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The EPA’s Endocrine Disruptor Screening Program

The EPA’s Endocrine Disruptor Screening Program
When the Environmental Protection Agency’s (EPA) Endocrine Disruptor Screening Program (EDSP) was established in the late 1990s, it had the potential to be one of the largest animal testing exercises in U.S. history. The program resulted from a 1996 law that required the EPA to develop a plan to determine whether or not chemicals affect the body’s hormone systems (known as “endocrine disruption”).

The EPA started by putting together an advisory committee with representatives from environmental groups, industry, and 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. Because of concerns about endocrine effects on wildlife from chemicals entering the environment, the EPA also extended testing beyond rats to include fish and amphibians and potentially birds and invertebrates as well.

How Does the Program Work?
The EPA devised a two-tiered testing program to assess the approximately 10,000 chemicals slated to be screened for endocrine disruption. The Tier 1 screening tests consist of five in vitro (non-animal cell-based) and six in vivo (animal) tests and are intended to identify chemicals that may have the potential to cause endocrine disruption. Any chemicals that display possible impacts are then further evaluated with additional animal testing in Tier 2, which is designed to confirm the adverse endocrine effects on animals and determine at what dose the chemical affects the endocrine system. Tier 2 tests are animal-intensive reproductive studies that consume thousands of rats, fish, birds, and amphibians.

What Are Some Criticisms of the Program?
PETA and other stakeholders have criticized many aspects of the program, including a failure to validate adequately  many of the Tier 1 tests. Validation is a process through 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 sound 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.)

The EDSP has other scientific problems, including the fact that three of the tests often incorrectly produce false positives, showing that a chemical affects the endocrine system when, in fact, it doesn’t, as well as the fact that the EPA had no clear method in place to interpret inconclusive results. In fact, inconclusive results can easily occur as some of the tests measure the same effects, and it’s possible for a chemical to have a positive result in one test and a negative result in another. Visit our “Scientific Problems” page for more information.

How Has PETA Responded to the Program?
After the scope of the EDSP was significantly expanded, PETA filed a legal petition in 2005 calling on the EPA to limit the scope to an assessment of effects in humans, as specified by the 1996 law. Unfortunately, the lawsuit was unsuccessful because of the court’s determination that PETA lacked the legal standing to initiate the lawsuit.

Despite our efforts and scientific critiques of the program from numerous stakeholders, the EPA issued 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 tests on animals. Pesticides, for example, are among the most data-rich substances in existence. Before they can be sold, their active ingredients and final products are usually subjected 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 test for many of the same hazards as the presumptive EDSP Tier 2 tests. Similarly, the EPA’s HPV chemical-testing 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 huge waste of resources and massive animal suffering. The letter and two subsequent meetings successfully convinced the OMB that the high cost of new testing might pose an unreasonable burden on both the EPA and companies while potentially yielding little benefit, particularly since many of the chemicals being evaluated were already so data-rich. As a result—and in a move that was highly unusual for the OMB—the agency instructed the EPA to use information about chemicals that already existed, known as “other scientifically relevant information” (OSRI), whenever available, in lieu of performing some or all of the tests in the Tier 1 battery. The use of existing information would save taxpayer dollars and the lives of tens of thousands of animals. For example, it was suggested that the EPA use information from its own ToxCastTM program, launched in 2007, which employs numerous rapidly conducted (high-throughput) in vitro tests to assess a chemical’s potential to act on the body’s endocrine system. At the time of the first test orders, however, the EPA had claimed that the ToxCast results could not be used as a substitute for Tier 1 tests.

The OMB also instructed the EPA to “ensure sufficient opportunity … for public comment and peer review … on whether a chemical must proceed to Tier 2.” Such a period of assessment and review is critical to allowing the EPA to review the cost/benefit of each test within the Tier 1 group in order to discontinue tests that offer no added “value” and to develop a transparent, scientifically rational method for interpreting the results of Tier 1 tests. This period of assessment can also create an opportunity to incorporate new non-animal tests that have been developed since the 1998 decision to use the current test methods.

The First Test Orders Are Issued
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 tests. In response to this call for OSRI, PETA submitted detailed reviews of data for 14 chemicals. In addition, PETA scientists suggested an integrated strategy that would more efficiently assess chemicals for endocrine-disrupting potential and applied this approach in detail to two of the List 1 chemicals. In 2011, we published an article that described this process in detail in the peer-reviewed journal Toxicological Sciences.

