Chemicals are an essential component of our daily lives. But some chemicals, known as endocrine disruptors, can have harmful effects on the body’s endocrine (hormone) system. Hormones act in very small amounts and at precise moments in time to regulate the body’s development, growth, reproduction, metabolism, immunity and behaviour. Endocrine disruptors interfere with natural hormone systems, and the health effects can be felt long after the exposure has stopped. Exposure to endocrine disruptors in the womb can have life-long effects and can even have consequences for the next generation.
There is growing concern in the EU and worldwide about negative human health and environmental impacts possibly caused by endocrine disruptors. The EU has introduced specific legislative obligations aimed at phasing out endocrine disruptors in water, industrial chemicals, plant protection products and biocides. In REACH, endocrine disrupting chemicals are considered of similar regulatory concern as substances of very high concern.
– Roadmap for defining criteria for identifying endocrine disruptors in the context of the implementation of the plant protection products regulation and the biocidal products regulation
– The responses to the public consultation on defining criteria for identifying endocrine disruptors in the context of the implementation of the plant protection products regulation and the biocidal products regulation.
What is the endocrine system?
The endocrine system is a complex network of glands, hormones and receptors. It provides the key communication and control link between the nervous system and bodily functions such as reproduction, immunity, metabolism and behaviour.
In nearly all complex multicellular animals, there are two main systems controlling and coordinating the processes within the body:
– The nervous system, which exerts rapid point-to-point control by means of electrical signals passing down the nerves to particular organs or tissues.
– The endocrine system, which is a slower system based on chemical messengers, the hormones, which are secreted into the blood (or other extracellular fluids) and can reach all parts of the body.
The nervous system works in tandem with the endocrine system to control all bodily functions and processes.
The endocrine system has three main components:
– Endocrine glands, situated at various sites around the body, and in specialised areas of the brain. The cells in these glands secrete specific chemicals called hormones.
– Hormones circulate around the body via the blood stream and modulate cellular or organ functions by binding with receptors in the target cells. Hormones that stimulate and control the activity of other endocrine glands are called trophic hormones.
– Receptors in the target cells, once activated by binding of the hormone, regulate the functions and processes in the tissue through interactions with the cell’s DNA or other complex intracellular signalling processes.
The main human hormones and their functions are shown below:
|Hypothalamus||Releasing hormones||Stimulate pituitary activity|
|Pituitary||Trophic (stimulating) hormones||Stimulate thyroid, adrenal, gonadal and pancreatic activity|
|Thyroid||Thyroid hormones||Regulate metabolism, growth and development, behaviour and puberty|
|Adrenal||Corticosteroid hormones Catecholamines||Regulate metabolism Regulate behaviour|
|Pancreas||Insulin and glucagon||Regulate blood sugar levels|
|Gonads||Sex steroid hormones (androgens and oestrogens)||Regulate development & growth, reproduction, immunity, onset of puberty and behaviour|
The production and circulating levels of hormones are controlled by means of negative feedback processes. For example, synthesis of thyroid hormone is stimulated by thyroid stimulating hormone (TSH) produced by the pituitary gland. If blood levels of thyroid hormone fall, a part of the brain, the hypothalamus, responds to the change and releases thyroid hormone releasing hormone (TRH), which stimulates a particular cell type in the pituitary to increase TSH synthesis. As thyroid hormone levels in blood again rise in response to TSH, TRH production is reduced and, in turn, TSH secretion is suppressed. Such feedback systems maintain the balance of various body systems (operating in a fashion analogous to the system that controls a domestic central heating system) – a process known as homeostasis.
Why is it important for Life?
The endocrine system controls growth and development during childhood, regulation of bodily functions in adulthood, and the reproductive process.
The endocrine system is important for the control and regulation of all the major functions and processes of the body:
– Energy control
– Behaviour (e.g. fight or flight response)
– Growth and development
Hormones interact to maintain the above functions and help to regulate our responses to disease, our ability to reproduce and even influence our relationships and behaviour (such as mother: child bonding).
As can be seen, many of the hormones act on tissues and organs at several sites throughout the body. The target cells in these tissues or organs contain specialised structures (receptors) to which only a specific hormone can bind. The response that occurs in the cell will depend on the receptor and cell type, and the effects of other hormones to which that cell may also be exposed. Also, a hormone that stimulates the activity of one cell type may suppress that of a different cell type.
