generation of specific and complex chemicals will be introduced in the near future, because of new strategies of rational drug design based on knowledge of protein three-dimensional structure and chemical mechanisms, and because of high-throughput function-based screens of huge combinatorial chemical libraries. Still, mechanistic evaluations of the biological effects of chemicals should serve as an organizing principle for grouping compounds in a database and predicting their risk.

In the committee’s proposed hierarchy of four information levels for model animal systems, each higher level provides increasingly complex information concerning higher biological complexity and responses to environmental chemicals. Systems of lower complexity might be used to organize chemicals, for example, to reveal those chemicals that bind to the same protein (e.g., a nuclear-hormone receptor) or act in the same signaling pathway. This information would be useful for predicting effects at the next level, for example, on a particular kind of organogenesis in which a particular signaling pathway is used.

SUMMARY

The committee has developed a multilevel, multidisciplinary, interactive approach for improving risk assessment for developmental toxicity. Model animal systems and human epidemiological studies are shown to be valuable sources of information for risk assessment, and it is emphasized that the multilevel approach is not a tiered approach. To meet the goals of this approach, the committee has described what information is available from model systems of differing complexity, from in vitro assays to whole animals, for the assessment of toxicity and mechanism of action of chemicals. The committee has also described databases and database needs for assessing chemical exposure, susceptibility, and developmental effects in human populations and the continuing value of human epidemiological data for risk assessment. For each database, the committee has identified the type of information provided and how that information answers risk assessment questions. Examples are given of the anticipated interactive aspect of the approach, whereby new data and methods can be incorporated into the risk assessment process. Finally, the committee has described integrated approaches essential for the linkage of numerous relevant databases across chemicals, times of development, descriptions of toxic effects, and applications.



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