ways for oxidative stress, protein unfolding, and checkpoints (including those involving p21 or p53) have been used for developmental toxicity assessment (Wilson et al. 1999; Wubah et al 1997). Test animals might express a reporter gene in response to a chemical without suffering overt developmental damage. This result could be taken as an indicator of the need to retest the chemical at other doses and times, or in combinations with certain other chemicals, for synergistic detrimental effects. Mouse strains are available with sensitized signaling pathways (see Tables 6-4 and 6-5 on targeted disruption of genes encoding signaling components) in which null alleles are used in heterozygous or homozygous states and in various combinations. Animals could also be made to possess a variety of reporter genes by which the responses through specific signaling pathways could be assessed easily. Similar programs are already under way with sensitized mice for carcinogen assays (Eastin et al. 1998). Until recently, the lack of pathways with clearly identified developmental relevance has limited similar programs for developmental toxicity assessment.
Level 3 assessments provide the highest level of information routinely available to a regulatory agency for evaluation of risk—that is, information requiring the least default correction for estimating human risk, although some default corrections are still likely to be needed. The new information on development and genomics implies that different genetically modified mammals would be optimal for testing different chemicals. The choices could be guided by the results of levels 1 and 2 tests. The following kinds of information available from mammalian systems would include
structure-activity information, with activity carried to the level of effects on mammalian organogenesis,
relative in vivo potency information,
some information about activity of chemical mixtures,
mechanistic information from sensitized animals, and
quantitative information on shape of dose-response relationships in in vivo organ systems.
Perhaps only 10 chemicals per year can be studied at this level. Those studied should be those for which further research would give important information about (1) chemical effects on development, (2) basic mechanisms of developmental toxicity, and (3) significant clues for human risk assessment (e.g., analyzing differences between test animals and humans). Such chemicals might be prototype members of families of chemicals for which other derivatives would deserve testing at lower levels for relative toxicity, where mechanisms of action can be elucidated or where the effects are difficult to score, as in behavioral and other functional assessments. These chemicals might also represent compounds