Rising levels of cancers and fertility problems have attracted scientists’ attention to endocrine disrupting chemicals, with some calling for strict regulation of the substances, in line with the precautionary principle. Others meanwhile, stress the worthiness of those chemicals in everyday products such as plastics and warn that the foundations of science risk being turned upside down if precautionary measures are taken.

Overview

Endocrine disruptors are chemical substances that are suspected of triggering diseases such as cancer or diabetes and contributing to people becoming overweight or infertile through changes to the endocrine (or hormone) system.

The controversy has gone beyond the traditional confrontation between the chemicals industry and environmental and health activists.

Among scientists, too, opinions vary on whether a link exists between these chemicals and diseases. But all parties agree on one point, that the protection of consumers and the environment must be ensured.

The European Union has been at the forefront of efforts to regulate those substances, for example by banning the use of Bisphenol A in baby bottles, or trying to reduce the amount of pesticides used by farmers.

Most importantly, EU lawmakers adopted in 2006 the REACH regulation, which for the first time requested chemical producers to prove that their products are safe before they can be allowed on the market.

The European Commission has now started a review of endocrine disruptors and is expected to submit proposals in 2015 on how to identify and regulate substances with endocrine disruptive properties in products such as pesticides and biocides.

But this is no easy task for regulators, who are torn between the precautionary principle and their promise to root decision-making in rock-solid scientific evidence.

Issues

Public health worries

Hormones are the body’s chemical messengers. They regulate key functions such as metabolism, growth, development, sleep and mood.

From a public health perspective, it is therefore crucial that the endocrine system (or the hormonal system) is not disrupted over the long-term, particularly during critical development phases – in the womb, during infancy or puberty – otherwise there is a risk of abnormal development, according to the World Health Organization.

Endocrine disruptors threaten the healthy development of living organisms. They can contribute to malformations, particularly among fish and amphibians, and are suspected by some scientists and environmentalists of also contributing to a whole range of diseases in humans.

These include testicular and prostate cancer, reduced sperm count, infertility, undescended testes in men, and breast, ovarian and cervical cancer in women. Other suspected conditions linked to them include thyroid cancer, premature births, precocity, overweight, diabetes and attention deficit hyperactivity disorder (ADHD).

Endocrine active vs. endocrine disrupting chemicals

However, important distinctions need to be made as not all endocrine 'active' substances are necessarily endocrine 'disrupting', scientists point out.

The devil is in the detail: to identify a substance as an endocrine disruptor, it must be proven to have a damaging impact on health linked to an endocrine mechanism, which is not easy to demonstrate.

The German Federal Institute for Risk Assessment (BfR), a government body, has attempted to clarify the fundamentals in the debate by describing how endocrine disruptors influence the hormonal system.

Some bind themselves directly to a receptor, where they have a hormone-like effect. Others block receptors and thus the effect of hormones. And others still influence the synthesis and breakdown of hormones. The transportation of hormones in the body may also be disrupted.

To clarify the endocrine mechanisms of action, the Organisation for Economic Co-operation and Development (OECD) has developed various test methods and an assessment framework over the last 15 years. Test methods that have been used for some time are also integrated into this framework.

Yet a potential causal link is difficult to demonstrate in epidemiological studies, as a long time may elapse between the absorption of substances and their presumed impact on the body.

People are also exposed to an abundance of other environmental factors, making it difficult to isolate the impact of a specific endocrine substance on human health with certainty.

Determining the origin of EDCs

Drawing up a complete list of endocrine disruptors and endocrine active substances is also a challenge because there are no generally accepted criteria to do this.

A first major difficulty lies in estimating their number and origin. A recent study by the World Health Organization (WHO) and the United Nations Environment Programme (UNEP) is based on the assumption that there are around 800 endocrine active substances.

But identifying chemicals with endocrine disrupting potential among all of the chemicals used and released worldwide “is a major challenge,” it warns, saying “it is likely that we are currently assessing only the tip of the iceberg”.