A similar, but not identical, endocrine system to that of humans is found in nearly all vertebrates including other mammals, fish, amphibians, reptiles and birds, although the precise structures and roles of the various organs and hormones differ between different groups, particularly in relation to the different life cycle and development stages in different species. Invertebrates such as molluscs, crustacea and insects also have endocrine systems that control a similar range of body functions although these have evolved along markedly different lines to those of vertebrates.
The main glands and hormones of mammals are:
|Gland||Hormones||Target organs||Main actions|
|Hypothalamus (specialised region of the brain)||Releasing or inhibiting hormones (e.g. growth hormone releasing hormone (GHRH), somatostatin, corticotropin releasing hormone (CRH), arginine vasopressin (AVP), gonadotropin releasing hormone (GnRH) & thyrotropin releasing hormone (TRH)||Anterior pituitary||Controls production/release of other hormones|
|Antidiuretic hormone (ADH)||Kidney||Controls water loss|
|Oxytocin (OT) -released via the posterior pituitary (neurohypothysis)||Uterus, Mammary glands|
|Anterior pituitary [adenohypophysis]||Luteinizing hormone (LH)||Gonads||Control of ovarian oestrus cycle & Leydig cells in testis Control of ovarian oestrus cycle & Sertoli cells in testis Promotes milk production|
|Follicle stimulating hormone (FSH)||Gonads|
|Thyroid stimulating hormone (TSH)||Thyroid glands||Stimulates T4 production/release Affects growth and metabolism|
|Growth hormone (GH)||Generalised|
|Adrenocorticotropic hormone (ACTH)||Adrenal glands||Stimulates adrenal cortex|
|Thyroid||Thyroxine (T4) [active form is tri-iodothyronine T3]||Many tissues||Control of general metabolic rate, also important for development and reproductive functions|
|Adrenal [suprarenal] cortex||Glucocorticoids (e.g. cortisol & corticosterone||Many tissues||Diverse effects on inflammation and protein synthesis|
|Mineralocorticoids (e.g. aldosterone)||Many tissues||Salt balance|
|Adrenal [suprarenal] medulla||Adrenaline (Epinephrine)||Many tissues||Glycogenolysis, lipid mobilisation, smooth muscle contraction, cardiac function|
|Noradrenaline (Norepinephrine)||Many tissues||Lipid mobilisation, arteriole contraction|
|Pancreas||Insulin||Many tissues including liver, adipose tissue & muscle||Facilitates utilisation of glucose by cells & prevents excessive glycogen breakdown in liver & muscle|
|Glucagon||Many tissues including liver, adipose tissue & muscle||Prevents hypoglycaemia through action on carbohydrate, fat & protein metabolism|
|Gonads||Sex steroids (e.g. oestradiol, testosterone, progesterone)||Brain, gonads, accessory sex organs||Sexual development & maintainance of reproductive function and behaviour|
Mechanisms of disruption
Some chemicals can act on the endocrine system to disturb the homeostatic mechanisms of the body or to initiate processes at abnormal times in the life cycle. The chemicals can exert their effects through a number of different mechanisms:
– They may mimic the biological activity of a hormone by binding to a cellular receptor, leading to an unwarranted response by initiating the cell’s normal response to the naturally occurring hormone at the wrong time or to an excessive extent (agonistic effect).
– They may bind to the receptor but not activate it. Instead, the presence of the chemical on the receptor will prevent binding of the natural hormone (antagonistic effect).
– They may bind to transport proteins in the blood, thus altering the amounts of natural hormones that are present in the circulation.
– They may interfere with the metabolic processes in the body, affecting the synthesis or breakdown rates of the natural hormones.
Oestrogens: a group of chemicals of similar structure mainly responsible for female sexual development and reproduction. They are produced mainly by the ovaries but also by the adrenal glands and adipose (fat) tissue. The principal human oestrogen is 17beta-oestradiol.
Androgens: chemicals responsible for the development and maintenance of the male sexual characteristics. They are structurally similar to oestrogens; indeed, oestrogens are produced in the body from androgenic precursors. Testosterone, produced mainly by the testes, is the principal human androgen.
