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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.

Background: Human exposure to bisphenol A (BPA) is ubiquitous, yet there are concerns about whether BPA can be measured in human blood. This Round Robin was designed to address this concern through three goals: 1) to identify collection materials, reagents and detection apparatuses that do not contribute BPA to serum; 2) to identify sensitive and precise methods to accurately measure unconjugated BPA (uBPA) and BPA-glucuronide (BPA-G), a metabolite, in serum; and 3) to evaluate whether inadvertent hydrolysis of BPA-G occurs during sample handling and processing. Methods: Four laboratories participated in this Round Robin. Laboratories screened materials to identify BPA contamination in collection and analysis materials. Serum was spiked with concentrations of uBPA and/or BPA-G ranging from 0.09-19.5 (uBPA) and 0.5-32 (BPA-G) ng/mL. Additional samples were preserved unspiked as 'environmental' samples. Blinded samples were provided to laboratories that used LC/MSMS to simultaneously quantify uBPA and BPA-G. To determine whether inadvertent hydrolysis of BPA metabolites occurred, samples spiked with only BPA-G were analyzed for the presence of uBPA. Finally, three laboratories compared direct and indirect methods of quantifying BPA-G. Results: We identified collection materials and reagents that did not introduce BPA contamination. In the blinded spiked sample analysis, all laboratories were able to distinguish low from high values of uBPA and BPA-G, for the whole spiked sample range and for those samples spiked with the three lowest concentrations (0.5-3.1 ng/ml). By completion of the Round Robin, three laboratories had verified methods for the analysis of uBPA and two verified for the analysis of BPA-G (verification determined by: 4 of 5 samples within 20% of spiked concentrations). In the analysis of BPA-G only spiked samples, all laboratories reported BPA-G was the majority of BPA detected (92.2 - 100%). Finally, laboratories were more likely to be verified using direct methods than indirect ones using enzymatic hydrolysis. Conclusions: Sensitive and accurate methods for the direct quantification of uBPA and BPA-G were developed in multiple laboratories and can be used for the analysis of human serum samples. BPA contamination can be controlled during sample collection and inadvertent hydrolysis of BPA conjugates can be avoided during sample handling.

The "common sense" intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a recently published, and is in our considered opinion inaccurate and factually incorrect, editorial that has appeared in several journals in toxicology. Some of the shortcomings of the editorial are discussed in detail. We call for a better founded scientific debate which may help to overcome a polarisation of views detrimental to reaching a consensus about scientific foundations for endocrine disrupter regulation in the EU. © 2013 Bergman et al.; licensee BioMed Central Ltd.

Background: The issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent C exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs. Methods: We have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity. Results: Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs. Conclusions: When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible.

Background: Scientists who communicate societally relevant information face challenging contexts in which misinformation, disinformation, hype, and spin are prevalent. As a result, they often face difficult decisions about how to frame their work in a socially responsible manner., Objectives: Drawing from the literature on science communication and framing, we identify tradeoffs that environmental health scientists face when deciding how to communicate their work, and we propose strategies for handling these tradeoffs. We use research on the human health effects of environmental endocrine disruptors as a case study to illustrate these challenges and strategies., Discussion: We examine four major frames (i.e., ways of packaging information that draw attention to facets of an issue or topic) in discussions of the effects of endocrine-disrupting chemicals on sexual and neural development and obesity. We show how these frames can be beneficial (e.g., focusing public attention on environmental health threats and promoting actions to address environmental pollution) while simultaneously having harmful effects (e.g., contributing to stigmatization of particular groups or the promotion of harmful political ideologies)., Conclusions: Researchers who seek to responsibly communicate societally relevant work can employ several strategies to mitigate difficult tradeoffs, including a ) striving for sensitivity to the social context and its relationship to their framing choices, b ) choosing to avoid some frames, c ) employing frames that alleviate ethical tensions, d ) fostering education to alleviate harms, e ) developing interdisciplinary and community collaborations, and f ) working with institutions like scientific societies and journals to develop guidance on responsible communication practices. https://doi.org/10.1289/EHP14527.

The mammary gland is responsive to endogenous hormones and environmental chemicals that are estrogen receptor (ER) agonists. The mouse mammary gland offers the opportunity to dissect the most sensitive windows of exposure. 17α-ethinyl estradiol (EE2) is a pharmaceutical ER agonist that often serves as a positive control for estrogen-active chemicals. Here, adult female mice were exposed to EE2 starting either at pregnancy day 7, or on lactational day 1, and exposures continued until the litters were weaned. The pups were therefore exposed during gestation + the juvenile period, or during the juvenile period alone. The morphology of the mammary gland was evaluated in both male and female offspring at two life stages: weaning (postnatal day [PND]21) and at puberty (PND32). Other hormone-sensitive outcomes evaluated included body weight, anogenital index, frequency of open vagina, and weight of the uterus. We found age- and sex-dependent effects of EE2 on these estrogen-responsive endpoints including the morphology of the mammary gland. Importantly, EE2 altered mammary gland morphology even when exposures were limited to the juvenile period. However, the number of endpoints that were affected in animals from the EE2-Juvenile-Only period were fewer, and typically of a lower magnitude, compared to those observed in the EE2-Gest-Juvenile group. Understanding the effects of environmental estrogen exposures during the juvenile period is critical because humans are exposed to estrogenic pollutants throughout life, including in early childhood., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laura N. Vandenberg reports financial support was provided by SUDOC, LLC. Joshua P. Mogus reports financial support was provided by UMass Amherst School of Public Health & Health Sciences. Additional support was provided by the National Institutes of Health. Laura N. Vandenberg reports a relationship with Sudoc LLC that includes: consulting or advisory. LNV serves on the editorial board of Reproductive Toxicology. The other authors do not have conflicts to disclose., (Copyright © 2024. Published by Elsevier Inc.)

