toolkit.

Only through concerted and well-executed research endeavors can we gain the requisite knowledge to advance pregnancy care and have a positive impact on maternal and newborn health. Yet the heterogeneity inherent in individual studies limits our ability to compare and synthesize study results, thus impeding the capacity to draw meaningful conclusions that can be trusted to inform clinical care. The PhenX Toolkit (http://www.phenxtoolkit.org), supported since 2007 by the National Institutes of Health, is a web-based catalog of standardized protocols for measuring phenotypes and exposures relevant for clinical research. In 2016, a working group of pregnancy experts recommended 15 measures for the PhenX Toolkit that are highly relevant to pregnancy research. The working group followed the established PhenX consensus process to recommend protocols that are broadly validated, well established, nonproprietary, and have a relatively low burden for investigators and participants. The working group considered input from the pregnancy experts and the broader research community and included measures addressing the mode of conception, gestational age, fetal growth assessment, prenatal care, the mode of delivery, gestational diabetes, behavioral and mental health, and environmental exposure biomarkers. These pregnancy measures complement the existing measures for other established domains in the PhenX Toolkit, including reproductive health, anthropometrics, demographic characteristics, and alcohol, tobacco, and other substances. The preceding domains influence a woman's health during pregnancy. For each measure, the PhenX Toolkit includes data dictionaries and data collection worksheets that facilitate incorporation of the protocol into new or existing studies. The measures within the pregnancy domain offer a valuable resource to investigators and clinicians and are well poised to facilitate collaborative pregnancy research with the goal to improve patient care. To achieve this aim, investigators whose work includes the perinatal population are encouraged to utilize the PhenX Toolkit in the design and implementation of their studies, thus potentially reducing heterogeneity in data measures across studies. Such an effort will enhance the overall impact of individual studies, increasing the ability to draw more meaningful conclusions that can then be translated into clinical practice.

Improving the risk assessment of lipophilic persistent environmental chemicals in breast milk.

Lipophilic persistent environmental chemicals (LPECs) have the potential to accumulate within a woman's body lipids over the course of many years prior to pregnancy, to partition into human milk, and to transfer to infants upon breastfeeding. As a result of this accumulation and partitioning, a breastfeeding infant's intake of these LPECs may be much greater than his/her mother's average daily exposure. Because the developmental period sets the stage for lifelong health, it is important to be able to accurately assess chemical exposures in early life. In many cases, current human health risk assessment methods do not account for differences between maternal and infant exposures to LPECs or for lifestage-specific effects of exposure to these chemicals. Because of their persistence and accumulation in body lipids and partitioning into breast milk, LPECs present unique challenges for each component of the human health risk assessment process, including hazard identification, dose-response assessment, and exposure assessment. Specific biological modeling approaches are available to support both dose-response and exposure assessment for lactational exposures to LPECs. Yet, lack of data limits the application of these approaches. The goal of this review is to outline the available approaches and to identify key issues that, if addressed, could improve efforts to apply these approaches to risk assessment of lactational exposure to these chemicals.

PFAS Modulate Osmotic Signaling Independent of Gravimetric Changes in the Rat Uterus.

