Endocrine disruptors

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A far-reaching challenge for research

Endocrine disruptors cover a huge class of compounds able to interact with the hormone system. Thus, these compounds potentially affect different functions of the body: metabolism, reproductive functions, nervous system...
Sources of exposure are numerous and difficult to control. The biological consequences of these exposures are still poorly understood and complex to study. This is why the research on endocrine disrupters is now a major challenge for the medical profession and public authorities.

 

  • Substances which interfere with our hormones by modifying their production, preventing them from acting, replacing them
  • Fertility, thyroid, cancer : Numerous consequences for the body
  • Multiple sources of exposure: water, air, food, manufactured goods
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Report drawn up in collaboration with Robert Barouki (Inserm Unit 1124/Paris Descartes University, Toxicology, Pharmacology and Cell Signaling, Paris)

Loupe comprendre Understanding endocrine disruption

There are numerous definitions for endocrine disruptors. The definition adopted by the World Health Organization in 2002 is the most widely accepted: An endocrine disruptor is "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".

In French : C’est quoi la perturbation endocrinienne ? – Interview – 1 min 14 (2015)

The hormone system under fire from endocrine disruptors

The endocrine system includes the hormone-secreting organs: thyroid, ovaries, testicles, pituitary gland, etc. It releases these chemical mediators into the blood circulation to remotely act on certain body functions, such as growth, metabolism, sexual development, brain development, reproduction, etc. Endocrine disruptors alter the body's normal function by interacting with the synthesis, degradation, transport and action mechanism of the hormones. These molecules are therefore characterized by a toxic effect which is not direct, but indirect, via their resulting physiological changes.

Historically, endocrine disruptors began to attract attention among researchers as early as the 1950s. However, it was the diethylstilbestrol scandal in the 1970s which propelled the issue onto the scientific and media stage (see text box). Since then, the action mechanisms of these substances have come to light. Depending on the product concerned, they:

  • modify the natural production of our natural hormones (estrogens, testosterone) by interfering with their synthesis, transport, or excretion mechanisms;
  • mimic the action of these hormones by replacing them in the biological mechanisms which they control;
  • prevent the action of these hormones by binding to the receptors with which they normally interact.

This gives rise to a number of potential consequences on the body, specific to each endocrine disruptor: impaired reproductive functions, malformation of reproductive organs, development of tumors on tissues which produce or are the targets for hormones (thyroid, breast, testicles, prostate, uterus, etc.), thyroid dysfunction, impaired nervous system development and cognitive development, change in sex ratio, etc.

The scope of the effect of endocrine disruptors now has a broader definition. Certain key organs, not strictly speaking perceived as endocrine glands, produce messagers which also appear to be potential targets for endocrine disruptors: leptin in adipose tissue which plays a role in regulating the metabolism, IGF-1 produced by the liver, which acts as a growth factor, etc.

At this stage, it should be noted that the majority of the substances qualified as endocrine disrupters are most often only suspected of having this type of activity. There are very few proven endocrine disrupters. This is due to the great difficulty of demonstrating that a compound exerts its toxicity through the disruption of the endocrine system. This toxicity often results from long-term effects, which may only occur when exposure has occurred at specific developmental points.

Diethylstilbestrol, the retrospective tale of a hormonal dru

At the beginning of the 1970s, an American researcher, Arthur L Herbst, observed the upsurge of a rare form of gynecological cancers among female adolescents and young adults. Analysis of these cases revealed that these women were born to mothers having taken diethylstilbestrol, a synthetic estrogen, prescribed at the time to prevent miscarriage during pregnancy. The link between fetal exposure to diethylstilbestrol and damage to the reproductive organs (cancer, sterility) was rapidly established. Since then, it has emerged that infants born to this generation exposed in utero also have an increased risk of gynecological disorders.

 

Picto Pomme Air, water, food…: multiple sources of exposure

Endocrine disruptors are extremely diverse, and humans and animals are exposed to numerous sources of contamination. These compounds can be found in manufactured goods or plant or animal-based foods. Most originate from the agrochemical industry (pesticides, plastics, pharmaceuticals, etc.) and its waste products. Many are residual: they persist in the environment for many years and may be transferred from one environmental compartment to another (soil, water, air…) many years after they were produced.

Natural or synthetic hormones are a major source of endocrine disruptors: estrogens, testosterone, progesterone, etc. and synthetic products imitating their effects are often used in a therapeutic context (contraception, hormone replacement, hormone therapy). These give rise to an indirect risk when reaching the natural environment, after being excreted in human or animal waste.

In French : Le bisphénol, voleur d’identité – Video press release – 2 min 33 (2012)

A second, much larger, group of endocrine disruptors covers all chemical products and industrial by-products which can interfere with the endocrine system in humans or animals. This group currently comprises over a thousand products, of a varied chemical nature. The most common include:

  • combustion products, such as dioxins, furans, polycyclic aromatic hydrocarbons (PAH), etc.
  • industrial or domestic products, such as:
    • phthalates, or bisphenol A used in plastics;
    • parabens, preservatives used in cosmetics;
    • organochlorines (DDT, chlordecone, etc.) used in pesticides;
    • pewter and derivatives used in solvents.

Pictogramme microscope Challenges facing research

The study of endocrine disruptors is now of great importance to health, and also to the environment. However, this research raises several challenges related to the distinctive characteristics of these substances, in particular due to ongoing uncertainties.

The first challenges concerns the exposure doses: exposure to a high dose may not have the same impact as long-term exposure to a low dose. Hence, while exposure to a single dose of a product does not present a risk to the body, repeated exposure over time may disrupt the hormonal system. Furthermore, the time to onset of the harmful effects of endocrine disruptors, sometimes prolonged, may further complicate this analysis.

In French : Un dent contre le bisphénol – Video press release – 2 min 35 (2013)  

The second difficulty is related to the phases in which living beings are vulnerable to the toxic risk: the body does not experience the same effects when contact with an endocrine disruptor occurs in utero, before or after puberty. The transgenerational effect of some of these molecules also shows that the health risk does not only concern the individual exposed, but also their progeny.

Lastly, the cocktail effect of endocrine disruptors is difficult to evidence: this some times results from the additive harmful effects of several compounds at low doses, which act on the same biological mechanisms. Together, they can disrupt the body, even though individually they would have no effect. Furthermore, interactions may occur between endocrine disruptors which act according to different mechanisms.

Alongside the specific characteristics related to the incriminated substances, the complexity of the hormone system further complicates research: endocrine regulation involves not one but several hormones interacting with each other. It can therefore be particularly difficult to predict all of the biological consequences of an endocrine disruptor.

In French : Cohorte SEPAGES, les bébés alertés – reportage – 8 min 28 (2015)

Despite all these difficulties, the authorities and researchers take precautions on several levels to reduce the risks of exposure and identify potential endocrine disruptors:

  • ecotoxicological studies, conducted in an aquatic environment, and epidemiological studies, conducted in a given population, are useful in correlating specific events, sometimes rare, with exposure to certain substances. The suspected causal relationship in these studies should, however, be based on in vitro and/or in vivo studies;

National cohorts for more in-depth assessment of exposure among vulnerable populations

The ELFE (Etude longitudinale française depuis l’enfance) child cohort study was initiated in 2011, coordinated by the Ined-Inserm-EFS Elfe joint research unit: it currently monitors 20,000 children, born in 2011. Its main objective is to study the environmental and social decisive factors which can impact child health and development, from the in utero stage to adolescence. One phase of this study allowed biological samples to be collected from 8,000 mothers. These could help identify possible correlations between a health event and contamination with endocrine disruptors in utero.

The PELAGIE (Perturbateurs endocriniens : étude longitudinale sur les anomalies de la grossesse, l’infertilité et l’enfance - Endocrine Disruptors: Longitudinal Study on Disorders of Pregnancy, Infertility and Children) cohort has been monitoring 3,500 mother-child pairs living in Brittany, since 2002. Conducted by the "Epidemiological research on the environment, reproduction and development" team from the Institute of Research in Environmental and Occupational Health (Irset, Inserm Unit 625/University of Rennes 1/EHESP), PELAGIE aims to study the impact of environmental contaminants on in utero then infant development. It has already evidenced several correlations, such as exposure to certain organic pollutants (DDT, PCB) on the time taken to conceive, or exposure to a corn herbicide and intrauterine growth retardation. This study is still in progress.

  • in vitro toxicology studies shed light on the toxicity of suspect chemical compounds. To finalize this research, different cell culture systems are used: pituitary gland, liver, mammary cells, reproductive cells, etc. New approaches using 3D cultured cells are being tested. Since 2007, European legislation has required manufacturers to submit each of their chemicals to different toxicological tests depending on the nature of the product (REACH system). To improve the effectiveness of this measure, a European research programme aims to identify the most relevant tests to detect risks among emerging chemicals and to identify the chemical mixtures of greatest concern.
  • in vivo studies (in animals) are vital in order to shed light on the general toxic effect of an endocrine disruptor. However, recent high-throughput and systems biology techniques are attempting to replace, reduce as much as possible, or even eliminate the use of animals.

A national strategy

In 2014, the government adopted the first national strategy on endocrine disruptors. This aims to establish links between research, surveillance and regulations with a view to preventing and limiting population exposure to these substances, particularly among the most vulnerable groups (pregnant women and children). This strategy is now part of the Third National Plan on Health-Environment (PNSE3). 

This strategy comprises four main themes:

  • information for citizens,
  • support for research on endocrine disruptors and the development of non-toxic alternatives to these products. In order to accelerate this movement, the government wishes to propose a public/private platform for test evaluation and validation methods for these substances, to enable early, routine and formal evaluation of new compounds;
  • the planning of expert reports conducted by the institutions in charge of safety in the field of health (ANSM, ANSES) so as to issue annual rulings on several substances suspected to present a risk,
  • the creation of specific regulations. France, along with Denmark, is one of the countries most committed to regulations relating to endocrine disruptors. Testing for phthalates in toys and the ban on the use of bisphenol A in receipts were recently adopted as part of this strategy. The government intends to support this strategy at European level, by supporting the definition of specific European legislation.

A new national strategy is being developed.