An Endocrine Society Position Statement
Endocrine-disrupting chemicals (EDCs) are chemicals, or mixtures of chemicals, that interfere with any aspect of hormone action. These chemicals are designed, produced, and marketed largely for specific industrial purposes (plasticizers, pesticides, food-packaging, etc). They are present in the environment, consumer products, food storage containers, personal care products, and elsewhere. Some EDCs are also found in certain natural foods and may become further concentrated during processing. Over the last decade, endocrine research has highlighted the potential impacts on human health and the environment following widespread exposure to EDCs. Consequently, public interest in possible health threats posed by EDCs has intensified in recent years, leading to the development of policies, laws and regulations designed to mitigate EDC related health risks. The European Union (EU) has introduced specific legislative obligations aimed at phasing out endocrine disruptors in water, industrial chemicals, plant protection products and biocides.i After many years of debate, the criteria to identify endocrine disrupters in the context of the EU biocides law were adopted in 2017, entering into force June 2018.
The Endocrine Society aims to ensure that policies governing EDCs consider the full body of research into EDCs. As the largest global professional organization for endocrine research and the clinical practice of endocrinology, the Society counts among its members the world’s leading experts in endocrine science, including experts on EDCs and their effects. In its 2009 Scientific Statementii, its 2012 Statement of Principlesiii, and in the 2015 Scientific Statementiv, the Society calls for additional research and updated regulatory processes for the identification of EDCs, which overtly or potentially, depending on the chemicals and endpoints, pose a significant global public health threat. The evaluation of chemicals for endocrine effects must consider the scientific issues of latent and transgenerational effects, low-dose effects, nonmonotonic dose responses (NMDR), and mixture effects. It is also critical that regulatory agencies appreciate that the consequences of EDC exposures depend upon the timing of exposure. Developmental stages—from prenatal life through adolescence—represent particularly vulnerable periods during which irreversible damage can result from exposure to low levels of EDCs. These scientific issues are not adequately addressed under the current Organization for Economic Cooperation and Development (OECD) screening guidelines, and require updated methodology and incorporation of newer, more sensitive endpoints for evaluating endocrine activity.v For example, while the fish life-cycle toxicity test focuses on GnRH development in the brain after chronic exposure, developmental neuroendocrine disruption may not alter GnRH neuron proliferation or structure directly, but rather through alteration of one or more neuromodulators controlling GnRH secretion. The primary aim of the Endocrine Society is human health protection; however, impacts on wildlife are also of concern. The idea that humans and wildlife share the same eco-systems is in line with the ‘One Health’ concept developed by the World Health Organization (WHO).vi
The understanding that environmental chemicals can interfere with hormone action has developed slowly over the past half century. The European Union has been engaged in policy work relevant to EDCs since the late 1990s.vii Some milestones include Europe’s Strategy on EDCsviii (1999); the Regulation on Registration, Evaluation, Authorization and Restriction of Chemicalsix (REACH, 2007); pesticides regulationx (2009); and biocides regulationx (2011). In 2013, the European Parliament adopted a resolution on the protection of public health from endocrine disruptorsxi and the 7th Environmental Action Programme called for minimizing exposures to EDCs. After several years of debate in which the Endocrine Society actively participated, the Commission finally adopted criteria for the identification of endocrine disrupting biocides in 2017.xii
The European Chemicals Agency (ECHA) and European Food Safety Agency (EFSA) are charged with providing guidance to establish the details of the scientific information needed for identifying an EDC based on its adverse effect, endocrine activity and plausible link between the two. The Endocrine Society has argued that identification strategies should not restrict “endocrine-mediated action” to perturbation of a single class or system of hormones interacting with a receptor.xiii Cells need to react to a wide variety of hormones, and hormone-receptor interaction can activate many different endocrine pathways, which are typically linked via mutual interrelationships and crosstalk. A single chemical or class of chemicals can interact with different endocrine pathways, disrupting regulatory mechanisms, altering homeostasis and predisposing individuals to endocrine diseases. Therefore, “endocrine-mediated” should specifically indicate that the adverse outcome is plausibly caused by a substance interfering with hormone synthesis, transport, metabolism, and/or receptor-mediated action. Receptormediated action should recognize that many hormones have multiple receptor isoforms including nuclear and/or membrane or other receptors that convert an extracellular signal into a specific cellular response. It should also reflect the World Health Organization’s International Program on Chemical Safety (WHO-IPCS) definition, which encompasses all endocrine systems and effects including a) receptormediated effects; b) interference with endogenous ligand delivery to the receptor; and c) epigenetic effects.
While the original EU strategy on EDCs from 1999 identified important short, medium, and long-term actions to address EDCs and their public health consequences, new scientific information has emerged in recent years that is not reflected in the strategy. In July 2017, the European Commission announced that it would begin work on a new strategy to minimize exposure of EU citizens to endocrine disruptors, beyond pesticides and biocides.xiv The new strategy is supposed to include consumer products such as toys, cosmetics, and food packaging regulated through specific EU legislation.
EU policymakers need to protect citizens from harmful chemical exposures, and they rely on scientific experts to help them determine how best to do this. Endocrinological research into EDCs over the past 20 years has revealed important issues that have not yet been incorporated into testing paradigms, guideline studies, or in regulatory analyses. It is now clear that multiple hormone systems, including those involved in fetal development, immune response, reproduction, metabolism, obesity, and brain development, can be targets of EDCs. Furthermore, EDCs can produce effects that do not exactly mimic or block those of natural hormones.xv
EDCs can also act on multiple generations simultaneously. For example, exposure of pregnant women to EDCs can act on the pregnant woman, her fetus, and on the fetal gametes, affecting three generations. Individuals exposed to EDCs in the womb face a greater risk of disease later in life, and some EDCs have multi-generational effects through epigenetic modification of DNA and other heritable mechanisms, thereby placing future generations at higher risk of disease. In the case of the female fetus, germ cell numbers are maximized by 7 months gestation and EDC exposure can alter the germ cells during this critical developmental period. Therefore, the endocrine-disrupting potential of a compound extends far beyond actions at hormone receptors, and testing paradigms and public policy must incorporate these aspects of EDC exposure. Recent biomonitoring studies from across Europe have shown that people in the general population are typically exposed to multiple chemicals throughout their life.xvi,xvii,xviii As is the case in the US, it is likely that nearly all babies born in the EU are exposed to industrial chemicals and are potentially at risk for EDC hazards.xix Regulatory paradigms must incorporate new endpoints that reflect the sensitivity of organisms to endocrine disruption and are relevant to disease states to which exposure has been linked.
Current EDC policy relies largely on data produced from guideline studies examining the effects of high doses of chemicals, relative to human exposure. A substance must show evidence of a narrow set of adverse effects that increase proportionally with dose in order to be considered dangerous by classical standards. However, many EDC effects occur at low doses irrespective of effects seen at high doses. In fact, increasing amounts of hormone or a hormone mimic can squelch a measured adverse effect by overwhelming or down-regulating the endocrine system’s ability to respond. In this circumstance, an effect seen at low levels of exposure would not be observed at higher levels of exposure. By eliminating low-dose studies from policy considerations, the regulatory community may be excluding crucial evidence of harmful EDC actions that exhibit hormone-like dose-response profiles.
EDC effects may not be detectable until years after the initial exposure occurs and may affect the offspring of the exposed individual. This was first demonstrated for diethylstilbestrol (DES), which was given to pregnant women in the mid-20th century with the intention of preventing miscarriage. However, DES caused male and female reproductive abnormalities. Additionally, in early adulthood, the daughters of these women were observed to develop a rare cancer at a higher rate than women who had not been exposed to DES before birth. The observation led to basic research studies in animal models that confirmed the causal relationship of prenatal DES exposure to the development of cancer later in life. The confirmation of DES’ effects illustrates in reverse the power of research in appropriate animal models.
Several countries in North America and the EU have banned baby bottles and other baby food containers that contain bisphenol-A (BPA), a chemical used in many polycarbonate plastics, based on in vivo studies in humans and animals and other in vitro studies. Some companies have also taken independent measures to remove BPA from consumer products due to public concern over safety. However, no measures whatsoever have been taken so far to protect other vulnerable individuals such as pregnant women and adolescents. Similar concerns exist over other EDCs, such as perchlorate and phthalates.
