metabolic potentiation or detoxification of chemicals, as part of the research program of ecogenetics, pharmacogenetics, and the Environmental Genome Project. Much study of the roles of DMEs is done in the mouse, for example, with null mutants of individual enzymes. The committee fully favors this direction of study and the support for it. As described later, it will also be valuable for animal assays of toxicants to know the DME similarities and differences from humans, as a part of the validation of the extrapolation of data from animals to humans. Some studies with other model organisms are probably of use. Some DMEs are widely conserved among animals (e.g., CYP1A1 in fish) and would be easier to study in other model organisms.

1.2. In pursuing mechanisms of toxicity, the committee recommends research to explore how molecular perturbations lead to dysmorphogenesis and other adverse outcomes of development in different species.

A decade ago it would have seemed impossible to analyze how a toxicant’s initial interaction with a molecule is connected with the ultimate developmental defect. The complexity of development seemed daunting, and there was little knowledge of the activities and interactions of components and their roles in developmental processes. In the past decade, however, the situation for analysis has improved greatly. The activities of numerous components are known, and there are insights into the organization and coupling of processes. The understanding of the early developmental steps of axis formation, gastrulation, and neurulation is increasing, and various examples of organogenesis are available for study. The new information on development provides the framework for analysis of toxicant effects on developmental processes and the connection of dysfunctional processes to structural and functional defects in the newborn. The analysis of development in model organisms has been crucial to the progress in mammals, specifically the mouse. Some efforts in connecting molecular effects to dysmorphologies have been successful. For example, the analysis of cyclopamine (a plant alkaloid) in causing cyclopia (a diminished head and single median eye) in cattle was possible once it was realized that mouse mutants of some components of the Hedgehog signaling pathway are also cyclopic; once the basic developmental studies showed the importance of sonic Hedgehog signal for inhibiting eye development in the ventral midline of the prospective diencephalon, leaving bilateral eye development, the mechanism of the cyclopamine-induced birth-defect became better understood.

Scrutiny of the developmental defects of mutants of developmental components in genetically favorable model organisms, and the scrutiny of toxicant-caused developmental defects, might provide informative parallels. In some mutants, a component is inactive due to a mutated gene; in others, a mutated component can be overactive or underactive, but not absent. If a toxicant interacts with one component and modifies its activity, single-gene mutant studies serve as a guide for the interpretation of how molecular perturbations result in



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