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Background: The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to 0.2  ng / kg  body weight  ( BW ) / day . BPA is an extensively studied high production volume endocrine disrupting chemical (EDC) associated with a vast array of diseases. Prior risk assessments of BPA by EFSA as well as the US Food and Drug Administration (FDA) have relied on industry-funded studies conducted under good laboratory practice protocols (GLP) requiring guideline end points and detailed record keeping, while also claiming to examine (but rejecting) thousands of published findings by academic scientists. Guideline protocols initially formalized in the mid-twentieth century are still used by many regulatory agencies. EFSA used a 21st century approach in its reassessment of BPA and conducted a transparent, but time-limited, systematic review that included both guideline and academic research. The German Federal Institute for Risk Assessment (BfR) opposed EFSA's revision of the TDI for BPA., Objectives: We identify the flaws in the assumptions that the German BfR, as well as the FDA, have used to justify maintaining the TDI for BPA at levels above what a vast amount of academic research shows to cause harm. We argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications using the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) nonguideline academic studies in a collaborative government-academic program model., Discussion: We strongly endorse EFSA's revised TDI for BPA and support the European Commission's (EC) apparent acceptance of this updated BPA risk assessment. We discuss challenges to current chemical risk assessment assumptions about EDCs that need to be addressed by regulatory agencies to, in our opinion, become truly protective of public health. Addressing these challenges will hopefully result in BPA, and eventually other structurally similar bisphenols (called regrettable substitutions) for which there are known adverse effects, being eliminated from all food-related and many other uses in the EU and elsewhere. https://doi.org/10.1289/EHP13812.

The European Food Safety Authority (EFSA) has revised their estimate of the toxicity of bisphenol A (BPA) and, as a result, have recommended reducing the tolerable daily intake (TDI) by 20 000-fold. This would essentially ban the use of BPA in food packaging such as can liners, plastic food containers, and in consumer products. To come to this conclusion, EFSA used a systematic approach according to a pre-established protocol and included all guideline and nonguideline studies in their analysis. They found that Th-17 immune cells increased with very low exposure to BPA and used this endpoint to revise the TDI to be human health protective. A number of regulatory agencies including the European Medicines Agency (EMA) have written formal disagreements with several elements of EFSA's proposal. The European Commission will now decide whether to accept EFSA's recommendation over the objections of EMA. If the Commission accepts EFSA's recommendation, it will be a landmark action using knowledge acquired through independent scientific studies focused on biomarkers of chronic disease to protect human health. The goal of this Perspective is to clearly articulate the monumental nature of this debate and decision and to explain what is at stake. Our perspective is that the weight of evidence clearly supports EFSA's proposal to reduce the TDI by 20 000-fold., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: In the US, the Food and Drug Administration (US FDA) is charged with protecting the safety of food from both pathogens and chemicals used in food production and food packaging. To protect the public in a transparent manner, the FDA needs to have an operational definition of what it considers to be an "adverse effect" so that it can take action against harmful agents. The FDA has recently published two statements where, for the first time, it defines the characteristics of an adverse effect that it uses to interpret toxicity studies., Objective: In this brief review, we examine two recent actions by the FDA, a proposed rule regarding a color additive used in vegetarian burgers and a decision not to recall fish with high levels of scombrotoxin. We evaluated the FDA's description of the criteria used to determine which outcomes should be considered adverse., Overview: We describe three reasons why the FDA's criteria for "adverse effects" is not public health protective. These include an unscientific requirement for a monotonic dose response, which conflates hazard assessment and dose response assessment while also ignoring evidence for non-linear and non-monotonic effects for many environmental agents; a requirement that the effect be observed in both sexes, which fails to acknowledge the many sex- and gender-specific effects on physiology, disease incidence and severity, and anatomy; and a requirement that the effects are irreversible, which does not acknowledge the role of exposure timing or appreciate transgenerational effects that have been demonstrated for environmental chemicals., Conclusions: The FDA's criteria for identifying adverse effects are inadequate because they are not science-based. Addressing this is important, because the acknowledgement of adverse effects is central to regulatory decisions and the protection of public health., (© 2023. The Author(s).)

Background: While fluoride can have thyroid-disrupting effects, associations between low-level fluoride exposure and thyroid conditions remain unclear, especially during pregnancy when insufficient thyroid hormones can adversely impact offspring development., Objectives: We evaluated associations between fluoride exposure and hypothyroidism in a Canadian pregnancy cohort., Methods: We measured fluoride concentrations in drinking water and three dilution-corrected urine samples and estimated fluoride intake based on self-reported beverage consumption. We classified women enrolled in the Maternal-Infant Research on Environmental Chemicals Study as euthyroid (n = 1301), subclinical hypothyroid (n = 100) or primary hypothyroid (n = 107) based on their thyroid hormone levels in trimester one. We used multinomial logistic regression to estimate the association between fluoride exposure and classification of either subclinical or primary hypothyroidism and considered maternal thyroid peroxidase antibody (TPOAb) status, a marker of autoimmune hypothyroidism, as an effect modifier. In a subsample of 466 mother-child pairs, we used linear regression to explore the association between maternal hypothyroidism and child Full-Scale IQ (FSIQ) at ages 3-to-4 years and tested for effect modification by child sex., Results: A 0.5 mg/L increase in drinking water fluoride concentration was associated with a 1.65 (95 % confidence interval [CI]: 1.04, 2.60) increased odds of primary hypothyroidism. In contrast, we did not find a significant association between urinary fluoride (adjusted odds ratio [aOR]: 1.00; 95%CI: 0.73, 1.39) or fluoride intake (aOR: 1.25; 95%CI: 0.99, 1.57) and hypothyroidism. Among women with normal TPOAb levels, the risk of primary hypothyroidism increased with both increasing water fluoride and fluoride intake (aOR water fluoride concentration: 2.85; 95%CI: 1.25, 6.50; aOR fluoride intake: 1.75; 95%CI: 1.27, 2.41). Children born to women with primary hypothyroidism had lower FSIQ scores compared to children of euthyroid women, especially among boys (B coefficient: -8.42; 95 % CI: -15.33, -1.50)., Discussion: Fluoride in drinking water was associated with increased risk of hypothyroidism in pregnant women. Thyroid disruption may contribute to developmental neurotoxicity of fluoride., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rick Hornung reports financial support was provided by National Institute of Environmental Health Sciences. Christine Till reports a relationship with Health Research Board, Dublin that includes: consulting or advisory. Meaghan Hall reports a relationship with NIEHS that includes: travel reimbursement. Christine Till reports a relationship with National Institute of Environmental Health Sciences that includes: travel reimbursement. Dr. Lanphear served as a non-retained expert witness in the federal fluoride case to describe the results of the fluoride studies using the MIREC cohort (Food & Water Watch, et al. vs. U.S. Environmental Protection Agency, United States District Court for the Northern District of California at San Francisco). He received no payment for his service., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Maternal thyroid function plays an important role in foetal brain development; however, little consensus exists regarding the relationship between normal variability in thyroid hormones and common neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD)., Objective: We sought to examine the association between mid-pregnancy maternal thyroid function and risk of clinically diagnosed ADHD in offspring., Methods: We conducted a nested case-control study in the Norwegian Mother, Father and Child Cohort Study. Among children born 2003 or later, we randomly sampled singleton ADHD cases obtained through linkage with the Norwegian Patient Registry (n = 298) and 554 controls. Concentrations of maternal triiodothyronine (T3), thyroxine (T4), T3-Uptake, thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPO-Ab) were measured in maternal plasma, collected at approximately 17 weeks' gestation. Indices of free T4 (FT4i) and free T3 (FT3i) were calculated. We used multivariable adjusted logistic regression to calculate odds ratios and accounted for missing covariate data using multiple imputation. We used restricted cubic splines to assess non-linear trends and provide flexible representations. We examined effect measure modification by dietary iodine and selenium intake. In sensitivity analyses, we excluded women with clinically significant thyroid disorders (n = 73)., Results: High maternal T3 was associated with increased risk of ADHD (5th vs 1st quintile odds ratio  2.27, 95% confidence interval 1.21, 4.26). For FT4i, both the lowest and highest quintiles were associated with an approximate 1.6-fold increase in risk of ADHD, with similar trends found for T4. The FT4i association was modified by dietary iodine intake such that the highest risk strata were confined to the low intake group., Conclusions: Both high and low concentrations of maternal thyroid hormones, although within population reference ranges, increase the risk of ADHD in offspring. Increased susceptibility may be found among women with low dietary intake of iodine and selenium., (© 2022 John Wiley & Sons Ltd.)

