proaches being pursued. Interference with estrogen, androgen, glucocorticoid, or thyroxine receptor function can result in developmental and endocrine toxicities. Major efforts are under way to devise screening methods to assess interference with those receptors (EPA 1998b). This task is complex, because chemicals could be agonists, partial agonists, antagonists, or negative antagonists (Limbird and Taylor 1998) or interact with other steps in the pathway. Caution is needed, therefore, in extrapolating from simple tests. Nevertheless, a variety of tests have been devised to assess receptor binding, activation of response elements, and cellular responses (e.g., proliferation). Similar approaches could be devised for other signaling pathway receptors involved in developmental toxicity.

Animal Bioassays

In vivo animal bioassays are a critical component in human health risk assessment. A basic underlying premise of risk assessment is that mammalian animal bioassays are predictive of potential adverse human health impacts. This assumption, and the assumption that humans are the most sensitive mammalian species, have served as the basis for human health risk assessment.

Several study protocols to test for developmental toxicity in animals are accepted and used by regulatory agencies such as EPA and FDA. Describing the various protocols goes beyond the scope of this report and the reader is referred to the original guidelines (EPA 1991, 1996a, 1998c,d,e; FDA 1994; OECD 1998) for detailed descriptions. T.F. Collins et al. (1998) contains a discussion and a comparison of EPA, FDA, and OECD guidelines.

Information obtained from in vivo bioassays includes the identification of potentially sensitive target organ systems; maternal toxicity; embryonic and fetal lethality; specific types of malformations including gross, visceral, and skeletal malformations; and altered birth weight and growth retardation. These assays can also provide information on reproductive effects, multigenerational effects, and prenatal and postnatal function. In vivo bioassays determine critical effects that are used for quantitative assessments by taking the no-observed-adverse-effect level (NOAEL) for the most sensitive effects.

The focus of animal bioassays primarily has been toxicity assessment, including hazard identification and dose-response assessment. The aim of such studies is to identify qualitatively what spectrum of effects a test chemical can produce and to put those effects in the context of dose-response relationships. Because there is uncertainty in extrapolation from animal studies to humans, several assumptions are made, including the following: (1) an agent that causes an adverse developmental effect in experimental animals might cause an effect in humans; (2) all end points (i.e., death, structural abnormalities, growth alterations, and functional deficits) of developmental toxicity are of potential concern; and (3) specific types of developmental effects observed in experimental animals might not be manifested in the exact same manner as those observed in humans.



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