form, as well as analyzing such data, pose serious issues in bioinformatics. Current efforts are ongoing in cancer research to store and retrieve vast amounts of data; however, there is no equivalent example for birth defects and developmental toxicology.

Biomarkers of susceptibility would include polymorphism sequence data for which susceptibility has been correlated with protein function, as in the case of decreased DME activity. The use of data on DME genetic polymorphisms has lagged in carcinogen risk assessment, and in developmental toxicity risk assessment, their use is even more delayed. The committee believes that DME polymorphisms can serve as excellent biomarkers of susceptibility and encourages development of programs to ensure these applications. Biomarkers of toxicodynamic (developmental) susceptibility are less advanced but might include polymorphisms of genes encoding components of signaling pathways, genetic regulatory circuits, or molecular-stress pathways. Biomarkers of effect might include indicators of early activation of molecular-stress pathways or signaling pathway inhibition (e.g., due to exposure of a person to environmental chemicals and pharmaceuticals).

Biomarkers would, in principle, provide risk assessors with better information than that available from the human developmental outcome and human genome database to link human exposure, developmental effect, and heritable susceptibility. To conclude, the benefits of biomarkers for risk assessment include (1) identification of susceptible populations (addressing intraspecies variability); (2) improved dose-response information where subtle changes of biomarkers of effect can be linked with biomarkers of exposure (addressing issues of extrapolation from high to low doses); and (3) improved linkage between biological effects in humans and mechanisms of toxic action as developed from human and animal studies.

Database of Human Gene-Environment Interactions

Similar to level 4 of the model systems, this database would be a domain of research inquiry in a few cases where detailed epidemiological information might yield widespread value, and where assessment of gene-environment interactions in birth defects is feasible given the available resources. Investigative epidemiological inquiries, such as those on endocrine disruptors, methylmercury, lead, and organophosphates, might provide adequately robust data for linkage with adverse birth outcomes. Several of these databases have provided information supporting interesting proposals about genetic polymorphisms (e.g., on lead and organophosphates) or exposure conditions (e.g., on lead and mercury). In contrast to pharmaceuticals, many environmental agents interact with a wide range of targets and with different targets at different doses. Yet, the identification of critical early biological effects that dominate or initiate subsequent disease states is essential for risk assessment. Thus, some of these environmental agents are candi-



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