The World Wildlife Fund (WWF) was largely responsible for initiating, and has been one of the chief architects in designing, the EPA's notorious Endocrine Disruptor Screening Program (EDSP). The purpose of the EDSP is to screen thousands of chemicals to detect endocrine (hormone) disrupting effects, even though scientists have been unable to even define what an "endocrine disruptor" is or does. However, as a result of lobbying by the WWF and others, the EDSP has become the largest animal-testing program of all time, with the potential to kill as many as 100 million animals.

The Natural Resources Defense Council (NRDC) has aggressively lobbied the EPA to initiate several large animal-testing initiatives. Dissatisfied with the rate at which the EDSP was being developed, the NRDC filed a lawsuit in an attempt to force the EPA to begin the testing process sooner—without properly validating the animal tests that would be used—and has fought every attempt by PETA to ensure that animal tests undergo the same scientific scrutiny as their non-animal counterparts. The NRDC also coordinated a joint letter calling on the EPA to require that all pesticides undergo developmental neurotoxicity testing on animals. The nonvalidated developmental neurotoxicity test kills between 1,200 and 2,500 animals every time it is performed. In addition, EPA officials have admitted that they don’t even know how to interpret the results of this test.

Environmental Defense was one of the chief architects, and is largely responsible for initiating, EPA's notorious high production volume (HPV) chemical testing program. The HPV program was created to pressure chemical manufacturers to test (or retest) thousands of chemicals using a "checklist" approach that relies on numerous crude, painful, and uninformative animal tests. Environmental Defense opposed the incorporation of non-animal tests into the program. Even though the animal protection community has reviewed and commented on every proposed HPV test plan in an attempt to limit the number of animal tests performed, Environmental Defense has only commented on a small handful of HPV test plans. Yet in virtually all cases, Environmental Defense has called for more animal tests, even on substances well known to be blinding and corrosive.