How 80,000 chemicals are waging sex war on us

January 23, 2003

Barnacles are undergoing sex reversal, male birds are taking over female nest-sitting duties, the male-to-female ratio in alligators is skewed and even humanity is experiencing changes. Martin Ince previews the Academy of Medical Sciences meeting on the possible effect of chemicals on the endocrine system.

Birth is the end result of development," says Ieuan Hughes.

Today in Cambridge, where Hughes is professor of paediatrics, scientists will gather to discuss one of the trickiest conundrums in our knowledge of this complex process. Are natural and artificial chemicals in the environment increasingly disrupting the development process in humans and animals, and, if so, what can be done about it?

The story involves a clutch of chemical processes that dictate the development of male and female sexual organs and that, in later life, may also be related to breast, prostate and testicular cancers. The evidence is that many of these cancers have been increasing in recent years, as have conditions involving the disruption of sexual development in the womb.

Hughes points to hypospadius, a condition in which newborn boys have a urethra that has not formed properly. "It affects about 1 per cent of boys but is increasing, so we know that its incidence cannot be solely genetic.

We know that whatever is happening in this case is taking place during the first 16 weeks of pregnancy."

Hypospadius is one of a clutch of disorders that may occur during development and that seem to be on the rise. They appear to be linked to adult reproductive problems, such as undescended testicles in boys. The most publicised problem is the fall in male sperm counts, down by half in some areas in the past 40 years. Hughes points out that this effect differs within and between countries. For example, it is far more marked in Denmark than in Finland, which suggests that the cause is environmental. At the same time, a clutch of changes in female development, such as earlier breast development, show that the effects are not confined to males.

At the heart of the debate is the issue of whether chemicals in the environment are affecting the endocrine system that controls male and female body chemistry, notably the androgen and oestrogen chemicals that characterise male and female development respectively.

Hughes has his suspicions but is also cautious about the available data.

For example, he says, the UK database of birth defects is notably incomplete. He is, however, enthusiastic about a long-running study of 14,000 children born in Avon in the 1990s and now arriving at puberty.

Among these children, he says, female development seems to be accelerated and hypospadius is on the rise. Is chemical pollution the cause? Perhaps, but many of the boys in question also have vegetarian mothers, which could suggest a dietary explanation. A study at Imperial College London, this time looking at London and East Anglia, has found clusters of hypospadius cases and a possible correlation with drinking water, although Hughes stresses the need for more data.

His Cambridge team is now looking at the ability of chemicals in the environment to affect the endocrine system by disrupting the ability of androgen chemicals to turn on the genes responsible for producing male body tissue. So far, prime suspects include plasticisers used to make polymers and an array of fungicides and pesticides. "People can become exposed to plasticisers when these leach from clingfilm," says Huges, "and fungicides and pesticides can come from food and water." He adds that there are about 80,000 chemicals in the environment.

Proving the effect of any one on human biochemistry is feasible, but isolating the effect that differing amounts might have in combination is another story. "Some chemicals," he says, "have a U-shaped effect, where a very small or large amount has a bigger effect than a medium-sized dose.

For example, there is a debate about low doses of oestrogens and their possible contribution to breast cancer."

Hughes adds that increased understanding of the endocrine system has positive aspects as well. Oestrogen and androgen can be replaced as their production falls in later life. Such an approach could help prevent osteoporosis, a bone disease common in older people. It might also be possible to treat rare conditions such as precocious puberty, in which an overproductive endocrine system causes puberty to arrive as early as three or four.

John Sumpter of Brunel University, a speaker at today's meeting, has been working on endocrine disruption in animals, for which, Hughes says, the evidence is better and experiments are simpler than for humans. There has already been legislation to ban paints used to prevent barnacle-fouling of ships' hulls. The paints were causing sex-reversal in male barnacles. In Florida, the male-to-female ratio is askew in the alligator population, and the males are showing developmental abnormalities. And in trout, oestrogen-induced changes seem to be linked to effluent in rivers, some of it near drinking water for the human population. Remoteness offers no protection either: there is evidence of endocrine disruption among polar bears in the Arctic.

The upshot, Hughes says, is that "there could be a demand for changes in manufacturing methods in a few years when the evidence is better". Some research is being funded by the Department for the Environment, Food and Rural Affairs, and the topic, he says, is "higher than it was on the agenda of the Department of Health" a few years ago.

But John Ashby, a toxicologist at agrichemical producer Syngenta and a speaker at today's meeting, points to problems with our current knowledge of endocrine disruption. "We know that breast, testicular and prostate cancers are on the rise," he says, "and that all these tissues are hormonally controlled. We need to know more, but there is still a risk that huge effort will be put into investigating chemicals in the environment when the real problem lies somewhere else. At the moment a new agrochemical needs a three-generation trial that proves it has no harmful effects, so our information is almost as good as it would be for a new drug."

He thinks the case is stronger for wildlife, for which the link between pollution and adverse reproductive and developmental effects is established. In the Great Lakes of North America, endocrine-active chemicals called polychlorinated biphenyls were blamed for sex effects that saw male birds taking over nest-sitting duties traditionally reserved for the female. After the lakes were cleaned up, normal gender roles were resumed. But even with wildlife examples there are complex factors at play, Ashby says, especially global warming. In addition, endocrine-active chemicals are naturally present in sewage because humans excrete them. It could be that better sewage treatment would reduce exposure more than banning some pesticides.

Ashby adds that opposition to endocrine-disruptor chemicals has turned into a mission for some environmental groups, which have polarised the debate by concentrating their fire on pesticides instead of food and other possible contributors to exposure. He points to the example of Japan, where prostate cancer is rising fast. According to a recent paper, the key link may be to increasing consumption of dairy products. Japanese boys consume most milk and other dairy products in their early teenage years, a developmentally critical age. More importantly, the cows producing the milk now have a massive amount of hormonal intervention to make them produce more milk more regularly, which could increase human exposure to endocrine disruption.

On the plus side, Ashby says that the modern era of molecular biology means that endocrine disruption can now be studied in more detail than before.

"Not long ago, animal studies were carried out by counting and weighing a litter of newborn animals," he points out. Now there is detailed knowledge of how disruption occurs at cellular level. Sometimes this leads to discoveries that can alter our understanding fundamentally, such as the finding that there are sensors activated by male androgen chemicals in growth-critical parts of the developing uterus. And new money is coming into the field to test the effects of mixtures of chemicals on living systems.

Ashby agrees with Hughes that the sheer number of chemicals and the combinations in which they can occur is immense. There is also a school of thought that there may be no safe level of exposure to some endocrine-disrupting chemicals, with effects seen at ten or 100 times lower exposures than have traditionally been tested. "This is a provocative and unproven idea, but I have been unable to reproduce the findings," Ashby says.

"If you apply the precautionary principle of not allowing chemicals to be used if there is a potential problem, you could cut vast swathes through the modern way of life," Ashby says. "You can't ban everything."

The Academy of Medical Sciences meeting "Are Endocrine Active Chemicals Bad for your Health?" is being held on Friday at the Moller Centre at Churchill College, Cambridge.

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