FIFRA SUBDIVISION-F TESTING GUIDELINES - ARE THESE TESTS ADEQUATE TO DETECT POTENTIAL HORMONAL ACTIVITY FOR CROP PROTECTION CHEMICALS

Recently, a major topic of discussion has been the impact of synthetic chemicals that possess the capacity to alter hormonal activity, the s o-called ''endocrine modulators,'' with potentially the capacity to al ter the reproductive capability of humans. Particularly, various synth etic pesticides and industrial chemicals that persist in the environme nt and/or bioaccumulate have been implicated. Further, it has been all eged that the standard tests for pesticide registration as required by the U.S. Environmental Protection Agency (EPA) and other regulatory a gencies may be inadequate to detect endocrine modulating effects. To a ddress these shortcomings, it has been proposed thar very specific tes ts for estrogen receptor binding, or in vitro cell response to chemica ls, 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 si ngle chemical event per test. Such tests do not measure toxicity or bi ological response. isolated systems are very important for studying me chanisms of action or structure activity relationships, but can only p rovide a preliminary screen for a single mechanism of toxicity. Isolat ed systems can not be used to regulate a chemical without additional i nformation. Second, they fail to test many other parts of the neuroend ocrine control of the reproductive system. Testing for adverse effects in highly specific in vitro systems failed to replace whole-animal mo dels in carcinogenesis and will also fail in reproductive toxicology b ecause this system is too complicated for such as in vitro approach to be accurately predictive. Advanced tests, such as the EPA multigenera tion study, are more effective and reliable means for evaluation than any specific and narrowly focused screening tests. Experience has show n that a better approach to testing chemicals is to evaluate their eff ects on the whole animal. When one part of the system is adversely aff ected various processes may be indirectly affected and can be detected in the animal model. For example, a modulation of testosterone synthe sis could lead to (7) altered accessory sex organ morphology, size, an d function; (2) decreased sperm counts; and (3) even decreased fertili ty. These and many other effects would be noted in toxicity studies th at are already required for the registration of crop protection chemic als. The developmental and reproductive toxicity guidelines were recen tly reviewed in a hearing that included the representatives from the E PA, the public, and the Scientific Advisory Panel. The EPA kept the ba sic study design the same, but added a few new endpoints to further as sess chemical-induced effects on reproductive development and function . The review presented herein concentrates on the required Federal Ins ecticide, Fungicide, and Rodenticide Act (FIFRA) testing for pesticide s, and demonstrates how the massive arrays of sensitive endocrine endp oints that are delineated in FIFRA Subdivision F have been successfull y used to detect both weak and potent hormonally modulating chemicals. For example, (1) diethylstilbestrol (DES), which is a potent syntheti c therapeutic estrogen, (2) DDT, which is weakly estrogenic but persis tent and bioaccumulating, and (3) dioxins, which have antiestrogenic p roperties, were all found as being hormonally active in tests similar or identical to FIFRA tests. All food-use pesticides have been evaluat ed 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 heal th.