Various PFAS have been identified as potential endocrine-disrupting chemicals due to estrogen receptor activation, impacts on puberty timing, or impacts on hormonally sensitive endpoints in fish. This study screened multiple PFAS in the rat uterotrophic assay to determine potential estrogenic effects on the uterus with PFAS exposure. This study also explored PFAS-dependent uterine signaling with an osmotic stress mRNA gene expression array. Briefly, Sprague-Dawley rats (26-39 days old) were ovariectomized, and uterine tissue was allowed to regress for a 3-week period of recovery. Animals were then exposed daily via oral gavage to PFAS for 4 days, and then uterine weight was determined. In contrast to the positive control estrogens, the PFAS tested (4:2, 6:2, and 8:2FTOH; perfluorooctanesulfonamide (PFOSA), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), nafion byproduct 2 (NBP2), 1H,1H,8H,8H-perfluorooctane-1,8-diol (FC8-diol) and 1H,1H,10H,10H-perfluorodecane-1,10-diol (FC10-diol)) caused no significant changes in the uterine weight. Hormonally active compounds can act as carcinogens, and because earlier rodent work has demonstrated that chronic PFOA exposure is associated with increased risk of uterine cancer, uterine mRNA gene expression was explored with an osmotic stress RT-qPCR array. PFAS exposure significantly upregulated multiple genes across the array, with PFOSA being the compound most similar to the reference estrogens (estradiol benzoate and ethinyl estradiol) in its expression pattern. Also, across all PFAS, pathway analysis revealed that the paxillin pathway, a pathway important in tumor suppressor gene SHP-2 signaling, was significantly upregulated with PFAS exposure. These results demonstrate that in vitro estrogen screens or impacts in fish may show different responses from direct impacts on mammalian uterine weight as assessed with the uterotrophic assay. This study also builds out new mechanisms that may contribute to understanding of carcinogenic changes seen in the uterus after PFAS exposure.

Current Breast Milk PFAS Levels in the United States and Canada: After All This Time, Why Don't We Know More?

BACKGROUND: Despite 20 y of biomonitoring studies of per- and polyfluoroalkyl substances (PFAS) in both serum and urine, we have an extremely limited understanding of PFAS concentrations in breast milk of women from the United States and Canada. The lack of robust information on PFAS concentrations in breast milk and implications for breastfed infants and their families were brought to the forefront by communities impacted by PFAS contamination. OBJECTIVES: The objectives of this work are to: a) document published PFAS breast milk concentrations in the United States and Canada; b) estimate breast milk PFAS levels from maternal serum concentrations in national surveys and communities impacted by PFAS; and c) compare measured/estimated milk PFAS concentrations to screening values. METHODS: We used three studies reporting breast milk concentrations in the United States and Canada We also estimated breast milk PFAS concentrations by multiplying publicly available serum concentrations by milk:serum partitioning ratios for perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA). Measured and estimated breast milk concentrations were compared to children's drinking water screening values. DISCUSSION: Geometric means of estimated breast milk concentrations ranged over approximately two orders of magnitude for the different surveys/communities. All geometric mean and mean estimated and measured breast milk PFOA and PFOS concentrations exceeded drinking water screening values for children, sometimes by more than two orders of magnitude. For PFHxS and PFNA, all measured breast milk levels were below the drinking water screening values for children; the geometric mean estimated breast milk concentrations were close to-or exceeded-the children's drinking water screening values for certain communities. Exceeding a children's drinking water screening value does not indicate that adverse health effects will occur and should not be interpreted as a reason to not breastfeed; it indicates that the situation should be further evaluated. It is past time to have a better understanding of environmental chemical transfer to-and concentrations in-an exceptional source of infant nutrition. https://doi.org/10.1289/EHP10359.

Perspective: Human Milk Composition and Related Data for National Health and Nutrition Monitoring and Related Research.

National health and nutrition monitoring is an important federal effort in the United States and Canada, and the basis for many of their nutrition and health policies. Understanding of child exposures through human milk (HM) remains out of reach due to lack of current and representative data on HM's composition and intake volume. This article provides an overview of the current national health and nutrition monitoring activities for HM-fed children, HM composition (HMC) and volume data used for exposure assessment, categories of potential measures in HM, and associated variability factors. In this Perspective, we advocate for a framework for collection and reporting of HMC data for national health and nutrition monitoring and programmatic needs, including a shared vision for a publicly available Human Milk Composition Data Repository (HMCD-R) to include essential metadata associated with HMC. HMCD-R can provide a central, integrated platform for researchers and public health officials for compiling, evaluating, and sharing HMC data. The compiled compositional and metadata in HMCD-R would provide pertinent measures of central tendency and variability and allow use of modeling techniques to approximate compositional profiles for subgroups, providing more accurate exposure assessments for purposes of monitoring and surveillance. HMC and related metadata could facilitate understanding the complexity and variability of HM composition, provide crucial data for assessment of infant and maternal nutritional needs, and inform public health policies, food and nutrition programs, and clinical practice guidelines.