Context: Phthalates are endocrine-disrupting chemicals that could disrupt normal physiologic function, triggering detrimental impacts on bone., Objective: We evaluated associations between urinary phthalate biomarkers and BMD in postmenopausal women participating in the prospective Women's Health Initiative (WHI)., Methods: We included WHI participants enrolled in the BMD substudy and selected for a nested case-control study of phthalates and breast cancer (N = 1255). We measured 13 phthalate biomarkers and creatinine in 2 to 3 urine samples per participant collected over 3 years, when all participants were cancer free. Total hip and femoral neck BMD were measured at baseline and year 3, concurrent with urine collection, via dual-energy x-ray absorptiometry. We fit multivariable generalized estimating equation models and linear mixed-effects models to estimate cross-sectional and longitudinal associations, respectively, with stratification on postmenopausal hormone therapy (HT) use., Results: In cross-sectional analyses, mono-3-carboxypropyl phthalate and the sum of di-isobutyl phthalate metabolites were inversely associated with total hip BMD among HT nonusers, but not among HT users. Longitudinal analyses showed greater declines in total hip BMD among HT nonusers and with highest concentrations of mono-3-carboxyoctyl phthalate (-1.80%; 95% CI, -2.81% to -0.78%) or monocarboxynonyl phthalate (-1.84%; 95% CI, -2.80% to -0.89%); similar associations were observed with femoral neck BMD. Among HT users, phthalate biomarkers were not associated with total hip or femoral neck BMD change., Conclusion: Certain phthalate biomarkers are associated with greater percentage decreases in total hip and femoral neck BMD. These findings suggest that phthalate exposure may have clinically important effects on BMD, and potentially fracture risk., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Thyroid hormones (predominantly thyroxine, T4, and triiodothyronine, T3) are essential for normal development and for adult physiology. There are several challenges, however, that make identifying chemicals that produce adverse effects by interfering with the thyroid system difficult. First, individual variability in serum concentrations of thyroid hormones represent only about 10% of the population reference range that is considered to be "normal." This means that populations studies evaluating the relationship between chemical exposure and serum thyroid hormones must be large enough to overcome this internal variance. In addition, we know that there are chemicals that do not produce changes in thyroid hormone levels, but nevertheless impact thyroid signaling in target tissues. A good example is that of polychlorinated biphenyls (PCBs). PCB exposure during development are clearly associated with cognitive deficits in humans. But PCB exposure isn't uniformly associated with a reduction in serum thyroid hormone in human populations despite mechanistic studies showing that PCBs reduce serum T4 in animals. In contrast, perchlorate is a chemical that inhibits iodide uptake, thereby reducing thyroid hormone synthesis and serum hormone levels. Human studies have been variable in identifying a relationship between thyroid hormone and perchlorate exposure, but studies also show that dietary iodine, cigarette smoking and other factors can modify this relationship. The conclusion is that identifying chemicals that interfere with thyroid hormone could depend on in vitro analysis of chemicals that interact with different proteins important for thyroid hormone to function properly., Competing Interests: Conflict of interest The author has not received funding from any source for this chapter. The views expressed here are the professional opinions of the author and do not necessarily reflect those of his employers or any agencies that have funded his work. There are no contractual relations or proprietary considerations that restrict the authors' publication or dissemination of the findings described in the manuscript. Dr. Zoeller has served on various advisory boards and panels of the US EPA, the National Institutes of Health and Pew Charitable Trusts in relation to issues of EDCs. He is currently a member of the Endocrine Society's EDC Advisory Group and is co-chair of one of its Task Force groups. His travel has been sponsored by various government, academic, and industry groups to present findings of his research. Dr. Zoeller's research has been funded by government agencies in the United States and the European Union., (Copyright © 2021 Elsevier Inc. All rights reserved.)

"Consortium Linking Academic and Regulatory Insights on BPA Toxicity" (CLARITY-BPA) was a comprehensive "industry-standard" Good Laboratory Practice (GLP)-compliant 2-year chronic exposure study of bisphenol A (BPA) toxicity that was supplemented by hypothesis-driven independent investigator-initiated studies. The investigator-initiated studies were focused on integrating disease-associated, molecular, and physiological endpoints previously found by academic scientists into an industry standard guideline-compliant toxicity study. Thus, the goal of this collaboration was to provide a more comprehensive dataset upon which to base safety standards and to determine whether industry-standard tests are as sensitive and predictive as molecular and disease-associated endpoints. The goal of this report is to integrate the findings from the investigator-initiated studies into a comprehensive overview of the observed impacts of BPA across the multiple organs and systems analyzed. For each organ system, we provide the rationale for the study, an overview of methodology, and summarize major findings. We then compare the results of the CLARITY-BPA studies across organ systems with the results of previous peer-reviewed studies from independent labs. Finally, we discuss potential influences that contributed to differences between studies. Developmental exposure to BPA can lead to adverse effects in multiple organs systems, including the brain, prostate gland, urinary tract, ovary, mammary gland, and heart. As published previously, many effects were at the lowest dose tested, 2.5μg/kg /day, and many of the responses were non-monotonic. Because the low dose of BPA affected endpoints in the same animals across organs evaluated in different labs, we conclude that these are biologically - and toxicologically - relevant., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The concept of a threshold of adversity in toxicology is neither provable nor disprovable. As such, it is not a scientific question but a theoretical one. Yet, the belief in thresholds has led to traditional ways of interpreting data derived from regulatory guideline studies of the toxicity of chemicals. This includes, for example, the use of standard "uncertainty factors" when a "No Adverse Effect Level" (or similar "benchmark dose") is either observed, or not observed. In the context of endocrine-disrupting chemicals (EDCs), this approach is demonstrably inappropriate. First, the efficacy of a hormone on different endpoints can vary by several orders of magnitude. This feature of hormone action also applies to EDCs that can interfere with that hormone. For this reason, we argue that the choice of endpoint for use in regulation is critical, but note that guideline studies were not designed with this in mind. Second, the biological events controlled by hormones in development not only change as development proceeds but are different from events controlled by hormones in the adult. Again, guideline endpoints were also not designed with this in mind, especially since the events controlled by hormones can be both temporally and spatially specific. The Endocrine Society has laid out this logic over several years and in several publications. Rather than being extreme views, they represent what is known about hormones and the chemicals that can interfere with them., (© Endocrine Society 2020.)

Background: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous. Previous studies have found associations between PFAS and thyroid hormones in maternal and cord sera, but the results are inconsistent. To further address this research question, we used mixture modeling to assess the associations with individual PFAS, interactions among PFAS chemicals, and the overall mixture., Methods: We collected data through the Health Outcomes and Measures of the Environment (HOME) Study, a prospective cohort study that between 2003 and 2006 enrolled 468 pregnant women and their children in the greater Cincinnati, Ohio region. We assessed the associations of maternal serum PFAS concentrations measured during pregnancy with maternal (n = 185) and cord (n = 256) sera thyroid stimulating hormone (TSH), total thyroxine (TT 4 ), total triiodothyronine (TT 3 ), free thyroxine (FT 4 ), and free triiodothyronine (FT 3 ) using two mixture modeling approaches (Bayesian kernel machine regression (BKMR) and quantile g-computation) and multivariable linear regression. Additional models considered thyroid autoantibodies, other non-PFAS chemicals, and iodine deficiency as potential confounders or effect measure modifiers., Results: PFAS, considered individually or as mixtures, were generally not associated with any thyroid hormones. A doubling of perfluorooctanesulfonic acid (PFOS) had a positive association with cord serum TSH in BKMR models but the 95% Credible Interval included the null (β = 0.09; 95% CrI: -0.08, 0.27). Using BKMR and multivariable models, we found that among children born to mothers with higher thyroid peroxidase antibody (TPOAb), perfluorooctanoic acid (PFOA), PFOS, and perfluorohexanesulfonic acid (PFHxS) were associated with decreased cord FT 4 suggesting modification by maternal TPOAb status., Conclusions: These findings suggest that maternal serum PFAS concentrations measured in the second trimester of pregnancy are not strongly associated with thyroid hormones in maternal and cord sera. Further analyses using robust mixture models in other cohorts are required to corroborate these findings., (Copyright © 2020 Elsevier Inc. All rights reserved.)

For many endocrine-disrupting chemicals (EDCs) including Bisphenol A (BPA), animal studies show that environmentally relevant exposures cause harm; human studies are consistent with these findings. Yet, regulatory agencies charged with protecting public health continue to conclude that human exposures to these EDCs pose no risk. One reason for the disconnect between the scientific consensus on EDCs in the endocrinology community and the failure to act in the regulatory community is the dependence of the latter on so-called "guideline studies" to evaluate hazards, and the inability to incorporate independent scientific studies in risk assessment. The Consortium Linking Academic and Regulatory Insights on Toxicity (CLARITY) study was intended to bridge this gap, combining a "guideline" study with independent hypothesis-driven studies designed to be more appropriate to evaluate EDCs. Here we examined an aspect of "guideline" studies, the use of so-called "historical controls," which are essentially control data borrowed from prior studies to aid in the interpretation of current findings. The US Food and Drug Administration authors used historical controls to question the plausibility of statistically significant BPA-related effects in the CLARITY study. We examined the use of historical controls on 5 outcomes in the CLARITY "guideline" study: mammary neoplasms, pituitary neoplasms, kidney nephropathy, prostate inflammation and adenomas, and body weight. Using US Food and Drug Administration-proposed historical control data, our evaluation revealed that endpoints used in "guideline" studies are not as reproducible as previously held. Combined with other data comparing the effects of ethinyl estradiol in 2 "guideline" studies including CLARITY-BPA, we conclude that near-exclusive reliance on "guideline" studies can result in scientifically invalid conclusions., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The test methods that currently exist for the identification of thyroid hormone system-disrupting chemicals are woefully inadequate. There are currently no internationally validated in vitro assays, and test methods that can capture the consequences of diminished or enhanced thyroid hormone action on the developing brain are missing entirely. These gaps put the public at risk and risk assessors in a difficult position. Decisions about the status of chemicals as thyroid hormone system disruptors currently are based on inadequate toxicity data. The ATHENA project (Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies) has been conceived to address these gaps. The project will develop new test methods for the disruption of thyroid hormone transport across biological barriers such as the blood-brain and blood-placenta barriers. It will also devise methods for the disruption of the downstream effects on the brain. ATHENA will deliver a testing strategy based on those elements of the thyroid hormone system that, when disrupted, could have the greatest impact on diminished or enhanced thyroid hormone action and therefore should be targeted through effective testing. To further enhance the impact of the ATHENA test method developments, the project will develop concepts for better international collaboration and development in the area of thyroid hormone system disruptor identification and regulation.

Purpose: Maternal thyroid function during pregnancy may influence offspring thyroid function, though relations between maternal and child thyroid function are incompletely understood. We sought to characterize relations between maternal, cord and child thyroid hormone concentrations in a population of mother-child pairs with largely normal thyroid function., Methods: In a prospective birth cohort, we measured thyroid hormone concentrations in 203 mothers at 16 gestational weeks, 273 newborns and 159 children at 3 years among participants in the Health Outcomes and Measures of the Environment (HOME) Study. We used multivariable linear regression to estimate associations of maternal thyroid hormones during pregnancy with cord serum thyroid hormones and also estimated associations of maternal and cord thyroid hormones with child thyroid-stimulating hormone (TSH)., Results: Each doubling of maternal TSH was associated with a 16.4% increase of newborn TSH (95% CI: 3.9%, 30.5%), and each doubling of newborn TSH concentrations was associated with a 10.4% increase in child TSH concentrations at 3 years (95% CI: 0.1%, 21.7%). An interquartile range increase in cord FT4 concentrations was associated with an 11.7% decrease in child TSH concentrations at 3 years (95% CI: -20.2%, -2.3%)., Conclusions: We observed relationships between maternal, newborn and child thyroid hormone concentrations in the HOME Study. Our study contributes to understandings of interindividual variability in thyroid function among mother-child pairs, which may inform future efforts to identify risk factors for thyroid disorders or thyroid-related health outcomes., (© 2020 John Wiley & Sons Ltd.)