Some are in fact produced unintentionally, during combustion processes and via environmental transformations, the WHO study said, adding to the complexity of determining their origin. “While the active ingredients in pharmaceuticals and pesticides have to be documented on the final product, this is not the case for chemicals in articles, materials and goods,” it says.

“Many sources of EDCs are not known because of a lack of chemical constituent declarations in products, materials and goods. We need to know where the exposures are coming from.”

Substances under scrutiny

Not everything is uncertain however. Some substances have been singled out by scientists and have become the subject of intense public debate.

Ethinylestradiol, which is contained in birth control pills, has particularly high endocrine activity for instance. It can enter wastewater via the urine of women who take birth-control pills. The substance is chemically highly stable, with the result that it passes through the treatment process and enters the groundwater if treatment plants are not retrofitted with appropriate filters.

These substances can have an impact on fish and amphibians even in low concentrations. However, the impact on groundwater and drinking water is generally so low that its potential negative effects cannot be demonstrated.

Numerous everyday products may also contain endocrine active substances. Familiar substances with a potential endocrine impact include:

  • tributyltin (TBT), on printed textiles, outdoor jackets and the 10-euro note,
  • surfactants, in shampoos and laundry and dishwasher detergents,
  • flame retardants such as polybrominated diphenyl ethers (PBDE), and
  • plastic components such as bisphenol A, which is used in crown cork tops, inner coatings for cans, food packaging, drink bottles, till receipts and children’s toys.

Many of these substances are now banned across Europe for certain uses, for example Bisphenol A in baby bottles.

And there are many more. Dioxins occurring in combustion processes, polychlorinated biphenyls (PCBs) and the insecticide dichlorodiphenyltrichloroethane (DDT), which is still used in many areas of the world, are also endocrine active.

Even cosmetic products and sunscreen may contain estrogen-like substances.

However, endocrine active substances are also found in natural products such as soybeans, nuts, clover (isoflavones), flax seeds (lignans) and licorice (glycyrrhizin). Common substances as alcohol and caffeine can also demonstrate hormonal effects even though they are not considered as EDCs.

Many women even deliberately consume foodstuffs and dietary supplements containing isoflavones, as they hope this will ease the symptoms of the menopause. The German BfR therefore conducted a risk assessment on isoflavones in 2007. According to the assessment, increased consumption of these substances is “not without risk”, particularly among women during and after the menopause. The BfR sees a need for closer examination, especially among women with breast cancer or at increased risk of it.

Phthalates under the spotlight

Among the substances under scrutiny, Phthalates have probably attracted the highest public attention.

Phthalates are chemical substances which are used to make plastic soft and more flexible. They can be found in everyday products such as rubber boots, oilcloths and vinyl flooring. They can also be found in adhesives, electronic goods and packaging as well as construction materials and some of them have already been banned in Europe for use in children's toys.

Some phthalates with low molecular weight – namely DEHP, DBP, DIBP and BBP – have been linked to reduced sperm count, causing male sterility. They are also being accused of pushing young girls into puberty too early and causing liver cancer in rats.

Such worries have encouraged some countries to introduce restrictions on some phtalates. In 2012, Denmark decided to ban four of them, moving the country ahead of the European Union which has started a process of phasing them out.

"This is an area in the EU which is unregulated, so therefore I think it's correct to do this and let Denmark move ahead," said Danish Environment Minister Ida Auken as she announced the ban.

How dangerous?

However, debate continues to rage over how dangerous EDCs really are.

According to the Bavarian State Office for the Environment (LfU) “environmental chemicals with an estrogenic effect in the human body have an impact 1,000 to 10,000 times less than the body’s own natural hormones have,” and should therefore not be a reason for concern.

For the LfU, the relatively low concentrations of these substances in the environment are well below the therapeutic activity thresholds. The human diet is also much more varied and balanced than that of a fish, for example, with the result that regular, continuous absorption of harmful substances through food is unlikely. The LfU thus assesses the risks posed to people by endocrine environmental pollutants as “relatively low”.