Concentrations of phthalate metabolites in milk, urine, saliva, and Serum of lactating North Carolina women.

BACKGROUND: Phthalates are ubiquitous in the environment, but concentrations in multiple media from breast-feeding U.S. women have not been evaluated. OBJECTIVES: The objective of this study was to accurately measure and compare the concentrations of oxidative monoester phthalate metabolites in milk and surrogate fluids (serum, saliva, and urine) of 33 lactating North Carolina women. METHODS: We analyzed serum, saliva, urine, and milk for the oxidative phthalate metabolites mono(3-carboxypropyl) phthalate, mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-hydroxyhexyl) phthalate, and mono(2-ethyl-5-oxohexyl) phthalate using isotope-dilution high-performance liquid chromatography tandem mass spectroscopy. Because only urine lacks esterases, we analyzed it for the hydrolytic phthalate monoesters. RESULTS: We detected phthalate metabolites in few milk (< 10%) and saliva samples. MECPP was detected in > 80% of serum samples, but other metabolites were less common (3-22%). Seven of the 10 urinary metabolites were detectable in > or = 85% of samples. Monoethyl phthalate had the highest mean concentration in urine. Metabolite concentrations differed by body fluid (urine > serum > milk and saliva). Questionnaire data suggest that frequent nail polish use, immunoglobulin A, and fasting serum glucose and triglyceride levels were increased among women with higher concentrations of urinary and/or serum phthalate metabolites; motor vehicle age was inversely correlated with certain urinary phthalate concentrations. CONCLUSIONS: Our data suggest that phthalate metabolites are most frequently detected in urine of lactating women and are less often detected in serum, milk, or saliva. Urinary phthalate concentrations reflect maternal exposure and do not represent the concentrations of oxidative metabolites in other body fluids, especially milk.

Associations between longitudinal serum perfluoroalkyl substance (PFAS) levels and measures of thyroid hormone, kidney function, and body mass index in the Fernald Community Cohort.

Perfluoroalkyl substances (PFAS) are a diverse class of manufactured compounds used in a wide range of industrial processes and consumer products and have been detected in human serum worldwide. Previous cross-sectional and cohort studies in humans have suggested exposure to PFAS is associated with a wide array of chronic diseases, including endocrine disruption, developmental health effects, cancer and metabolic changes. We examined the associations between a panel of eight PFAS and indicators of thyroid disruption, kidney function, and body mass index (BMI), all of which were measured at repeated time points (1990-2008) over the course of the study. Participants (N = 210) were selected from the Fernald Community Cohort based on household water supply from a PFAS-contaminated aquifer. In adjusted repeated measures models, we observed several notable associations between serum PFAS and thyroid hormones as well as kidney function as measured by estimated glomerular filtration rate (eGFR). An interquartile (IQR) increase in serum PFOS was associated with a 9.75% (95% CI = 1.72, 18.4) increase in thyroid stimulating hormone. An IQR increase in serum PFNA, PFHxS, and PFDeA was associated with a -1.61% (95% CI = -3.53, -0.59), -2.06% (95% CI = -3.53, -0.59), and -2.20% (95% CI = -4.25, -0.14) change in eGFR, respectively. On the other hand, an IQR increase in serum Me-PFOSA was associated with a 1.53% (95% CI = 0.34, 2.73) increase in eGFR. No significant associations with BMI and serum PFAS were noted. Our findings are in agreement with previous reports that serum PFAS are associated with altered kidney and thyroid function.

Environmental Chemicals in Breast Milk and Formula: Exposure and Risk Assessment Implications.

BACKGROUND: Human health risk assessment methods have advanced in recent years to more accurately estimate risks associated with exposure during childhood. However, predicting risks related to infant exposures to environmental chemicals in breast milk and formula remains challenging. OBJECTIVES: Our goal was to compile available information on infant exposures to environmental chemicals in breast milk and formula, describe methods to characterize infant exposure and potential for health risk in the context of a risk assessment, and identify research needed to improve risk analyses based on this type of exposure and health risk information. METHODS: We reviewed recent literature on levels of environmental chemicals in breast milk and formula, with a focus on data from the United States. We then selected three example publications that quantified infant exposure using breast milk or formula chemical concentrations and estimated breast milk or formula intake. The potential for health risk from these dietary exposures was then characterized by comparison with available health risk benchmarks. We identified areas of this approach in need of improvement to better characterize the potential for infant health risk from this critical exposure pathway. DISCUSSION: Measurements of chemicals in breast milk and formula are integral to the evaluation of risk from early life dietary exposures to environmental chemicals. Risk assessments may also be informed by research investigating the impact of chemical exposure on developmental processes known to be active, and subject to disruption, during infancy, and by analysis of exposure-response data specific to the infant life stage. Critical data gaps exist in all of these areas. CONCLUSIONS: Better-designed studies are needed to characterize infant exposures to environmental chemicals in breast milk and infant formula as well as to improve risk assessments of chemicals found in both foods. https://doi.org/10.1289/EHP1953.

Infant Dietary Exposures to Environmental Chemicals and Infant/Child Health: A Critical Assessment of the Literature.

BACKGROUND: The benefits of breastfeeding to the infant and mother have been well documented. It is also well known that breast milk contains environmental chemicals, and numerous epidemiological studies have explored relationships between background levels of chemicals in breast milk and health outcomes in infants and children. OBJECTIVES: In this paper, we examine epidemiological literature to address the following question: Are infant exposures to background levels of environmental chemicals in breast milk and formula associated with adverse health effects? We critically review this literature a) to explore whether exposure-outcome associations are observed across studies, and b) to assess the literature quality. METHODS: We reviewed literature identified from electronic literature searches. We explored whether exposure-outcome associations are observed across studies by assessing the quality (using a modified version of a previously published quality assessment tool), consistency, and strengths and weaknesses in the literature. The epidemiological literature included cohorts from several countries and examined infants/children either once or multiple times over weeks to years. Health outcomes included four broad categories: growth and maturation, morbidity, biomarkers, and neurodevelopment. RESULTS: The available literature does not provide conclusive evidence of consistent or clinically relevant health consequences to infants exposed to environmental chemicals in breast milk at background levels. CONCLUSIONS: It is clear that more research would better inform our understanding of the potential for health impacts from infant dietary exposures to environmental chemicals. A critical data gap is a lack of research on environmental chemicals in formula and infant/child health outcomes. https://doi.org/10.1289/EHP1954.

Assays for endogenous components of human milk: comparison of fresh and frozen samples and corresponding analytes in serum.

Breast milk is a primary source of nutrition that contains many endogenous compounds that may affect infant development. The goals of this study were to develop reliable assays for selected endogenous breast milk components and to compare levels of those in milk and serum collected from the same mother twice during lactation (2-7 weeks and 3-4 months). Reliable assays were developed for glucose, secretory IgA, interleukin-6, tumor necrosis factor-a, triglycerides, prolactin, and estradiol from participants in a US EPA study called Methods Advancement in Milk Analysis (MAMA). Fresh and frozen (-20 degrees C) milk samples were assayed to determine effects of storage on endogenous analytes. The source effect (serum vs milk) seen in all 7 analytes indicates that serum should not be used as a surrogate for milk in children's health studies. The authors propose to use these assays in studies to examine relationships between the levels of milk components and children's health.

Exposure to Perfluorinated Alkyl Substances and Health Outcomes in Children: A Systematic Review of the Epidemiologic Literature.

Perfluoroalkyl substances (PFAS), chemicals used to make products stain and stick resistant, have been linked to health effects in adults and adverse birth outcomes. A growing body of literature also addresses health effects in children exposed to PFAS. This review summarizes the epidemiologic evidence for relationships between prenatal and/or childhood exposure to PFAS and health outcomes in children as well as to provide a risk of bias analysis of the literature. A systematic review was performed by searching PubMed for studies on PFAS and child health outcomes. We identified 64 studies for inclusion and performed risk of bias analysis on those studies. We determined that risk of bias across studies was low to moderate. Six categories of health outcomes emerged. These were: immunity/infection/asthma, cardio-metabolic, neurodevelopmental/attention, thyroid, renal, and puberty onset. While there are a limited number of studies for any one particular health outcome, there is evidence for positive associations between PFAS and dyslipidemia, immunity (including vaccine response and asthma), renal function, and age at menarche. One finding of note is that while PFASs are mixtures of multiple compounds few studies examine them as such, therefore the role of these compounds as complex mixtures remains largely unknown.