Food packaging is of high societal value because it conserves and protects food, makes food transportable and conveys information to consumers. It is also relevant for marketing, which is of economic significance. Other types of food contact articles, such as storage containers, processing equipment and filling lines, are also important for food production and food supply. Food contact articles are made up of one or multiple different food contact materials and consist of food contact chemicals. However, food contact chemicals transfer from all types of food contact materials and articles into food and, consequently, are taken up by humans. Here we highlight topics of concern based on scientific findings showing that food contact materials and articles are a relevant exposure pathway for known hazardous substances as well as for a plethora of toxicologically uncharacterized chemicals, both intentionally and non-intentionally added. We describe areas of certainty, like the fact that chemicals migrate from food contact articles into food, and uncertainty, for example unidentified chemicals migrating into food. Current safety assessment of food contact chemicals is ineffective at protecting human health. In addition, society is striving for waste reduction with a focus on food packaging. As a result, solutions are being developed toward reuse, recycling or alternative (non-plastic) materials. However, the critical aspect of chemical safety is often ignored. Developing solutions for improving the safety of food contact chemicals and for tackling the circular economy must include current scientific knowledge. This cannot be done in isolation but must include all relevant experts and stakeholders. Therefore, we provide an overview of areas of concern and related activities that will improve the safety of food contact articles and support a circular economy. Our aim is to initiate a broader discussion involving scientists with relevant expertise but not currently working on food contact materials, and decision makers and influencers addressing single-use food packaging due to environmental concerns. Ultimately, we aim to support science-based decision making in the interest of improving public health. Notably, reducing exposure to hazardous food contact chemicals contributes to the prevention of associated chronic diseases in the human population.

Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with hormone action, thereby increasing the risk of adverse health outcomes, including cancer, reproductive impairment, cognitive deficits and obesity. A complex literature of mechanistic studies provides evidence on the hazards of EDC exposure, yet there is no widely accepted systematic method to integrate these data to help identify EDC hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we have developed ten KCs of EDCs based on our knowledge of hormone actions and EDC effects. In this Expert Consensus Statement, we describe the logic by which these KCs are identified and the assays that could be used to assess several of these KCs. We reflect on how these ten KCs can be used to identify, organize and utilize mechanistic data when evaluating chemicals as EDCs, and we use diethylstilbestrol, bisphenol A and perchlorate as examples to illustrate this approach.

Background: Growing laboratory and animal model evidence supports the potentially carcinogenic effects of some phthalates, chemicals used as plasticizers in a wide variety of consumer products, including cosmetics, medications, and vinyl flooring. However, prospective data on whether phthalates are associated with human breast cancer risk are lacking., Methods: We conducted a nested case-control study within the Women's Health Initiative (WHI) prospective cohort (n = 419 invasive case subjects and 838 control subjects). Control subjects were matched 2:1 to case subjects on age, enrollment date, follow-up time, and WHI study group. We quantified 13 phthalate metabolites and creatinine in two or three urine samples per participant over one to three years. Multivariable conditional logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for breast cancer risk associated with each phthalate biomarker up to 19 years of follow-up., Results: Overall, we did not observe statistically significant positive associations between phthalate biomarkers and breast cancer risk in multivariable analyses (eg, 4th vs 1st quartile of diethylhexyl phthalate, OR = 1.03, 95% CI = 0.91 to 1.17). Results were generally similar in analyses restricted to disease subtypes, to nonusers of postmenopausal hormone therapy, stratified by body mass index, or to case subjects diagnosed within three, five, or ten years., Conclusions: In the first prospective analysis of phthalates and postmenopausal breast cancer, phthalate biomarker concentrations did not result in an increased risk of developing invasive breast cancer., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Groundwater, the major source of drinking water in Bengal Delta Plain, is contaminated with geogenic arsenic (As) enrichment affecting millions of people. Children exposed to tubewell water containing As may be associated with thyroid dysfunction, which in turn may impact neurodevelopmental outcomes. However, data to support such relationship is sparse. The purpose of this study was to examine if chronic water As (WAs) from Holocene alluvial aquifers in this region was associated with serum thyroid hormone (TH) and if TH biomarkers were related to neurobehavioral (NB) performance in a group of adolescents. A sample of 32 healthy adolescents were randomly drawn from a child cohort in the Health Effects of Arsenic Longitudinal Study (HEALS) in Araihazar, Bangladesh. Half of these participants were consistently exposed to low WAs (<10 μg/L) and the remaining half had high WAs exposure (≥10 μg/L) since birth. Measurements included serum total triiodothyronine (tT 3 ), free thyroxine (fT 4 ), thyrotropin (TSH) and thyroperoxidase antibodies (TPOAb); concurrent WAs and urinary arsenic (UAs); and adolescents' NB performance. WAs and UAs were positively and significantly correlated with TPOAb but were not correlated with TSH, tT 3 and fT 4 . After accounting for covariates, both WAs and UAs demonstrated positive but non-significant relationships with TSH and TPOAb and negative but non-significant relationships with tT 3 and fT 4 . TPOAb was significantly associated with reduced NB performance indicated by positive associations with latencies in simple reaction time (b = 82.58; p < 0.001) and symbol digit (b = 276.85; p = 0.005) tests. TSH was significantly and negatively associated with match-to-sample correct count (b = -0.95; p = 0.05). Overall, we did not observe significant associations between arsenic exposure and TH biomarkers although the relationships were in the expected directions. We observed TH biomarkers to be related to reduced NB performance as hypothesized. Our study indicated a possible mechanism of As-induced neurotoxicity, which requires further investigations for confirmatory findings., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The CLARITY-BPA experiment, a large collaboration between the National Institute of Environmental Health Sciences, the National Toxicology Program, and the US Food and Drug Administration, is designed to test the effects of bisphenol A (BPA) on a variety of endocrine systems and end points. The specific aim of this subproject was to test the effect of BPA exposure on thyroid functions and thyroid hormone action in the developing brain. Timed-pregnant National Center for Toxicological Research Sprague-Dawley rats (strain code 23) were dosed by gavage with vehicle control (0.3% carboxymethylcellulose) or one of five doses of BPA [2.5, 25, 250, 2500, or 25,000 µg/kg body weight (bw) per day] or ethinyl estradiol (EE) at 0.05 or 0.50 µg/kg bw/d (n = 8 for each group) beginning on gestational day 6. Beginning on postnatal day (PND) 1 (day of birth is PND 0), the pups were directly gavaged with the same dose of vehicle, BPA, or EE. We also obtained a group of animals treated with 3 ppm propylthiouracil in the drinking water and an equal number of concordant controls. Neither BPA nor EE affected serum thyroid hormones or thyroid hormone‒sensitive end points in the developing brain at PND 15. In contrast, propylthiouracil (PTU) reduced serum T4 to the expected degree (80% reduction) and elevated serum TSH. Few effects of PTU were observed in the male brain and none in the female brain. As a result, it is difficult to interpret the negative effects of BPA on the thyroid in this rat strain because the thyroid system appears to respond differently from that of other rat strains., (Copyright © 2019 Endocrine Society.)