The Breast Cancer UK-Breast Cancer Prevention Conference addressed risk from environmental pollutants and health behaviour-related breast-cancer risk. Epidemiological studies examining individual chemicals and breast cancer risk have produced inconclusive results including endocrine disrupting chemicals (EDCs) Bisphenol A, per- and polyfluorinated alkyl substances as well as aluminium. However, laboratory studies have shown that multiple EDCs, can work together to exhibit effects, even when combined at levels that alone are ineffective. The TEXB-α/β assay measures total estrogenic load, and studies have provided evidence of a link between multiple-chemical exposures and breast cancer. However, prospective studies using TEXB-α/β are needed to establish a causative link. There is also a need to assess real-life exposure to environmental-chemical mixtures during pregnancy, and their potential involvement in programming adverse foetal health outcomes in later life. Higher rates of breast cancer have occurred alongside increases in potentially-modifiable risk factors such as obesity. Increasing body-mass index is associated with increased risk of developing postmenopausal breast cancer, but with decreased risk of premenopausal breast cancer. In contrast, lower rates of breast cancer in Asian compared to Western populations have been linked to soya/isoflavone consumption. Risk is decreased by breastfeeding, which is in addition to the decrease in risk observed for each birth and a young first-birth. Risk is lower in those with higher levels of self-reported physical activity. Current evidence suggests breast-cancer survivors should also avoid weight gain, be physically active, and eat a healthy diet for overall health. A broad scientific perspective on breast cancer risk requires focus on both environmental exposure to chemicals and health behaviour-related risk. Research into chemical exposure needs to focus on chemical mixtures and prospective epidemiological studies in order to test the effects on breast cancer risk. Behaviour-related research needs to focus on implementation as well as deeper understanding of the mechanisms of cancer prevention., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Tetra-amido macrocyclic ligands (TAMLs) are catalysts designed to mimic endogenous peroxidases that can degrade pollutants. Before TAMLs gain widespread use, it is first important to determine if they have endocrine disrupting properties. In this study, we evaluated the effects of the iron TAML, NT7, on hormone-sensitive outcomes in mice exposed during pregnancy and lactation, and on their litters prior to weaning. We administered NT7 at one of three doses to mice via drinking water prior to and then throughout pregnancy and lactation. Two hormonally active pharmaceuticals, ethinyl estradiol (EE2) and flutamide (FLUT), a known estrogen receptor agonist and androgen receptor antagonist, respectively, were also included. In the females, we measured pre- and post-parturition weight, length of pregnancy, organ weights at necropsy, and morphology of the mammary gland at the end of the lactational period. We also quantified maternal behaviors at three stages of lactation. For the offspring, we measured litter size, litter weights, and the achievement of other developmental milestones. We observed only one statistically significant effect of NT7, a decrease in the percentage of pups with ear opening at postnatal day 5. This contrasts with the numerous effects of EE2 on both the mother and the litter, as well as several modest effects of FLUT. The approach taken in this study could provide guidance for future studies that aim to evaluate novel compounds for endocrine disrupting properties., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laura N. Vandenberg reports financial support was provided by SUDOC, LLC. Joshua P. Mogus reports financial support was provided by UMass Amherst School of Public Health & Health Sciences. Laura N. Vandenberg reports a relationship with Sudoc LLC that includes: consulting or advisory. LNV serves on the editorial board of Reproductive Toxicology., (Copyright © 2024. Published by Elsevier Inc.)

Estrogenic chemicals are common pollutants in wastewater and current effluent treatment processes are not typically effective in removing these compounds. Tetra-amido macrocyclic ligands (TAMLs) are catalysts that mimic endogenous peroxidases that may provide a solution to remove environmental pollutants including low concentrations of estrogenic compounds. Yet relatively little is known about the toxicity of TAMLs, and few studies have evaluated whether they may have endocrine disrupting properties. We administered one of three doses of a TAML, NT7, to mice via drinking water throughout pregnancy and lactation. Two pharmacologically active compounds, ethinyl estradiol (EE2) and flutamide were also included to give comparator data for estrogen receptor agonist and androgen receptor antagonist activities. Male pups were evaluated for several outcomes at weaning, puberty, and early adulthood. We found that EE2 exposures during gestation and the perinatal period induced numerous effects that were observed across the three ages including changes to spleen and testis weight and drastic effects on the morphology of the mammary gland. Flutamide had fewer effects but altered anogenital distance at weaning as well as spleen, liver, and kidney weight. In contrast, relatively few effects of NT7 were observed, but included alterations to spleen weight and modest changes to adult testis weight and morphology of the mammary gland at weaning. Collectively, these results provide some of the first evidence suggesting that NT7 may alter some hormone-sensitive outcomes, but that the effects were distinct from either EE2 or flutamide. Additional studies are needed to characterize the biological activity of this and other TAML catalysts., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laura N. Vandenberg reports financial support was provided by SUDOC, LLC. Joshua P. Mogus reports financial support was provided by UMass Amherst School of Public Health & Health Sciences. Laura N. Vandenberg reports a relationship with Sudoc LLC that includes: consulting or advisory. LNV serves on the editorial board of Reproductive Toxicology., (Copyright © 2023. Published by Elsevier Inc.)

Background: Environmental exposures to non-biodegradable and biodegradable plastics are unavoidable. Microplastics (MPs) and nanoplastics (NPs) from the manufacturing of plastics (primary sources) and the degradation of plastic waste (secondary sources) can enter the food chain directly or indirectly and, passing biological barriers, could target both the brain and the gonads. Hence, the worldwide diffusion of environmental plastic contamination (PLASTAMINATION) in daily life may represent a possible and potentially serious risk to human health., Objective: This review provides an overview of the effects of non-biodegradable and the more recently introduced biodegradable MPs and NPs on the brain and brain-dependent reproductive functions, summarizing the molecular mechanisms and outcomes on nervous and reproductive organs. Data from in vitro, ex vivo, non-mammalian and mammalian animal models and epidemiological studies have been reviewed and discussed., Results: MPs and NPs from non-biodegradable plastics affect organs, tissues and cells from sensitive systems such as the brain and reproductive organs. Both MPs and NPs induce oxidative stress, chronic inflammation, energy metabolism disorders, mitochondrial dysfunction and cytotoxicity, which in turn are responsible for neuroinflammation, dysregulation of synaptic functions, metabolic dysbiosis, poor gamete quality, and neuronal and reproductive toxicity. In spite of this mechanistic knowledge gained from studies of non-biodegradable plastics, relatively little is known about the adverse effects or molecular mechanisms of MPs and NPs from biodegradable plastics., Conclusion: The neurological and reproductive health risks of MPs/NPs exposure warrant serious consideration, and further studies on biodegradable plastics are recommended., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Pollution by chemicals and waste impacts human and ecosystem health on regional, national, and global scales, resulting, together with climate change and biodiversity loss, in a triple planetary crisis. Consequently, in 2022, countries agreed to establish an intergovernmental science-policy panel (SPP) on chemicals, waste, and pollution prevention, complementary to the existing intergovernmental science-policy bodies on climate change and biodiversity. To ensure the SPP's success, it is imperative to protect it from conflicts of interest (COI). Here, we (i) define and review the implications of COI, and its relevance for the management of chemicals, waste, and pollution; (ii) summarize established tactics to manufacture doubt in favor of vested interests, i.e., to counter scientific evidence and/or to promote misleading narratives favorable to financial interests; and (iii) illustrate these with selected examples. This analysis leads to a review of arguments for and against chemical industry representation in the SPP's work. We further (iv) rebut an assertion voiced by some that the chemical industry should be directly involved in the panel's work because it possesses data on chemicals essential for the panel's activities. Finally, (v) we present steps that should be taken to prevent the detrimental impacts of COI in the work of the SPP. In particular, we propose to include an independent auditor's role in the SPP to ensure that participation and processes follow clear COI rules. Among others, the auditor should evaluate the content of the assessments produced to ensure unbiased representation of information that underpins the SPP's activities.

