Scientific Issues
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The following examples illustrate some of the key shortcomings to animal-based screens and tests for endocrine disruption:
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• Most of the animal tests under development involve a single,
high-dose exposure to a single test chemical. This fails to mimic the
human experience of repeated, low-dose exposure to many chemicals over
a lifetime. Certain tests may also involve animals being exposed via
injections under the skin or into the abdominal cavity, neither of which
is remotely relevant to the ways in which humans are exposed to environmental
chemicals in the “real world.”
• Recently published reports indicate that even different strains of the same animal species can exhibit drastically different hormonal reactions to chemicals. For example, one study found that rats of the Fischer 344 strain were up to 10,000-times more sensitive to the effects of the chemical bisphenol A than the closely related Sprague-Dawley strain. Many more examples can be found in an EPA White Paper on Species/Strain Differences in Endocrine Assays.
• Even minor changes in experimental conditions, such as lighting, noise, individual or group housing, and the relative position of animals in the womb before birth, have been shown to significantly alter test results.
• Mathematical “uncertainty factors” have to be used in an attempt to compensate for the differences between rodents and humans in lifespan, body weight, body volume, and/or metabolic rate. However, these uncertainty factors are of unproven validity in extrapolating animal test results to humans.
• Because so little is known about the actual human health effects that may follow from so-called “endocrine disrupting” actions in the body, it will be difficult to interpret the significance of results from animal studies. For example, the uterotrophic assay might detect an estrogen-mediated effect in vivo, but the conclusions that can be drawn regarding a chemical with this property are dependent on the relationship between estrogen activity and health, which is poorly understood.
• For most associations between hormonally active agents and various biological outcomes, the specific mechanism of action is not well understood, which makes it difficult if not impossible to correctly interpret the results of animal-based assays. For example, the drug tamoxifen is an extremely potent anti-estrogen in human breast tissue, making it the breast cancer therapy of choice. However, tamoxifen functions as an estrogen in endometrial tissue and is classified as a human carcinogen. Therefore, two opposite endocrine-related health effects can be caused by the same chemical. In fact, the estrogenic/anti-estrogenic activity of this chemical produces conflicting results in rats and mice.
What Scientists Have Said …
Dr. Iain Purchase, professor, School of Biological Sciences, University
of Manchester:
“The current [endocrine-disruptor testing] proposals are the most
extravagant in the use of animals. Between 600,000 and 1.2 million animals
would be required for each 1,000 chemicals tested. The EDSTAC proposals
are difficult to justify from an ethical perspective, as equally effective
detection rates may be achieved with fewer animals.”
Final report of the U.S. EPA’s Scientific Advisory Panel/Science
Advisory Board joint subcommittee on endocrine disruptors:
“We are concerned about the large number of animals that would be
needed by the EDSTAC program. The agency has an obligation to conserve
all resources in developing new testing protocols, and the use of animals
in such tests poses both ethical and practical problems. The subcommittee
recommends ... minimizing the number of animals needed for testing.”
Dr. Ernest McConnell, chair of the U.S. EPA’s Scientific Advisory
Panel/Science Advisory Board joint subcommittee on endocrine disruptors:
“There was an undercurrent through the whole discussion that the
EPA program was ahead of the science. ... This may not be the best use
of our nation’s resources.”
Dr. John Giesy, professor of environmental toxicology and member of
the U.S. National Academy of Sciences:
“Legislating endocrine testing at this time is unbelievably stupid
and a waste of resources that will lead not only to false positives in
screening, but, more importantly, to false negatives.”
Dr. Robert Combes, director of the Fund for the Replacement of Animals
in Medical Experiments (FRAME):
“There are fundamental concerns about the validity of modeling human
hormonal effects by using rodents. The endocrine system is extremely complex,
and there are many important species-specific differences between humans
and rodents.”
The U.S. National Research Council Report, "Hormonally Active
Agents in the Environment":
“There are important differences among species and between adult
and developing organisms in their responses to endocrine disruptors. These
differences could have important implications when assessing toxicity
studies or extrapolating data from one species to another.”
Dr. Genevieve Matanoski, former chair of the U.S. EPA’s Science
Advisory Board, on the difficulty of reproducing the results of endocrine-disruptor
animal tests in different laboratories:
“You can’t go across labs because each lab tends to be unique.
I find that a big problem.”
Dr. Michael Balls, former head of the European Centre for the Validation
of Alternative Methods (ECVAM):
“It has even been said that the validation phase of the new test
development and acceptance sequence should be applied flexibly in this
situation because of the pressure being applied by the U.S. Congress.
Validation is concerned with the reliability and relevance of methods
for particular purposes. How can there possibly be flexibility about whether
or not methods are reliable and relevant and about what they should be
used for? What would be the value of the data such tests would provide,
and with what confidence could they be applied in making decisions?”
