Disagreements over the health effects of so-called endocrine-disrupting chemicals could eventually be resolved by studying the genetic variablity of human and animal reactions to chemicals, researchers believe.

An international symposium on endocrine disrupters in Yokohama last month revealed a growing consensus that some of these chemicals can produce toxic effects at surprisingly low doses. But the meeting, the third in an annual series sponsored by the Japanese government's Environment Agency, found that the mechanisms underlying such effects are still poorly understood.

Endocrine disrupters are chemicals that affect human or animal health by interfering with normal hormonal processes. They are mediated by hormone receptors, and so could produce toxic effects at very low doses. Adherents to this hypothesis argue that applying standard risk assessments for toxic chemicals, which were developed mainly for carcinogens, does not adequately gauge the risk that endocrine disrupters pose to public health.

"The discussion at the first of these conferences was about whether 'low-dose effects' exist at all," says Hirozo Ueda, a director in the environmental health and safety division at the Japanese Environment Agency. "But now we are talking about which chemicals are associated with low-dose effects and which are not."

Researchers diverge sharply on the question of whether there is a threshold dose below which the chemicals can be regarded as safe. "There is no consensus yet that thresholds do not exist," says Robert Kavlock, director of the reproductive toxicology division of the National Health and Environmental Effects Research Laboratory at the US Environmental Protection Agency.

Results from animal studies on suspect compounds, such as bisphenol A, a chemical widely used in the manufacture of plastics and glues, are inconclusive. "I am particularly perplexed by the data for bisphenol A, where some labs see it as a relatively potent oestrogen, and others fail to see much activity. This enigma needs to be understood at the mechanistic level," Kavlock says.

Pointing to data indicating that there is large genetic variability in the response to endocrine-disrupting chemicals, some scientists now argue that research in toxicogenetics, and novel tools such as gene-expression profiling and proteomics, may hold the key to understanding the effects of these chemicals in animals and humans.

"The evidence is that there can be as much as a 1,000-fold, or greater, range of responses to these chemicals in different strains of mice. The regulatory default assumption of a ten-fold correction or safety factor for genetic variability is completely out of touch with the data," says Frederick vom Saal, a professor of biology at the University of Missouri-Columbia.

"Toxicogenetics clearly has the potential to make a difference to how toxicology is conducted," says Kavlock. But he points out that there are still problems with the approach. "It remains to be shown that these new technologies can indeed provide tools for understanding the modes of action of endocrine-disrupting chemicals, and whether they can be used to monitor exposure signals in populations," he says.

Government regulation of endocrine disrupters is still years away. The US Environmental Protection Agency is undertaking a programme to validate test methods for the chemicals that will take several years to complete. No regulation can be implemented until then. And officials in Japan say that regulation there is at least ten years off.

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