The mammary gland undergoes comprehensive reorganization during pregnancy, lactation, and subsequent involution. Following involution, the mammary gland has structural and functional differences compared to the gland of a nulliparous female. These parity-associated changes are regulated by hormones and may be vulnerable to endocrine-disrupting chemicals (EDCs). In this study, we evaluated the long-term effects of butyl benzyl phthalate (BBP), an estrogenic plasticizer, on the parous mouse mammary gland. Pregnant BALB/c mice were treated with 0, 3, 500, or 18000 µg/kg/day BBP throughout both pregnancy and the lactational period. The litters born to these females were evaluated for litter size and growth. The parous females were then kept for five weeks following weaning of the pups, during which period there was no exposure to BBP. After five weeks of post-weaning, mammary glands were collected and assessed for changes in histomorphology, steroid receptor expression, innate immune cell number, and gene expression. An unexposed age-matched nulliparous control was also evaluated as a comparator group. BBP increased male and female pup weight at puberty and female offspring in adulthood. BBP also altered innate immune cells in the post-involution mammary gland, reducing the effect of parity on macrophages. Lastly, BBP modestly increased mammary gland ductal complexity and periductal structure, but had no effect on expression of estrogen receptor, progesterone receptor, or a marker of proliferation. These results suggest that BBP may interfere with some effects of parity on the mouse mammary gland and induce weight gain in exposed offspring., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laura N. Vandenberg reports financial support was provided by National Institute of Environmental Health Sciences. D. Joseph Jerry reports financial support was provided by National Institute of Environmental Health Sciences. Laura N. Vandenberg reports a relationship with Sudoc LLC that includes: consulting or advisory. LNV serves on the editorial board of Reproductive Toxicology. Disclosure statement LNV is a scientific advisor (unpaid) to two Horizon 2020 EDC grants and a paid scientific advisor to SUDOC, LLC. Her travel has been sponsored by various government, academic and industry groups to present findings of her research and her EDC-related research has been funded by US government agencies, the University of Massachusetts Amherst, NGOs including the Cornell Douglas Foundation and the Great Neck Breast Cancer Coalition, and an unrestricted gift to her lab from SUDOC, LLC. The other authors have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Food contact materials (FCMs) and food contact articles are ubiquitous in today's globalized food system. Chemicals migrate from FCMs into foodstuffs, so called food contact chemicals (FCCs), but current regulatory requirements do not sufficiently protect public health from hazardous FCCs because only individual substances used to make FCMs are tested and mostly only for genotoxicity while endocrine disruption and other hazard properties are disregarded. Indeed, FCMs are a known source of a wide range of hazardous chemicals, and they likely contribute to highly prevalent non-communicable diseases. FCMs can also include non-intentionally added substances (NIAS), which often are unknown and therefore not subject to risk assessment. To address these important shortcomings, we outline how the safety of FCMs may be improved by (1) testing the overall migrate, including (unknown) NIAS, of finished food contact articles, and (2) expanding toxicological testing beyond genotoxicity to multiple endpoints associated with non-communicable diseases relevant to human health. To identify mechanistic endpoints for testing, we group chronic health outcomes associated with chemical exposure into Six Clusters of Disease (SCOD) and we propose that finished food contact articles should be tested for their impacts on these SCOD. Research should focus on developing robust, relevant, and sensitive in-vitro assays based on mechanistic information linked to the SCOD, e.g., through Adverse Outcome Pathways (AOPs) or Key Characteristics of Toxicants. Implementing this vision will improve prevention of chronic diseases that are associated with hazardous chemical exposures, including from FCMs., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare. For the sake of transparency, the authors list their relationships with various research funders and other organizations in the following. As researchers employed by the Food Packaging Forum Foundation (FPF) (JMB, BG, JM, LZ) or working pro bono as members of the Foundation’s board (TB, JPM, MS) and its Scientific Advisory Board (SAB) (AMA, TJC, KJG, JJH, MVM, OVM, AN, CN, AMS, LT, MW, RTZ), we are reporting that the FPF receives donations from diverse companies that may be affected by the research reported in the enclosed paper. FPF funders have no influence on any of the work at FPF and were not involved in any way in the preparation of this manuscript. TB declares that he serves as the board member of the International Panel on Chemical Pollution (IPCP), the Swedish Toxicological Council and the EU Commission’s Committee on Health, Environmental and Emerging Risks (SCHEER). All those activities are pro bono and have no bearing on the content of the manuscript. None of the aforementioned organizations have had any impact on the content of the manuscript. TJC declares that he is the creator-founder of Sudoc, LLC, which deploys TAML catalysts for many applications and has potential for remediating FCCs in water. JL reports that she receives funding for another research project (ZonMw/Health-Holland Microplastics and Health project MOMENTUM 458001101) of which some partners may be affected by the research reported here. MVM is a paid consultant to the FPF. OVM is one of the representatives of the European Parliament on the European Chemical Agency’s Management Board. JPM is co-founder and board member of Sudoc and he declares to have given all his shares to an irrevocable grantor trust so that he will not benefit financially if the company is successful. AN declares to have received travel reimbursement from universities, NGOs and scientific societies, to speak about endocrine-disrupting chemicals. LNV has received travel reimbursements from universities, governments, NGOs, and industry. She has received research funding from the US National Institutes of Health, the University of Massachusetts Amherst, and NGOs including the Cornell Douglas Foundation, the Allen Family Foundation, and the Great Neck Breast Cancer Coalition. She is a scientific advisor to Sudoc LLC. The FPF foundation board, whose members have no connection with any of the FPF’s funders and receive no remuneration for their work, is legally obliged to guarantee that the work of the FPF is in no way influenced by the interests or views of the funders., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Endocrine-disrupting chemicals (EDCs) are substances generated by human industrial activities that are detrimental to human health through their effects on the endocrine system. The global societal and economic burden posed by EDCs is substantial. Poorly defined or unenforced policies can increase human exposure to EDCs, thereby contributing to human disease, disability and economic damage. Researchers have shown that policies and interventions implemented at both individual and government levels have the potential to reduce exposure to EDCs. This Review describes a set of evidence-based policy actions to manage, minimize or even eliminate the widespread use of these chemicals and better protect human health and society. A number of specific challenges exist: defining, identifying and prioritizing EDCs; considering the non-linear or non-monotonic properties of EDCs; accounting for EDC exposure effects that are latent and do not appear until later in life; and updating testing paradigms to reflect 'real-world' mixtures of chemicals and cumulative exposure. A sound strategy also requires partnering with health-care providers to integrate strategies to prevent EDC exposure in clinical care. Critical next steps include addressing EDCs within global policy frameworks by integrating EDC exposure prevention into emerging climate policy., (© 2023. Springer Nature Limited.)

