example, if a chemical (parent compound or metabolite) shows toxicity in a mammalian test, with hints of interference with a particular cell signaling pathway, the next step might be to analyze the mechanism of toxicity in a genetically sensitized invertebrate model system specifically designed to evaluate that cell signaling pathway. Likewise, observations from receptor-binding assays might prompt a re-examination of the overall impacts of a compound on organ development in a mammal. Thus, assessments are anticipated to have implications for analyses in both directions in the information levels. As new scientific observations are made, this approach allows the incorporation of new data into the risk-assessment framework.

Ultimately, risk assessment has much to gain from the multidirectional flow of information across these information levels. In Figure 3-1, the committee introduced two-way arrows to indicate the importance of the responsiveness of the whole process to issues and ideas raised not only by science but also by risk-assessment needs. In light of the gaps in knowledge of toxicant effects, risk assessment is most likely to improve when research and risk assessment reinforce each other. Understanding mechanisms of toxicity can then be useful for predicting which other potential toxicants might act by the same mechanism, improving the ability to develop structure-activity relationships. Understanding the basis for extrapolations between test animals or in vitro assays and humans will give risk assessment greater validity. An iterative and interactive process for risk assessment was first defined in the National Research Council (NRC) report Science and Judgment (1994). However, such a process has yet to be fully implemented in risk assessment for developmental toxicology.

Table 8-1 summarizes the committee’s multilevel approach. There are two components, each with four sources of information: (A) assessment in model systems of toxicity and mechanism of action of developmental toxicants (Table 8-1A), and (B) assessment in human populations of toxicity, susceptibility, and exposure to toxicants (Table 8-1B). The left column in both tables lists for each information level the experimental description of the tests, the application of the tests, the number of tests that can be done per year, and the value of the test information for risk assessment.

Toxicity Assessment in Model Systems

Information levels 1 and 2 of model systems in Table 8-1A generally involve relatively inexpensive and fast characterizations of chemicals and developmental effects. They should provide valuable information about which developmental pathways (signaling pathways and transcriptional regulatory circuits) are affected by which toxicants. Although extrapolations to human risk would be very limited without additional toxicokinetic and toxicodynamic information, the testing capacity should be available to characterize a large number of chemicals, and indeed, most of the several million chemicals in the environment, including chemi-



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