Recommendation 1. To improve the understanding of the mechanisms of action of toxicants, the committee recommends that critical molecular targets of toxicants be identified among the components of developmental processes.

  • In searching for mechanisms of toxicity, it will be important to explore how toxicants perturb evolutionarily conserved molecular targets and pathways of development.

    • Conserved signaling pathways and genetic regulatory circuits as potential targets of toxicants.

    • Molecular-stress and checkpoint pathways as potential targets of toxicants, and

    • Toxicokinetic components, especially drug-metabolizing enzymes.

  • In pursuing mechanisms of toxicity, it is important to explore how molecular perturbations lead to dysmorphogenesis and other adverse outcomes of development in different species.

  • Define the genetic and epigenetic basis of variability in human response to developmental toxicants.

    • Individual toxicokinetic differences, especially in the metabolism and transport of chemicals.

    • Toxicodynamics: individual differences in developmental components.

    • Individual differences in molecular-stress and checkpoint pathways, which normally operate to counteract failure of cell function.

  • In seeking to understand molecular mechanisms of toxicity, it is important to clarify how these approaches and this information can be applied to a comprehensive assessment of human developmental risk.

    • The metabolism of developmental toxicants.

    • Toxicodynamics: toxicant effects on developmental components-information about mechanism and susceptibility.

    • Molecular-stress and checkpoint pathways.

1.1.1. Conserved signaling pathways and genetic regulatory circuits as potential targets of toxicants.

Approximately 10 kinds of signaling pathways are repeatedly used at all times and places of development before cytodifferentiation (i.e., during cleavage, gastrulation, neurulation, and organogenesis). Development is built on coupled signaling and genetic regulation. As differentiated cell function begins during cytodifferentiation, seven other pathways are added. Thus, in the mammalian fetus, all 17 pathways are in use. Almost all activities of cells of multicellular organisms, including all embryonic stages, are contingent on extracellular signals. These activities include secretion, motility, adhesion, proliferation, differ-

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