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The EPA’s Endocrine Disruptor Screening Program

The EPA’s Endocrine Disruptor Screening Program
The Endocrine Disruptor Screening Program (EDSP) is a massive chemical-testing program intended to screen chemicals for effects on the body’s natural hormone systems (known as “endocrine disruption”). The program resulted from a 1996 law that requires the Environmental Protection Agency (EPA) to “develop a screening program … to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other endocrine effect as the [agency] may designate.” However, once in the hands of the EPA, this simple mandate quickly mutated into what has become one of the largest animal testing exercises in U.S. history.

First, the EPA put together an advisory committee with representatives from environmental groups, industry, and all other interested parties except members of the animal-protection community. Then, on the advice of its committee, the EPA expanded the scope of its EDSP to examine not only estrogen-like effects but also effects on androgen and thyroid hormones. Then the EPA took it even further by vastly expanding the program’s scope beyond testing on rats to include toxicity testing not only on fish and amphibians but also potentially on birds and invertebrates as well. The wildlife toxicity tests alone kill twice the number of animals who are killed during assessments of human health effects in this program.

How Does the Program Work?
To assess the chemicals, the EPA has devised a two-tiered testing program. Tier 1 screening assays consist of five in vitro (cell-based) and six in vivo (animal) assays (the Tier 1 battery) and are intended to identify chemicals that may have the potential to cause endocrine disruption. These chemicals would then be further evaluated with additional animal testing in Tier 2, which is designed to confirm the adverse endocrine effect on animals and establish a dose-response relationship.

What Are Some Criticisms of the Program?
PETA and other stakeholders have criticized many aspects of the program, such as a failure to adequately validate many of the Tier 1 assays. Validation is a process in which a test method is evaluated to determine whether the information that it produces is reliable, reproducible, and relevant to humans. Test-method validation is a prerequisite for good science, and in the case of the EDSP, it is also required by law. The Food Quality Protection Act of 1996 states that only appropriate validated test systems can be used in the program. Interestingly, prior to the EDSP, only non-animal tests were required to undergo validation. (The dozens of animal tests that have been used for decades were never validated.) Other criticisms of the EDSP include the lack of selectivity of many of these assays, the high false-positive rates of three of the assays, and the fact that the EPA has no clear method in place to interpret mixed results. In fact, mixed results can easily occur as the assays overlap with regard to the effects that they measure, so a chemical could conceivably test positive in one assay and negative in another. Visit our “Scientific Problems” page for more information.

How Has PETA Responded to the Program?
In an effort to limit the damage caused by environmental and wildlife-protection groups that favor increased animal testing, PETA filed a legal petition with the EPA in 2005, calling on the agency to limit the scope of its endocrine program to an assessment of effects in humans, as specified by the 1996 law. In fact, there were already some non-animal methods available at the time that pertained to human health effects. The EPA and the animals used in this testing program would have been far better off if the EPA had begun with this legally mandated scope and explored scientifically whether or not this program even had regulatory merit. Unfortunately, the lawsuit was unsuccessful because of the court’s determination that PETA lacked standing.

Despite our efforts and criticisms of the program from numerous stakeholders, the EPA issued requests for information on a draft list of chemicals slated for the first round of EDSP testing in June 2007. Click here to read PETA’s comments to the EPA about the list. All chemicals on the list are either pesticides or chemicals from the EPA’s High Production Volume (HPV) Chemical Testing Program that had already undergone numerous animal tests. Pesticides, for example, are among the most data-rich substances in existence. In order to be registered, their active ingredients and final products are usually subject to dozens of separate animal tests, including reproductive and chronic/lifecycle studies in rodents, fish, dogs, and birds. These tests kill thousands of animals and include many of the same endpoints addressed in the presumptive EDSP Tier 2 tests. Similarly, the EPA’s HPV program also provides for the collection of data that can be used in the assessment of potential reproductive effects.

In a May 2009 letter to the Office of Management and Budget (OMB), PETA and other stakeholders questioned the usefulness of the EDSP and alerted the OMB to the potential for a waste of resources and massive animal suffering. The letter and two subsequent meetings successfully convinced the OMB that the cost/benefit for the program was inadequate—that there was very little benefit for such an extraordinary cost. As a result—and in a move that was highly unusual for the OMB—the agency instructed the EPA to use existing data, known as “other scientifically relevant information” (OSRI), whenever available, in lieu of performing some or all of the tests in the Tier 1 battery, which would save taxpayer dollars and the lives of tens of thousands of animals. For example, the EPA could use information from its own ToxCastTM program, launched in 2007, which uses information from in vitro assays and allows connections to be made rapidly between in vitro assay results and existing data on chemicals. Most of the first group of chemicals to be evaluated in the EDSP have already been tested in ToxCastTM screens, and nearly half of these showed no evidence of endocrine activity.

The OMB also instructed the EPA to “ensure sufficient opportunity … for public comment and peer review … on whether a chemical must proceed to Tier II.” Such a period of assessment and review is critical for allowing the EPA to review the cost/benefit of each assay within the Tier 1 battery to delete assays that offer no added “value” and for developing a transparent, scientifically rational method for interpreting the results of Tier 1 assays. This period of assessment can also create an opportunity to incorporate new non-animal assays that have been developed since the 1998 decision to use the current battery of assays.

Where Is the Program Now?
In October 2009, the EPA issued test orders to chemical companies for the first 67 chemicals to be evaluated in the EDSP (List 1 chemicals). Prior to testing, companies and stakeholders had the option to submit OSRI that could potentially satisfy the data requirements of one or more Tier 1 assays. In response to this call for OSRI, PETA submitted detailed reviews of existing data for 14 chemicals. In addition, PETA scientists suggested an integrated strategy that would more efficiently assess chemicals for endocrine-disrupting potential, applied this approach in detail to two of the List 1 chemicals, and in 2011, published an article about this approach in the peer-reviewed journal Toxicological Sciences.

Chemical companies submitted their own OSRI for 47 of the 67 List 1 pesticides, seeking test waivers for some or all of the Tier 1 assays, and by the end of 2010, the EPA had issued its responses to all the OSRI that had been submitted. PETA presented an analysis of the OSRI submissions and EPA responses at the 2013 Society of Toxicology annual meeting. (See PETA’s poster on OSRI.) We found that companies sought test waivers based on existing data for 412 Tier 1 assays and agreed to conduct 105 new tests. The EPA waived only 93 assays, however, requiring 424 new tests to be conducted, 307 of which were animal tests consuming approximately 24,000 animals. Manufacturers of another seven chemicals did not submit any OSRI and conducted the full Tier 1 battery, using an additional 4,000 animals.

Most companies sent their results from the Tier 1 testing to the EPA by August 2012, and the agency is conducting a weight-of-evidence analysis of the data and OSRI to determine which (if any) Tier 2 tests it will require. The EPA is expected to complete this analysis sometime in the first half of 2013, thereby taking three and a half years from the issuance of test orders in October 2009 to identify any potential endocrine disruptors from the List 1 chemicals. It could conceivably take another three years or more before Tier 2 testing is completed and endocrine effects on animals, if any, are confirmed. How a confirmed endocrine disruptor might affect humans would still be largely unknown at that point, however, since results from rodent assays do not necessarily transfer to humans.

Also in late 2010, the EPA published a second list of 134 chemicals (List 2 chemicals) before testing had even begun on the 67 List 1 chemicals. Once more, PETA submitted comments to the EPA, criticizing the agency for moving forward with a second list before it had evaluated the results from List 1 and demonstrated the utility of the Tier 1 assays in supplying the type of information necessary for making supportable decisions. We again urged the agency to adopt a tiered testing strategy that uses data from all existing sources to determine which tests, if any, would yield the information most relevant for making rational decisions. (See our discussion of an integrated test strategy in “Non-Animal Methods.”) Because of the length of time that the EPA has taken to complete work on the List 1 chemicals, progress with List 2 has halted and test orders have not yet been issued.

The EPA has been charged with assessing thousands of chemicals for endocrine disruption. Given this daunting task, the time that it has taken to implement the first phase, and the amount of criticism that it has received, the EPA reconsidered its approach and released a summary work plan in September 2011 called EDSP21, which commits to incorporating more advanced and less animal-intensive toxicity testing methods into its program for identifying possible endocrine disruptors. In June 2012, the EPA issued a Comprehensive Management Plan for the program covering the period from 2012 to 2017, which also discusses the new approach that it plans to take. In short, the EPA intends to rely more on computer models and in vitro high-throughput screening assays (see “Non-Animal Methods”) to make initial determinations about a chemical’s endocrine-disrupting ability. At first, these methods will be used to prioritize chemicals for screening in Tier 1 and, eventually, as they become validated, will constitute the screening methods themselves, thereby eliminating the Tier 1 assays completely. The strategies laid out in both EDSP21 and the Comprehensive Management Plan closely follow the integrated testing strategy that commits to incorporating more advanced and less animal-intensive toxicity-testing methods into its program for identifying possible endocrine disruptors. (See PETA’s reaction to the announcement of EDSP21 here.)

In November 2012, the EPA released a document describing the general principles that it will use for validating computational toxicology tools. These tools will be used to prioritize a universe of approximately 10,000 chemicals for EDSP testing over the next five years. The ultimate goal will be to use these tools as a replacement for the Tier 1 battery and drastically reduce the number of animals used in testing. The EPA submitted a draft methodology for assessing a chemical’s potential to disrupt the estrogen hormone system using computational tools and high-throughput assay results from ToxCastTM to its advisory panel in January 2013 as a first step toward meeting the goals of EDSP21.

How Can I Help?
Please send polite letters to the EPA’s director of the Endocrine Disruptor Screening Program, Mary Manibusan, telling her that you support EDSP21 and the EPA’s adoption of non-animal methods for assessing chemicals in the EDSP program and also requesting that the EPA expeditiously validate and use new non-animal methods before allowing any new animal testing.

Mary Manibusan, Director
Endocrine Disruptor Screening Program
Office of Science Coordination and Policy
Office of Chemical Safety and Pollution Prevention
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Ave. N.W.
Mail Code: 7201M
Washington, DC 20460
Manibusan.mary@epa.gov

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