Analyses of human and model animal gene sequences will increase the understanding of gene function and gene expression. For example, methods are available that can be used to determine the changes in gene expression in embryos following exposure to toxicants and to allow for assessment of the consequences of such changes for development within a species and among various species.
Charge 3: Evaluate How Recent Advances in Developmental Biology and Genomics Can Be Used to Improve Qualitative and Quantitative Risk Assessment for Developmental Effects. The committee concludes that the major recent advances in developmental biology and genomics can be used to improve qualitative and quantitative risk assessments by integrating toxicological and mechanistic data on a variety of model test animals with data on human variability in genes encoding components of developmental processes, genes encoding enzymes involved in the metabolism of chemicals, and genes encoding receptors and transporter proteins that move these chemicals and their metabolites in and out of the cell.
For example, as described in Chapter 7 of this report, chemicals could be evaluated for their potential to alter signaling pathways central to normal development by using nonmammalian model animal systems, such as the fruit fly, roundworm, and zebrafish. Those systems are inexpensive, and the assays can be performed rapidly; therefore, large numbers of chemicals, chemical mixtures, and testing conditions could be evaluated for impacts on these key developmental processes. Such mechanistic information from those systems could be used to improve the identification of potential mammalian hazards, because molecular components and processes of development are well understood in those model animals and because the conservation of signaling pathway components is pervasive and extends to humans. The nonmammalian systems, and the laboratory mouse, can be genetically modified to facilitate the identification of vulnerable developmental pathways, target organs, and times of susceptibility during development.
In addition, the model animals can be assessed to define their differences from humans in toxicokinetic and toxicodynamic properties. They also can be genetically modified to contain human metabolism genes, which will reduce the toxicokinetic differences between experimental animals and humans. Such information could be used to improve extrapolation of toxicological data from model animals to humans.
Individual human susceptibility to toxicants and genotype-environment interactions could be explored using sequence information from genes encoding DMEs and molecular components, such as components of signaling pathways, involved in development. This information would improve the understanding of human variability in metabolism and the identification of genes encoding molecular components that might be particularly susceptible to chemicals during development.