Effects of perfluorinated chemicals on thyroid function, markers of ovarian reserve, and natural fertility.

Perfluorinated chemicals (PFCs) can act as endocrine-disrupting chemicals, but there has been limited study of their effects on ovarian reserve or fecundability. 99 women, 30-44 years old, without infertility were followed until pregnancy. Initially, serum was evaluated for Antimullerian hormone (AMH), thyroid hormones: thyroid stimulating hormone (TSH), thyroxine (T4), free thyroxine (fT4), and triiodothyronine (T3), and PFCs: perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS). Bivariate analyses assessed the relationship between thyroid hormones, AMH, and PFCs. Fecundability ratios (FR) were determined for each PFC using a discrete time-varying Cox model and a day-specific probability model. PFC levels were positively correlated with each other (r 0.24-0.90), but there was no correlation with TSH (r 0.02-0.15) or AMH (r -0.01 to -0.15). FR point estimates for each PFC were neither strong nor statistically significant. Although increased exposure to PFCs correlates with thyroid hormone levels, there is no significant association with fecundability or ovarian reserve.

Polybrominated Diphenyl Ethers in Human Milk and Serum from the U.S. EPA MAMA Study: Modeled Predictions of Infant Exposure and Considerations for Risk Assessment.

BACKGROUND: Serum concentrations of polybrominated diphenyl ethers (PBDEs) in U.S. women are believed to be among the world's highest; however, little information exists on the partitioning of PBDEs between serum and breast milk and how this may affect infant exposure. OBJECTIVES: Paired milk and serum samples were measured for PBDE concentrations in 34 women who participated in the U.S. EPA MAMA Study. Computational models for predicting milk PBDE concentrations from serum were evaluated. METHODS: Samples were analyzed using gas chromatography isotope-dilution high-resolution mass spectrometry. Observed milk PBDE concentrations were compared with model predictions, and models were applied to NHANES serum data to predict milk PBDE concentrations and infant intakes for the U.S. population. RESULTS: Serum and milk samples had detectable concentrations of most PBDEs. BDE-47 was found in the highest concentrations (median serum: 18.6; milk: 31.5 ng/g lipid) and BDE-28 had the highest milk:serum partitioning ratio (2.1 ± 0.2). No evidence of depuration was found. Models demonstrated high reliability and, as of 2007-2008, predicted U.S. milk concentrations of BDE-47, BDE-99, and BDE-100 appear to be declining but BDE-153 may be rising. Predicted infant intakes (ng/kg/day) were below threshold reference doses (RfDs) for BDE-99 and BDE-153 but above the suggested RfD for BDE-47. CONCLUSIONS: Concentrations and partitioning ratios of PBDEs in milk and serum from women in the U.S. EPA MAMA Study are presented for the first time; modeled predictions of milk PBDE concentrations using serum concentrations appear to be a valid method for estimating PBDE exposure in U.S. infants.

Concentrations of environmental phenols and parabens in milk, urine and serum of lactating North Carolina women.

Phenols and parabens show some evidence for endocrine disruption in laboratory animals. The goal of the Methods Advancement for Milk Analysis (MAMA) Study was to develop or adapt methods to measure parabens (methyl, ethyl, butyl, propyl) and phenols (bisphenol A (BPA), 2,4- and 2,5-dichlorophenol, benzophenone-3, triclosan) in urine, milk and serum twice during lactation, to compare concentrations across matrices and with endogenous biomarkers among 34 North Carolina women. These non-persistent chemicals were detected in most urine samples (53-100%) and less frequently in milk or serum; concentrations differed by matrix. Although urinary parabens, triclosan and dichlorophenols concentrations correlated significantly at two time points, those of BPA and benzophenone-3 did not, suggesting considerable variability in those exposures. These pilot data suggest that nursing mothers are exposed to phenols and parabens; urine is the best measurement matrix; and correlations between chemical and endogenous immune-related biomarkers merit further investigation.

