The Conflict between Regulatory Agencies over the 20,000-Fold Lowering of the Tolerable Daily Intake (TDI) for Bisphenol A (BPA) by the European Food Safety Authority (EFSA).

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.

Obesogens: a unifying theory for the global rise in obesity.

Despite varied treatment, mitigation, and prevention efforts, the global prevalence and severity of obesity continue to worsen. Here we propose a combined model of obesity, a unifying paradigm that links four general models: the energy balance model (EBM), based on calories as the driver of weight gain; the carbohydrate-insulin model (CIM), based on insulin as a driver of energy storage; the oxidation-reduction model (REDOX), based on reactive oxygen species (ROS) as a driver of altered metabolic signaling; and the obesogens model (OBS), which proposes that environmental chemicals interfere with hormonal signaling leading to adiposity. We propose a combined OBS/REDOX model in which environmental chemicals (in air, food, food packaging, and household products) generate false autocrine and endocrine metabolic signals, including ROS, that subvert standard regulatory energy mechanisms, increase basal and stimulated insulin secretion, disrupt energy efficiency, and influence appetite and energy expenditure leading to weight gain. This combined model incorporates the data supporting the EBM and CIM models, thus creating one integrated model that covers significant aspects of all the mechanisms potentially contributing to the obesity pandemic. Importantly, the OBS/REDOX model provides a rationale and approach for future preventative efforts based on environmental chemical exposure reduction.

A vision for safer food contact materials: Public health concerns as drivers for improved testing.

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.

Obesogens and Obesity: State-of-the-Science and Future Directions Summary from a Healthy Environment and Endocrine Disruptors Strategies Workshop.

On September 7 and 8, 2022, Healthy Environment and Endocrine Disruptors Strategies, an Environmental Health Sciences program, convened a scientific workshop of relevant stakeholders involved in obesity, toxicology, or obesogen research to review the state of the science regarding the role of obesogenic chemicals that might be contributing to the obesity pandemic. The workshop's objectives were to examine the evidence supporting the hypothesis that obesogens contribute to the etiology of human obesity; to discuss opportunities for improved understanding, acceptance, and dissemination of obesogens as contributors to the obesity pandemic; and to consider the need for future research and potential mitigation strategies. This report details the discussions, key areas of agreement, and future opportunities to prevent obesity. The attendees agreed that environmental obesogens are real, significant, and a contributor at some degree to weight gain at the individual level and to the global obesity and metabolic disease pandemic at a societal level; moreover, it is at least, in theory, remediable.

Obesity II: Establishing causal links between chemical exposures and obesity.

Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.

Obesity III: Obesogen assays: Limitations, strengths, and new directions.

There is increasing evidence of a role for environmental contaminants in disrupting metabolic health in both humans and animals. Despite a growing need for well-understood models for evaluating adipogenic and potential obesogenic contaminants, there has been a reliance on decades-old in vitro models that have not been appropriately managed by cell line providers. There has been a quick rise in available in vitro models in the last ten years, including commercial availability of human mesenchymal stem cell and preadipocyte models; these models require more comprehensive validation but demonstrate real promise in improved translation to human metabolic health. There is also progress in developing three-dimensional and co-culture techniques that allow for the interrogation of a more physiologically relevant state. While diverse rodent models exist for evaluating putative obesogenic and/or adipogenic chemicals in a physiologically relevant context, increasing capabilities have been identified for alternative model organisms such as Drosophila, C. elegans, zebrafish, and medaka in metabolic health testing. These models have several appreciable advantages, including most notably their size, rapid development, large brood sizes, and ease of high-resolution lipid accumulation imaging throughout the organisms. They are anticipated to expand the capabilities of metabolic health research, particularly when coupled with emerging obesogen evaluation techniques as described herein.

Obesity I: Overview and molecular and biochemical mechanisms.

Obesity is a chronic, relapsing condition characterized by excess body fat. Its prevalence has increased globally since the 1970s, and the number of obese and overweight people is now greater than those underweight. Obesity is a multifactorial condition, and as such, many components contribute to its development and pathogenesis. This is the first of three companion reviews that consider obesity. This review focuses on the genetics, viruses, insulin resistance, inflammation, gut microbiome, and circadian rhythms that promote obesity, along with hormones, growth factors, and organs and tissues that control its development. It shows that the regulation of energy balance (intake vs. expenditure) relies on the interplay of a variety of hormones from adipose tissue, gastrointestinal tract, pancreas, liver, and brain. It details how integrating central neurotransmitters and peripheral metabolic signals (e.g., leptin, insulin, ghrelin, peptide YY3-36) is essential for controlling energy homeostasis and feeding behavior. It describes the distinct types of adipocytes and how fat cell development is controlled by hormones and growth factors acting via a variety of receptors, including peroxisome proliferator-activated receptor-gamma, retinoid X, insulin, estrogen, androgen, glucocorticoid, thyroid hormone, liver X, constitutive androstane, pregnane X, farnesoid, and aryl hydrocarbon receptors. Finally, it demonstrates that obesity likely has origins in utero. Understanding these biochemical drivers of adiposity and metabolic dysfunction throughout the life cycle lends plausibility and credence to the "obesogen hypothesis" (i.e., the importance of environmental chemicals that disrupt these receptors to promote adiposity or alter metabolism), elucidated more fully in the two companion reviews.

Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies.

"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.

Impacts of food contact chemicals on human health: a consensus statement.

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.

Interventions to Address Environmental Metabolism-Disrupting Chemicals: Changing the Narrative to Empower Action to Restore Metabolic Health.

Metabolic disease rates have increased dramatically over the last four decades. Classic understanding of metabolic physiology has attributed these global trends to decreased physical activity and caloric excess; however, these traditional risk factors insufficiently explain the magnitude and rapidity of metabolic health deterioration. Recently, the novel contribution of environmental metabolism-disrupting chemicals (MDCs) to various metabolic diseases (including obesity, diabetes, and non-alcoholic fatty liver disease) is becoming recognized. As this burgeoning body of evidence has matured, various organic and inorganic pollutants of human and natural origin have emerged as metabolic disease risk factors based on population-level and experimental data. Recognition of these heretofore underappreciated metabolic stressors now mandates that efforts to mitigate the devastating consequences of metabolic disease include dedicated efforts to address environmental drivers of disease risk; however, there have not been adequate recommendations to reduce exposures or to mitigate the effects of exposures on disease outcomes. To address this knowledge gap and advance the clinical translation of MDC science, herein discussed are behaviors that increase exposures to MDCs, interventional studies to reduce those exposures, and small-scale clinical trials to reduce the body burden of MDCs. Also, we discuss evidence from cell-based and animal studies that provide insights into MDC mechanisms of action, the influence of modifiable dietary factors on MDC toxicity, and factors that modulate MDC transplacental carriage as well as their impact on metabolic homeostasis. A particular emphasis of this discussion is on critical developmental windows during which short-term MDC exposure can elicit long-term disruptions in metabolic health with potential inter- and transgenerational effects. While data gaps remain and further studies are needed, the current state of evidence regarding interventions to address MDC exposures illuminates approaches to address environmental drivers of metabolic disease risk. It is now incumbent on clinicians and public health agencies to incorporate this knowledge into comprehensive strategies to address the metabolic disease pandemic.

History of the Obesogen Field: Looking Back to Look Forward.

The Obesogen field developed from two separate scientific research areas, endocrine disruptors and the Developmental Origins of Health and Disease (DOHaD). Endocrine Disrupting Chemicals (EDCs) are exogenous chemicals or mixtures of chemicals that interfere with the action of hormones. Exposure to EDCs during early development (DOHaD) has been shown to increase susceptibility to a variety of diseases including infertility, asthma, breast and prostate cancer, early puberty, susceptibility to infections, heart disease, autoimmune disease, and attention deficit hyperactivity disorder/learning disability. The effects of EDCs on obesity and fat cell development first gained attention around the turn of the twenty-first century. In 2002 Dr. Paula Baillie-Hamilton wrote the first review article focusing on environmental chemicals and obesity. She suggested that the obesity epidemic correlated with the increased production of chemicals after World War II. Baillie-Hamilton identified studies showing that exposures to a variety of chemicals led to weight gain. Shortly after that a commentary on an article showing that nonylphenol would increase fat cell differentiation in vitro noted the Baillie-Hamilton article and made the point that perhaps obesity was due in part to exposure to EDCs. In 2006 the field of DOHaD/EDCs and obesity made a giant leap forward when Dr. Bruce Blumberg published a paper showing that tributyltin could lead to weight gain in mice and coined the term obesogen for a chemical that caused weight gain and lead to obesity. In 2011, the NIEHS developed the first funding initiative focused on obesogens. In the following years there have been several workshops focused on obesogens. This paper describes these early days that lead to the obesogen hypotheses and the growth of the field for a decade, leading to its prominence today, and provides some insight into where the field is moving.

Environmental Obesogens: Mechanisms and Controversies.

