agenda. The agenda would address basic scientific questions about which there is inadequate information. Specific areas of opportunity include:

  • Intraspecies differences in sensitivity to toxicants. Genetic differences are suspected to be a major factor in intraspecies differences within human populations and within test-animal populations. Do individual differences concern mostly genetic variation in toxicokinetics, particularly in DMEs? Do they also include genetic variation in developmental components, such as those of the 17 intercellular signaling pathways used throughout development? Do multiple genetic differences have additive effects for the individual’s toxicant susceptibility? Is genetic variation in components of molecular-stress pathways also important in the individual’s response to toxicants? What is the contribution to individual susceptibility of nongenetic differences, such as those of age, history of disease, nutrition, and exposure to other chemicals and pharmaceuticals?

  • Cross-species extrapolation. What are the toxicokinetic differences, particularly in the activities of drug-metabolizing enzymes (DMEs), between test animals and humans? Are differences in susceptibility to developmental toxicants due to differences in developmental molecular components and processes? Can some of the differences between test animals and humans be reduced or eliminated?

  • Extrapolation of high-dose exposure of small populations of test animals to low-dose, long-term exposure of a large human population. Do chemicals have different toxicokinetic and toxicodynamic effects at high doses versus low doses? Does the organism rely on different protective responses to chemicals at different doses, such as enzymatic detoxification at low doses, molecular-stress reactions at intermediate doses, and the apoptotic response at high doses?

  • Expanded test information for numerous chemicals and, especially, mixtures of chemicals. Can structure-activity relationships be obtained for a larger variety of chemicals by using in vitro tests with purified components (e.g., DMEs and developmental components of signaling pathways and transcriptional regulation)? Can model animals be genetically modified so that more mechanistic information can be obtained from them than from standard animal tests? As mechanisms are better understood for certain chemicals, can the effects of related chemicals be better predicted?

THE MULTIDISCIPLINARY, MULTILEVEL, INTERACTIVE APPROACH

The committee will outline in the remainder of this chapter a multidisciplinary, multilevel, interactive approach in which recent and future advances in developmental biology and genomics can be integrated with developmental toxicology to improve risk assessment for human developmental defects. This approach is not simply an alternative to current practices, but represents a novel



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