More recently, research has indicated that some chemicals may disrupt thyroid function, with concerns focusing particularly on the role of the thyroid in the developmental process.
There is some evidence that known endocrine disruptors may affect the immune system and may also have some neurotoxicity although the mechanisms by which these effects may occur have not been elucidated.
What do we know about endocrine disruptors?
The main evidence suggesting that exposure to environmental chemicals can lead to disruption of endocrine function comes from changes seen in a number of wildlife species. Effects suggested as being related to endocrine disruption have been reported in molluscs, crustacea, fish, reptiles, birds and mammals in various parts of the world.
There is also some evidence in humans that adverse endocrine-mediated effects have followed either intentional or accidental exposure to high levels of particular chemicals. The clearest example of an endocrine disruptor in humans is diethylstilbestrol (DES), a synthetic oestrogen prescribed in the 1950s and 1960s to five million pregnant women for the prevention of spontaneous abortion. It was found that some of the children who had been exposed in the uterus had developmental abnormalities, and that some of the girls developed an unusual form of vaginal cancer when they reached puberty. As a consequence, DES was banned in the 1970s. In addition, a number of adverse changes have been suggested to have occurred in a population living near a chemical plant in Seveso, Italy as a result of the accidental release of the chemical dioxin, a suspected endocrine disruptor.
Chemicals with hormonal activity, i.e. potential endocrine disruptors, include:
– Natural hormones from any animal, released into the environment, and chemicals produced by one species that exert hormonal actions on other animals, e.g. human hormones unintentionally reactivated during the processing of human waste in sewage effluent, may result in changes to fish
– Natural chemicals including toxins produced by components of plants (the so-called phytoestrogens, such as genistein or coumestrol) and certain fungi
– Synthetically produced pharmaceuticals that are intended to be highly hormonally active, e.g. the contraceptive pill and treatments for hormone-responsive cancers may also be detected in sewage effluent
– Man-made chemicals and by-products released into the environment. Laboratory experiments have suggested that some man-made chemicals might be able to cause endocrine changes. These include some pesticides (e.g. DDT and other chlorinated compounds), chemicals in some consumer and medical products (e.g. some plastic additives), and a number of industrial chemicals (e.g. polychlorinated biphenols (PCBs), dioxins). The hormonal activity of these chemicals, is many times weaker than the body’s own naturally present hormones, e.g. nonyl phenol (a breakdown product of alkylphenol ethoxylate surfactants), found as a low level contaminant in some rivers in Europe, has an oestrogenic activity only about one-ten-thousandth that of the natural hormone, oestrogen.
What areas might they affect?
In wildlife, endocrine disruptors have been clearly shown to cause abnormalities and impaired reproductive performance in some species, and to be associated with changes in immunity and behaviour and skeletal deformities.
In humans, endocrine disruptors have been suggested as being responsible for apparent changes seen in human health patterns over recent decades. These include declining sperm counts in some geographical regions, increased incidences in numbers of male children born with genital malformations, and increases in incidences of certain types of cancer that are known to be sensitive to hormones. More controversially, links have been suggested with impairment in neural development and sexual behaviour.
A number of observations of adverse effects have been made in which endocrine disruptors could play a role, including:
Congenital malformations in children: In recent years there has been an increase in the incidence of hypospadias (a congenital abnormality of the urethra in the penis) and cryptorchidism (undescended testes) in humans.
Cancer: Increased incidences of hormone-related cancers of both women (breast & ovary) and males (testes & prostate) have been observed in the West and in countries adopting Western lifestyles.
Retarded sexual development: A few reports have been published suggesting that adolescents in polluted areas may take longer to reach puberty.
Retarded neurobehavioural development: Studies in Denmark and USA have suggested that children born in polluted areas have some impairment of memory and intelligence.
Unlike the situation for humans, the evidence for endocrine disruption occurring in some wildlife species is much more compelling. This may reflect a greater level of exposure for some wildlife populations or it may be due to differences in susceptibility between humans and animals.
Some well-established examples of adverse effects in wildlife include:
Imposex (male genitalia in female) in marine molluscs; known to be due to exposure to antifouling paints on ships that contain organotin compounds.