Unlike pharmaceuticals, for which clinical trials are undertaken to prove benefits and rule out adverse effects, it would be unethical to perform human studies to uncover harmful EDC effects. One cannot imagine a scenario in which DES would have been given to pregnant women after animal studies revealed its harmful effects. Thus, calls for “definitive proof of harm to humans” present an unachievable goal. It is imperative that strong evidence from animal models be heavily weighted in assessment paradigms.
Identifying direct links between EDC exposure and childhood or adult disease is difficult for many reasons, including the challenge of accurately assessing a lifetime of exposure to a complex mixture of potentially harmful agents. However, the reality is that humans and wildlife are already exposed to many EDCs on a daily basis and their future health is in question today. It is therefore important to synthesize information from animal model systems, detailed laboratory analyses of EDC mechanisms, and epidemiological studies to predict and quantify potential effects in humans so that exposure reductions can be taken where needed.xx Endocrine scientists have unique expertise and experience in experimental endocrinology, and this expertise is critical for high-quality evaluation of endocrine studies by advisory committees and other groups that provide insight on regulatory policy for EDCs.
Systematic review is an approach to the evaluation of scientific data and literature that ensures that the evaluation of information is conducted in a transparent, unbiased, and reproducible method. Key features of systematic review include a clearly stated set of objectives with pre-defined eligibility criteria for study inclusion; an explicit, reproducible methodology for identifying relevant literature; an assessment of the validity and/or quality of the findings of each included study; and a systematic presentation, and synthesis, of the characteristics and findings of the included studies. Taken together, these features lead to more reproducible results between different groups of experts than earlier approaches, such as “weight of evidence” evaluations. Systematic review methodologies relevant to endocrine-disrupting chemicals have been developed, including the SYRINA methodxxi and in a report by the United States National Academies.xxii
Emerging scientific discoveries on EDCs can influence relevant policy decisions. The Endocrine Society encourages further research to resolve scientific discrepancies and uncertainty, and recommends that policymakers consider taking a precautionary approach when developing policy about chemicals that may be harmful to the public. When conclusive evidence is lacking, but sound scientific studies indicate a strong possibility for adverse health effects, it is the responsibility of government to adopt measures that protect people from the risk of exposure to certain chemicals. While some chemicals have been shown to have endocrine-disrupting activity, there are no data on the universe of chemicals in use and in the environment today, including replacement chemicals for known EDCs. In many cases, replacements for harmful chemicals such as BPA include structural analogues with uncertain safety profiles. Thus, appropriate testing strategies must be developed to consistently and comprehensively examine all chemicals for potential EDC activity. Widely applicable, sciencebased criteria for identification of EDCs are required.
As more information about EDC effects and mechanisms becomes available, it will be increasingly important to carefully assess the extent of human exposure to EDCs and assess the inherent risk in that exposure as far as this is possible. Additionally, it will become necessary to provide research funding so that scientists can further examine EDC effects, in particular those already manifesting in people.
To better inform EU guidelines, endocrine research is needed to further elucidate the mechanisms whereby EDCs interfere with endocrine systems necessary for normal development and physiology, including the sources of lowdose effects and NMDR. Toxicologic research is needed to understand the dose-response relationship between general endpoints of toxicity and chemical exposures that typically involve doses higher than those which alter endocrine systems. Epidemiologic research is needed to identify and quantify levels of human exposure that correlate with disease development. Environmental science is needed to identify sources of exposure. Research on “green” chemistry approaches are needed to identify safer chemical alternatives. All disciplines must work together with policymakers, non-governmental organizations, scientific societies, and other stakeholders to ensure that a comprehensive examination of EDC exposure and its effects on human health are used as the basis for policy decisions.
The Endocrine Society is concerned that the European public may be placed at risk because critical information about potential health effects of endocrine-disrupting chemicals is being overlooked in the development of guidelines and regulations, hindering the efficient identification of EDCs. EDC effects know no disciplinary boundaries; teams of scientists, including endocrine scientists, toxicologists, epidemiologists, chemists, environmental scientists and others, must work together to inform EDC-related policies. Legislators, regulators, and others involved in EDC-related policies must develop comprehensive programs for all chemicals and regulations governing EDCs in manufactured products, the food supply, and the environment.
Therefore, the Endocrine Society supports the following positions:
