cals from natural products such as plants, have never been characterized for developmental toxicity. (It must be noted, however, that the EDSP plans to test 87,000 chemicals.) Of course, it will take years to develop, standardize, and validate these assays; however, the potential utility in screening with validated tests is high and justifies the effort. At information levels 3 and 4, the cost is higher and the test times are longer, but extrapolation to human risk potential can be more direct.
Information levels 1 and 2 make use of model systems of far less complexity than humans. The results from these specialized cell assays and model organisms would be useful to organize chemicals according to their effects (e.g., to reveal chemicals that bind to the same protein—e.g., a nuclear-hormone receptor—or interfere with the same conserved cell signaling pathway). Assays in information levels 3 and 4 are likely to improve in their relevance to humans in the near future as differences between rodents and humans are better understood and as genetically modified model animals become available. These models will more closely resemble humans with respect to toxicant uptake, metabolism, and developmental response.
The information level approach integrates risk assessment information from a variety of sources, both model systems and humans, and incorporates steadily improving methods into these sources of information. The recent advances in developmental biology that reveal the conservation of cell signaling pathways and genetic regulatory circuits across species, even phyla, gives a new demonstration to the toxicological principle that chemical impacts in humans can be predicted from animal systems. Further research will clarify the similarities and differences between model animals and humans and will improve the ability to extrapolate risk across species.
How the test results will inform risk assessment will depend in part on the questions asked. The bottom row of Table 8-1A describes the information available to risk assessment from each assay type. Until scientists gain a better understanding of embryonic development and the mechanisms of toxicity, especially the effects of chemicals on the highly conserved signaling pathways, the approach in risk assessment should be to use combined information about predicted chemical activity, bioassays on model animals, and identification of individuals with susceptible genotypes to predict potential risk for developmental defects in humans. For example, knowing that a chemical disrupts the activity of a component of the Hedgehog signaling pathway in a high-throughput cell assay (a level 1 result) has limited value for direct human risk assessment. However, from level 1, it might be useful to know that four structurally related compounds all cause inhibition of a specific kinase involved in the phosphorylation of an intermediate of the Hedgehog pathway but with widely varying potency. If the most potent compound is the one proposed for widespread use and release into the environment, the level 1 information would prioritize testing of that compound for effects in mammals in vivo. Thus, information on molecular and biochemical ac-