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French Agency for Food, Environmental and Occupational Health & Safety

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Updated on 24/07/2019

Endocrine disruptors

Presentation and ANSES's work in the field

Keywords : Endocrine disruptors, Chemical risks, Bisphenol A (BPA)

Endocrine disruptors are substances that can interfere with our hormonal system. Faced with multiple sources of exposure, scientists need to understand the role played by these substances in the development of certain diseases. Assessing their health effects is therefore a scientific challenge and a major public health issue. ANSES is one of the major players in this area. In particular, it carries out important assessment work to identify endocrine-disrupting substances and is leading a research programme, the PNR EST, part of which is dedicated to endocrine disruptors.

What are endocrine disruptors?

Endocrine disruptors are substances that disrupt the hormonal functions of living organisms and can therefore have harmful effects on health and the environment.

"An endocrine disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse effects in an intact organism, or its progeny, or (sub)populations."

WHO 2002

Endocrine disruptors can interfere with all the major functions of living organisms: growth, reproduction, behaviour, nutrition, metabolism, nervous system, etc.

By disrupting the endocrine system, these substances can alter different processes such as communication between cells or tissues and the regulation of key stages of an organism's development.

Some of these substances may also have toxic effects, including reprotoxic effects, and may impair fertility or disrupt foetal development. Recent studies show that endocrine disruptors can also have other effects on the body such as metabolic, neurodevelopmental or immune effects.

 

How do endocrine disruptors act?

Several mechanisms are described. Endocrine disruptors can:

  • mimic the action of a natural hormone, thereby causing the response due to this hormone >> this is the mimetic or agonist effect;
  • prevent a hormone from binding to its receptor and thus prevent the transmission of the hormonal signal >> this is the blocking or antagonistic effect;
  • disrupt the production/degradation or regulation of hormones or their receptors;
  • disrupt the transport of a hormone within the organism.

 

The endocrine system

Health depends on a well-functioning endocrine system made up of several organs called glands (composed of endocrine cells) which produce hormones and then release them into the blood. Distributed throughout the body, hormones act as “chemical messengers”. They have a variety of essential functions: stimulating growth and development, regulating impulses and moods (e.g. sexual impulses, violence, anger), and controlling major physiological constants (e.g. body temperature, blood sugar, blood pressure). This means that the slightest alteration in the endocrine system can disrupt our balance, as in diabetes, for example.

Multiple sources of exposure

There are a wide variety of endocrine disruptors and the sources of contamination to which humans and animals are exposed are also numerous. Disruptors have many origins and can, depending on their physico-chemical properties, be transferred to different media. Various compounds suspected of being endocrine disruptors can be found in trace amounts in the environment.

Organisms can in this way be exposed by multiple routes (ingestion, inhalation, dermal contact) to minute doses of several compounds, the effects of which can be varied and could combine.

 

Effects and particularities of endocrine disruptors

While the toxic effects of certain substances are clearly established at high doses, the question of identifying adverse effects linked to long-term hormonal disruption, or even over several generations, and potentially at low doses, has yet to be addressed.

The low-exposure dose

Usually, below a certain level of exposure, the body's defence mechanisms prevent the appearance of health effects. This is called a threshold effect. For certain hazardous substances such as carcinogenic compounds, there is sometimes no threshold effect, at least on a population scale, so effects are possible even at low doses. Endocrine disruptors are suspected of acting in the same way.

Non-monotonic dose-response relationships

Traditionally, the adverse effects of chemicals are described in toxicology studies as proportional to the dose tested. Typically, a low dose produces no effect, the median dose produces low toxic effects, while a high tested dose induces more pronounced or harmful effects. However, toxicologists have noted that some chemicals can follow inverted curves, i.e. have greater (or even opposite) effects at low doses than those observed at high doses; this is called a non-monotonic dose response.

Windows of exposure

Susceptibility to endocrine disruptors may vary with the stage of life. This applies in particular to the foetal and embryonic development period, and to infants and young children, who exhibit greater sensitivity to these substances. The onset of puberty is also a sensitive period during which a hormonal disorder can irreversibly alter certain functions of the body.

Cocktail effects

Understanding the effects of endocrine disruptors requires also taking into account the individual’s exposure to a mixture of chemicals and understanding their interactions in the human body over the long term, right from the period of foetal-embryonic development.

In view of this complexity, knowledge of the effects of endocrine disruptors at the concentration levels observed in the environment is hindered by the limitations of traditional toxicology and risk assessment methods. The challenge is therefore to develop new ones, adapted to the unique properties of these compounds. Understanding the potential environmental and human health effects requires that research projects take into account the potential synergistic effects of mixtures of environmental contaminants.

 

Chemicals and endocrine disruptors: a complex regulatory framework

The regulation of chemicals is governed by the REACh Regulation, which applies without transposition in all EU Member States. It requires that substances with endocrine-disrupting properties and considered to be at the same level of concern as carcinogenic, mutagenic and reprotoxic substances (CMRs), be identified as substances of very high concern, and thus be included in the list of substances subject to authorisation.

The CLP Regulation requires specific labelling for CMR 1A and 1B substances, some of which are potential endocrine disruptors (EDs). However, it excludes certain products (food, food supplements, medical devices, medicines, cosmetics) that are subject to specific sector-based regulations.

Only the regulations on plant protection and biocidal products explicitly require the exclusion of substances with ED effects.

 

Overview of ANSES’s work on endocrine disruptors

The assessment of biocidal and plant protection substances: identification criteria now defined and implemented

A definition of endocrine disruptors for substances in plant protection and biocidal products was adopted in 2017 at European level (EU Regulations 2017/2100 and 2018/605). Consideration is being given to extending this approach to other regulated sectors (cosmetics, medical devices, food contact materials, etc.). ANSES contributed to this work on the criteria for the identification of endocrine disruptors. See the 2016 Opinion.

From now on, a plant protection or biocidal substance is identified as an endocrine disruptor if:

  1. the substance has a mode of action that alters the functions of the endocrine system;
  2. it produces an adverse effect in an intact organism or its descendants;
  3. the adverse effect is a consequence of this mode of action.

For all plant protection and biocidal substances for which an evaluation was ongoing or due to be carried out (new substance or renewal of approval of an existing substance), the endocrine disruption assessment must be conducted in accordance with the criteria set out in the appropriate European Regulations and the methodology developed in the EFSA/ECHA Joint Guidance Document published on 5 June 2018. See news item.

As soon as the European regulations were adopted, ANSES conducted an assessment of the substance epoxiconazole and confirmed its endocrine-disrupting nature. See news item.

France and the other Member States will assess the endocrine-disrupting properties of approximately 300 plant protection substances by 2025 and 100 biocidal substances by 2024.

ANSES, as the competent evaluation authority, will be responsible for evaluating several dozen of these.

 

Assessment of chemical substances

Many chemicals are suspected of having these properties: bisphenols, phthalates, parabens, brominated and perfluorinated compounds, and alkylphenols.

For nearly 10 years, ANSES has been carrying out extensive work to prioritise and then evaluate chemicals with regard to their potential endocrine-disrupting action. This work specifically contributes to identifying them as Substances of Very High Concern for their endocrine-disrupting properties under the REACh Regulation, leading to a ban on the use of the substance unless renewable authorisation is granted.  

ANSES thus identified bisphenol A as an endocrine disruptor for humans, and more recently TNPP, which contains nonylphenol.

 

Focus on bisphenol A

As a result of the Agency's expert appraisal (Sept. 2011), the French Parliament adopted a law in 2012 suspending the manufacture, import, export and marketing of all food packaging containing BPA. Therefore, since 1 January 2015 it has been prohibited in infant feeding bottles and other food containers. This legislation is expected to lead to a very significant reduction in the level of dietary exposure to bisphenol A.

Based on a request by France assessed by the Agency, the European Commission adopted a proposal in July 2016 to classify BPA as a category 1B reproductive toxicant.

In February 2017, ANSES also submitted a proposal to the European Chemicals Agency (ECHA) to classify bisphenol A (BPA) as a "substance of very high concern" (SVHC) in the context of the European REACh Regulation for its endocrine-disrupting properties in humans. This proposal was adopted by ECHA's Member State Committee in June 2017.

To learn more about ANSES's work on bisphenol A, click here

These studies served as the basis for ranking the substances to be assessed in the framework of the National Endocrine Disruptor Strategy (SNPE 2014-2016).

