present in the heterozygous condition, the animal is usually viable and apparently normal, although sometimes with minor developmental defects. These animals could be tested for toxicant sensitivity, to see if the genetic background biases certain outcomes. In general, the connection made between mutational alterations in developmental components and chemical induced developmental defects should be strong.

A further determination to be made is how much of the apparent specificity of the outcome of a toxicant-induced developmental defect is due to the specificity of the toxicant and how much is due to the particular genetic background of the exposed animal. This determination should be applied especially to broad-acting toxicants (e.g., ones causing widespread cell death). In model animals, such as Drosophila, C. elegans, or the mouse, various genetic constructs that are sensitized in various ways (e.g., a slightly reduced Hedgehog pathway or a slightly reduced TGF pathway) could be exposed to the same toxicants to see how the outcomes differ. Already there are human toxicant-induced differences in profiles of birth outcomes in Tp53 (-/-) knockout mice that vary with genetic background. The full implication of these observations has not yet been exploited for assessing developmental toxicants.

Ultimately, it is not known how similar a group of animals can ever be in individual responses to toxicants. In the standard rodent tests for toxicants the response of a group of animals exposed to a single intermediate dose is heterogeneous. The developmental outcome is affected in some animals and not affected at all in others. How much of the heterogeneity is genetic and how much is “epigenetic” (i.e., associated with variable histories of nutrition, disease, stress, or other chemical exposures) is an important issue. Conventional inbred strains, which are more than 98% genetically identical after 20 generations of inbreeding, are a valuable and easily available resource for studying epigenetic contributions.

1.3.3. Individual differences in molecular-stress and checkpoint pathways, which normally operate to counteract failure of cell function.

These components are part of the organism’s line of defense and might be activated by broad-specificity toxicants. The extent to which individual humans differ in their molecular-stress and checkpoint pathway components and, hence, in their responses to environmental chemicals, is unknown. These pathways are known to have important roles in other organisms and to be conserved across phyla. Individual differences in these pathways among humans should be explored. Model animals should be prepared with mutated components of these pathways in order to determine whether their sensitivity to toxicants is increased or decreased. Mouse and Drosophila mutants are already available.

1.4. In seeking to understand molecular mechanisms of toxicity, it is important to clarify how the approaches and information can be applied to a comprehensive assessment of human developmental risk.



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