The Endocrine Disrupter Screening Program (EDSP) is one of the largest testing programs ever devised by the Environmental Protection Agency (EPA). Unfortunately, the program, as it is currently designed, is inefficient and will generate data that will not ultimately be useful in determining risk. There is extensive scientific evidence documenting the failure of animal-based endocrine studies to accurately predict human reactions to chemicals. Such failures are not surprising, given the many differences that exist between species in terms of their physiology, biochemistry, and metabolism.
In addition, this program is subject to the limitations of all safety testing that relies on poisoning animals: Whole animal testing gives results that are variable, sometimes even contradictory, and of questionable relevance to humans. In order to see effects in animals, the animals are given extremely high doses of chemicals that often lead to the wrong conclusions about the effect of chemical exposure. These variables make the cross-species and high-dose to low-dose extrapolation of test results an extremely uncertain exercise. Some of the key shortcomings of animal-based screens and tests for endocrine disruption include the following:
- Most animal tests involve repeated 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 exposing animals to chemicals 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.” We come into contact with a combination of chemicals through food, home use, and drinking water.
- 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 rats of the closely related Sprague-Dawley strain were. 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, diet, noise, individual or group housing, arrangement of male and female fetuses in the womb, and the relative position in the womb before birth, have been shown to alter test results significantly.
- Endocrine active chemicals that can affect experimental results have been found in caging, cleaning products, and food.
- Mathematical “uncertainty factors” must 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 result from so-called “endocrine disrupting” actions in the body, it will be even more difficult to interpret the significance of results from animal studies for endocrine activity. For example, the uterotrophic assay might detect an estrogen-mediated effect in vivo, but the effect itself is not necessarily predictive of an adverse health effect. The link between assay results and actual biological adversity has not been demonstrated for most endocrine-related tests.
- 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.
- The individual assays of the Tier I battery have not been properly validated.
- Several of the Tier I assays have high false-positive rates. In fact, no chemical tested so far in the battery has had negative results for all tests. This drastically limits the usefulness of the Tier I battery as a screen since the purpose of a screen is to distinguish potentially hazardous chemicals in need of additional testing from those that do not.
- The EPA has not outlined how it will evaluate the results from the Tier 1 battery. It is likely that among 11 assays, several will give highly variable results and have questionable ability to distinguish positive from negative, some tests will give positive results, and some will be negative. In addition, many of the animal assays include a large number of different measurements, and the EPA has not outlined a plan for interpreting ambiguous or conflicting results.
- An enormous body of information already exists—much of which is relevant to endocrine activity—for most of the Phase I chemicals. Both pesticides and High Production Volume (HPV) chemicals undergo extensive animal testing, including the very same tests proposed for EDSP Tier II battery; therefore, it is unlikely that the Phase I exercise will provide any information relevant to regulating these chemicals and will only result in needless duplication and waste of resources and animal lives.
Click here for more information about the problems with the Tier 1 battery and its individual assays.
Criticisms of the EDSP
“… [S]ignificant concerns remain about the specificity of the male pubertal assay ….”
“A negative control substance(s) has not been identified for the pubertal assays. This stands as a major limitation to the Tier 1 battery, and more compounds should be tested.”
“Concerns of quality control and repeatability among laboratories for each assay were noted.”
“Given an initial evaluation of the preliminary data (from the Tier 1 assays) there may be a tendency towards positives. This may be due to the fact that [the] EPA has not provided a thorough evaluation with a sufficient number of compounds, or the screen is too sensitive, or perhaps the battery lacks specificity.”
“… [A]nti-estrogenicity … is weakly covered by the screening battery.”
—EPA’s Scientific Advisory Panel: Transmittal of Meeting Minutes of the FIFRA Scientific Advisory Panel Meeting Held on March 25-26, 200, to Review and Consider the Endocrine Disrupter Screening Program (EDSP) Proposed Tier 1 Screening Battery
“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.”
—Dr. Iain Purchase, Central and Eastern Cheshire Primary Care Trust
“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. John Giesy, professor of environmental toxicology and member of the U.S. National Academy of Sciences
“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.”
—Dr. Robert Combes, former director of the Fund for the Replacement of Animals in Medical Experiments (FRAME)
“It’s not the time now to offer expediency over scientific validity. This program is too significant, too important, and it’s going to have a huge impact.”
—Kristie Sullivan, Physician’s Committee for Responsible Medicine, on validation of Tier I assays
By industry experts:
“To start with the specificity for detecting estrogen, androgen, and thyroid active agents, the [animal] assays require a number of apical endpoints which can be altered by both endocrine and non-endocrine or systemic toxicity effects. … Target organ weights can be affected not only by endocrine active agents but also by stage of estrous cycle at the time of necropsy and changes in terminal body weight, so it may be difficult to determine when you see a positive in this assay whether or not you have estrogen, androgen, or thyroid active agents. … [T]here’s no evidence that the assays are specific for just endocrine acting materials. … The problem with this is that the 12 assays may produce a high rate of false positives…. Tier 2 testing is going to be costly, resource intensive, and is going to use large numbers of animals.“
—Dr. Sue Marty, senior toxicology leader, Dow Chemical, regarding sensitivity of the screens and tests
“… I would argue that complex animal-intensive assays such as the pubertal shouldn’t be used in a default routine requirement pending other available information.”
—Dr. J. Willie Owens, Procter & Gamble, on considering the implementation of assays within the context of existing information rather than default use of animal tests
“It seems a bit redundant to have such a large, a lot of animals required and a costly assay to be included when other rodent assays already in Tier 1 might [indentify] compounds as thyroid active.”
—Dr. Lisa Ortego, CropLife America, on redundancy of the amphibian assay
“Overall the design, in our opinion, goes beyond the requirements of a screen for detecting potential endocrine disruption.”
—Dr. Reinhard Fischer, Bayer CropScience, on the intensiveness of the Tier I screens
On the Scientific Value of Animal Experimentation
“Some animal tests haven’t changed in 60 years. The tests are frozen in time. This is not science. Science is always moving ahead.”
—Dr. Thomas Hartung, director, Center for Alternatives to Animal Testing (CAAT), Johns Hopkins University
“The reason we use animal tests is because we have a comfort level with the process … not because it is the correct process, not because it gives us any real new information we need to make decisions. Animal tests are no longer the gold standard. It is a marvelously new world.”
—Dr. Melvin E. Andersen, director, Division of Computational Biology and Program in Chemical Safety Sciences, The Hamner Institutes for Health Sciences
“Companies are putting infinitely more money into the development of alternatives and are much more aware of … new in vitro methods than government regulators. But the regulators say, ‘You still have to prove to me that it’s safe using an animal.’ “
—Dr. Rodger Curren, president, Institute for In Vitro Sciences