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

Abstract for TestSmart -- Endocrine Disruptors

The Endocrine Disruptor Screening Program: Animal Protection Concerns

Martin L. Stephens and Robert D. Combes
The Humane Society of the United States and Fund for the Replacement of Animals in Medical Experiments

This presentation summarizes the animal protection community's primary concerns about the Environmental Protection Agency's (EPA's) Endocrine Disruptor Screening Program (EDSP). We have attempted to emphasize those concerns shared by the various animal protection organizations working on the EDSP issue. However, each of these organizations probably would come up with a somewhat different list or put more or less emphasis on the particular concerns raised here.

General Expectations About Animal Testing Programs: In order to understand the animal protection community's perspective on the EDSP, it is helpful to review animal protectionists' key expectations whenever a federal agency or other entity proposes to develop a program that may involve animal testing. Of course, program developers that attempt to address these expectations do not thereby guarantee that animal protection organizations will support the program or remain neutral. However, failure to adequately address these issues will guarantee opposition from such organizations

Animal protectionists expect the agency in question to offer them meaningful opportunities to provide input into the program's formulation and execution. The program itself should be open and transparent. It should have a compelling public health rationale; the larger the proposed scale of animal testing, the more compelling the rationale. It should make full use of all pre-existing data, be based on the best available science, and include a clear plan for how the resulting data will be translated into public health gains.

Moreover, any animal testing program should fully implement available alternatives (Three Rs). The program sponsor should make meaningful financial investments in R&D of potential alternatives; the larger the proposed scale of animal testing, the more substantial the investments in alternatives should be. New tests, or pre-existing tests used for new endpoints, should be fully validated for their new purposes. Validation criteria and standards should be those promulgated by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) (or its overseas counterpart, the European Centre for the Validation of Alternative Methods (ECVAM)). ICCVAM itself should review the resulting validation effort and make recommendations regarding regulatory acceptance. The program should be coordinated with any similar programs being conducted nationally or internationally by, for example, other federal agencies, national governments, international bodies, and trade associations.

Unfortunately, the EPA and the EDSP fall short in many of these areas.

Summary of Concerns About the EDSP: The EDSP presents a serious challenge to the animal protection community. The program is likely to be one of the largest animal testing ventures in history, consuming millions of animals. Up to 87,000 chemicals will be sorted/screened in the program. It has been estimated that between 600,000 and 1.2 million animals will be killed for every 1,000 chemicals tested. Moreover, the use of single-sex tests, such the Hershberger and Uterotrophic assays, creates the potential for enormous animal wastage. Aside from the sheer numbers of animals involved, there is also considerable scope for animal pain and distress. Certain planned EDSP tests involve lengthy, complicated, invasive and/or repetitive procedures such as ovariectomies, testosterone implants, and repeated subcutaneous and intraperitoneal injections. Mice and rats will be the most commonly used animals in the program, yet they receive no regulatory protection under the Animal Welfare Act.

Animal protectionists view the EDSP as a head-long rush into large-scale animal testing. The program involves little or no attempt to characterize the nature, severity, and scope of the ED problem in the human population. Such human population studies would begin to address the rationale for a massive animal testing program. Their absence from the EDSP runs counter to the recommendations of the National Academy of Sciences and has been bluntly criticized by prominent scientists, such as Dr. Bernard Schwetz, Acting Deputy Commissioner of the Food and Drug Administration. In contrast to the human situation, ED problems in wildlife have been moderately well-characterized; ironically, the EDSP lacks a component for actually reducing wildlife exposure to hazardous chemicals.

Animal protectionists are appalled that the EPA is not aggressively investigating alternative methods for the EDSP. The High-Throughput Pre-Screen (HTPS) has been prematurely cast aside, despite a multi-million dollar Congressional allocation to develop it, and despite the obvious need for a test that rapidly sorts through the thousands of potential test chemicals in order to establish priorities for further testing. Quantitative Structure-Activity Relationships (QSAR) will be a poor substitute for HTPS if, as we argue, QSAR will have limited ability as a predictive and priority-setting tool in the absence of HTPS data.

The lack of a human studies component and the limited emphasis on alternative testing mean that the EPA is once again relying largely on animal testing to address a perceived public health problem. The animal protection community questions the value of relying so heavily on extrapolating from animals in laboratory tests to human health effects. Indeed, questions have been raised in the ED literature about whether subtle changes found in animals may correlate with human health effects. Scientists have questioned the relevance of injecting or force-feeding large doses of chemicals to animals in order to assess the effects of low-level exposures in humans. Scientists and toxicologists have cited differences between the endocrine systems of humans and animals. Even within a given animal species, important differences in test results have been documented from numerous factors, including strain and age, housing conditions, social rank, and womb position. Differences in test results may also arise from lack of test standardization.

Animal protectionists are concerned about a potential double-standard in the evaluation of the validation and regulatory acceptance of in vitro versus in vivo methods. The EPA has arranged to have evaluations of the in vitro methods conducted by ICCVAM and the in vivo methods by an EPA-appointed board. Animal protectionists are worried that the EPA's standards for animal-based tests will be lower than those of ICCVAM's standards for in vitro tests. The ICCVAM Advisory Committee on Alternative Toxicological Methods twice issued unanimous statements advising against this bifurcated approach, to no avail.

Finally, animal protectionists have been concerned about issues of transparency and opportunities for stakeholder input. Early on in the development of the EDSP, animal protection representatives were excluded from key meetings. Even now, only after the fact do we learn of important decisions concerning major developments in the program, such as the letting of a multi-million contract to Batelle to conduct the in vivo validation work.

Concluding Remarks: The key issue for animal protectionists is not whether the EPA moves forward with an ED program, but rather, what kind of program the EPA pursues. The agency is once again relying heavily of laboratory tests of rodents to solve a potential public health problem, notwithstanding the questionable relevance of these tests to the problem, as well as the potential for alternative methods to help address the issue. In its rush to animal testing, the EPA may run roughshod over the process of validation and the principles of openness, accountability, and stakeholder inclusion. In doing so, the agency continues to demonstrate a profound indifference to the concerns of the animal protection community.