For nearly 15 years, the Endocrine Society has engaged in a coordinated effort to engage the issue of endocrine-disrupting chemicals (EDCs). This effort is based on an effective collaboration between scientists and physician members of the Endocrine Society and a competent and professional staff that supports membership efforts to study EDC actions and translate this knowledge to regulatory agencies. This is a brief history of these important efforts to inform the broad readership of Endocrinology., (Copyright © 2019 Endocrine Society.)

Polychlorinated biphenyls (PCBs) pose significant risk to the developing human brain; however, mechanisms of PCB developmental neurotoxicity (DNT) remain controversial. Two widely posited mechanisms are tested here using PCBs identified in pregnant women in the MARBLES cohort who are at increased risk for having a child with a neurodevelopmental disorder (NDD). As determined by gas chromatography-triple quadruple mass spectrometry, the mean PCB level in maternal serum was 2.22 ng/mL. The 12 most abundant PCBs were tested singly and as a mixture mimicking the congener profile in maternal serum for activity at the thyroid hormone receptor (THR) and ryanodine receptor (RyR). Neither the mixture nor the individual congeners (2 fM to 2 μM) exhibited agonistic or antagonistic activity in a THR reporter cell line. However, as determined by equilibrium binding of [ 3 H]ryanodine to RyR1-enriched microsomes, the mixture and the individual congeners (50 nM to 50 μM) increased RyR activity by 2.4-19.2-fold. 4-Hydroxy (OH) and 4-sulfate metabolites of PCBs 11 and 52 had no TH activity; but 4-OH PCB 52 had higher potency than the parent congener toward RyR. These data support evidence implicating RyRs as targets in environmentally triggered NDDs and suggest that PCB effects on the THR are not a predominant mechanism driving PCB DNT. These findings provide scientific rationale regarding a point of departure for quantitative risk assessment of PCB DNT, and identify in vitro assays for screening other environmental pollutants for DNT potential.

Background: Some phthalates are endocrine disrupting chemicals used as plasticizers in consumer products, and have been associated with obesity in cross-sectional studies, yet prospective evaluations of weight change are lacking. Our objective was to evaluate associations between phthalate biomarker concentrations and weight and weight change among postmenopausal women., Methods: We performed cross-sectional (N = 997) and longitudinal analyses (N = 660) among postmenopausal Women's Health Initiative participants. We measured 13 phthalate metabolites and creatinine in spot urine samples provided at baseline. Participants' weight and height measured at in-person clinic visits at baseline, year 3, and year 6 were used to calculate body mass index (BMI). We fit multivariable multinomial logistic regression models to explore cross-sectional associations between each phthalate biomarker and baseline BMI category. We evaluated longitudinal associations between each biomarker and weight change using mixed effects linear regression models., Results: In cross-sectional analyses, urinary concentrations of some biomarkers were positively associated with obesity prevalence (e.g. sum of di (2-ethylhexyl) phthalate metabolites [ΣDEHP] 4th vs 1st quartile OR = 3.29, 95% CI 1.80-6.03 [p trend< 0.001] vs normal). In longitudinal analyses, positive trends with weight gain between baseline and year 3 were observed for mono-(2-ethyl-5-oxohexyl) phthalate, monoethyl phthalate (MEP), mono-hydroxybutyl phthalate, and mono-hydroxyisobutyl phthalate (e.g. + 2.32 kg [95% CI 0.93-3.72] for 4th vs 1st quartile of MEP; p trend < 0.001). No statistically significant associations were observed between biomarkers and weight gain over 6 years., Conclusions: Certain phthalates may contribute to short-term weight gain among postmenopausal women.

Background: Phthalates are ubiquitous endocrine disrupting chemicals present in a wide variety of consumer products. However, the personal characteristics associated with phthalate exposure are unclear., Objectives: We sought to describe personal, behavioral, and reproductive characteristics associated with phthalate metabolite concentrations in an ongoing study nested within the Women's Health Initiative (WHI)., Materials and Methods: We measured thirteen phthalate metabolites in two or three archived urine samples collected in 1993-2001 from each of 1257 WHI participants (2991 observations). We fit multivariable generalized estimating equation models to predict urinary biomarker concentrations from personal, behavioral, and reproductive characteristics., Results: Older age was predictive of lower concentrations of monobenzyl phthalate (MBzP), mono-carboxyoctyl phthalate (MCOP), mono-3-carboxypropyl phthalate (MCPP), and the sum of di-n-butyl phthalate metabolites (ΣDBP). Phthalate metabolite concentrations varied by race/region, with generally higher concentrations observed among non-Whites and women from the West region. Higher neighborhood socioeconomic status predicted lower MBzP concentrations, and higher education predicted lower monoethyl phthalate (MEP) and higher concentrations of the sum of metabolites of di-isobutyl phthalate (ΣDiBP). Overweight/obesity predicted higher MBzP, MCOP, monocarboxynonyl phthalate (MCNP), MCPP, and the sum of metabolites of di(2-ethylhexyl) phthalate (ΣDEHP) and lower MEP concentrations. Alcohol consumption predicted higher concentrations of MEP and ΣDBP, while current smokers had higher ΣDBP concentrations. Better diet quality as assessed by Healthy Eating Index 2005 scores predicted lower concentrations of MBzP, ΣDiBP, and ΣDEHP., Conclusion: Factors predictive of lower biomarker concentrations included increased age and healthy behaviors (e.g. lower alcohol intake, lower body mass index, not smoking, higher quality diet, and moderate physical activity). Racial group (generally higher among non-Whites) and geographic regions (generally higher in Northeast and West compared to South regions) also were predictive of phthalate biomarker concentrations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in children, yet its etiology is poorly understood. Early thyroid hormone disruption may contribute to the development of ADHD. Disrupted maternal thyroid hormone function has been associated with adverse neurodevelopmental outcomes in children. Among newborns, early-treated congenital hypothyroidism has been consistently associated with later cognitive deficits., Methods: We systematically reviewed literature on the association between maternal or neonatal thyroid hormones and ADHD diagnosis or symptoms. We searched Embase, Pubmed, Cinahl, PsycInfo, ERIC, Medline, Scopus, and Web of Science for articles published or available ahead of print as of April 2018., Results: We identified 28 eligible articles: 16 studies of maternal thyroid hormones, seven studies of early-treated congenital hypothyroidism, and five studies of neonatal thyroid hormones. The studies provide moderate evidence for an association between maternal thyroid hormone levels and offspring ADHD, some evidence for an association between early-treated congenital hypothyroidism and ADHD, and little evidence for an association between neonatal thyroid hormone levels and later ADHD., Conclusions: The reviewed articles suggest an association between maternal thyroid function and ADHD, and possibly between early-treated congenital hypothyroidism and ADHD. Study limitations, however, weaken the conclusions in our systematic review, underlining the need for more research. Importantly, there was much variation in the measurement of thyroid hormone function and of ADHD symptoms. Recommendations for future research include using population-based designs, attending to measurement issues for thyroid hormones and ADHD, considering biologically relevant covariates (e.g., iodine intake), and assessing nonlinear dose-responses.

Background: Phthalates, endocrine-disrupting chemicals that are commonly found in consumer products, may adversely affect thyroid hormones, but findings from prior epidemiologic studies are inconsistent., Objectives: In a prospective cohort study, we investigated whether maternal urinary phthalate metabolite concentrations and phthalate mixtures measured during pregnancy were associated with thyroid hormones among pregnant women and newborns., Methods: We measured nine phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate, mono-isobutyl phthalate, monobenzyl phthalate (MBzP), and four monoesthers of di(2-ethylhexyl) phthalate] in urine collected at approximately 16 and 26 weeks' gestation among women in the Health Outcomes and Measures of the Environment Study (2003-2006, Cincinnati, Ohio). Thyroid stimulating hormone (TSH) and free and total thyroxine and triiodothyronine were measured in maternal serum at 16 weeks' gestation (n = 202) and cord serum at delivery (n = 276). We used multivariable linear regression to assess associations between individual urinary phthalate metabolites and concentrations of maternal or cord serum thyroid hormones. We used weighted quantile sum regression (WQS) to create a phthalate index describing combined concentrations of phthalate metabolites and to investigate associations of the phthalate index with individual thyroid hormones., Results: With each 10-fold increase in 16-week maternal urinary MEP, maternal serum total thyroxine (TT 4 ) decreased by 0.52 μg/dL (95% CI: -1.01, -0.03). For each 10-fold increase in average (16- and 26-week) maternal urinary MBzP, cord serum TSH decreased by 19% (95% CI: -33.1, -1.9). Among mothers, the phthalate index was inversely associated with maternal serum TT 4 (WQS beta = -0.60; 95% CI: -1.01, -0.18). Among newborns, the phthalate index was inversely associated with both cord serum TSH (WQS beta = -0.11; 95% CI: -0.20, -0.03) and TT 4 (WQS beta = -0.53; 95% CI: -0.90, -0.16)., Conclusion: Our results suggest that co-exposure to multiple phthalates was inversely associated with certain thyroid hormones (TT 4 in pregnant women and newborns, and TSH in newborns) in this birth cohort. These findings highlight the need to study chemical mixtures in environmental epidemiology., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Background: Human fetal exposures to polybrominated diphenyl ethers (PBDEs) and their metabolites (OH-PBDEs) are unique from adults, and in combination with a different metabolic profile, may make fetal development more sensitive to adverse health outcomes from these exposures. However, we lack data to characterize human fetal PBDE exposures and the metabolic factors that can influence these exposures., Objective: We examined differences between 2nd trimester maternal and fetal exposures to PBDEs and OH-PBDEs. We also characterized fetal cytochrome P450 (CYP) mRNA expression and its associations with PBDE exposures., Methods: We collected paired samples of maternal serum and fetal liver (n=86) with a subset having matched placenta (n=50). We measured PBDEs, OH-PBDEs, and mRNA expression of CYP genes (e.g. CYP1A1, -2E1, -2J2, -2C9) in all samples. As a sensitivity analysis, we measured PBDEs and OH-PBDEs in umbilical cord serum from a subset (n=22)., Results: BDE-47 was detected in ≥96% of all tissues. Unadjusted ∑PBDEs concentrations were highest in fetal liver (geometric mean (GM)=0.72ng/g), whereas lipid-adjusted concentrations were highest in cord serum (111.12ng/g lipid). In both cases, fetal concentrations were approximately two times higher than maternal serum levels (GM=0.33ng/g or 48.75ng/g lipid). ΣOH-PBDEs were highest in maternal and cord sera and 20-200 times lower than PBDE concentrations. In regression models, maternal BDE-47 explained more of the model variance of liver than of placenta BDE-47 concentrations (adjusted R 2 =0.79 vs 0.48, respectively). In adjusted logistic regression models, ∑PBDEs were positively associated with expression of CYP2E1 and -2J2 (placenta), and -1A1 (liver) (p<0.05)., Conclusion: Our findings suggest that under normal conditions of mid-gestation, the human fetus is directly exposed to concentrations of PBDEs that may be higher than previously estimated based on maternal serum and that these exposures are associated with the expression of mRNAs coding for CYP enzymes. These results will help frame and interpret findings from studies that use maternal or cord blood as proxy measures of fetal exposures, and will inform the molecular pathways by which PBDEs affect human health., (Copyright © 2017. Published by Elsevier Ltd.)

Correction: After publication of the article [1], it has been brought to our attention that the thirteenth author of this article has had their name spelt incorrectly. In the original article the spelling "Laura Rizzir" was used. In fact the correct spelling should be "Laura Rizzi".

The Florence Statement on Triclosan and Triclocarban documents a consensus of more than 200 scientists and medical professionals on the hazards of and lack of demonstrated benefit from common uses of triclosan and triclocarban. These chemicals may be used in thousands of personal care and consumer products as well as in building materials. Based on extensive peer-reviewed research, this statement concludes that triclosan and triclocarban are environmentally persistent endocrine disruptors that bioaccumulate in and are toxic to aquatic and other organisms. Evidence of other hazards to humans and ecosystems from triclosan and triclocarban is presented along with recommendations intended to prevent future harm from triclosan, triclocarban, and antimicrobial substances with similar properties and effects. Because antimicrobials can have unintended adverse health and environmental impacts, they should only be used when they provide an evidence-based health benefit. Greater transparency is needed in product formulations, and before an antimicrobial is incorporated into a product, the long-term health and ecological impacts should be evaluated. https://doi.org/10.1289/EHP1788.

Background: Maternal thyroid function is a critical mediator of fetal brain development. Pregnancy-related physiologic changes and handling conditions of blood samples may influence thyroid hormone biomarkers. We investigated the reliability of thyroid hormone biomarkers in plasma of pregnant women under various handling conditions., Methods: We enrolled 17 pregnant women; collected serum and plasma were immediately frozen. Additional plasma aliquots were subjected to different handling conditions before the analysis of thyroid biomarkers: storage at room temperature for 24 or 48 hours before freezing and an extra freeze-thaw cycle. We estimated free thyroid hormone indices in plasma based on T3 uptake., Results: High correlations between plasma and serum (>0.94) and intraclass correlation coefficients for plasma handling conditions (0.96 to 1.00) indicated excellent reliability for all thyroid hormone biomarkers., Conclusion: Delayed freezing and freeze-thaw cycles did not affect reliability of biomarkers of thyroid function in plasma during pregnancy. See video abstract at, http://links.lww.com/EDE/B180.