In males, skeletal muscle function may be altered by shifts in either circulating testosterone or estrogen. We examined the effect of acute (2-week) exposures to 17α-ethinyl estradiol (EE2), an estrogen receptor (ER) agonist, or flutamide, an androgen receptor (AR) antagonist, on the contractile function of individual skeletal muscle fibers from slow-contracting soleus and fast-contracting extensor digitorum longus muscles from adult male mice. Single fiber specific tension (force divided by cross-sectional area) was decreased with flutamide treatment in all myosin heavy chain (MHC) fiber types examined (I, IIA, and IIB); similar effects were observed with EE2 treatment but only in the fastest-contracting MHC IIB fibers. The decreases in maximally Ca2+-activated specific tension were primarily a result of fewer strongly bound myosin-actin cross-bridges, with flutamide treatment also showing lower myofilament lattice stiffness. Myosin-actin cross-bridge kinetics were slower in MHC IIA fibers in flutamide-treated mice, but faster in EE2-treated mice, indicating that contractile velocity may be affected differently in this fiber type, which is commonly expressed in human skeletal muscle. Importantly, these effects were observed in the absence of outcomes previously used to evaluate ER agonists or AR antagonists in rodents including weight of reproductive organs or mammary gland morphology. Our findings indicate that substantial shifts in skeletal muscle function occur in male mice following acute exposures to low doses of a pharmacological ER agonist and an AR antagonist. These results suggest that countermeasures to maintain physical function may be needed early in situations that induce similar ER agonist and AR antagonist conditions., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Environmental chemicals are a persistent and pervasive part of everyday life. A subset of environmental chemicals are xenoestrogens, compounds that bind to the estrogen receptor (ER) and drive estrogen-related processes. One such chemical, benzophenone-3 (BP3), is a common chemical in sunscreen. It is a potent UV protectant but also is quickly absorbed through the skin. While it has been approved by the FDA, there is a renewed interest in the safety of BP3, particularly in relation to breast cancer. The focus of this study was to examine the impact that BP3 has on triple negative breast cancer (TNBC) through alterations to cells in the immune microenvironment. In this study, we exposed female mice to one of two doses of BP3 before injecting them with a TNBC cell line. Several immune endpoints were examined both in the primary tissues and from in vitro studies of T cell behavior. Our studies revealed that in the lung tumor microenvironment, exposure to BP3 not only increased the number of metastases, but also the total area of tumor coverage. We also found that BP3 caused alterations in immune populations in a tissue-dependent manner, particularly in T cells. Taken together, our data suggest that while BP3 may not directly affect the proliferation of TNBC, growth and metastasis of TNBC-derived tumors can be altered by BP3 exposures via the alterations in the immune populations of the tumor microenvironment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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: Obesity is a leading risk factor for chronic diseases, potentially related to excess abdominal adiposity. Phthalates are environmental chemicals that have been suggested to act as obesogens, driving obesity risk. For the associations between phthalates and adiposity, prior studies have focused primarily on body mass index. We hypothesize that more refined measures of adiposity and fat distribution may provide greater insights into these associations given the role of central adiposity in chronic disease risk., Objectives: To evaluate associations between urinary phthalate biomarkers and both visceral and subcutaneous adipose tissue (VAT and SAT) among postmenopausal women enrolled in the Women's Health Initiative (WHI)., Methods: We included 1125 WHI participants with available, coincident measurements of urinary phthalate biomarkers (baseline, year 3) and VAT and SAT (baseline, year 3, year 6). VAT and SAT measurements were estimated from DXA scans. Multilevel mixed-effects models estimated the prospective associations between urinary phthalate biomarkers at baseline and VAT and SAT three years later., Results: In multivariable adjusted models, we observed positive associations between some phthalate biomarkers, including the sum of di-isobutyl phthalate (ΣDiBP) biomarkers, MCNP, and ΣDEHP, with VAT three years later. For example, we observed positive associations between concentrations of ΣDiBP and VAT (Q4 vs Q1 β = 7.15, 95% CI -1.76-16.06; Q3 vs Q1 β = 10.94, 95% CI 3.55-18.33). Associations were generally attenuated but remained significant after additional adjustment for SAT. MBzP was positively associated with SAT. Other phthalate biomarkers investigated (MEP, MCOP, MCPP, ΣDBP) were not significantly associated with VAT or SAT., Discussion: Based on robust measures of adiposity, this study provides supportive evidence that higher urinary concentrations of select phthalate compounds were associated with higher VAT levels over time in postmenopausal women. Efforts to replicate these findings are needed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Katherine Reeves reports financial support was provided by National Institute of Environmental Health Sciences., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Milk formation in the breast during breastfeeding is a complex hormonally regulated process, potentially sensitive to the effects of endocrine-disrupting chemical exposures. The environmental chemicals, per- and polyfluoroalkyl substances (PFAS) are known endocrine disruptors. PFAS exposure have been associated with insufficient mammary gland development in mice and reduced breastfeeding duration in humans. The aim of this review was to gather the epidemiological evidence on the association between PFAS exposure and breastfeeding duration. Using PubMed and Embase, we performed a systematic literature search (on 23 January 2023) to identify epidemiological studies examining the association between maternal PFAS exposure and breastfeeding duration. Animal studies, reviews, and non-English studies were excluded. The risk of bias was assessed using the risk of bias in non-randomized studies of exposures tool. Estimates describing the association between PFAS exposure and the duration of breastfeeding were identified, and the data were synthesized separately for each type of PFAS and for the duration of exclusive and total breastfeeding. Six studies with between 336 and 2374 participants each were identified. PFAS exposure was assessed in serum samples (five studies) or based on residential address (one study). Five out of six studies found shorter total duration of breastfeeding with higher PFAS exposure. The most consistent associations were seen for perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA). The finding of a potential causal association between PFAS exposure and breastfeeding duration is in agreement with findings from experimental studies.

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection., (© 2022. The Author(s).)

Background: Understanding, characterizing, and quantifying human exposures to environmental chemicals is critical to protect public health. Exposure assessments are key to determining risks to the general population and for specific subpopulations given that exposures differ between groups. Exposure data are also important for understanding where interventions, including public policies, should be targeted and the extent to which interventions have been successful. In this review, we aim to show how inadequacies in exposure assessments conducted by polluting industries or regulatory agencies have led to downplaying or disregarding exposure concerns raised by communities; that underestimates of exposure can lead regulatory agencies to conclude that unacceptable risks are, instead, acceptable, allowing pollutants to go unregulated; and that researchers, risk assessors, and policy makers need to better understand the issues that have affected exposure assessments and how appropriate use of exposure data can contribute to health-protective decisions., Methods: We describe current approaches used by regulatory agencies to estimate human exposures to environmental chemicals, including approaches to address limitations in exposure data. We then illustrate how some exposure assessments have been used to reach flawed conclusions about environmental chemicals and make recommendations for improvements., Results: Exposure data are important for communities, public health advocates, scientists, policy makers, and other groups to understand the extent of environmental exposures in diverse populations. We identify four areas where exposure assessments need to be improved due to systemic sources of error or uncertainty in exposure assessments and illustrate these areas with examples. These include: (1) an inability of regulatory agencies to keep pace with the increasing number of chemicals registered for use or assess their exposures, as well as complications added by use of 'confidential business information' which reduce available exposure data; (2) the failure to keep assessments up-to-date; (3) how inadequate assumptions about human behaviors and co-exposures contribute to underestimates of exposure; and (4) that insufficient models of toxicokinetics similarly affect exposure estimates., Conclusion: We identified key issues that impact capacity to conduct scientifically robust exposure assessments. These issues must be addressed with scientific or policy approaches to improve estimates of exposure and protect public health., (© 2022. The Author(s).)

