ENVIRONMENTAL NEWS Panel urges quick validation of endocrine disrupter tests
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efore EPA begins evaluating thousands of chemicals for their potential to disrupt hormone systems, it should develop on an "accelerated schedule" a program to validate and standardize the tests used to screen the chemicals, according to the final recommendations of a federal advisory committee. The Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC), comprising some 40 scientists and policy makers from government, industry, academia and environmental groups, grew out of Congress' requirement that EPA develop a program to evaluate chemicals for their potential to disrupt hormone function. EDSTAC's final report was released last month. The suggested two-tiered evaluation program and the automated prescreening in the group's draft report, released in February, remains substantially unchanged {ES&T, April pp .68A). Both EPA and chemical company labs will perform the evaluations. Companies will be responsible for performing evaluations of their own chemicals, and EPA will be responsible for the remaining chemical "orphans." A full description of EPA's proposed testing and screening program should be published this month according to Gary Timm a senior technical advisor in EPA's Office of Prevention Pesticides and Toxir Suhstances and a member of EOSTAP On all controversial tonics EDSTAC consena rpmarkable achievement piven thp highlv nnlarized views nf manv particinants
EPA has already formed a group to oversee the standardization and validation process. The standardization procedure will describe how the screen or test should be performed, whereas the validation
EPA does not have the funds to implement the chemical screening and evaluation program in time to meet the timetable Congress has set said Gary Timm, technical adviser in the Office of Prevention, Pesticides and Toxic Substances. (Courtesy EPA).
process will ascertain how well the screen or test discriminates between known endocrine disrupters and other compounds. As one of the first and most important steps toward implementation, the validation process will be closely watched by industry and environmental groups. Environmental groups, concerned that the process could drag on if industry does not make a good-faith effort to move forward on the validation process, are urging mat the screening and validation be completed as quickly as possible, said EDSTAC committee member David Baltz with the environmental group Commonweal. Chemical industry representatives are committed to further financial and organizational involvement because tiiev want to that the tests will Droduce data that is reliable representative and readily interpretable said Chemical Manufacturers' tion Assistant Vice Presirlent for Rpcnilatory Affairs Sandra Tirev
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To start validation and standardization work on the screens and tests, a task force of government and nongovernment officials will carry forward the validation process, which is expected to take two to three years. The task is "unique and unprecedented," said Timm, in terms of the number of screens and tests, the number of chemicals that will be eventually evaluated and the timetable. The most comparable effort, the validation of genotoxicity tests in the 1970s to identify chemicals capable of causing genetic mutations took some 15 to 20 years Timm said Although there are scientists of all affiliations who believe that government policy is running too far ahead of science, many reproductive toxicologists insist that the proposed Tier 1 battery of screens should, in theory, meet the desired goal of detecting a chemical's potential to affect estrogen, androgen, and thyroid hormone activities. "The tests are good ones," said Bernard Schwetz director of the Food and Drug Administration's National Center for Toxicological Research and a member of EDSTAC "Whether or not they are good pnough remains to be seen " Validation is primarily an issue for the Tier 1 screens—three in vitro and five in vivo tests intended to determine whether chemicals have endocrine disruptive potential, added George Daston, a principal research scientist at Procter and Gamble and an EDSTAC member. The longer duration, more complicated Tier 2 mammalian tests are well accepted and either are validated or are close to it. Some of the Tier 2 wildlife tests also represent a major validation challenge as many ecotoxicologists have pointed out Of the Tier 1 screens, the most widely accepted is the rat utero-