Endocrine disruption is a specific form of toxicity, where natural and/or anthropogenic chemicals, known as "endocrine disruptors" (EDs), trigger adverse health effects by disrupting the endogenous hormone system. There is need to harmonize guidance on the regulation of EDs, but this has been hampered by what appeared as a lack of consensus among scientists. This publication provides summary information about a consensus reached by a group of world-leading scientists that can serve as the basis for the development of ED criteria in relevant EU legislation. Twenty-three international scientists from different disciplines discussed principles and open questions on ED identification as outlined in a draft consensus paper at an expert meeting hosted by the German Federal Institute for Risk Assessment (BfR) in Berlin, Germany on 11-12 April 2016. Participants reached a consensus regarding scientific principles for the identification of EDs. The paper discusses the consensus reached on background, definition of an ED and related concepts, sources of uncertainty, scientific principles important for ED identification, and research needs. It highlights the difficulty in retrospectively reconstructing ED exposure, insufficient range of validated test systems for EDs, and some issues impacting on the evaluation of the risk from EDs, such as non-monotonic dose-response and thresholds, modes of action, and exposure assessment. This report provides the consensus statement on EDs agreed among all participating scientists. The meeting facilitated a productive debate and reduced a number of differences in views. It is expected that the consensus reached will serve as an important basis for the development of regulatory ED criteria.

Background: Endocrine-disrupting chemicals (EDCs) contribute to disease and dysfunction and incur high associated costs (>1% of the gross domestic product [GDP] in the European Union). Exposure to EDCs varies widely between the USA and Europe because of differences in regulations and, therefore, we aimed to quantify disease burdens and related economic costs to allow comparison., Methods: We used existing models for assessing epidemiological and toxicological studies to reach consensus on probabilities of causation for 15 exposure-response relations between substances and disorders. We used Monte Carlo methods to produce realistic probability ranges for costs across the exposure-response relation, taking into account uncertainties. Estimates were made based on population and costs in the USA in 2010. Costs for the European Union were converted to US$ (€1=$1·33)., Findings: The disease costs of EDCs were much higher in the USA than in Europe ($340 billion [2·33% of GDP] vs $217 billion [1·28%]). The difference was driven mainly by intelligence quotient (IQ) points loss and intellectual disability due to polybrominated diphenyl ethers (11 million IQ points lost and 43 000 cases costing $266 billion in the USA vs 873 000 IQ points lost and 3290 cases costing $12·6 billion in the European Union). Accounting for probability of causation, in the European Union, organophosphate pesticides were the largest contributor to costs associated with EDC exposure ($121 billion), whereas in the USA costs due to pesticides were much lower ($42 billion)., Interpretation: EDC exposure in the USA contributes to disease and dysfunction, with annual costs taking up more than 2% of the GDP. Differences from the European Union suggest the need for improved screening for chemical disruption to endocrine systems and proactive prevention., Funding: Endocrine Society, Ralph S French Charitable Foundation, and Broad Reach Foundation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Evidence increasingly confirms that synthetic chemicals disrupt the endocrine system and contribute to disease and disability across the lifespan. Despite a United Nations Environment Programme/WHO report affirmed by over 100 countries at the Fourth International Conference on Chemicals Management, 'manufactured doubt' continues to be cast as a cloud over rigorous, peer-reviewed and independently funded scientific data. This study describes the sources of doubt and their social costs, and suggested courses of action by policymakers to prevent disease and disability. The problem is largely based on the available data, which are all too limited. Rigorous testing programmes should not simply focus on oestrogen, androgen and thyroid. Tests should have proper statistical power. 'Good laboratory practice' (GLP) hardly represents a proper or even gold standard for laboratory studies of endocrine disruption. Studies should be evaluated with regard to the contamination of negative controls, responsiveness to positive controls and dissection techniques. Flaws in many GLP studies have been identified, yet regulatory agencies rely on these flawed studies. Peer-reviewed and unbiased research, rather than 'sound science', should be used to evaluate endocrine-disrupting chemicals., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Endocrine disruptors (EDs) are defined by the World Health Organization (WHO) as exogenous compounds or mixtures that alter function(s) of the endocrine system and consequently cause adverse effects in an intact organism, or its progeny, or (sub)populations. European regulations on pesticides, biocides, cosmetics, and industrial chemicals require the European Commission to establish scientific criteria to define EDs., Objectives: We address the scientific relevance of four options for the identification of EDs proposed by the European Commission., Discussion: Option 1, which does not define EDs and leads to using interim criteria unrelated to the WHO definition of EDs, is not relevant. Options 2 and 3 rely on the WHO definition of EDs, which is widely accepted by the scientific community, with option 3 introducing additional categories based on the strength of evidence (suspected EDs and endocrine-active substances). Option 4 adds potency to the WHO definition, as a decision criterion. We argue that potency is dependent on the adverse effect considered and is scientifically ambiguous, and note that potency is not used as a criterion to define other particularly hazardous substances such as carcinogens and reproductive toxicants. The use of potency requires a context that goes beyond hazard identification and corresponds to risk characterization, in which potency (or, more relevantly, the dose-response function) is combined with exposure levels., Conclusions: There is scientific agreement regarding the adequacy of the WHO definition of EDs. The potency concept is not relevant to the identification of particularly serious hazards such as EDs. As is common practice for carcinogens, mutagens, and reproductive toxicants, a multi-level classification of ED based on the WHO definition, and not considering potency, would be relevant (corresponding to option 3 proposed by the European Commission)., Citation: Slama R, Bourguignon JP, Demeneix B, Ivell R, Panzica G, Kortenkamp A, Zoeller RT. 2016. Scientific issues relevant to setting regulatory criteria to identify endocrine disrupting substances in the European Union. Environ Health Perspect 124:1497-1503; http://dx.doi.org/10.1289/EHP217., Competing Interests: The authors declare they have no actual or potential competing financial interests.

Unconventional oil and gas operations using hydraulic fracturing can contaminate surface and groundwater with endocrine-disrupting chemicals. We have previously shown that 23 of 24 commonly used hydraulic fracturing chemicals can activate or inhibit the estrogen, androgen, glucocorticoid, progesterone, and/or thyroid receptors in a human endometrial cancer cell reporter gene assay and that mixtures can behave synergistically, additively, or antagonistically on these receptors. In the current study, pregnant female C57Bl/6 dams were exposed to a mixture of 23 commonly used unconventional oil and gas chemicals at approximately 3, 30, 300, and 3000 μg/kg·d, flutamide at 50 mg/kg·d, or a 0.2% ethanol control vehicle via their drinking water from gestational day 11 through birth. This prenatal exposure to oil and gas operation chemicals suppressed pituitary hormone concentrations across experimental groups (prolactin, LH, FSH, and others), increased body weights, altered uterine and ovary weights, increased heart weights and collagen deposition, disrupted folliculogenesis, and other adverse health effects. This work suggests potential adverse developmental and reproductive health outcomes in humans and animals exposed to these oil and gas operation chemicals, with adverse outcomes observed even in the lowest dose group tested, equivalent to concentrations reported in drinking water sources. These endpoints suggest potential impacts on fertility, as previously observed in the male siblings, which require careful assessment in future studies.

