dysmorphogenesis and other adverse outcomes. The phenotypes for the large variety of mouse null mutants, prepared by targeted gene disruption, are a resource for such analysis. Many of these show well-defined developmental defects at birth, or prenatal death at various stages.

If a toxicant affects several developmental components, the mutant comparisons are not as good as those of one component, although some multiple mutations have been prepared. If a toxicant affects cellular activities, setting off molecular-stress and checkpoint pathways, and causes cell death, comparison mutants could be generated and analyzed to understand the consequences for development.

The committee recommends basic research on toxicant-affected developmental processes in well-understood model organisms. Drosophila mutants can be prepared with a chosen sensitized signaling pathway in a chosen kind of organogenesis, such as the wing or compound eye. In such animals, the effects of toxicants can be most favorably associated with specific processes of organogenesis.

1.3. The committee recommends research to define the genetic and epigenetic basis of variability in human response to developmental toxicants.

Variability is a large problem, covering a variety of issues. It is apparent even in the heterogeneous developmental response of individuals in a group of inbred test animals (rodents) exposed to a toxicant under controlled conditions. Two approaches to address this large problem might be useful: (1) a human epidemiological approach making use of genome information, and (2) a model animal research approach making use of new molecular biological techniques and insights to learn about the sources of variability. The following aspects of individual variability in response to developmental toxicants deserve study:

1.3.1. Individual toxicokinetic differences, especially in the metabolism and transport of chemicals.

Human individuals are known to differ substantially in their levels of DMEs of both the P450 oxidative group and the group of conjugating enzymes. For example, differences are found in ethnic groups from different parts of the world and in individuals with varied lifestyles (smoking and alcohol intake) and nutrition. These differences are being explored rapidly, and data indicate that, in cases of genetic variability, the genes encoding these enzymes might be unusually polymorphic compared with other kinds of genes. In current research, which this committee favors, the differences are being defined in terms of base sequence, protein function (e.g., loss of function, reduction of function, increase of function, and change of function), and the basis for the change (e.g., altered time and place of expression and altered catalytic activity). Differences in metabolism of chemicals by individuals with different gene combinations are also being analyzed, because some allele combinations are strongly synergistic. Current genetic, epidemiological, and genome data can greatly assist in identifying human

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