used in level 3 of the model systems, because test animals can be made more similar to humans in their DMEs and signaling-pathway components, in order to improve the extrapolation from test animals to humans. The rat and mouse genome projects are expected to reach completion not long after the time of completion of the Human Genome Project, and useful information about gene identity, location, and mutants should flow both ways between researchers focusing on humans and those focusing on rodents.
This domain would provide the best information on human exposure to chemicals and on human susceptibility to developmental effects from chemical exposure. Biomarkers of exposure indicate the actual level of a chemical in the individual (e.g., lead concentrations in blood or dentine in children; organophosphate metabolites in urine). Biomarkers of effect allow researchers to examine dose-response relationships at environmentally relevant exposures in humans, and biomarkers of susceptibility allow researchers to identify sensitive subpopulations of humans. Used in combination, such biomarkers are essential for improving human risk assessment. There remains a need to improve biomarkers based on incisive new information about toxicokinetics and toxicodynamics. Thus, a linked database on the Internet for biomarkers of exposure, effect, and susceptibility in humans should be developed.
Advances in DNA microarray technology discussed in information level 1 of the model systems will help immensely in the development of human biomarkers. Eventually, all the gene expression profiles of all organs and embryonic parts at different developmental stages will be catalogued; this will provide the control condition for detecting chemical-induced departures in gene expression. The potential to monitor thousands of gene expression changes simultaneously in regard to dose-response relationships and temporal patterns will provide a critical link of exposure biomarkers with early effect biomarkers. Applications in human birth defects research could be immense. However, the relevant developing databases must be linked so that the numerous changes are connected to functional effects in a developmental framework—that is, a framework organized around the temporal and spatial changes of the embryo and fetus.
Given the sensitivity of reverse transcription polymerase chain reaction (RT-PCR) techniques, small maternal and embryonic or fetal samples could be simultaneously monitored for gene-expression changes. The gene expression changes could serve as biomarkers of effect, and responses in utero could be compared with maternal responses to evaluate differential sensitivity. If successful, the amount of information in such databases will challenge the organizational abilities of scientists. When temporal changes in developmental patterns of gene expression are combined with changes at different doses for thousands of genes, the data set grows to immense size. Obviously, the storage of data in a retrievable