Endocrine active substances (EAS) are substances that can interact or interfere with normal hormonal action. When this leads to adverse effects, they are called endocrine disruptors (ED).
The endocrine system is important for human and animal health because it regulates and controls the release of hormones. Scientific knowledge in this area is still growing and, therefore, understanding of what is an EAS/ED continues to be the subject of scientific debate.
Humans and animals may be exposed to a wide range of endocrine active substances through the diet as well as other sources. EAS can be naturally-occurring (such as phytoestrogens in soya) or man-made. Examples of EAS sometimes found in food include several pesticides, environmental pollutants like dioxins and PCBs, and the food contact material, bisphenol A. Some EAS are intentionally used in medicines (birth control pills, thyroid hormone substitutes) because of their endocrine active properties.
EFSA and the European Chemicals Agency (ECHA) are developing Guidance that will enable applicants and regulatory authorities to identify endocrine disrupting properties among chemical substances proposed as pesticides and biocides under EU legislation. In December 2016, the two agencies published an outline of how they will proceed with the work. The outline includes a projected table of contents, as well as a plan of the drafting process, including timelines, responsibilities, consultations with relevant parties and an explanation of how the document will be endorsed.
The Guidance was requested by the European Commission, which is currently working with Member States to set hazard-based scientific criteria for identifying endocrine disrupting properties in pesticides and biocides.
2015 EFSA’s scientists made significant strides in addressing the issue of potential “endocrine disruptors” in the area of pesticides. Their work is a response to recent EU rules that changed, from 2014 onwards, how EFSA evaluates active substances used in pesticides.
2014 the European Commission launched an on-line consultation to help define criteria for “endocrine disruptors” as required by EU regulations on biocides and plant protection products (used in pesticides).
2013 EFSA’s Scientific Committee published a scientific opinion on the hazard assessment of endocrine disruptors. This describes scientific criteria for identification of endocrine disruptors and appropriateness of existing test methods for assessing effects mediated by these substances on human health and the environment.
EFSA’s experts concluded that internationally agreed testing methods were available or soon to be available for the most important endocrine pathways in mammals and fish known to be sensitive to endocrine disruption: these relate to oestrogen, androgen, and thyroid hormones as well as steroidogenesis (the biological process for production of steroid hormones). EFSA concluded that a risk assessment approach which considers both the likelihood of exposure together with potential adverse effects of endocrine active substances makes best use of available information to regulate their use.
2012 European Commission asks EFSA to provide, in collaboration with the Commission Scientific Committees and the other EU agencies with similar tasks (EMA, ECHA), scientific advice on the assessment and testing of endocrine active substances. EFSA agreed to take stock of existing information, current insights and scientific activities on ‘endocrine disruptors’.
2010 EFSA’s Scientific Committee established an Endocrine Active Substances Task Force, with the support of EFSA’s Advisory Forum of national competent authorities, to clarify the state-of-play on endocrine active substances and to provide recommendations for scientific and communication issues. In a scientific report, the Task Force proposed that EFSA contributed to the work of the European Commission and OECD activities on chemical testing guidelines.
EFSA’s role in the European Union (EU) food safety system is to assess and communicate on all risks associated with the food chain. Endocrine-associated effects are amongst the toxicological endpoints (that is, the expected outcomes of a test or trial) which EFSA’s scientists take into consideration when carrying out risk assessments of chemical substances present in the food chain. The Authority’s scientific advice informs the decisions of EU risk managers (the European Commission, European Parliament and Member States) who regulate the use of these substances in a variety of areas.
- Some EFSA Scientific Panels are sometimes involved in the evaluation of substances with endocrine active properties in the course of their work: the Panel on Contaminants in the Food Chain, the Panel on Plant Protection Products and their Residues, and the Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids.
- EFSA’s Scientific Committee provides scientific advice on cross-cutting issues related to the Authority’s risk assessment work. Its advice supports further development of harmonised and consistent approaches for risk assessment, including where these may be relevant to endocrine active substances.
Reliable test methods and testing strategies are needed to allow the identification and assessment of the endocrine disruptive properties of substances. In this context, the harmonisation of the testing of chemicals has been an on-going activity of the Organisation for Economic Co-operation and Development (OECD) since the 1980s. A core activity on endocrine disrupters was initiated in 1997 and under this umbrella both specific tests and a conceptual framework for such tests have been developed. EFSA provides technical support to a number of such activities of the OECD.
Between 1996 and 2000, the European Commission co-ordinated and developed together with the European Parliament, EU Member States and European scientific advisory bodies, a Community strategy for endocrine disruptors. The objectives were to identify the problem of endocrine disruption, its causes and consequences and to propose appropriate policy action in order to respond quickly and effectively to the problem, thereby alleviating public concern. This strategy set out the short, medium and long-term actions to be undertaken to address the potential environmental and health impacts of endocrine disruptors within the EU.
- Community strategy for endocrine disruptors – European Commission
- Endocrine disruptors website – European Commission
The Commission was called on to identify substances to be prioritised for immediate action. These lists of substances led to the development of European legislation to regulate their use in specific areas:
- Chemicals – Regulation EC 1907/2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) – substances having endocrine disrupting properties may be identified as Substances of Very High Concern (SVHC) and be made subject to authorisation.
- Pesticides – Regulation EC 1107/2009 concerning the placing of plant protection products on the market – substances regarded as having endocrine disrupting properties that may be harmful to humans or non-target organisms cannot be authorised. However, non-approval does not apply if the exposure is negligible under the conditions of use, or if the substance is necessary to control a serious danger to plant health which cannot be contained by other available means including non-chemical methods.
- Biocides – Regulation EU 528/2012 concerning the making available on the market and use of biocidal products – these substances are not approved if they have endocrine disrupting properties. However, non-approval does not apply if the risk to humans and the environment is negligible, if the substance is essential to combat a serious health risk, or if non-approval would result in disproportionate negative impacts on society relative to the risks to humans and the environment.
- Cosmetics – Regulation EC 1223/2009 on cosmetic products – endocrine disrupting substances are currently not restricted; however, this will be reviewed when EU or internationally agreed criteria for identifying substances with endocrine-disrupting properties are available.
- Water quality – Water Framework Directive (2000/60/EC) – sets out a strategy against pollution of surface waters by chemical pollutants and the substances of particular concern in the EU, including some candidate endocrine disrupting substances. In 2012, the Commission proposed to amend the list of priority substances. Although no direct reference is made, endocrine disruption could become an important criterion for sorting substances or groups of substances into this group.
Review of the EU strategy
In 2009, the Commission’s Directorate-General for the Environment commissioned a study on the ‘State of the Art of the Assessment of Endocrine Disruptors’ to provide a basis for the development of scientific criteria for the identification of endocrine disruptors; and the review and possible revision of the EU (previously ‘Community’) Strategy on endocrine disruptors. The resulting study was published in January 2012 and reviewed scientific knowledge published in the literature in the previous 10 years. Its scope followed also a review of approaches for assessment of endocrine disruptors used in selected Member States, in other countries outside the EU, and in international bodies (e.g. the World Health Organisation).
As a follow-up to this study, in June 2012, the Commission organised a conference on ‘Endocrine Disruptors: Current challenges in science and policy’. Together these two initiatives provided the platform for the review of the Strategy and also input to the Commission’s above-mentioned upcoming legislative proposal for establishing criteria for the identification of substances with endocrine disrupting properties. In addition, the European Environment Agency (EEA) published a report on ‘The Impacts of Endocrine Disrupters on Wildlife, People and their Environments – The Weybridge+15 (1996–2011)’.
In late 2014, the Commission held an on-line consultation to help define criteria for endocrine disruptors as required by EU regulations on biocides and plant protection products (used in pesticides).
On 15 June 2016, the European Commission presented criteria to identify endocrine disruptors in the field of plant protection products and biocides. The Commission proposed to the Council and the European Parliament to adopt a strong science-based approach to the identification of endocrine disruptors and to endorse the WHO definition.
1. What is the endocrine system? Why is it important for health?
The endocrine system is a network of glands which regulates and controls the release and levels of hormones in the body. Hormones are chemical messengers that are essential for the body to carry out functions such as metabolism, growth and development, sleep and mood. Only a tiny amount of hormone may be needed to trigger the intended action. The endocrine system is complex and the interactions within this system which regulate hormonal release are dependent on a variety of biological and physiological factors. Scientific knowledge of this system is still growing.
Imbalances and malfunctions of the endocrine system can result in well-known diseases, such as diabetes and obesity, infertility and certain types of cancer. Also, disruption of the endocrine system can cause birth defects and learning disabilities.
2. What are endocrine active substances? Are they the same as “endocrine disruptors”?
Endocrine active substances are chemicals that can interact or interfere with the endocrine system. This may take place in different ways: some such substances mimic natural hormones but trigger unwarranted responses, or they may block the effects of natural hormones. Others change hormone levels in the body or alter metabolic processes that breakdown natural hormones. Importantly, these effects are not necessarily adverse. The endocrine system is capable of adjusting and adapting to these stimuli depending on factors such as the nature and dose of the substance, its timing, the type of effect and the condition of the body. This ability of the endocrine system is sometimes called adaptive response or ‘physiological modulation’. However, when this interaction or interference leads to adverse effects these substances are called endocrine disruptors.
