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.