POLLUTION

The elusive case of endocrinian disruption

Today we live in an environment teeming with industrial chemicals. Under certain conditions, some can disrupt hormonal systems. This thorny issue has been the focus of European research for more than 10 years.

The freshwater snail Marisa cornuarietis, being studied by Jörg Oehlmann’s team at the Institute for Ecology, Evolution and Diversity of the Wolfgang Goethe University in Frankfurt (DE). © Institute for Ecology, Evolution and Diversity – Frankfurt
The freshwater snail Marisa cornuarietis, being studied by Jörg Oehlmann’s team at the Institute for Ecology, Evolution and Diversity of the Wolfgang Goethe University in Frankfurt (DE). © Institute for Ecology, Evolution and Diversity – Frankfurt
Effect of Bisphenol A (BPA) on the species Marisa cornuarietis, characterised by enlargement of the sexual glands in females. The photo compares snail uteruses: a control specimen on the left and, on the right, a ‘super female’ that has been exposed to BPA. The two glands forming the uterus are considerably enlarged due to exposure to an oestrogen-activating endocrine disruptor. © Institute for Ecology, Evolution and Diversity – Frankfurt
Effect of Bisphenol A (BPA) on the species Marisa cornuarietis, characterised by enlargement of the sexual glands in females. The photo compares snail uteruses: a control specimen on the left and, on the right, a ‘super female’ that has been exposed to BPA. The two glands forming the uterus are considerably enlarged due to exposure to an oestrogen-activating endocrine disruptor. © Institute for Ecology, Evolution and Diversity – Frankfurt

The oestrogens found at outlets from water treatment plants have an impact on river fauna by feminising fish species and destroying the fertility of stocks. © Shutterstock
The oestrogens found at outlets from water treatment plants have an impact on river fauna by feminising fish species and destroying the fertility of stocks. © Shutterstock

The endocrine disruption issue bears all the hallmarks of a police investigation.

This now worldwide problem is enough to baffle the most astute detective: overwhelming suspicions backed by little evidence, a host of sparse and disparate clues, victims that are hard to identify... and above all, a huge cast of suspects. So what exactly is endocrine disruption? It is the ability of certain chemical compounds to modify not only the human hormonal system but also that of virtually all animals. Hormones govern most of the key body functions: not only foetal and child development and reproduction, but also the immune system - in other words, our natural defences. It is a threat that needs to be taken seriously.

The problem is that hormones, which act as messengers within the organism, are present in extraordinarily low concentrations. This means that endocrine disruptors, which imitate hormones or counter their effects (in which case they are called antagonists), can cause problems even at infinitesimal doses. For example, it has been demonstrated that one of the world's most commonly used herbicides, Atrazine, has a feminising effect on amphibians at a concentration of only 0.1 millionth of a gram per litre, which is the current level found in rainwater in the United States.

A study recently published by the American Academy of Sciences revealed that 5 ng/l (nanogrammes, or billionths of a gram per litre!) of oestrogens, which is more or less the level found at outlets from wastewater treatment plants, is enough to decimate the entire population of minnows in a lake, once again by feminisation or even sterilisation of the males, in the space of only two years... Studies to measure the fish feminised population in the rivers of industrialised countries are already legion, from the Seine in France to the Potomac in the United States. It could of course be argued that all we need to do is improve water treatment, which is the avenue being explored by the European NEPTUNE project. Although we already have the technology to neutralise endocrine disrupting chemicals, the problem is one of cost. Project researchers calculate that it would take between 0.02 and 0.1 euros per cubic meter to eliminate them - equivalent to around €5 per European per year.

Even worse than the problem of low doses is that of synergies. "This is a ‘something from nothing' sort of problem," explains Jörg Oehlmann, a professor at the department of aquatic ecotoxicology at the University of Frankfurt (DE). "Here we have a new kind of mathematics where 0 + 0 + 0 = 6 or 7! In other words, by combining products at concentrations where they are inactive individually, we end up with a mixture that is fully active at endocrine level." These disquieting results were obtained by the Cluster of research into endocrine disruption in Europe (CREDO), financed by the 5th Framework Programme, in which the German scientist was involved. The conclusion in terms of methodology is that it is not good enough to work on a single suspect substance, because it may prove to be much more active than expected when combined with others...

Another disturbing property of hormones is that some are active during specific stages of the human life cycle. Child development, especially in utero, appears to be a particularly sensitive time, with significant delayed, or even transgenerational, effects (consequences observed several decades after exposure). "We need only remember the case of DES (diethylstilboestrol), a synthetic oestrogen used to prevent abortion in the 1960s," says Jan-Åke Gustafsson, of the Karolinska Institutet (SE), which coordinates the European project CASCADE (Chemicals as contaminants in the food chain, a Network of Excellence (NoE) for research, risk assessment and education), which is developing new test methods to screen for endocrine-disrupting chemicals in food. "Although DES worked well and had no harmful effects on the mothers, later it was clearly shown to predispose their daughters to vaginal cancer.

Similar effects have been identified in certain animals where they develop prostate cancer." As a result, many researchers are dubious about some manufacturer's trials to prove that their products are harmless. For instance, in a recent study in Denmark, a sun cream containing a controversial type of compound called phthalates was applied to 26 healthy young male volunteers. The trade organisation American Chemical Council issued jubilant reports when, after just one week of the treatment, no change was observed in the volunteers' hormonal composition, even though they had phthalates in their bloodstream. But why did no reports point out that studies like this fail to take into account synergies, or the delayed effects of chronic exposure, or the special risks during early developmental stages (such as during a woman's pregnancy)? Case in point.