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trophic assay, which measures a chemical's estrogenicity through changes in the weight of a rat's uterus. But even for this test, important details such as the number of rats to use and their ages differ between labs. At the other end of the spectrum, an assay to screen for endocrine disruption in fish, the fish gonadal recrudescence assay, is still under development. This assay measures a chemical's endocrine disruptive potential by exposing mature fish of both sexes to a chemical and then observing whether the animal's sexual characteristics reSDond in a normal way to simulated spring time conditions The task may be daunting, but according to FDA's Schwetz, broad-scale scientific advances give this validation effort some advantages over previous programs. The proposed screens are designed to reveal specific, understood, biological mechanisms, for example, binding to a particular hormone receptor, he said. This understanding means that the screens can be used with confidence and that they will not require a validation program as extensive as the genotoxicity validation Timm estimates that 20-30 chemicals will be used for the Tier 1 validation with about 10 other chemicals for Tier 2 Another advantage for the screpnine and validation effort is that nrinHples for scientific and rppnlatory validation of testinp mpthods have hppn develonpd hv thp Tn tprappnrv Coordinating Pnmmit tpp fnr thp Validation nf Alterna tivp Methndc m m enpd hv the National Institute of Environment a l Wp»altVi ^f^ifances
EPA and the Organization for Economic Cooperation and Development are coordinating work on separate but similar projects. European efforts are focused on validating in vivo screens. The United States and Japan are cooperating on the in vitro screens. The U.S. EPA is planning to do the work on validating the mam-
including the Food and Drug Administration, National Institute of
ease Registry, universities, and contract labs, he said, both because of their special expertise and because of the enormity of the task. A project to demonstrate the feasibility of initial, automated prescreening assays intended to provide some basic data for highvolume chemicals, should be completed by December. Also in development is a research project to address the underlying uncertainties and controversy about low-dose testing (see companion story below). Although the entire standardization and validation process is expected to take at least two to three years, EPA should be able to implement some validated screens by the
congressionally imposed deadline of August 1999, according to many EDSTAC members. EDSTAC has recommended that once an assay is validated, it can begin to be used; it will not be necessary to wait for the entire Tier 1 screening or Tier 2 battery of tests to be validated before individual screens and tests can be run. Timm noted, however, that at this point, EPA does not have the funds to pay for the entire validation program, let alone the evaluation program, and meet the timetable Congress has set. "We will have to go back to Congress and inform them that this is the price tag for what they have asked us to do." —REBECCA RENNER
Results of low-dose exposure research may challenge the theoretical basis of toxicology The most controversial issue considered by the Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC) was the question of whether very low doses can cause significant biological effects, according to EDSTAC member Gary Timm, a senior technical adviser with EPA's Office of Prevention, Pesticides and Toxic Substances. Indeed, low-dose response research is one of the most controversial topics related to studies on endocrine disrupters todav as arguments about its significance and validity rage among toxicologists (1) During EDSTAC deliberations, chemical industry representatives said that they would not allow their products to be, "held hostage to 10 mice." The mice they were referring to belonged to developmental toxicologist Frederick vom Saal and colleagues at University of Missouri-Columbia. Their work includes a study in which a high, 200 parts per billion daily (ppb/day) dose of diethylstibestrol (DES) was fed to pregnant mice and found to inhibit normal development of the prostate in male offspring In contrast, a 10,000-times lower dose of DES, 20 parts per trillion per day (based on body weight, led to the opposite re-
sponse, a permanent increase in prostate size in male offspring (2). The dose-response curve formed a humped, inverted U. This means that data from the highdose part of the curve would not predict the low-dose effects. With a more limited data set, Vom Saal's group also found that very low doses of bisphenol A, part of a widely used polycarbonate plastic, increased prostate weights (3). An additional and equally fundamental challenge is posed by the apparent lack of a threshold for some hormonal responses, Sheehan said. Classical toxicology assumes there is a safe dose, a level at which no harm occurs, thanks to mechanisms in the body which can block, metabo-lize, or repair a certain degree of chemical insult. But a growing body of research suggests that for hormonal systems, there are circumstances such that a threshold does not exist. Classical toxicology assumes that a biological response always increases if the dose is increased. As a result, the inverted U and the lack of an apparent threshold dose "represent a fundamental challenge to the theoretical basis of toxicology—a paradigm shift is in progress," said Daniel Sheehan, a developmental toxicologist at
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