The German BfR agrees, saying that the risk for consumers is next to zero. Damaging effects from endocrine active substances on vulnerable groups of consumers such as small children and young people in puberty have not been proven, it argues. Still, it recommends keeping exposure to these substances as low as possible.

Low-dose chemical exposure and ‘cocktail effect’

Yet, there is mounting evidence that low-dose exposure to endocrine disruptors may have a negative impact on human health. According to some scientists, chemical substances would be potentially damaging even at very low amounts, working in a similar way to homeopathic medicines.

"If you combine a very large number of chemicals at very low doses, you can see significant hormonal effects with them. It can even happen that the hormonal strength of natural estrogens can be modulated," argued Professor Andreas Kortenkamp, the head of the Centre for Toxicology at the University of London, who presented a study to the European Parliament in 2008.

However, the effects of low-dose chemical exposure has not yet been confirmed with certainty. As the European Food Safety Authority (EFSA) stated: “Based on the scientific evidence, many scientists are not convinced of its validity.”

Kortenkamp and others acknowledge that in science there is always something to be further explained or clarified, but said he believes that there is already enough scientific evidence to start regulatory action while at the same time continuing research in parallel. 

"You can't wait for perfect clarity. That would be really unethical," he said at the time, supporting a precautionary approach to regulation.

Nowadays, the cocktail effect is generally accepted by regulators. In 2009, the EU’s 27 environment ministers invited the European Commission to assess whether existing legislation addressed this problem and to suggest appropriate guidelines.

Follow up reports were drawn up but have been bogged down in complexity. “The number of chemical combinations is potentially enormous and it is neither realistic nor useful to test every possible combination,” the European Commission said, inviting further scientific studies.

A ‘State of the Art Report on Mixture Toxicity’ was completed in 2009 to provide a more systematic way of testing the combination effects of chemicals.

The long road towards a ‘priority list’ of substances

The European Commission’s interest in endocrine disruptors is not new and dates back to 1996, when the issue was for the first time put on the agenda of a conference in the small English town of Weybridge.

In March 1999, its Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE) published a first report on the matter that classified endocrine disruptors as a “potentially global problem”, blaming them for health changes in certain animal species.

In the same year, the Commission then agreed on a community strategy for endocrine disruptors in which it defined short-, medium- and long-term measures to respond to the potential consequences of endocrine disruptors on health and the environment.  (To date, the Commission has reported on progress made in implementing the strategy in four updates – 2001, 2004, 2007 and 2011).

The process culminated in 2012, when the European Commission organised the conference 'Endocrine Disruptors: Current challenges in science and policy' (see programme and presentations). The conference was based on a State of the Art report on the assessment of endocrine disruptors and established a priority list of substances that should be placed under scrutiny and potentially regulated or banned.

One substance, one assessment

This is where the chemical industry starts getting nervous.

The EU already has various regulations in place for chemicals, starting with the 2007 REACH regulation, which for the first time requested chemical producers to prove that their products were safe before they could be allowed on the market.

However, REACH does not cover all substances. Pesticidesbiocides, cosmetics and water quality are all subject to separate regulations.

For the chemical industry, this means that the same substance can be subject to several legal provisions, which raises issues related to legal certainty and cross-compliance.

The German BfR has listened to those concerns and advocates the principle of ‘One substance – one assessment’. “If a substance is dealt with in various areas of the law, the evaluation must nonetheless be identical and be performed only on the basis of the properties inherent in the substance,” says BfR President Andreas Hensel. He adds that different toxicological thresholds cannot be used as the basis for one and the same substance, as the toxicity is always the same.

The Commission is therefore considering a uniform “horizontal” assessment system that evaluates the substances in all legal regulations governing chemicals, using the same criteria.

At the Commission’s request, EFSA produced a report that defined scientific criteria for identifying endocrine disruptors. The report emphasised the importance of distinguishing between endocrine active substances and endocrine disruptors and paved the way for regulating endocrine disruptors in food.

According to the report, a substance can be identified as an endocrine disruptor if it is endocrine active and if a causal link exists between endocrine activity and impact on health.

Parliament pressure to regulate

But some EU lawmakers have criticised the whole process for being too slow and have asked the Commission to list endocrine disruptors as "substances of very high concern" under the REACH chemicals regulation.

While question marks remain over how those substances end up in humans, MEPs said legislative action should be taken quickly to protect human health, especially in vulnerable groups such as pregnant women and infants.

"Even if we do not have all the answers, we do know enough to regulate these substances in accordance with the precautionary principle," the resolution said.

Positions

  • EFSA: Assessing toxicity on a case-by-case basis

In a report submitted at the request of the European Commission, the European Food Safety Authority (EFSA) considers that available testing methods are sufficient to determine whether a substance with endocrine effects should be regulated or not.

Its recommendations make a distinction between the “hazard” and “risk” posed by endocrine active substances. While “hazard” refers to the inherent toxicity of a substance, a “risk” only exists if humans (or the environment) come into contact with the substance, causing damage. Relevant factors here include the dose, the duration of exposure and whether this occurs at a particularly unfavorable time such as pregnancy.

Even though EFSA has clarified key terminology issues, there is still no precise and universal definition for what exactly is meant by the term endocrine disruptor and what is not. EFSA therefore advocates that experts should assess the toxicity of each substance on a case-by-case basis.

  • Parliament: Speeding up regulation

In the European Parliament’s view, the Commission’s efforts on endocrine disruptors do not go far enough. In March 2013, the Assembly adopted an own-initiative resolution calling on the EU executive to pass further measures in order to protect consumers against endocrine disruptors, in line with the precautionary principle.

Given the remaining scientific uncertainty, there should be no delay in taking preventive steps against the potential risks of endocrine disruptors, said Swedish MEP Åsa Westlund, who authored the report for the Committee on the Environment, Public Health and Food Safety.

“Even if we do not have all the answers, we do know enough to regulate these substances in accordance with the precautionary principle,” she said.

By 2015, the European Commission is requested to submit a revised legislative proposal to restrict endocrine disruptors. MEPs consider that the substances should be classified as “particularly hazardous” under the REACH regulation.

Given the potential interaction with other substances, the European Parliament also wants endocrine active substances to be treated as “non-threshold substances” if the manufacturer cannot provide scientific proof that a threshold can be determined.

  • Scientists: Split down the middle

These calls for action have left the scientific community split down the middle. While some support precautionary action, others have resisted it, saying further research is needed to trace back the substances and routes of exposure to them.

Reacting to the Parliament’s call for action, 71 scientists have sent an open letter to Anne Glover, the Commission’s Chief Scientific Adviser, stating that a precautionary approach on endocrine disruptors would “rewrite current accepted scientific and regulatory principles.”

The letter expresses concern that the EU is choosing an approach to regulating endocrine active substances that has neither a scientific basis nor broad support from scientists, for example by drawing up a priority list of substances.

“Development of horizontal lists ignores the long-standing principle that an assessment of a substance should be based on data obtained from toxicity testing on this specific substance and derived information on potency,” the letter says.

“If the Commission will adopt a policy stating that it is impossible to define a safe limit or threshold for a substance with classified as endocrine disruptor, this would reverse current scientific and regulatory practices and, more importantly, ignore broadly developed and accepted scientific development and accepted knowledge regarding thresholds of adversity,” the authors warn.

Other scientists however have rebutted the open letter and accused the authors of blurring the boundaries between science and politics.

In May 2013, a group of 89 leading public health scientists from around the world signed the 2013 Berlaymont Declaration on endocrine disruptors, associating EDCs with rising levels of cancer along with increasing brain, thyroid and reproductive problems.

According to the signatories, current regulations stating that low levels of exposure EDCs are safe ignore the possibility that many endocrine disruptors may act without thresholds, causing disruption at any concentration.

“A major problem is that for many endocrine disrupting effects, internationally agreed and validated test methods do not exist, although scientific tools and laboratory methods are available,” said Professor Susan Jobling from Brunel University in the United Kingdom. “This seriously hampers progress in understanding the full risks,” she explained.

