Charge 4: Develop Recommendations for Research in Developmental Toxicology and Developmental Biology; Focus on Those Areas Most Likely to Assist in Risk Assessment for Developmental Effects. The committee recommends a multilevel, multidisciplinary approach to risk assessment that incorporates information from a range of model systems intended to

  1. evaluate chemicals for potential developmental toxicity;

  2. provide mechanistic information on toxicants;

  3. address several key areas of uncertainty about the relevancy of cross species extrapolation of toxicological information from animals to humans; and

  4. further the exploration of the genotype-environment interactions that might underlie a large fraction of developmental defects and could help to explain human variability in response to environmental agents.

This novel approach should provide a guide for obtaining the kinds of data that are needed for a comprehensive cross-species model of exposure and development. Specifically, as described in Chapter 9 of this report, the committee recommends that research be conducted in the following areas.

  • Greater use of model systems for developmental toxicity and risk assessment. Model systems should be used to assess and understand chemical effects (or absence of effects). This recommendation is based on the conclusion that model-animal research has been highly informative about mammalian development, especially human development, and therefore, is likely to be informative about mammalian developmental toxicity. The model systems that should be considered include in-vitro and cellular assays, nonmammalian (e.g., fruit fly, roundworm, and zebrafish) developmental assays, mammalian (e.g., the mouse) developmental assays, and in-depth mammalian tests of mechanism and susceptibility.

  • Evaluation of chemicals for developmental toxicity. In-vitro and cellular assays and nonmammalian tests should be used for evaluating chemicals and chemical mixtures so that patterns of toxicity can be more readily recognized. The number of chemicals in commerce is rapidly expanding, and it is a continuing challenge to obtain toxicity data on them. These model systems could be used quickly and are inexpensive, and their use would permit a large number of chemicals and doses to be evaluated for their potential impact on many key developmental processes.

  • Analysis of mechanisms of toxicity. Mechanistic information is essential to our understanding of how chemicals can perturb development and, thus, is an important component of risk evaluation. To improve the understanding of the mechanisms of action of toxicants, critical molecular targets of components of developmental processes should be identified. Potential critical molecular targets that should be further investigated include (1) evolutionarily conserved pathways of development, such as intercellular signaling pathways (including their



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