The influence of declining air lead levels on blood lead-air lead slope factors in children.

BACKGROUND: It is difficult to discern the proportion of blood lead (PbB) attributable to ambient air lead (PbA), given the multitude of lead (Pb) sources and pathways of exposure. The PbB-PbA relationship has previously been evaluated across populations. This relationship was a central consideration in the 2008 review of the Pb national ambient air quality standards. OBJECTIVES: The objectives of this study were to evaluate the relationship between PbB and PbA concentrations among children nationwide for recent years and to compare the relationship with those obtained from other studies in the literature. METHODS: We merged participant-level data for PbB from the National Health and Nutrition Examination Survey (NHANES) III (1988-1994) and NHANES 9908 (1999-2008) with PbA data from the U.S. Environmental Protection Agency. We applied mixed-effects models, and we computed slope factor, d[PbB]/d[PbA] or the change in PbB per unit change in PbA, from the model results to assess the relationship between PbB and PbA. RESULTS: Comparing the NHANES regression results with those from the literature shows that slope factor increased with decreasing PbA among children 0-11 years of age. CONCLUSION: These findings suggest that a larger relative public health benefit may be derived among children from decreases in PbA at low PbA exposures. Simultaneous declines in Pb from other sources, changes in PbA sampling uncertainties over time largely related to changes in the size distribution of Pb-bearing particulate matter, and limitations regarding sampling size and exposure error may contribute to the variability in slope factor observed across peer-reviewed studies.

Histopathologic changes in the uterus, cervix and vagina of immature CD-1 mice exposed to low doses of perfluorooctanoic acid (PFOA) in a uterotrophic assay.

The estrogenic and antiestrogenic potential of perfluorooctanoic acid (PFOA) was assessed using an immature mouse uterotrophic assay and by histologic evaluation of the uterus, cervix and vagina following treatment. Female offspring of CD-1 dams were weaned at 18days old and assigned to groups of equal weight, and received 0, 0.01, 0.1, or 1mg PFOA/kg BW/d by gavage with or without 17-ß estradiol (E(2), 500µg/kg/d) from PND 18-20 (n=8/treatment/block). At 24h after the third dose (PND 21), uteri were removed and weighed. Absolute and relative uterine weights were significantly increased in the 0.01mg/kg PFOA only group. Characteristic estrogenic changes were present in all E(2)-treated mice; however, they were minimally visible in the 0.01 PFOA only mice. These data suggest that at a low dose PFOA produces minimal histopathologic changes in the reproductive tract of immature female mice, and does not antagonize the histopathologic effects of E(2).

Endocrine disrupting properties of perfluorooctanoic acid.

Perfluoroalkyl acids (PFAAs) have attracted attention in recent years for their environmental ubiquity, as well as their toxicity. Several PFAAs are found in human tissues globally, as humans are exposed on a daily basis through intake of contaminated food, water, and air, irrespective of proximity to industry. Perfluorooctanoic acid (PFOA) is a PFAA shown to be developmentally toxic in mice, with broad and varied health consequences that may include long-lasting effects in reproductive tissues and metabolic reprogramming. To date, the only demonstrated mode of action by which the health effects of PFOA are mediated is via the activation of the peroxisome proliferator-activated receptor alpha (PPARα). The endogenous roles for this receptor, as well as the adverse outcomes of activation by exogenous agents during development, are currently under investigation. Recent studies suggest that PFOA may alter steroid hormone production or act indirectly, via ovarian effects, as a novel means of endocrine disruption. Here we review the existing literature on the known health effects of PFOA in animal models, focusing on sensitive developmental periods. To complement this, we also present epidemiologic health data, with the caveat that these studies largely address only associations between adult exposures and outcomes, rarely focusing on endocrine-specific endpoints, susceptible subpopulations, or windows of sensitivity. Further research in these areas is needed.