FIFRA Subdivision F testing Guidelines: are these tests adequate to detect potential hormonal activity for crop protection chemicals? Federal Insecticide, Fungicide, and Rodenticide Act.

Recently, a major topic of discussion has been the impact of synthetic chemicals that possess the capacity to alter hormonal activity, the so-called "endocrine modulators," with potentially the capacity to alter the reproductive capability of humans. Particularly, various synthetic pesticides and industrial chemicals that persist in the environment and/or bioaccumulate have been implicated. Further, it has been alleged that the standard tests for pesticide registration as required by the U.S. Environmental Protection Agency (EPA) and other regulatory agencies may be inadequate to detect endocrine modulating effects. To address these shortcomings, it has been proposed that very specific tests for estrogen receptor binding, or in vitro cell response to chemicals, be used to identify potential endocrine modulators. However, such approaches have certain flaws that limit their application as screens. First, very specific tests, like receptor binding, evaluate only a single chemical event per test. Such tests do not measure toxicity or biological response. Isolated systems are very important for studying mechanisms of action or structure activity relationships, but can only provide a preliminary screen for a single mechanism of toxicity. Isolated systems can not be used to regulate a chemical without additional information. Second, they fail to test many other parts of the neuroendocrine control of the reproductive system. Testing for adverse effects in highly specific in vitro systems failed to replace whole-animal models in carcinogenesis and will also fail in reproductive toxicology because this system is too complicated for such as in vitro approach to be accurately predictive. Advanced tests, such as the EPA multigeneration study, are more effective, and reliable means for evaluation than any specific and narrowly focused screening tests. Experience has shown that a better approach to testing chemicals is to evaluate their effects on the whole animal. When one part of the system is adversely affected, various processes may be indirectly affected and can be detected in the animal model. For example, a modulation of testosterone synthesis could lead to (1) altered accessory sex organ morphology, size, and function; (2) decreased sperm counts; and (3) even decreased fertility. These and many other effects would be noted in toxicity studies that are already required for the registration of crop protection chemicals. The developmental and reproductive toxicity guidelines were recently reviewed in a hearing that included the representatives from the EPA, the public, and the Scientific Advisory Panel. The EPA kept the basic study design the same, but added a few new endpoints to further assess chemical-induced effects on reproductive development and function. The review presented herein concentrates on the required Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) testing for pesticides, and demonstrates how the massive arrays of sensitive endocrine endpoints that are delineated in FIFRA Subdivision F have been successfully used to detect both weak and potent hormonally modulating chemicals. For example, (1) diethyl-stilbestrol (DES), which is a potent synthetic therapeutic estrogen, (2) DDT, which is weakly estrogenic but persistent and bioaccumulating, and (3) dioxins, which have antiestrogenic properties, were all found as being hormonally active in tests similar or identical to FIFRA tests. All food-use pesticides have been evaluated using a comprehensive multigeneration reproduction test. Hence, the FIFRA testing procedures have been demonstrated to identify endocrine modulators of sufficient potency to represent a concern to human health.