As well as action to control the use of chemicals, the declaration also calls for a targeted endocrine disruptor research programme, focusing on exposure assessments and the identification of substances with endocrine disrupting properties and further research in support of human health studies.

“Although uncertainties remain, Commission-funded research has greatly contributed to substantiating the plausibility of serious, irreversible harm stemming from endocrine disruptors,” said Professor Åke Bergman of Stockholm University in Sweden.

“Scientific uncertainty should therefore not delay regulatory action.”

  • Environmental groups: Supporting the Parliament initiative

The European Parliament initiative has met with unanimous approval from environmental associations.

The Health and Environment Alliance (HEAL), an association of 65 European nature conservation and health protection organisations from all over Europe, particularly welcomed the Parliament’s recognition that the EU must shape its chemical policies to address vulnerable phases of life and the “cocktail effect” of different chemicals.

“We need an EU strategy and laws that catch up to the reality of EDC exposures that our bodies face every day. The laws should protect us before every last scientist and the chemical manufacturing industry organisations concede the relationship between our internal contamination and our expanding rates of endocrine-related diseases,” said Lisette van Vliet from HEAL.

In a letter dated 7 May, Genon Jensen, HEAL's executive director, called on the European Commission to take action. Jensen said that the evidence for the dangers of endocrine disruptors was overwhelming and that a turning point had been reached. In her view, the Commission should adapt European chemical legislation as quickly as possible to reflect the latest scientific findings.

She argued that, as there is no evidence of safe thresholds for endocrine disruptors, the Commission should adapt the REACH regulation in such a way that the relevant substances may only be authorised if they are “essential to society” and no safer alternatives are available.

  • Chemical industry: Urging science-based debate 

The chemical industry, for its part, fears that blanket application of the precautionary principle could damage companies and jobs without necessarily improving safety for people and the environment.

The European Chemical Industry Council (CEFIC) points out that endocrine active substances, contrary to widespread perception, are in fact thoroughly tested and regulated.

Where adverse effects are observed, appropriate measures are taken and, if necessary, substances are removed from the market, CEFIC said. This has worked in cases where adverse impacts resulting from endocrine effects could be demonstrated, for example with the DDT pesticide, which is now prohibited for agricultural use in most countries.

CEFIC said it hopes the ongoing discussion on endocrine disruptors will continue within the existing regulatory framework and that potential risks could be assessed on the basis of available scientific data.

According to the German Chemical Industry Association (VCI), the assessment of endocrine active substances should be based on scientifically proven fact. It warns particularly that any “rushed judgment” should be avoided.

“Despite massive research efforts over the past two decades, to date there is no widely accepted scientific evidence of hormone active substances in the field of the chemical industry being a source of danger that is either new or was under-estimated previously,” VIC said in a position paper.

The association also warned against calls to classify endocrine disruptors as non-threshold substances. It maintains that, in contrast to certain carcinogenic and mutagenic substances that have a damaging effect even in minute amounts and for which no thresholds can be defined, it is indeed possible to define thresholds for endocrine disruptors that will not cause any damage if they are complied with.

Timeline

  • Dec. 1996: Weybridge meeting on endocrine-disrupting chemicals (EDCs)
  • Mar. 1999: Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE) publishes report classifying endocrine disruptors as a “potentially global problem”
  • Dec. 1999: EU Commission agrees on 'Community Strategy for Endocrine Disrupters' (updated in 2001, 2004, 2007 and 2011)
  • June 2007: REACH Regulation comes into force, requiring chemical producers and downstream users to prove their products are safe before they can be authorised on the EU market
  • Mar. 2013: Following a request from the Commission, EFSA develops opinion clarifying scientific criteria for identifying an endocrine disruptor, paving the way for regulating EDCs in food
  • Mar. 2013: EU Parliament adopts resolution calling on Commission to pass further measures to protect consumers against endocrine disruptors
  • By 2015: European Commission to submit a revised legislative proposal to regulate endocrine disruptors