3. Why are there concerns about endocrine disruptors?
Exposure to endocrine disruptors could increase the likelihood of harmful effects in the short-term or later in life. Concern about the possible harmful effects of endocrine disruptors has been growing in recent years because of observations in humans and wildlife. These indicate rising rates of endocrine diseases and disorders, including reproductive and developmental harm in human populations. However, the scientific basis for linking all such trends to endocrine disruptors (as opposed to other factors such as lifestyle changes and genetic background) is not conclusive.
4. What are windows of susceptibility?
The risk of harmful effects from endocrine disruptors may increase when exposure to them takes place during critical stages of development (for instance, conception, pregnancy, infancy, childhood and puberty). Scientists refer to these critical stages when the body is more sensitive to hormonal activity as ‘windows of susceptibility’. However, windows of susceptibility are not unique to endocrine disruptors; exposure during critical life stages to other potentially harmful substances (that do not affect the endocrine system) can also increase the risk of an adverse health effect.
5. Are endocrine active substances present in food or other products?
We are potentially exposed to a wide range of endocrine active substances – these can be naturally present in the diet or be present as a result of human activity. Examples of substances naturally present in food which may exert hormonal effects are plant phytoestrogens such as isoflavones, which are often present in nuts, oilseeds and soy products. Another example is glycirrhizine in liquorice, which may disrupt the hormonal regulation of the balance of minerals and fluids (or ‘electrolytic balance’) in blood and various organs, important for the regulation of blood pressure. Examples of endocrine active substances sometimes found in food and feed include some pesticides, the food contact material bisphenol A (BPA) as well as environmental pollutants like dioxins and PCBs. Some endocrine active substances are intentionally used in medicines (birth control pills, substitutes for thyroid hormones) because of their endocrine active properties.
6. What was EFSA asked to do in relation to endocrine disruptors and endocrine active substances?
EFSA was given the mandate to identify and characterise the effects of endocrine active substances found in the food chain. The European Commission’s Directorate General for Health and Consumers (DG SANCO) asked EFSA to prepare a scientific opinion to take stock of the available scientific information on three key questions:
- What scientific criteria are used for identifying endocrine disruptors
- What criteria can be applied to distinguish potential adverse effects of an endocrine disruptor from the normal regulation of body function in humans and in the ecosystem
- Whether existing toxicity testing methods appropriately cover the effects of endocrine active substances.
The Commission asked EFSA to provide its scientific opinion by March 2013.
The Authority’s previous work in this area includes a report on endocrine active substances published in 2010 that clarified the state-of-play and provided recommendations for scientific and communication issues. EFSA also held a scientific colloquium in June 2012 on low dose response in toxicology and risk assessment attended by over 100 experts from 21 countries.
7. Why was EFSA asked to do this work?
EFSA’s contribution forms part of a wider EU initiative. The European Commission’s Directorate General for the Environment is co-ordinating the review of the EU strategy on endocrine disruptors. The Commission is required to present proposals for legislation setting down criteria for the identification of endocrine disrupting properties of substances. EFSA’s scientific advice is part of this review and supports and informs EU decision-makers’ updating of current legislation in a variety of areas (chemicals, pesticides, biocides).
EFSA’s opinion also supported its own ongoing and future scientific work in such areas as food contact materials, pesticides and contaminants in food and feed.
8. What does EFSA’s opinion add to the debate about these substances?
EFSA reviewed the available testing methods to assist risk managers in defining what may or may not be an endocrine disruptor using science-based criteria. EFSA highlights that not all endocrine active substances are endocrine disruptors. This depends on whether there is reasonable evidence that the substance can cause an adverse effect as a result of its interaction or interference with the endocrine system. The review of current testing methods was an important part of this work and contributes to EU and international discussions in this area.
9. How can scientists identify “endocrine disrupting effects”?
EFSA endorses the World Health Organization’s definition that a substance must meet three criteria to be considered an endocrine disruptor: firstly, the presence of an adverse effect; second, the presence of endocrine activity; and thirdly, a causal relationship between the two. However, since there are no specific scientific criteria defined to distinguish potential adverse effects of endocrine disruptors (and of other substances) from normal regulation of body functions (so-called ‘adaptive responses’), experts need to assess the weight of available evidence on a case-by-case basis for each substance.