 

National Endocrine Disruptor Strategy

France is the first country to have a national strategy on endocrine disruptors (SNPE 2014-2016) that aims to reduce the exposure of the population and the environment to endocrine disruptors. In this context, ANSES has been tasked with the assessment of at least five substances per year over three years, which can also include potential substitutes for substances of concern.

When certain substances submitted to the Agency for appraisal are suspected of having endocrine-disrupting effects and/or posing a risk to health or the environment, ANSES is asked to propose appropriate risk management measures in the framework of the European regulations.

In 2014, ANSES produced a first report on five substances: MTBE, DEHTP, DINCH, BHA and methyl paraben.

in 2015, ANSES conducted an analysis of six substances: ATBC (acetyl-tributyl-citrate), TBC (tributyl citrate), BHT (butylated hydroxytoluene), terephthalic acid, methyl-salicylate, and iprodione. 

In 2016, in addition to investigating the endocrine-disrupting nature of bisphenol A, ANSES conducted an analysis of five substances:

  • TMBPF, triclocarban and RDP underwent an analysis of the best risk management options, according to the procedure in force used by ECHA and the Member States of the European Union.
  • Dicyclopentadiene and tin sulphate were assessed under the REACh Regulation because of a suspected reprotoxic effect, and suspected carcinogenic, mutagenic and reprotoxic (CMR) properties and sensitising effects, respectively. See news item.

In 2017, four substances were added to the Agency's work programme: homosalate, triflusulfuron-methyl, triphenyl phosphate and BDE-47. See Opinion.

In 2018, ANSES investigated three substances: Bisphenol B (CAS 77-40-7), HHCB (CAS 1222-05-5) and TNPP (EC 701-028-2).

Assessment results Number of substances among those assessed
Potential substitutes for EDs of lesser concern 4
Substance requiring additional data to assess the identification criteria 13
Substance likely to disrupt the endocrine system of animal species but already highly regulated 1
Endocrine-disrupting substance 3
Substance identified as an ED for human health (SVHC-57f under REACh) 1

At the end of the first SNPE, the government announced the implementation of the Second National Endocrine Disruptor Strategy, to which ANSES has also made a significant contribution. Find out more here (in French).

 

The Agency's other work on endocrine disruptors

ANSES has also conducted several expert appraisals:

  • on the potential health and environmental effects of flame retardants used in upholstered furniture. See news item.
  • on the presence of phthalates or substitute substances in flexible plastic toys and childcare articles that can be put in the mouth by children under three years of age. See news item.
  • on the handling of uncertainty in the process of health risk assessment of chemical substances. This work is the result of methodological developments implemented by the Agency over the past few years to better describe the uncertainties and strengthen the weight of evidence in health risk assessment. These developments are based on the expert appraisal work on endocrine disruptors. See the Report (French only).

 

The Agency has produced other studies in connection with the issue of endocrine disruptors:

  • Collection and analysis of data on the presence of pesticide residues in environmental media by the phytopharmacovigilance.
  • Total diet studies and in particular the study on the infant population (iTDS), published in 2016: dietary exposure of children under three years of age to substances of interest, some of which may have an endocrine-disrupting effect.
  • Study of the presence of compounds in water resources and in drinking water by ANSES’s Nancy Laboratory for Hydrology.
 

Funding research to better understand endocrine disruptors

ANSES runs the French National Research Programme for Environmental and Occupational Health (PNR EST) which, over the past ten years, has helped strengthen the acquisition and development of knowledge, mainly on the hazards, potential exposure and associated diseases in these two fields. 

Endocrine disruptors are an integral part of the research questions and therefore a priority in the PNR EST’s annual calls for research projects. For each of the 2018 and 2019 editions, an additional €2 million was allocated by the Ministry of the Environment to finance research projects on the topic (13 projects in 2018). To find out more about the projects funded in 2018 click here.

The results of projects funded through the PNR EST are promoted through ANSES’s Scientific Conferences events and the publication of research papers. The Scientific Conferences event of 8 July 2019, organised in partnership with the ANR, focuses on endocrine disruptors, and more specifically on the scientific advances concerning exposure to these substances, their effects on human health and their mechanisms of action. See the event website.

The topic is also featured in Cahiers de la Recherche Number 13.