times and places in an animal’s development, and these same components are used across widely different animal phyla. Species differences of development seem to be largely differences in the combinations and sequences of use of conserved molecular components and differences in the final target genes of the conserved genetic regulatory circuits. The committee believes that the newly accessed level of molecular components and processes of development is the level that will provide incisive understanding of mechanisms of toxicity and improved predictability of toxicant effects. Developmental processes are increasingly understood in terms of the activities and ordered interactions of molecular components. Because of the recent advances in developmental biology and genomics, the committee is optimistic about the ability to improve testing procedures and the interpretation of data in the future.
Recent and ongoing studies of mammalian development have benefitted greatly from the study of nonmammalian model organisms that are genetically tractable and suited for rapid systematic analysis, such as Drosophila and Caenorhabditis elegans. Although not anticipated at the outset, the information from these model organisms proved to be extensively transferable to mammals, because molecular components and many developmental processes are deeply conserved across animal phyla. In particular, development in diverse animals, including mammals, depends on cell-cell signaling at all stages before cytodifferentiation, and this signaling involves repeated use of the same 10 intercellular signaling pathways. (Seven additional conserved pathways are used in the functions of cytodifferentiated cells.) Genetic regulatory circuits, involving certain transcription factors, are also conserved from Drosophila to mammals, as are components of most basic cellular processes, such as the cell cycle, secretion, and motility. The success in using nonmammalian organisms to illuminate mammalian development suggests that the same organisms could be useful in illuminating toxicodynamic mechanisms in mammals and useful in testing certain kinds of toxicants. Based on the past decade of progress in cellular and developmental biology research, it seems likely that this information will be relevant to mammals, including humans.
Charge 3: Evaluate how that information can be used to improve qualitative and quantitative risk assessment for developmental effects.
Throughout its deliberations, the committee kept in mind that the decisions of risk assessors about a chemical’s potential for developmental toxicity are ideally derived from mechanism-based, quantitative data on test animals for which the validity of extrapolation to humans is known. Unfortunately, such data are rarely available. As currently designed, rodent tests for developmental toxicity are limited in their capacity to provide both qualitative and quantitative mechanistic information for human health risk assessment. They are costly in time and resources, and therefore only a small fraction of the more than 80,000 chemicals in commercial use (and the much larger number, about 6 million, of natural prod-