10. Can current testing methods provide adequate data for this work?
EFSA’s experts examined (internationally) standardised test methods for the identification of endocrine active substances. They concluded that a reasonably complete set of ‘assays’ (tests or trials) is or will shortly be available to cover adequately four important pathways of the endocrine system in mammals and fish currently known to be sensitive to endocrine disruption, but with fewer tests available for birds and amphibians. The hormone pathways best addressed by testing methods relate to oestrogen, androgen, thyroid and steroid hormones.
Importantly, no single test is likely to provide all the information needed to decide whether a substance is or is not an endocrine disruptor. One reason for this is that tests are generally designed to ascertain either endocrine activity or different types of adverse effects, but not both. Therefore, several tests need to be done and then assessed together by experts in a weight-of-evidence approach.
11. What does EFSA say about so-called “low dose effects” in its opinion?
According to the so-called low-dose hypothesis, there are substances that are believed to cause adverse effects at doses or concentrations below those which are considered to be ‘no effect’ levels. In its scientific opinion EFSA’s Scientific Committee notes the lack of international consensus on the existence/relevance of low-dose effects. On a case-by-case basis, if triggered by unusual findings, an extended dose-response analysis of doses administered at wider ranges could be performed. Generally, EFSA considers that adverse effects occurring at the lowest observable effect level should continue to be used to guide safety assessments, whether due to endocrine activity or another toxic effect. This will protect against other possible endocrine-related effects at higher doses.
An issue that is often confused with the low-dose hypothesis but should be considered separately is ‘non-monotonic dose-response relationships’. In most toxicity testing of chemicals it is understood that the higher the dose of a chemical, the greater the effect and the likelihood of an adverse effect. Non-monotonic dose-response curves are produced when the response is increasing with the dose at some points and decreasing as the dose increases at others. This can result in U-shaped curves or other irregular patterns. In its opinion EFSA recommends that these relationships should be the subject of future scientific activities. However, EFSA notes that these effects are not unique to endocrine active substances and should be considered across the spectrum of chemical substances.
12. Does the opinion address the issue of “chemical mixtures”?
Combined exposures to multiple chemicals (or ‘chemical mixtures') could occur in such a way that combined toxicity could arise. This is another issue that EFSA does not consider to be unique to endocrine active substances. The Authority is addressing this issue through other activities.
In 2013, EFSA published a scientific report reviewing international frameworks for assessing chemical mixtures. The report supports the roll-out of harmonised terminology and methodologies for risk assessors and provided a platform for future EFSA work in this area. A second report on modern methodologies and tools for human hazard assessment of chemicals came out in 2014. The report includes examples from the scientific literature and international efforts as well as future perspectives for the potential application of these modern methodologies and tools in the risk assessment of chemical mixtures.
13. What does EFSA’s scientific advice on endocrine active substances mean for consumers?
EFSA’s assessment of the currently available testing methods will assist EU decision-makers in defining what may or may not be an endocrine disruptor using science-based criteria. This will help establish protection goals that ensure the highest possible level of protection for consumers, animals and the environment.
14. How specifically will this work be used?
EFSA’s work on this topic is concerned chiefly with endocrine active substances related to the food chain (for example, pesticides). Its contribution forms part of a wider initiative co-ordinated by the European Commission and is intended to support and inform EU decision-makers’ updating of current legislation on the regulation of endocrine active substances in a variety of areas (chemicals, pesticides, biocides).
EFSA also makes concrete recommendations for future activities, including testing methods and testing strategies that will help to generate the data adequate for the assessment of possible endocrine disrupting properties. EFSA also recommends clarifying in a broader context how a number of issues not unique to endocrine active substances (criteria for defining adverse and non-adverse health effect, combined exposure to multiple chemicals and non-monotonic dose response relationships) could impact on current methodologies and testing strategies.
15. Does EFSA decide whether or not to ban endocrine disruptors?
The Authority neither authorises nor bans the use of substances in foods. It is the responsibility of risk managers in the European Commission, the European Parliament and the EU Member States to define and agree measures as and where required, taking into account scientific advice and other considerations.
EFSA’s role is to provide independent scientific advice to risk managers on food and feed safety and to communicate its advice to the public at large. It is in this context that EFSA’s Scientific Committee and Scientific Panels carry out safety assessments and review new evidence.
As a scientific organisation EFSA recommends that these substances – like all other substances present in the food chain – be subject to risk assessment in order to make the best use of available information in ensuring consumer safety. Such an approach considers both potential adverse effects of substances together with the likelihood of exposure to such substances. EFSA believes that scientists can clarify through expert judgement and the weight-of-evidence what may or may not be an endocrine disruptor.