"We know that there is a problem," says Jörg Oehlmann vehemently. "Recent sperm counts of young German men confirm a steady and worrying decline in male fertility. We are also seeing an increasing number of breast cancers, with a recent study finding that they are linked to higher than normal oestrogen activity. We must certainly not relax the research effort that began 10 years ago and we must give science time to gather the necessary proof." Speaking for industry, Gerhard Nohynek, a scientist responsible for safety issues at cosmetics and beauty company, L'Oréal, believes that "there has been a witch hunt for the past 15 years or so that has cost society millions and millions of dollars and has found nothing."

Against this background, several European research programmes are looking for innovative ways of pinpointing problems. The REEF project (Reproductive Effects of Environmental Chemicals in Females), launched in May 2008, plans to study sheep, which are relatively close to humans in reproductive terms. "We are going to put a group of ewes in a meadow fertilised with sludge from a waste treatment plant (which contains a wide range of synthetic chemical compounds), and a control group in a non-contaminated field," explains Paul Fowler, project coordinator and reproductive physiology specialist at the University of Aberdeen (UK). "Then we will examine the difference in adults, young animals and foetuses." This is a good way to switch the focus from a given product to its overall environmental contamination. This project is linked with two others: the CONTAMED project (Contaminant Mixtures and Human Reproductive Health), which concentrates specifically on the problem of mixtures, and the DEER project (Developmental Effects of the Environment on Reproductive Health), which studies the problems of male fertility, puberty and the links between obesity and endocrine disruption.

Europe's CASCADE network of excellence has already been working for four years on the potential problems of food contamination. "In my opinion, food poses the greatest endocrine disruption risk to humans," says network coordinator, Professor Jan-Ake Gustafsson. "Naturally, we must not overlook the transcutaneous or respiratory routes, but food (especially industrially-produced food) and to a lesser extent drinking water (which is easier to control), are the main gateways into the human body."

In their quest to resolve the problem of substance diversity, CASCADE researchers are pinning their hopes on nuclear receptors. They are proteins in the wall of the cell nucleus which are activated by most hormonally active compounds. This makes nuclear receptors an excellent target for use in general preliminary tests, even if it means that more thorough research is required to identify the culprit(s) in the event of a positive reaction. "We have devoted a good deal of effort to setting up satisfactory trials, and are now in the process of applying them to two specific food categories: baby food and bread," says Professor Gustafsson. The initial results from the baby food trials are rather reassuring, even though baby food contains several active substances, called phytoestrogens, owing to its high soya content. Professor Gustafsson explains that there are two types of nuclear receptor, ERα and ERβ (oestrogen receptors alpha and beta).

He goes on to say: "Only type α can trigger pathological endocrine activity. Type β is more associated with protective mechanisms. Baby foods tend to activate mainly type β. Of course these are only provisional results for the moment." Nevertheless, the results are consistent with the low prevalence of breast, colon and prostate cancer in Asia, where soya consumption is higher than in Western Europe. It is still too early to see the results from the bread trials.

The tests developed by CASCADE, which are designed for use by industry and regulatory authorities, have come to be added to the steadily growing arsenal of weapons for protecting public health from the endocrine threat.

But there is still a long way to go before scientists can produce proper risk analyses. In the meantime, decision-makers, both political and industrial, will be left to deal with the uncertainties surrounding endocrine disruption against a background where, thanks to the REACH directive, the burden of proof for safety is gradually being shifted onto industry.

And industry tends to take a bleak view of the extra costs entailed by the required precautionary measures...

Yves Sciama


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A few suspects...

Since the beginning of the industrial age, almost 100 000 new synthetic chemical compounds have been put into circulation. Only a small proportion have undergone in-depth studies, and there are probably still many surprises in store. The few substances listed below have known endocrine effects. But beware, not all endocrine activity poses a health hazard.

Other factors come into play - first and foremost being length of exposure.

  1. Dioxins are compounds generated mainly by industrial processes such as waste incineration, metallurgy and wood pulp manufacture.
  2. Bisphenol A is found in many plastics and has recently courted controversy because it is used to make certain baby bottles.
  3. The product could migrate into milk, especially when heated.
  4. Phthalates are plasticisers, widely used in food-grade plastic and even in some children's toys. Various tests have demonstrated their hormonal action, particularly on rodents.
  5. Brome flame retardants are fire-retardant materials used in certain textiles and electrical appliances. Despite their proven endocrine effects, they are now frequently used in place of polychloribiphenyls (PCBs), which were themselves endocrine disruptors!

Many pesticides have serious endocrine effects. This is the case of dichlorodiphenyltrichloroethane (DDT), Atrazine and a large number of other compounds. Naturally, endocrine activity does not preclude other, possibly more acute, forms of toxicity.



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Europe and endocrine disruption

Europe has made steady progress on this thorny issue since the international meeting of scientists from Europe, Japan, the United States, the Organization for Economic Cooperation and Development (OECD) and the World Health Organization (WHO) was held in Weybridge (UK) in 1996.

The event is generally considered to have triggered the anti-endocrine disruption movement. The Community Strategy for Endocrine Disruptors was adopted in 1999, with short-, medium- and long-term actions,and can be consulted at:ec.europa.eu/environment/endocrine/documents/index_en.htm

As a result, a large number of research projects have been,or are still being, supported (for the complete list see:ec.europa.eu/research/endocrine/index_en.html ).

A provisional list of morethan 500 priority substances has beendefined and preliminary investigations have begun. There is also ongoing international consultation and exchanges of information, particularly with the United States Environmental Protection Agency (EPA), WHO and the United Nations Environment Programme (UNEP).



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