Introduction to TestSmart -- Endocrine Disruptors

Proceedings

In February, the Johns Hopkins Center for Alternatives to Animal Testing (CAAT) organized a two-day workshop in Fairfax, Va., to consider humane approaches for testing 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 the 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 James Yager, who presented "The State of the Science." Progress must occur along two fronts, he said, to support the creation of alternative methods: in the discovery phase, where we focus on cellular mechanisms to understand how endocrine disruptors work; and in the translation of this knowledge into endpoints for in vitro tests. Current issues in the "discovery phase" include understanding the mechanisms of membrane and mitochondrial endocrine receptors, as well as the role of estrogen metabolites as signaling molecules and genotoxins. Issues of translation include understanding the effects of interlaboratory variability on screens and tests, and moving tests from a general indication of negative effects to a specific measurement of changes at the cellular level (i.e., mRNA).

The next two presentations focused on validation efforts in the United States and internationally. A number of in vitro and in vivo tests are currently in the process of validation. With respect to Tier 1 screening, one in vivo test (uterotropic) has been validated for the program; another in vivo test (Hershberger) and an in vitro test (ER/AR binding) have completed pre-validation studies and are in formal validation. No tests have been validated yet for Tier 2 studies, but three are in the pre-validation stage.

Richard Becker of the American Chemistry Council expressed industry's desire to minimize animal use, duplication of efforts, and cost in the process of ED testing. He discussed industry's experience with many of the tests recommended for use in Tier 1 and Tier 2 testing, as well as the advantages and limitations of each test, and made several recommendations for further progress.

Martin Stephens of the Humane Society of the United States, speaking on behalf of the animal welfare community, echoed many of Becker's concerns about limitations and problems inherent in many of the tests under consideration. He also challenged the international toxicology community to do far more to develop non-animal alternatives, and to use the same level of rigor for validating in vivo tests as is applied to in vitro ones.

Following the general presentations, attendees participated in breakout sessions focusing on the themes of replacement and reduction, and then convened to share their recommendations. Each theme had four breakout sessions, and each session produced recommendations and a research question. Generally, the groups pointed out the need to mine existing data for as much information as possible before proceeding with testing; to refine and standardize Tier 1 screens as much as possible, so fewer tests will be necessary at Tier 2; and to continue seeking a better understanding of mechanisms of response to EDs at the cellular level and their relationship to endpoints that can be identified in vitro.

TestSmart Endocrine Disruptors

Introduction to TestSmart -- Endocrine Disruptors