Lactation is critical to infant short-term and long-term health and protects mothers from breast cancer, ovarian cancer and type 2 diabetes mellitus. The mammary gland is a dynamic organ, regulated by the coordinated actions of reproductive and metabolic hormones. These hormones promote gland development from puberty onwards and induce the formation of a branched, epithelial, milk-secreting organ by the end of pregnancy. Progesterone withdrawal following placental delivery initiates lactation, which is maintained by increased pituitary secretion of prolactin and oxytocin, and stimulated by infant suckling. After weaning, local cytokine production and decreased prolactin secretion trigger large-scale mammary cell loss, leading to gland involution. Here, we review advances in the molecular endocrinology of mammary gland development and milk synthesis. We discuss the hormonal functions of the mammary gland, including parathyroid hormone-related peptide secretion that stimulates maternal calcium mobilization for milk synthesis. We also consider the hormonal composition of human milk and its associated effects on infant health and development. Finally, we highlight endocrine and metabolic diseases that cause lactation insufficiency, for example, monogenic disorders of prolactin and prolactin receptor mutations, maternal obesity and diabetes mellitus, interventions during labour and delivery, and exposure to endocrine-disrupting chemicals such as polyfluoroalkyl substances in consumer products and other oestrogenic compounds., (© 2022. Springer Nature Limited.)

Population studies show worrisome trends towards earlier breast development, difficulty in breastfeeding, and increasing rates of breast cancer in young women. Multiple epidemiological studies have linked these outcomes with chemical exposures, and experimental studies have shown that many of these chemicals generate similar effects in rodents, often by disrupting hormonal regulation. These endocrine-disrupting chemicals (EDCs) can alter the progression of mammary gland (MG) development, impair the ability to nourish offspring via lactation, increase mammary tissue density, and increase the propensity to develop cancer. However, current toxicological approaches to measuring the effects of chemical exposures on the MG are often inadequate to detect these effects, impairing our ability to identify exposures harmful to the breast and limiting opportunities for prevention. This paper describes key adverse outcomes for the MG, including impaired lactation, altered pubertal development, altered morphology (such as increased mammographic density), and cancer. It also summarizes evidence from humans and rodent models for exposures associated with these effects. We also review current toxicological practices for evaluating MG effects, highlight limitations of current methods, summarize debates related to how effects are interpreted in risk assessment, and make recommendations to strengthen assessment approaches. Increasing the rigor of MG assessment would improve our ability to identify chemicals of concern, regulate those chemicals based on their effects, and prevent exposures and associated adverse health effects., (© 2022. The Author(s).)

Work from numerous fields of study suggests that exposures to hormonally active chemicals during sensitive windows of development can alter mammary gland development, function, and disease risk. Stronger links between many environmental pollutants and disruptions to breast health continue to be documented in human populations, and there remain concerns that the methods utilized to identify, characterize, and prioritize these chemicals for risk assessment and risk management purposes are insufficient. There are also concerns that effects on the mammary gland have been largely ignored by regulatory agencies. Here, we provide technical guidance that is intended to enhance collection and evaluation of the mammary gland in mice and rats. We review several features of studies that should be controlled to properly evaluate the mammary gland, and then describe methods to appropriately collect the mammary gland from rodents. Furthermore, we discuss methods for preparing whole mounted mammary glands and numerous approaches that are available for the analysis of these samples. Finally, we conclude with several examples where analysis of the mammary gland revealed effects of environmental toxicants at low doses. Our work argues that the rodent mammary gland should be considered in chemical safety, hazard and risk assessments. It also suggests that improved measures of mammary gland outcomes, such as those we present in this review, should be included in the standardized methods evaluated by regulatory agencies such as the test guidelines used for identifying reproductive and developmental toxicants., (Copyright © 2022. Published by Elsevier Inc.)

Background: Endocrine disrupting chemicals (EDCs) are found in plastics, personal care products, household items, and other consumer goods. Risk assessments are intended to characterize a chemical's hazards, identify the doses at which adverse outcomes are observed, quantify exposure levels, and then compare these doses to determine the likelihood of risk in a given population. There are many problems with risk assessments for EDCs, allowing people to be exposed to levels that are later associated with serious health outcomes in epidemiology studies., Objective: In this review, we examine issues that affect the evaluation of EDCs in risk assessments (e.g., use of insensitive rodent strains and absence of disease-oriented outcomes in hazard assessments; inadequate exposure assessments). We then review one well-studied chemical, Bisphenol A (BPA; CAS #80-05-7) an EDC found in plastics, food packaging, and other consumer products. More than one hundred epidemiology studies suggest associations between BPA exposures and adverse health outcomes in environmentally exposed human populations., Results: We present support for the use of systematic review methodologies in the evaluation of BPA and other EDCs. Systematic reviews would allow studies to be evaluated for their reliability and risk of bias. They would also allow all data to be used in risk assessments, which is a requirement for some regulatory agencies., Conclusion: Systematic review methodologies can be used to improve evaluations of BPA and other EDCs. Their use could help to restore faith in risk assessments and ensure that all data are utilized in decision-making. Regulatory agencies are urged to conduct transparent, well-documented and proper systematic reviews for BPA and other EDCs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

While mammographic breast density is associated with breast cancer risk in humans, there is no comparable surrogate risk measure in mouse and rat mammary glands following various environmental exposures. In the current study, mammary glands from mice and rats subjected to reproductive factors and exposures to environmental chemicals that have been shown to influence mammary gland development and/or susceptibility to mammary tumors were evaluated for histologic density by manual and automated digital methods. Digital histological density detected changes due to hormonal stimuli/reproductive factors (parity), dietary fat, and exposure to environmental chemicals, such as benzophenone-3 and a combination of perfluorooctanoic acid and zeranol. Thus, digital analysis of mammary gland density offers a high throughput method that can provide a highly reproducible means of comparing a measure of histological density across independent experiments, experimental systems, and laboratories. This methodology holds promise for the detection of environmental impacts on mammary gland structure in mice and rats that may be comparable to human breast density, thus potentially allowing comparisons between rodent models and human breast cancer studies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

It has been 25 years since the U.S. Congress passed the Food Quality Protection Act of 1996, an amendment to the Food Drug and Cosmetic Act, which mandated that the US Environmental Protection Agency (EPA) test all pesticide chemicals used in food for endocrine disruption. Soon after the law passed, EPA established the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) to provide recommendations to the agency on how its Endocrine Disruptor Screening Program (EDSP) should work. Among them, the committee recommended that EDSP screening should 1) evaluate both human and ecological effects; 2) test for disruption of the estrogen, androgen, and thyroid systems; 3) evaluate pesticide and non-pesticide chemicals; and 4) implement a tiered approach. EPA adopted the recommendations and the EDSP was created in 1998. To date, the EPA has yet to fully implement the law; in other words, it has failed to test all pesticide chemicals for endocrine disruption. Of the small number that have been tested, not a single pesticide chemical has been determined to be an endocrine disruptor, and no regulatory actions have been taken. Here, we review the missed opportunities EPA had to make the EDSP a functional and effective program aimed at protecting human health and the environment. Two reports by the EPA's Office of Inspector General from 2011 to 2021 provide the framework for our discussion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Maffini and Vandenberg.)