Obesity is a worldwide pandemic in adults as well as children and adds greatly to health care costs through its association with type 2 diabetes, metabolic syndrome, cardiovascular disease, and cancers. The prevailing medical view of obesity is that it results from a simple imbalance between caloric intake and energy expenditure. However, numerous other factors are important in the etiology of obesity. The obesogen hypothesis proposes that environmental chemicals termed obesogens promote obesity by acting to increase adipocyte commitment, differentiation, and size by altering metabolic set points or altering the hormonal regulation of appetite and satiety. Many obesogens are endocrine disrupting chemicals that interfere with normal endocrine regulation. Endocrine disrupting obesogens are abundant in our environment, used in everyday products from food packaging to fungicides. In this review, we explore the evidence supporting the obesogen hypothesis, as well as the gaps in our knowledge that are currently preventing a complete understanding of the extent to which obesogens contribute to the obesity pandemic.

The developmental basis of disease: Update on environmental exposures and animal models.

At the Prenatal Programming and Toxicity (PPTox) Conference I in 2008, I presented an overview of the developmental origins of health and disease field focusing on environmental chemical exposures and disease outcomes. At that time, I noted that the field was getting off the ground with a focus on developmental exposure to a small number of endocrine disrupting chemicals (EDCs) and disease outcomes across the lifespan in animal models. In this update, I note that the DOHaD field has changed significantly over the last decade. There are new windows of susceptibility including preconception, prepuberty, a focus on the mother and not just the offspring, and a significant focus on the new field of epigenetic transgenerational inheritance. New disease focus areas have sprung up including obesity, type 2 diabetes and fatty liver disease, all with a connection to developmental exposures to EDCs. There is also a focus on the study of new EDCs, molecular mechanisms, the development of new biomarkers of exposure and disease outcomes and studies focusing on intervention and prevention studies.

Timescales of developmental toxicity impacting on research and needs for intervention.

Much progress has happened in understanding developmental vulnerability to preventable environmental hazards. Along with the improved insight, the perspective has widened, and developmental toxicity now involves latent effects that can result in delayed adverse effects in adults or at old age and additional effects that can be transgenerationally transferred to future generations. Although epidemiology and toxicology to an increasing degree are exploring the adverse effects from developmental exposures in human beings, the improved documentation has resulted in little progress in protection, and few environmental chemicals are currently regulated to protect against developmental toxicity, whether it be neurotoxicity, endocrine disruption or other adverse outcome. The desire to obtain a high degree of certainty and verification of the evidence used for decision-making must be weighed against the costs and necessary duration of research, as well as the long-term costs to human health because of delayed protection of vulnerable early-life stages of human development and, possibly, future generations. Although two-generation toxicology tests may be useful for initial test purposes, other rapidly emerging tools need to be seriously considered from computational chemistry and metabolomics to CLARITY-BPA-type designs, big data and population record linkage approaches that will allow efficient generation of new insight; epigenetic mechanisms may necessitate a set of additional regulatory tests to reveal such effects. As reflected by the Prenatal Programming and Toxicity (PPTOX) VI conference, the current scientific understanding and the timescales involved require an intensified approach to protect against preventable adverse health effects that can harm the next generation and generations to come. While further research is needed, the main emphasis should be on research translation and timely public health intervention to avoid serious, irreversible and perhaps transgenerational harm.

Correction to: Parma consensus statement on metabolic disruptors.

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".

Endocrine Disruptors and Health Effects in Africa: A Call for Action.

BACKGROUND: Africa faces a number of unique environmental challenges. Unfortunately, it lacks the infrastructure needed to support the comprehensive environmental studies that could provide the scientific basis to inform environmental policies. There are a number of known sources of endocrine-disrupting chemicals (EDCs) and other hazardous chemicals in Africa. However, a coordinated approach to identify and monitor these contaminants and to develop strategies for public health interventions has not yet been made. OBJECTIVES: This commentary summarizes the scientific evidence presented by experts at the First African Endocrine Disruptors meeting. We describe a "call to action" to utilize the available scientific knowledge to address the impact of EDCs on human and wildlife health in Africa. DISCUSSION: We identify existing knowledge gaps about exposures to EDCs in Africa and describe how well-designed research strategies are needed to address these gaps. A lack of resources for research and a lag in policy implementation slows down intervention strategies and poses a challenge to advancing future health in Africa. CONCLUSION: To address the many challenges posed by EDCs, we argue that Africans should take the lead in prioritization and evaluation of environmental hazards, including EDCs. We recommend the institution of education and training programs for chemical users, adoption of the precautionary principle, establishment of biomonitoring programs, and funding of community-based epidemiology and wildlife research programs led and funded by African institutes and private companies. https://doi.org/10.1289/EHP1774.