for which widespread environmental exposure is anticipated or is occurring. Presumably, this information would feed back into improvements of the level 1, 2, and 3 assays and would provide valuable input for the chemical databases. The animals used in these studies would probably be mammals, especially genetically optimized rodents.
The committee recognizes that the action of some toxicants might fall outside the realm of current understanding of development (i.e., of areas emphasized in this report). Studies of such mechanisms would necessarily fall into level 4 assays (i.e., basic research). Two approaches of note are (1) DNA microarray surveys of changes in gene expression of cells or test organisms treated with potential toxicants, which then require the researcher to interpret the changes and substantiate the interpretation; and (2) phage display methods to screen and isolate cellular proteins that bind particular toxicants, which then require the researcher to identify the role of the protein in the cell and its relevance to a toxicity mechanism.
The committee believes that the quality and the accessibility of human epidemiological information need re-examination, in light of its present and increasing relevance for developmental toxicity risk assessment. The committee considered ways to link data from human surveillance studies with data from in vitro studies and in vivo animal studies and discussed how new biomarkers of exposure and susceptibility in humans could be linked more effectively with new biomarkers of effect, in order to improve the assessment of human risk for developmental toxicity. The committee defined four informational databases as domains of information about humans. These databases were not referred to as “levels,” because they provide different kinds of information and cannot be ranked, as the model systems can, by remoteness or immediacy of human relevance. All the databases contain information of use to risk assessors.
This database is the domain of information from epidemiology and surveillance. The quality of various case reports of birth defects and possible toxicant exposure varies widely. Many are incomplete and of unknown accuracy. However, most known human developmental toxicants were first identified by case reports, including thalidomide, diphenylhydantoin, diethylstilbestrol (DES), and valproic acid. At the outset, case report information is of unknown value to risk assessment and cannot be used without extensive follow-up, a situation similar to information from the level 1 assays of the model systems. When correlations are strong enough or the developmental effects are incontrovertible, the prospective