The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.

 

Johns Hopkins School of Public Health

Introduction to TestSmart -- Endocrine Disruptors

Proceedings

In February, the Johns Hopkins Center for Alternatives to Animal Testing (CAAT) organized a two-day workshop to set the agenda for a later public meeting on environmental chemicals that act as endocrine disruptors. Representatives of the U.S. Environmental Protection Agency (EPA), the chemical industry, the animal protection community, and academia were invited to participate.

CAAT organized the meeting in response to a federal program to test chemicals for their potential to disrupt endocrine systems in both human beings and wildlife. That program requires a battery of tests to determine whether chemicals might mimic-or block-the effects of estrogen, androgen, and thyroid hormones in animals and people, with harmful consequences.

The current testing plan, known as the Endocrine Disruptor Screening Program (EDSP), was developed in response to mandates included within the Food Quality Protection Act and amendments to the Safe Drinking Water Act. Those laws require EPA to screen pesticides and other chemicals for their potential to disrupt endocrine systems in both human beings and wildlife. Based on recommendations from a scientific panel known as the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), the EPA has proposed a battery of in vivo and in vitro tests. These tests, currently undergoing validation, have the potential to use an enormous number of animals to determine which chemicals are hormonally active.

CAAT decided to investigate whether endocrine disruptor tests can be done more humanely and efficiently, by applying the TestSmart approach to the testing plan. CAAT called this workshop with EPA, industry, and other stakeholders to identify mechanisms for either replacing animals, reducing their numbers, or refining some of the proposed tests to eliminate any pain or distress involved.

The first speaker was Theo Colborn, whose book "Our Stolen Future" raised concerns about the effects environmental chemicals may be having on people and wildlife. She set the stage for the workshop by describing the history of the endocrine disruptor issue. She reviewed more than 20 years of environmental studies that suggest endocrine disruption by chemicals in the environment may be responsible for widespread illness, population decline, and extinctions among wildlife populations. Moreover, she suggested that these data indicate a potential for endocrine disruptors to cause adverse health effects in humans. She called on workshop participants to find an answer to the question "How do we serve the shared goal of decreasing animal use in the laboratory without compromising the health of humans and animals?"

Subsequent presentations provided a summary of our current understanding of how chemicals disrupt endocrine function and the criteria used to select specific tests to screen for endocrine disrupting activity. Discussion focused on the validation issue: What makes a test valid? Participants acknowledged that there are differences between the proof required for scientists to agree a test is "scientifically valid" for their own use and that required for a regulatory agency to agree a test is validated for a specific regulatory use.

Both industry and the animal protection community offered their perspectives on the battery of tests proposed for the EDSP. Each group expressed concern for the large number of animals required to complete the tests. This concern was magnified by the following problems: 1) the relevancy of the data produced in some tests to adverse health effects; 2) practical difficulties associated with implementing the EDSP in many industry labs; 3) the effect of strain and/or gender differences on test results; and 4) the pain and distress likely to be associated with the more invasive tests.

The rest of the meeting was devoted to an evaluation of the status of potential alternative methods: QSARs, in vitro assays, high-throughput screens, and innovative in vivo methods, including the use of noninvasive imaging. In applying these methods to a screening program, however, many of the same concerns were raised: the availability of reliable data (especially problematic in the development of QSARs), the relevance of the end results, the effectiveness of the method, and the ability to identify and measure endpoints. In particular, participants expressed a need to find new approaches for identifying chemicals that serve as thyroid disruptors. Unlike tests that measure the effects of chemicals on estrogen or androgen receptors, thyroid tests typically measure only the levels of thyroid hormone, not physiological markers of dysfunction. Participants also noted the difficulties in developing tests that can distinguish between the effects of xenoestrogens (estrogen-like compounds in the environment) and phytoestrogens (plant-based estrogens and nutritional supplements).

The discussion also focused on barriers to test development/refinement: for example, current patent laws and the unavailability of negative test data. Participants agreed that it is important to find opportunities and mechanisms for sharing data (including negative data), methods, and results and to have the freedom to apply those to new tests.

The meeting concluded with agreement on several points. First, there are chemicals in our environment that are hormonally active and that potentially pose health risks for humans and wildlife. Second, the federal government's EDSP, as mandated by Congress, allows for the program to evolve and become more humane and efficient. Third, industry, government, academia, the environmental protection community and the animal protection community all want to apply the 3Rs of alternatives (replacement, reduction, and refinement) to the EDSP and will continue to strive to do so.

Participants agreed on the need to work together to address the concerns about assay efficiency, relevance, and validation. Greater coordination of research efforts, integration of outcomes, and data/method sharing (and barriers to this process) are all topics that require further discussion. Finally, a number of areas require more investigation: identification of valid endpoints for thyroid dysfunction; consideration of hormone receptors as transducers; consideration of other EDs (retinoids); development of assays for non-receptor-mediated effects (such as metabolism) and applying the knowledge from new fields such as genomics, proteomics, and bioinformatics to the development of in vitro assays.

The workshop ended with plans to organize a public meeting in 2002 focused on developing a TestSmart approach to the EDSP. The meeting is set for March 12-13, 2002, at the Hyatt Fair Lakes Hotel in Fairfax, Va.