Mammary stroma is a prominent modulator of epithelial development, and a complex set of interactions between these tissue compartments is essential for normal development, which can be either permissive or restrictive in tumor initiation and progression. During perinatal development, exposures of mice to oxybenzone, a common UV filter, environmental pollutant and endocrine disruptor, induce alterations in mammary epithelium. Our prior research indicates that oxybenzone alters mammary epithelial structures at puberty and in adulthood. We had also previously observed changes in the expression of hormone receptors at puberty (e.g., oxybenzone induced a decrease in the number of epithelial cells positive for progesterone receptor) and in adulthood (e.g., oxybenzone induced a decrease in the number of estrogen receptor-positive epithelial cells), and increased body weight in adulthood. Here, we investigated mammary stromal changes in BALB/c animals exposed during gestation and perinatal development to 0, 30, or 3000 μg oxybenzone/kg/day. In mice exposed to 30 μg/kg/day, we observed morphological changes in adulthood (e.g., a thicker periductal stroma and adipocytes that were considerably larger). We also observed an increased number of mast cells in the mammary stroma at puberty which may represent a transient influence of oxybenzone exposure. These results provide additional evidence that even low doses of oxybenzone can disrupt hormone sensitive outcomes in the mammary gland when exposures occur during critical windows of development, and some of these effects manifest in later life., Competing Interests: LV has received funding from the Cornell Douglas foundation and Paul G. Allen Foundation. She has been reimbursed for travel expenses by numerous organizations including SweTox, Israel Environment Fund, the Mexican Endocrine Society, Advancing Green Chemistry, ShiftCon, US EPA, CropLife America, BeautyCounter, and many universities, to speak about endocrine disrupting chemicals. LV is a paid scientific advisor to Sudoc LLC. KM, JB and SS have no conflicts to disclose., (Copyright © 2022 Matouskova, Bugos, Schneider and Vandenberg.)

Background: Technological advancements make lives safer and more convenient. Unfortunately, many of these advances come with costs to susceptible individuals and public health, the environment, and other species and ecosystems. Synthetic chemicals in consumer products represent a quintessential example of the complexity of both the benefits and burdens of modern living. How we navigate this complexity is a matter of a society's values and corresponding principles., Objectives: We aimed to develop a series of ethical principles to guide decision-making within the landscape of environmental health, and then apply these principles to a specific environmental chemical, oxybenzone. Oxybenzone is a widely used ultraviolet (UV) filter added to personal care products and other consumer goods to prevent UV damage, but potentially poses harm to humans, wildlife, and ecosystems. It provides an excellent example of a chemical that is widely used for the alleged purpose of protecting human health and product safety, but with costs to human health and the environment that are often ignored by stakeholders., Discussion: We propose six ethical principles to guide environmental health decision-making: principles of sustainability, beneficence, non-maleficence, justice, community, and precautionary substitution. We apply these principles to the case of oxybenzone to demonstrate the complex but imperative decision-making required if we are to address the limits of the biosphere's regenerative rates. We conclude that both ethical and practical considerations should be included in decisions about the commercial, pervasive application of synthetic compounds and that the current flawed practice of cost-benefit analysis be recognized for what it is: a technocratic approach to support corporate interests., (© 2021. The Author(s).)

In the past several decades, the incidence of two male breast diseases, gynecomastia and male breast cancer, have increased in human populations. Whereas male breast cancer remains a rare disease, gynecomastia, a condition that arises due to abnormal development and growth of the male breast epithelium, is fairly common. In this review, we present the male mouse mammary gland as a potential model to understand human male breast diseases. Even though the male mouse typically lacks nipples, the male retains a small mammary rudiment with epithelium that is highly sensitive to estrogenic chemicals during the perinatal and peripubertal periods. In just the last few years, our understanding of the biology of the male mouse mammary gland has expanded. Researchers have characterized the complexity and size of the male mammary epithelium across the life course. Studies have documented that the male mouse mammary gland has left-right asymmetric morphologies, as well as asymmetries in the responsiveness of the left and right glands to estrogens. Recent studies have also revealed that the effect of xenoestrogens on the male mammary gland can differ based on the timing of evaluation (prior to puberty, in puberty, and in adulthood) and the administered dose. Based on the available evidence, we argue that there is a strong case that estrogenic chemicals promote the growth of the male mouse epithelium, consistent with human gynecomastia. We also argue that these outcomes should be characterized as adverse effects and should be considered in regulatory decision-making.

The mammary gland is a hormone sensitive organ that is susceptible to endocrine-disrupting chemicals (EDCs) during the vulnerable periods of parous reorganization (ie, pregnancy, lactation, and involution). Pregnancy is believed to have long-term protective effects against breast cancer development; however, it is unknown if EDCs can alter this effect. We examined the long-term effects of propylparaben, a common preservative used in personal care products and foods, with estrogenic properties, on the parous mouse mammary gland. Pregnant BALB/c mice were treated with 0, 20, 100, or 10 000 µg/kg/day propylparaben throughout pregnancy and lactation. Unexposed nulliparous females were also evaluated. Five weeks post-involution, mammary glands were collected and assessed for changes in histomorphology, hormone receptor expression, immune cell number, and gene expression. For several parameters of mammary gland morphology, propylparaben reduced the effects of parity. Propylparaben also increased proliferation, but not stem cell number, and induced modest alterations to expression of ERα-mediated genes. Finally, propylparaben altered the effect of parity on the number of several immune cell types in the mammary gland. These results suggest that propylparaben, at levels relevant to human exposure, can interfere with the effects of parity on the mouse mammary gland and induce long-term alterations to mammary gland structure. Future studies should address if propylparaben exposures negate the protective effects of pregnancy on mammary cancer development., (© 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.)