Feminisation (development of female gonadal tissue and production of an egg yolk protein, vitellogenin) in male fresh water fish in rivers or lakes exposed to treated sewage effluents, in many parts of Europe; similar changes also being noted in estuaries.
Impaired reproductive development, and abnormalities of the reproductive system in alligators in a polluted lake in Florida USA, and in turtles in the Great Lakes, USA.
Other adverse changes in wildlife species that have been suggested, but not proven, to relate to exposure to pollutants, include:
– Reproductive impairment or abnormalities in whales, seals and polar bears.
– Impaired immune function in seals.
– Skeletal deformities in frogs.
The Definition of Endocrine disruptor in the World
In 2002, the International Programme on Chemical Safety, a joint programme of various UN Agencies, including the World Health Organisation, made an authoritative definition of an endocrine disruptor as
« an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations ».
The novelty in this definition was the introduction of a second element. The usual approach to defining the toxicity of chemical substances is « end points » – whether there is an adverse effect. The new, additional, element is the concept of « mode of action », the way in which a chemical substance has an impact.
Protection of Citizens in European Union
In 1999, the Commission adopted a Strategy on Endocrine Disruptors. The revision of the legislation on chemicals performed during subsequent years took this strategy into consideration.
EU legislation in force already considers endocrine disruptors. As a consequence, consumers are protected from endocrine disruptors via the authorization of chemical substances to be used in plant protection products, biocidal products, chemicals (REACH), and cosmetics. However, no formal criteria have been established, internationally or at EU level, for identifying substances with endocrine disrupting properties.
The Commission presented on 15 June 2016 two draft legal acts – one under the Biocidal Products legislation, the other under the Plant Protection Products legislation – which set the criteria to identify endocrine disruptors.
These two drafts will now need to be adopted according to their relevant procedures, which in both cases involve Parliament and Council.
In 2009, the EU regulation governing the placing on the market of pesticides in Europe was adopted, promising to restrict or to prohibit before the product is placed on the market the endocrine disruptors that may be harmful to humans.
But with the proposal of the European Commission currently on the table, the level of evidence is so high that we will have to wait many years of damage on health before withdrawing an endocrine disruptor from the market. To be clear, people will first have to suffer. The ban on a substance will come at a second stage, which runs counter the very essence of the precautionary principle, enshrined in European law.
See Commission Definition, pages 6 to 8, adopted by European Commission on the 4th of July 2017
Very few of substances fill all these criteria. This process may take years, if not decades, to establish a definitive causal link between an endocrine disruption and a given pathology. There are hundreds of molecules more or less strongly suspected. Almost 800 chemical substances are recognised or suspected to interfere with the hormone receptors, according to a report from 2 Agencies of the United Nations (the United Nations Environment Programme and the World Health Organization).
Another contentious issue is about introducing derogations for the agricultural community and other sectors.
What are the next steps in terms of procedure for these criteria?
The text agreed on the 4th of July 2017 will now be sent to the Council and the European Parliament. They will have three months to examine it before final adoption by the Commission.The text will enter into force 20 days after its publication in the Official Journal and be applicable six months after this.
– Article from Le Figaro, 03/07/2017
– Petition from Sumofus, ongoing
– Communication from the Commission to the European Parliament and the Council on endocrine disruptors and the draft Commission acts setting out scientific criteria for their determination in the context of the EU legislation on plant protection products and biocidal products – 15 June 2016
– European Commission / DG Environment – Endocrine disruptors
– European Commission / DG Environment – Endocrine disruptors, Policy
– European Commission / DG Environment – Endocrine disruptors, Next Steps
– European Commission / DG Environment – Endocrine disruptors, Strategy
– European Commission / DG Environment – Endocrine disruptors, Legislation
– BfR report 2016
– EFSA Opinion March 2013
– ECHA Endocrine Disruptor Expert Group
– SCCS Opinion 2014
– JRC Report March 2013
– European Parliament resolution on the protection of public health from endocrine disruptors (2012/2066(INI))
– EEA Report 2012
– WHO/IPCS Report 2012
– Kortenkamp Report Dec 2011
– OECD webpage on endocrine disruptors
– Press Release European Commission – 4 July 2017
– European Commission – Fact Sheet, Endocrine disruptors – Frequently Asked Questions
– Draft commission adopted on the 4th of July