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).

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 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 that the screening and validation be comp leted 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 they want to ensure that the tests will produce data that is reliable, representative, and readily interpretable, said Chemical Manufacturers’ Association Assistant Vice President for Regulatory Affairs, Sandra Tirey. 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 enough 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 uterotrophic 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 respond 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 screening and validation effort is that principles for scientific and regulatory validation of testing methods have been developed by the Interagency Coordinating Committee for the Validation of Alternative Methods, convened by the National Institute of Environmental Health Sciences. 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 mammalian tests in its own labs. EPA wants to involve other agencies including the Food and Drug Administration, National Institute of Environmental Health Sciences, Agency for Toxic Substances Disease 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 high-volume 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