Antibiotics are gaining attention due to their roles as emerging pollutants and environmental obesogens, yet several aspects between their environmental exposure and obesogenic influence on organisms remain poorly explored. Here, Drosophila melanogaster were exposed to erythromycin (ERY, 0.1 μg/L) for three consecutive generations (F1 to F3). Body weight, circadian rhythm (represented by eclosion timing) and lipid metabolism were measured. ERY increased the size of lipid droplets in larvae of all three generations. It modestly inhibited body weight in adults that abnormally eclosed in the morning (AM adults) in the F1 and F2 generations, and the inhibition was less in adults that eclosed in the afternoon (PM adults). In contrast, it stimulated body weight in F3 adults. Notably, ERY promoted morning eclosion of females. Combining the effects from F1 to F3, acyl-CoA oxidase (ACO) was commonly increased in AM female and male adults and also in PM female ones, while it was commonly decreased in PM male adults. Glucokinase (GCK) was commonly increased in both sexes of AM adults but decreased in PM male adults across generations. The IIS pathway showed a common up-regulation in the AM adults despite some differences between sexes, but it did not show any shared changes in the PM adults with dysrhythmia. The AMPK pathway was involved across generations without particular shared changes. Collectively, the effects of ERY on the key metabolites and enzymes in glucolipid metabolism and the genetic regulations depended on sex, rhythm and exposure generation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction : Endocrine-disrupting chemicals (EDCs) are chemicals that alter the actions of hormones. In the 21 st Century, numerous expert groups of clinicians, scientists, and environmental activists have called for action to protect present and future generations from the harm induced by EDC exposures. These demands for regulatory responses come because of the strong weight of the evidence from epidemiology, wildlife, and controlled laboratory studies. Areas covered : In this review, we examine the conclusions drawn by experts from different scientific and medical disciplines. We also address several areas where recent findings or work has changed the landscape of EDC work including new approaches to identify and evaluate the evidence for EDCs using a key characteristics approach, the need to expand our understanding of vulnerable periods of development, and the increasing concern that traditional methods used to evaluate toxicity of environmental chemicals are insufficient for EDCs and how collaborative science could help to address these gaps. Expert opinion : The science is clear: there is more than enough evidence to demonstrate that EDCs affect the health of humans and wildlife. Waiting to act is a decision that puts the health of current and future generations at risk.

Background: Numerous groups, such as the tobacco industry, have deliberately altered and misrepresented knowable facts and empirical evidence to promote an agenda, often for monetary benefit, with consequences for environmental and public health. Previous research has explored cases individually, but none have conducted an in-depth comparison between cases. The purpose of this study was to compile a comprehensive list of tactics used by disparate groups and provide a framework for identifying further instances of manufactured doubt., Methods: We examined scholarly books, peer-reviewed articles, well-researched journalism pieces, and legal evidence related to five disparate industries and organizations selected for their destructive impacts on environmental and public health (tobacco, coal, and sugar industries, manufacturers of the pesticide Atrazine, and the Marshall Institute, an institute focused on climate change research, and other scientists from the era that associated with those in the Institute). These documents provided evidence for a list of tactics used to generate pro-industry spin and manufacture doubt about conferred harm. We then identified trends among sets of strategies that could explain their differential use or efficacy., Results: We recognized 28 unique tactics used to manufacture doubt. Five of these tactics were used by all five organizations, suggesting that they are key features of manufactured doubt. The intended audience influences the strategy used to misinform, and logical fallacies contribute to their efficacy., Conclusions: This list of tactics can be used by others to build a case that an industry or group is deliberately manipulating information associated with their actions or products. Improved scientific and rhetorical literacy could be used to render them less effective, depending on the audience targeted, and ultimately allow for the protection of both environmental health and public health more generally.

In 1997, the first in vivo bisphenol A (BPA) study by endocrinologists reported that feeding BPA to pregnant mice induced adverse reproductive effects in male offspring at the low dose of 2 µg/kg/day. Since then, thousands of studies have reported adverse effects in animals administered low doses of BPA. Despite more than 100 epidemiological studies suggesting associations between BPA and disease/dysfunction also reported in animal studies, regulatory agencies continue to assert that BPA exposures are safe. To address this disagreement, the CLARITY-BPA study was designed to evaluate traditional endpoints of toxicity and modern hypothesis-driven, disease-relevant outcomes in the same set of animals. A wide range of adverse effects was reported in both the toxicity and the mechanistic endpoints at the lowest dose tested (2.5 µg/kg/day), leading independent experts to call for the lowest observed adverse effect level (LOAEL) to be dropped 20 000-fold from the current outdated LOAEL of 50 000 µg/kg/day. Despite criticism by members of the Endocrine Society that the Food and Drug Administration (FDA)'s assumptions violate basic principles of endocrinology, the FDA rejected all low-dose data as not biologically plausible. Their decisions rely on 4 incorrect assumptions: dose responses must be monotonic, there exists a threshold below which there are no effects, both sexes must respond similarly, and only toxicological guideline studies are valid. This review details more than 20 years of BPA studies and addresses the divide that exists between regulatory approaches and endocrine science. Ultimately, CLARITY-BPA has shed light on why traditional methods of evaluating toxicity are insufficient to evaluate endocrine disrupting chemicals., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Parabens are chemicals containing alkyl-esters of p-hydroxybenzoic acid, which give them antimicrobial, antifungal, and preservative properties. Propylparaben (PP) is one paraben that has been widely used in personal care products, cosmetics, pharmaceuticals, and food. In this review, we address the ongoing controversy over the safety of parabens, and PP specifically. These chemicals have received significant public attention after studies published almost 20 years ago suggested plausible associations between PP exposures and breast cancer., Recent Findings: Here, we use key characteristics, a systematic approach to evaluate the endocrine disrupting properties of PP based on features of "known" endocrine disruptors, and consider whether its classification as a "weak" estrogen should alleviate public health concerns over human exposures. We also review the available evidence from rodent and human studies to illustrate how the large data gaps that exist in hazard assessments raise concerns about current evaluations by regulatory agencies that PP use is safe. Finally, we address the circular logic that is used to suggest that because PP has been used for several decades, it must be safe. We conclude that inadequate evidence has been provided for the safe use of PP in food, cosmetics, and consumer products.

Development of the mammary gland requires coordination of hormone signaling pathways including those mediated by estrogen, progesterone, androgen and prolactin receptors. These hormones play important roles at several distinct stages of life including embryonic/fetal development, puberty, pregnancy, lactation, and old age. This also makes the gland sensitive to perturbations from environmental agents including endocrine disrupting chemicals (EDCs). Although there is evidence from human populations of associations between EDCs and disruptions to breast development and lactation, these studies are often complicated by the timing of exposure assessments and the latency to develop breast diseases (e.g., years to decades). Rodents have been instrumental in providing insights-not only to the basic biology and endocrinology of the mammary gland, but to the effects of EDCs on this tissue at different stages of development. Studies, mostly but not exclusively, of estrogenic EDCs have shown that the mammary gland is a sensitive tissue, that exposures during perinatal development can produce abnormal mammary structures (e.g., alveolar buds, typically seen in pregnant females) in adulthood; that exposures during pregnancy can alter milk production; and that EDC exposures can enhance the response of the mammary tissue to hormones and chemical carcinogens. Other studies of persistent organic pollutants have shown that EDC exposures during critical windows of development can delay development of the gland, with lifelong consequences for the individual. Collectively, this work continues to support the conclusion that EDCs can harm the mammary gland, with effects that depend on the period of exposure and the period of evaluation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Regulatory agencies around the world depend on standardized testing approaches to evaluate environmental chemicals for endocrine disrupting properties. The US Environmental Protection Agency (EPA) has developed a two-tiered testing approach within its Endocrine Disruptor Screening Program (EDSP). The eleven Tier 1 and three Tier 2 EDSP assays can be used to identify chemicals that act as agonists or antagonists of estrogen receptor, androgen receptor, or thyroid hormone receptor, or chemicals that interfere with steroidogenesis. Additional assays have been developed in the context of Tox21, and others have been validated by the OECD. In spite of the availability of validated toxicity tests, problems have been identified with the approaches and methods used to identify endocrine disrupting chemicals (EDCs). This chapter will provide an overview of several of these issues including: (1) The way an EDC is defined by an agency impacts whether a specific test can be used to determine if a chemical is an EDC. This is especially important when considering which assays examine outcomes that are considered "adverse effects." (2) Some assumptions about the validated studies used to identify EDCs may not be true (e.g., their reproducibility has been questioned). (3) Many of the validated assays are less sensitive than other methods that have not yet been validated. Ultimately, these and other problems contribute to the current landscape, where testing approaches have failed to protect the public from known EDCs. The chapter concludes with a review of approaches that have been taken to improve current guideline studies., Competing Interests: Conflict of interest statement Dr. Vandenberg has received travel reimbursements from Universities, Governments, NGOs and Industry to speak about endocrine disrupting chemicals. Her research has been funded by US government agencies, the University of Massachusetts Amherst, and NGOs including the Cornell Douglas Foundation, the Allen Family Foundation, and the Great Neck Breast Cancer Coalition. Dr. Vandenberg is a member of the EPA's Chemical Assessment Advisory Committee and is a paid scientific advisor for Sudoc, LLC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Adolescence is a vulnerable period of breast development, and environmental chemical exposures that occur during this period can increase the risk of breast cancer in adulthood. Discussing breast health with adolescent girls can be difficult for several reasons. In this project, we worked to not only inform adolescent researchers about environmental risks for breast cancer but to also involve them in research studies. We taught adolescents about the stages of mammary gland development using samples collected from mice, with a specific focus on pre-pubertal and pubertal stages of development. Our analysis shows that adolescent researchers, with relatively modest training, can collect reliable and reproducible data on aspects of mammary gland biology that are known to be disrupted by environmental chemicals, with coefficients of variation < 2.5% for basic mammary gland parameters and 5-7% for more complex measures. Finally, we provided these adolescents with information about environmental risk factors for breast cancer that they could share with their peers and community and action items to potentially modify their individual risk. We hope that researchers working in this field will engage adolescent researchers in projects to evaluate chemicals that influence breast cancer risk. Summer research programs that inform young adolescents about breast cancer risk factors not only benefit these novice researchers individually but also benefit their communities when they are encouraged to talk about the value of basic science studies, discuss vulnerable periods of mammary gland development, and share what they have learned about cancer and the environment.

Many agrochemicals have endocrine disrupting properties. A subset of these chemicals is characterized as "estrogenic". In this review, we describe several distinct ways that chemicals used in crop production can affect estrogen signaling. Using three agrochemicals as examples (DDT, endosulfan, and atrazine), we illustrate how screening tests such as the US EPA's EDSP Tier 1 assays can be used as a first-pass approach to evaluate agrochemicals for endocrine activity. We then apply the "Key Characteristics" approach to illustrate how chemicals like DDT can be evaluated, together with the World Health Organization's definition of an endocrine disruptor, to identify data gaps. We conclude by describing important issues that must be addressed in the evaluation and regulation of hormonally active agrochemicals including mixture effects, efforts to reduce vertebrate animal use, chemical prioritization, and improvements in hazard, exposure, and risk assessments., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Endocrine-disrupting chemicals (EDCs) substantially cost society as a result of increases in disease and disability but-unlike other toxicant classes such as carcinogens-have yet to be codified into regulations as a hazard category. This Series paper examines economic, regulatory, and policy approaches to limit human EDC exposures and describes potential improvements. In the EU, general principles for EDCs call for minimisation of human exposure, identification as substances of very high concern, and ban on use in pesticides. In the USA, screening and testing programmes are focused on oestrogenic EDCs exclusively, and regulation is strictly risk-based. Minimisation of human exposure is unlikely without a clear overarching definition for EDCs and relevant pre-marketing test requirements. We call for a multifaceted international programme (eg, modelled on the International Agency for Research in Cancer) to address the effects of EDCs on human health-an approach that would proactively identify hazards for subsequent regulation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Unconventional oil and natural gas extraction (UOG) combines directional drilling and hydraulic fracturing and produces billions of liters of wastewater per year. Herein, we review experimental studies that evaluated the potential endocrine-mediated health impacts of exposure to a mixture of 23 UOG chemicals commonly found in wastewater. The purpose of this manuscript is to synthesize and summarize a body of work using the same UOG-mix but with different model systems and physiological endpoints in multiple experiments. The studies reviewed were conducted in laboratory animals (mice or tadpoles) and human tissue culture cells. A key feature of the in vivo studies was the use of four environmentally relevant doses spanning three orders of magnitude ranging from concentrations found in surface and ground water in UOG dense areas to concentrations found in UOG wastewater. This UOG-mix exhibited potent antagonist activity for the estrogen, androgen, glucocorticoid, progesterone, and thyroid receptors in human tissue culture cells. Subsequently, pregnant mice were administered the UOG-mix in drinking water and offspring were examined in adulthood or to tadpoles. Developmental exposure profoundly impacted pituitary hormone concentrations, reduced sperm counts, altered folliculogenesis, and increased mammary gland ductal density and preneoplastic lesions in mice. It also altered energy expenditure, exploratory and risk-taking behavior, the immune system in three immune models in mice, and affected basal and antiviral immunity in frogs. These findings highlight the diverse systems affected by developmental EDC exposure and the need to examine human and animal health in UOG regions., (Copyright © 2020. Published by Elsevier B.V.)

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.)

Antibiotics have recently gained attention because they are emerging environmental pollutants with obesogenic properties. In this study, Drosophila melanogaster were exposed to sulfamethoxazole (SMX), a sulfonamide antibiotic, and the effects were measured on circadian rhythm (represented by the eclosion rhythm), lipid metabolism, and microbiota. Circadian rhythm disorder was considered due to its connection with lipid metabolism and microbiota in association with obesity. SMX decreased the proportion of adult flies that eclosed in the morning (AM adults) and increased the proportion of PM adults. Moreover, SMX increased the body weight of PM adults, indicating that SMX exposure caused dysrhythmia in eclosion together with obesity. In measurements of key metabolites and metabolic enzymes, SMX exposure stimulated 3 indices in AM adults and 10 indices in PM adults. In AMP-activated protein kinase and insulin/IGF-1 signaling pathways, SMX upregulated six genes in AM adults and nine genes in PM adults. Finally, microbiota analysis demonstrated that SMX increased the Firmicutes/Bacteroides ratios (F/B) by 79.6- and 5.8-fold compared to concurrent controls in AM and PM adults. Collectively, these results suggest that SMX showed obesogenic effects accompanied with dysrhythmia and disturbances in lipid metabolism and microbiota. Further studies on the intrinsic connection are needed.

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.)