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image European Research News Centre > Medecine and Health > Tracking down endocrine disrupters
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image image image Date published : 24/02/03
  image Tracking down endocrine disrupters
RTD info 36
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  Concerns were first expressed more than a decade ago when a growing number of strange phenomena involving hormone changes and 'sexual mutations' were observed in natural environments. The possible cause was an insidious - and previously unsuspected - form of pollution caused by the ever more sophisticated nature of waste chemical and organic ingredients entering the environment. Their potential impact on human health is now taken very seriously indeed. True to the precautionary principle, a number of European research projects have been set up to track down and evaluate this creeping threat.
   
     
   

They can feminise males and lend male characteristics to females in species as diverse as molluscs, fish, frogs and birds, seriously reducing their fertility. They may also harm their development, undermine their immune systems and make them prone to tumours. They are even suspected of having an effect on human health, possibly being responsible for - statistically observed - lower sperm counts or the increase in testicular, breast and prostrate cancer. So what exactly are these malevolent forces? They are known as endocrine disrupters, a vast and varied range of substances whose common characteristic is to interfere with the proper hormone functioning of living organisms and therefore - why not? - of humans.

Mobilising scientists

European Union officials decided not to underestimate the dangers of this new kind of threat and, most notably, increased support for the research effort in this field (see box A serious European warning). As well as increasing efforts to monitor and study the disruptions observed in ecosystems, and in man, closely, scientists also set about identifying the potentially guilty materials. The list is growing all the time.

In May 2002, the Research DG demonstrated its commitment to stepping up the European effort, in no uncertain terms, when it decided to allocate €20 million to a cluster of four projects. Known as Credo (Cluster of Research on Endocrine Disruption in Europe), the group includes 64 research teams dedicated solely to these disturbing molecules. 'In addition to the significant resources, one of Credo's strong points is our integrated approach to human health and environmental problems, which were previously the subject of separate European research actions,' stresses project coordinator Andreas Kortenkamp of London University's School of Pharmacy. 'Bringing the projects together in this way is a positive step. We are finally going to see experts on human endocrinology, naturalists and chemists all working together. That is a very exciting prospect.'

A complex affair

The complex nature of the problem demanded nothing less than such a concentrated research effort. First of all, there is the sheer diversity of the substances involved. Pesticides, flame retardants, cosmetics, medicines, paints and combustion products are all seen as potential endocrine disrupters. The way they act is also worrying. As their structure resembles a particular hormone, some of these molecules are able to act by triggering the same reaction in the organism which the hormone would produce naturally. Others, on the contrary, attach themselves to the hormone receptors to subsequently block its action. A third category disrupts hormone synthesis, transport, metabolism or excretion, thereby changing natural concentrations in living organisms.

'The mix of potential culprits is another problem,' explains Andreas Kortenkamp. 'A single endocrine disrupter is not generally found in any given environment, but rather many different ones of different origin. It is not easy to study how they interact, although it is essential for evaluating the risk. We showed in previous projects that a dozen elements, all present in quantities below their observable activity threshold, had a major impact due to the synergy effect. It is this aspect in particular that the Eden project is seeking to investigate further.'

Untangling the similarities

Finally, it is particularly difficult to untangle the biochemical web as vertebrates alone possess around 50 known hormones. One of the most exciting questions will be to discover to what extent invertebrates, about whose hormone systems very little is known, 'resemble' vertebrates in terms of endocrine systems.

This is one of the aims of the Comprendo project which is studying androgenic and antiandrogenic compounds, in particular. 'We know,' explains project coordinator Jörg Oehlmann of Frankfurt University's Institute of Zoology, 'that some hormones are particular to invertebrates - such as the very specific hormones which control metamorphosis in insects. But we also have reason to believe that, in the course of the long evolution of life, areas of endocrine systems have been able to remain virtually intact. Tributyltin (TBT), for example, is known for acting on the same enzyme as that which converts androgens into oestrogens in molluscs and mammals, despite the fact that these are very different groups. We want to check this hypothesis as it would make it possible to construct animal models from which we could extrapolate the effects on man.'

Identifying the sentries

If primitive aquatic organisms, such as echinoderms (sea urchins, starfish, etc.) or molluscs, were shown to carry the same hormone receptors as man, this similarity would bring many benefits. We could use these species in their natural environments as 'sentries' able to indicate when contamination levels give cause for alarm. But most importantly, these organisms could provide the basis for developing test systems with which to evaluate the harmlessness to human health of a given chemical compound.

'Aquatic invertebrates or amphibians are themselves of interest to us as they are a part of ecosystems and warrant our protection. But they also interest us with a view to constructing protocols - recognised by scientists in general - with which to test the action of a given chemical compound on the endocrine system,' explains Jörg Oehlmann. Indeed, one of the current problems is the absence of recognised tests with which to quantify the harmfulness of a molecule for the hormone system.

An urgent need for tests

In fact, there are many tests, but controversy continues over the interpretation of their results. Some of them (such as those involving rodents) are also seen as insufficiently sensitive. Developing universally recognised protocols, and which could be validated by the OECD and then used in laboratories worldwide, would mark major progress, to which the scientists working on the Credo project certainly intend to contribute. However, it is not known how many protocols are needed to verify that a product is totally harmless. At present, interest is focused almost exclusively on oestrogenic or androgenic effects. It is likely that new tests will be required when we have more advanced knowledge of other hormones (especially those produced by the thyroid gland).

'It is a question of providing pertinent and usable scientific data to permit a Community strategy on endocrine disrupters. We are not doing research out of curiosity alone, but want to provide decision-making tools and are beginning to reflect on how our data on the mixtures of substances could be used for regulation purposes,' is how Andreas Kortenkamp sums up the situation.

553 'candidate' substances

In this respect, the most difficult aspect will certainly be to shed light on the relationships between these substances and human health. The drop in male fertility noted in several Northern European countries, as well as the general increase in certain types of cancer, are generally believed to be multifactor phenomena. Smoking, alcohol consumption, changes in diet, and a more sedentary lifestyle are among the factors which probably play a part. Given these conditions, it is a formidable challenge to estimate the degree of responsibility of a given chemical compound or group of compounds.

Even if this is just an initial empirical sample, the Commission has already identified no fewer than 553 candidate substances for a more in-depth study of their endocrine effects. These products are now awaiting the necessary data and tests to evaluate them effectively. However, the list remains provisional.


Boxes
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A serious European warning

In a Communication to the Council and Parliament, dated December 1999, the Commission stressed that studies on fish - in particular roach in the United Kingdom - showed an alarming proportion of males (13% on average, almost half in some rivers) with testes containing ovocytes - the cells destined to form eggs. On the other hand, female sea molluscs (oysters and winkles in particular) were found to be developing male characteristics associated with TBT, a compound previously used in paints for ships and which has a very serious impact on the reproduction of these species which, in some cases, have become extinct locally. There are also indications that the reproduction of birds is being threatened by these endocrine disrupters and researchers have reported cases of hermaphrodite gulls.

The growing number of cases of this kind caused the Commission to affirm that ' impaired reproduction and development causally linked to endocrine disrupting substances are well-documented in a number of wildlife species and have caused local population changes'.

Commission Communication, Community Strategy, December 1999

PDF file

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Focus on flame retardants

Fire, one of the projects in the Credo cluster, is interested in an important group of organo-halogenic compounds: Brominated Flame Retardants (BFRs). These are used extensively by industry in polymers and textiles and are often applied to construction materials, furniture and electronic devices. The group includes polybrominated biphenyl ethers (PBDEs) and tetrabromo bisphenol A (TBBPAs) which are the subject of particular attention. In 1999, the world market in these molecules was estimated to be 67 000 tonnes.

'We are going to study the distribution and development of the level of exposure to BFRs in wild coastal fauna, in particular among predators which are at the top of the food chain - such as terns, seals and bears - but we are also interested in human diet,' explains Joseph Vos of the National Institute for the Environment and Public Health in the Netherlands and FIRE coordinator. 'With the aid of in vitro cell cultures, studies of the toxicity of various BFRs on the endocrine and immune systems of rodents or fish should enable us to determine in more detail which compounds are the most significant.' The aim is to provide an estimate of the risks to man and the environment, on the basis of exposure levels and effects, that will enable us to 'say whether or not we have a sufficient safety margin'.

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Virility and œstrogens

According to Jörg Oehlmann (Institute of Zoology - Frankfurt University), '95% of funds for research on endocrine disrupters, whether in Europe or the United States, are allocated to compounds with oestrogenic effects, although such well-documented examples as those of TBT clearly prove that androgenic effects are of equal concern.' To explain the paradox, the researcher ventures this hypothesis: 'my women colleagues believe that as research is male dominated, they have chosen to spend most money on compounds that could present a risk to their own capacities...'

A shortcoming - whether real or imagined - which Credo has been able to guard against as the Comprendo project in which Jörg Oehlmann is participating is devoted exclusively to androgenic compounds.

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To find out more


Credo Contacts

EDEN: Endocrine Disrupters: exploring novel end-points, exposure, low-dose and mixture-effects in humans, aquatic wildlife and laboratory animals (22 partners in 10 countries, €8.7 million EC contribution).
Andreas Kortenkamp (overall coordination of Credo) - University of London - School of Pharmacy (UK)
E-mail - Site

COMPRENDO: Comparative research on endocrine disrupters - phylogenetic approach and common principles focusing on androgenic/antiandrogenic compounds (13 partners in 9 countries, €3.3 million EC contribution).
Ulrike Schulte-Oehlmann and Jörg Oehlmann - University of Frankfurt - Institute of Zoology - DE
E-mail - E-mail 2 - Site

EURISKED: Multi-organic risk assessment of selected endocrine disrupters (10 partners in 8 countries, €3.1 million EC contribution).
W. Wuttke - University of Goettingen - Faculty of Medicine - DE
E-mail

FIRE: Risk assessment of brominated flame retardants as suspected endocrine disrupters for human and wildlife health (19 partners in 7 countries, €4.9 million EC contribution)
J. Vos, National Institute of Public Health and the Environment (NL)
E-mail


Person responsible at the European Commission

Kirsi Haavisto - E-mail
Tuomo Karjalainen - E-mail


While many research projects are interested in those oestrogens which could have a disturbing effect on the male species, the Comprendo project is studying the androgenic factors threatening female elements. These electron microscope images show the effects produced by chemical compounds such as tributyltin and tripnenyltin – used in paints for boats and agricultural fungicides. They produce abnormal penis and sperm canal phenomena (PP and Vd, bottom picture) in female Hydrobia snails living in marine sediments. The cellular proliferation which results contributes to blocking the oviduct, sterilisation of female subjects (OvL, normal in top picture, blocked in lower picture) and, finally, to the increasing disappearance of these molluscs along the coast.

While many research projects are interested in those oestrogens which could have a disturbing effect on the male species, the Comprendo project is studying the androgenic factors threatening female elements. These electron microscope images show the effects produced by chemical compounds such as tributyltin and tripnenyltin - used in paints for boats and agricultural fungicides. They produce abnormal penis and sperm canal phenomena (PP and Vd, bottom picture) in female Hydrobia snails living in marine sediments. The cellular proliferation which results contributes to blocking the oviduct, sterilisation of female subjects (OvL, normal in top picture, blocked in lower picture) and, finally, to the increasing disappearance of these molluscs along the coast.


The main points sensitive to possible endocrinal changes in humans.

The main points sensitive to possible endocrinal changes in humans.
1. Pituitary gland
2. Thyroid and parathyroids
3. Thymus
4.Suprarenal gland
5. Pancreas
6. Ovaries
7. Testes

Diagram reproduced with the permission of the Institut National de Recherche et de Sécurité (INRS) - France

 


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