Chemical companies submitted their own OSRI for 47 of the 67 List 1 pesticides, seeking waivers so that they would not have to conduct some or all of the Tier 1 tests. By the end of 2010, the EPA had issued its responses to all of the OSRI that had been submitted. PETA scientists published an article in the peer-reviewed journal Birth Defects Research Part B: Developmental and Reproductive Toxicology in 2014 that analyzed the OSRI submissions as well as the EPA’s responses. We found that companies sought test waivers based on OSRI for 412 Tier 1 tests and agreed to conduct 105 new tests. The EPA waived only 93 tests, however, requiring 424 new tests to be conducted, 307 of which were animal tests that would consume approximately 24,000 animals. Manufacturers of another seven chemicals did not submit any OSRI and conducted all of the Tier 1 tests, using an additional 4,000 animals.

Before testing actually began, 15 chemicals were dropped from List 1 for various reasons, leaving 52 that moved forward under the program. Most companies sent their results from the Tier 1 testing to the EPA by August 2012, and it has taken until June 2015 for the agency to complete a weight-of-evidence analysis of the data and OSRI to determine which Tier 2 tests it will require.

Of the 52 chemicals evaluated, 20 showed no evidence of any endocrine effects. There were 14 showing potential effects that the EPA already had enough information on to conclude did not pose risks. Of the remaining 18 showing potential endocrine effects, the EPA did not yet have enough information to assess their risk.

For Tier 2, the EPA is recommending that four thyroid tests in mammals, 13 fish reproductive tests, and five amphibian growth and development tests be performed. 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 tests are not necessarily applicable to humans.

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 tests in supplying the type of information necessary to making supportable decisions. We again urged it 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 to 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 perform screening and analysis of the List 1 chemicals, progress with List 2 has halted and test orders have not yet been issued.

The Program Today

Some of the biggest criticisms of the EDSP were the amount of time and resources it used and the large numbers of animals needed to screen a small number of chemicals. As noted above, the EPA is responsible for screening up to 10,000 chemicals for endocrine effects, yet it has taken almost six years to complete the first Tier 1 tests and analyze the data on just 52 chemicals. It was easy to see that if things continued along this path, it would take decades or more to complete the screening process. Clearly, a better way was needed.

The EPA responded to issues raised by PETA and other stakeholders by releasing 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 agency issued a Comprehensive Management Plan for the program covering the period from 2012 to 2017, which discusses its new approach and its plan to rely more on computer models and non-animal high-throughput screening (HTS) tests (see “Non-Animal Methods”) to make initial determinations about a chemical’s endocrine-disrupting ability. The plan is to use these methods to prioritize chemicals for screening in Tier 1 and eventually, as they become validated, use them to screen chemicals, thereby eliminating some or all of the Tier 1 tests completely. The strategies laid out in both EDSP21 and the Comprehensive Management Plan closely follow the integrated testing strategy that PETA had suggested in its 2011 peer-reviewed article in Toxicological Sciences, “Application of an Integrated Testing Strategy to the U.S. EPA Endocrine Disruptor Screening Program.” (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 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 tests and drastically reduce the number of animals used in testing.

The EPA submitted a draft methodology for using computational tools and HTS test results from ToxCastTM to assess a chemical’s potential to disrupt the estrogen hormone system to its advisory panel in January 2013 as a first step toward meeting the goals of EDSP21.

Three more meetings have since been held that charged the advisory panel with reviewing additional steps in developing the EDSP21 approach. A July 2013 meeting dealt with how best to integrate the results of OSRI and Tier 1 in vitro and in vivo test results in order to arrive at a decision regarding whether or not a chemical has the potential to affect the endocrine system (see PETA’s comments here). A July 2014 meeting evaluated a proposed computational method to estimate the risk to humans and the environment of exposure to a chemical (see PETA’s comments here). Finally in December 2014, the advisory panel reviewed a method that uses the ToxCastTM HTS test results and information on the risk of chemical exposure in order to prioritize chemicals for further assessment (see PETA’s comments here).

Results from this work have been so promising that in June 2015, the EPA requested public comments on the use of these new technologies for substantially speeding up the screening of chemicals for their potential to disrupt hormones in humans and wildlife as well as for reducing animal testing. The plan is to adopt in vitro HTS tests and computational models as an alternative to three current Tier 1 tests, two of which use animals. The EPA is also working on using these methods to replace two additional Tier 1 tests but needs additional time to complete validation. To learn more about the EPA’s efforts to improve the EDSP and reduce animal use, visit its website here.

What You Can Do
You can show your support for EDSP21 and the EPA’s adoption of cutting-edge non-animal methods for assessing chemicals in the EDSP program by contacting the EPA:

Dr. David Dix, Director
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
Dix.david@epa.gov

Follow the links below to learn more about this program: