Ambitious Plan to Screen for Endocrine Disruptors Unveiled

A proposed plan to screen about 15,000 commercial chemicals that may interact harmfully with the endocrine system could be one of the most ambitious and expensive such efforts ever. The first tier of the two-part plan would cost an estimated $200,000 per chemical for high throughput screening. Those screens would test chemicals for interactions with five endocrine receptors, including estrogen, androgen, and thyroid receptors. Chemicals testing positive would move on to the next level, which could cost up to $2 million apiece. Chemicals in that level would be tested in a variety of animal models for damage to reproduction and development. A group of 39 scientists from government, academia, and industry drafted the plan, which was presented at the American Chemical Society's annual meeting in Boston last month. The Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC) was formed after 1996 amendments to the Food Quality Protection Act and Safe Drinking Water Act. The amendments required the U.S. Environmental Protection Agency to create a consensus plan that would set priorities for testing, including recommendations of specific screens and tests. Anecdotal evidence--such as masculinized snails and feminized birds exposed to pesticides, fertilizers, and other commercial chemicals that have seeped into the environment--already exists, Gary E. Timm, an EPA scientist, noted during an ACS press conference. "We have some clear links and some broad evidence," Timm commented. "But not enough to convict." EQUIPMENT AVAILABLE: OSI Pharmaceuticals high throughput robotic screening systems test millions of compounds per year. The devices will help make an ambitious plan to screen over 15,000 chemiclas for interaction with five endocrine receptors possible. The testing plan aims to provide that evidence. But even scientists who support that plan--including Timm--acknowledge that evidence won't come easily or cheaply. The high throughput testing will only yield a "suspect" list, Timm explains. And chemicals that pass that test successfully may interact with the endocrine system indirectly, perhaps involving other receptors, or in tandem with other chemicals. Still, creators of the plan maintain its utility and worth, given the abundance of these chemicals--especially commercial pesticides and herbicides that flow into groundwater--and the growing anecdotal evidence in animals. Timm notes that the U.S. government requires a higher burden of proof to regulate chemicals than does most European governments. Ideally, two sets of data will emerge over the course of the project--the level of exposure humans and animals have to endocrine disrupters, and the magnitude of effects such exposure causes. "I hope that somewhere down the line we will be able to put this information together," says Timm. Right now, the information is scattershot and limited. "The human data is very scant right now," John Brock , an epidemiologist with the Centers for Disease Control and Prevention explained. The problems in humans include small sample sizes and cases limited by self-reporting. Human data directly linked to levels of exposure or health outcome after exposure is almost nonexistent, Brock noted. Animal data, too, is confusing, noted James LeNoir, an environmental scientist with the Center for Environmental Sciences and Engineering in Reno, Nev. "Endocrine disrupters tend to have the greatest impact at low concentrations," LeNoir attested. That effect means that different dose levels will have to be screened for each receptor. So far, interpreting environmental evidence has been difficult. In a study he presented at the conference, LeNoir and colleagues found high concentrations of pesticides in Sequoia National Park, which borders farmland. The chemicals were detected in the park's air, water, vegetation, and in animals, including frogs and fish. Still, the chemicals on their own may not account for all the birth defects. He acknowledges, too, that theories on the causes of birth defects and species extinction tend to change over time--including competition from other species, urban sprawl. and ultraviolet rays. "UV exposure was big a couple years ago, but I don't think people buy into that anymore." Other deformities--such as the widely publicized cases of deformed frogs--result from viruses or other nonchemical causes. Population declines in frogs, for instance, may be related to the emergence of those viral diseases or endocrine disrupters, a combination of both, or neither. Pinning down specific chemicals as endocrine disrupters will be difficult, agrees Timothy Kubiak, national water quality coordinator at the U.S. Fish and Wildlife Service, a member of EDSTAC, despite the magnitude of the proposed testing. The first wave will likely miss some chemicals, because the tests are only for limited receptors. "If it's negative, it doesn't mean it's not an endocrine receptor disrupter," Kubiak told The Scientist. Even the second wave of testing, in animal models, won't conclusively prove for certain that a suspect chemical can be truly labeled an endocrine disrupter. Only observing generations of animals over time exposed to the chemicals will provide the answer, as scientists trace how exposure to trace amounts of the chemicals in one generation affect different tissues of animals in subsequent generations. Kubiak notes that the panel has already addressed one potential weakness of the study, by proposing that some combinations of chemicals--like pesticides and herbicides commonly used in tandem--be tested together. Sophisticated assays can also detect the separate effects of some compounds found in the chemical soup of the environment, rather than the isolated conditions of the lab. "We can approximate what we know is in the environment," Kubiak emphasized. But he acknowledged that even the best-thought assays have their limitations. "You're not going to catch every permutation and combination." At this stage, the committee must take two preliminary steps to ensure the project's success. The first is developing and validating the assays, then standardizing them so that each of the labs involved run the tests in exactly the same manner. The second is coming up with a way to pay for the testing. The government may foot some of the bill, especially for the start-up costs and infrastructure, Timm noted at the conference. But chemical companies who produce the compounds may be asked to pay for tests of each of their compounds. Kubiak admits he doesn't need any more evidence that endocrine disrupters are having an effect on wildlife. "You have alligators with shorter penises in the lakes in South Florida. You have a lot of reproductive effects in the birds of the Great Lakes," he says. "It's absolute. It's real. The circumstantial evidence is in humans. It's not in fish and wildlife." But he emphasizes that the chemical companies do require a higher burden of proof to convince them that certain chemicals cause specific effects in certain tissues, which, in turn, lead to specific diseases and birth defects. "If you want a high burden of proof, you have to pay for it," Kubiak concludes. The EDSTAC draft report can be found at http://www.epa.gov/opptintr/opptendo/.

Ambitious Plan to Screen for Endocrine Disruptors Unveiled

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Paul Smaglik

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September 1998

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