and neutral mutations). Instead, the population sample must be selected on the basis of a shared sequence difference known to result in the altered function of a gene product of suspected relevance to toxicant exposure and susceptibility. Information from model systems (e.g., mice) will be useful to establish altered function and suspected susceptibility.

Toxicant susceptibility genes are not well identified, but the current favorites for attention are those encoding products involved in the toxicokinetic aspects of exogenous chemicals (uptake, distribution, metabolic conversion, and clearance), particularly the DMEs. There are at least one thousand of these gene products, although several dozen probably metabolize 90% of chemicals. Individuals and ethnic groups are already known to have substantial differences in these genes, and a few such polymorphisms are associated with altered developmental toxicity (e.g., a polymorphism in the epoxide hydrolase gene that might result in fetal hydantoin syndrome in susceptible individuals; see Chapter 5 for details). However, most DME polymorphisms have not yet been associated with increased (or decreased) susceptibility to a chemical.

Polymorphisms of genes involved in toxicodynamics need to be investigated. As evident from the extensive discussions of conserved cell signaling pathways and genetic regulatory circuits, the committee suggests that polymorphisms in components of these pathways and circuits be tracked for the following reasons:

  • The pathways and circuits are used widely in embryonic development.

  • Polymorphisms of the genes encoding some components correlate with particular kinds of cancers (e.g., Patched (a component of the Hedgehog pathway) heterozygosity and basal-cell carcinoma; adenomatous polyposis coli (a component of the Wnt pathway) loss and colon carcinoma).

  • A few correlates already exist, such as higher frequency of cleft palate in humans who smoke cigarettes and have TGF variants. Identification of Hox A1 polymorphisms in autistic populations is also progressing, as described in Chapter 4.

Information from level 2 model-system studies and from basic developmental biology on model organisms will become ever more important for human evaluations because many aspects of embryonic development are conserved across phyla. It would be useful for epidemiologists interested in studying developmental defects to interact with their counterparts involved in NCI projects for profiling cancer-susceptibility polymorphisms (several of which concern signaling components). Some information from the epidemiological analysis of polymorphisms might be directly relevant to understanding birth defects that have mainly a genetic rather than a genotype-environment basis.

Information from the database on the human genome and human polymorphisms would benefit risk assessment by providing information on human diversity in relation to sensitivity to potential toxicants. This information would be

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