A previous report documented that endocrine disrupting chemicals contribute substantially to certain forms of disease and disability. In the present analysis, our main objective was to update a range of health and economic costs that can be reasonably attributed to endocrine disrupting chemical exposures in the European Union, leveraging new burden and disease cost estimates of female reproductive conditions from accompanying report. Expert panels evaluated the epidemiologic evidence, using adapted criteria from the WHO Grading of Recommendations Assessment, Development and Evaluation Working Group, and evaluated laboratory and animal evidence of endocrine disruption using definitions recently promulgated by the Danish Environmental Protection Agency. The Delphi method was used to make decisions on the strength of the data. Expert panels consensus was achieved for probable (>20%) endocrine disrupting chemical causation for IQ loss and associated intellectual disability; autism; attention deficit hyperactivity disorder; endometriosis; fibroids; childhood obesity; adult obesity; adult diabetes; cryptorchidism; male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation, and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median annual cost of €163 billion (1.28% of EU Gross Domestic Product) across 1000 simulations. We conclude that endocrine disrupting chemical exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those endocrine disrupting chemicals with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs., (© 2016 American Society of Andrology and European Academy of Andrology.)

Background: Women have elevated rates of thyroid disease compared to men. Environmental toxicants have been implicated as contributors to this dimorphism, including polybrominated diphenyl ethers (PBDEs), flame retardant chemicals that disrupt thyroid hormone action. PBDEs have also been implicated in the disruption of estrogenic activity, and estrogen levels regulate thyroid hormones. Post-menopausal women may therefore be particularly vulnerable to PBDE induced thyroid effects, given low estrogen reserves. The objective of this study was to test for an association between serum PBDE concentrations and thyroid disease in women from the United States (U.S.), stratified by menopause status., Methods: Serum PBDE concentrations (BDEs 47, 99, 100 and 153) from the National Health and Examination Survey (NHANES) and reports on thyroid problems were available in the NHANES 2003-2004 cycle. Odds ratios (ORs) were calculated using multivariate logistic regression models accounting for population-weighted survey techniques and controlling for age, body mass index (BMI), education, smoking, alcohol consumption and thyroid medication. Menopause status was obtained by self-reported absence of menstruation in the previous 12 months and declared menopause., Results: Women in the highest quartile of serum concentrations for BDEs 47, 99, and 100 had increased odds of currently having thyroid disease (ORs: 1.5, 1.8, 1.5, respectively) compared to the reference group (1st and 2nd quartiles combined); stronger associations were observed when the analysis was restricted to postmenopausal women (ORs: 2.2, 3.6, 2.0, respectively)., Conclusion: Exposure to BDEs 47, 99, and 100 is associated with thyroid disease in a national sample of U.S. women, with greater effects observed post-menopause, suggesting that the disruption of thyroid signaling by PBDEs may be enhanced by the altered estrogen levels during menopause.

We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is based on incomplete and misleading quoting of the report through omission of qualifying statements and inaccurate description of study objectives, results and conclusions. Lamb et al. define extremely narrow standards for synthesizing evidence which are then used to dismiss the UNEP/WHO 2013 report as flawed. We show that Lamb et al. misuse conceptual frameworks for assessing causality, especially the Bradford-Hill criteria, by ignoring the fundamental problems that exist with inferring causality from empirical observations. We conclude that Lamb et al.'s attempt of deconstructing the UNEP/WHO (2013) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

This Executive Summary to the Endocrine Society's second Scientific Statement on environmental endocrine-disrupting chemicals (EDCs) provides a synthesis of the key points of the complete statement. The full Scientific Statement represents a comprehensive review of the literature on seven topics for which there is strong mechanistic, experimental, animal, and epidemiological evidence for endocrine disruption, namely: obesity and diabetes, female reproduction, male reproduction, hormone-sensitive cancers in females, prostate cancer, thyroid, and neurodevelopment and neuroendocrine systems. EDCs such as bisphenol A, phthalates, pesticides, persistent organic pollutants such as polychlorinated biphenyls, polybrominated diethyl ethers, and dioxins were emphasized because these chemicals had the greatest depth and breadth of available information. The Statement also included thorough coverage of studies of developmental exposures to EDCs, especially in the fetus and infant, because these are critical life stages during which perturbations of hormones can increase the probability of a disease or dysfunction later in life. A conclusion of the Statement is that publications over the past 5 years have led to a much fuller understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability. These findings will prove useful to researchers, physicians, and other healthcare providers in translating the science of endocrine disruption to improved public health.

Bisphenol A (BPA) is a chemical used in the production of numerous consumer products resulting in potential daily human exposure to this chemical. The FDA previously evaluated the body of BPA toxicology data and determined that BPA is safe at current exposure levels. Although consistent with the assessment of some other regulatory agencies around the world, this determination of BPA safety continues to be debated in scientific and popular publications, resulting in conflicting messages to the public. Thus, the National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), and U.S. Food and Drug Administration (FDA) developed a consortium-based research program to link more effectively a variety of hypothesis-based research investigations and guideline-compliant safety testing with BPA. This collaboration is known as the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA). This paper provides a detailed description of the conduct of the study and a midterm update on progress of the CLARITY-BPA research program., (Published by Elsevier Inc.)

The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.

Oil and natural gas operations have been shown to contaminate surface and ground water with endocrine-disrupting chemicals. In the current study, we fill several gaps in our understanding of the potential environmental impacts related to this process. We measured the endocrine-disrupting activities of 24 chemicals used and/or produced by oil and gas operations for five nuclear receptors using a reporter gene assay in human endometrial cancer cells. We also quantified the concentration of 16 of these chemicals in oil and gas wastewater samples. Finally, we assessed reproductive and developmental outcomes in male C57BL/6J mice after the prenatal exposure to a mixture of these chemicals. We found that 23 commonly used oil and natural gas operation chemicals can activate or inhibit the estrogen, androgen, glucocorticoid, progesterone, and/or thyroid receptors, and mixtures of these chemicals can behave synergistically, additively, or antagonistically in vitro. Prenatal exposure to a mixture of 23 oil and gas operation chemicals at 3, 30, and 300 μg/kg · d caused decreased sperm counts and increased testes, body, heart, and thymus weights and increased serum testosterone in male mice, suggesting multiple organ system impacts. Our results suggest possible adverse developmental and reproductive health outcomes in humans and animals exposed to potential environmentally relevant levels of oil and gas operation chemicals.