ganisms can be used inexpensively and rapidly. Through straightforward genetic manipulation, they can be sensitized to toxicant effects and provided with reporter genes so that the impacts of chemicals on development can be easily scored. The organisms can be analyzed to define their toxicokinetic and toxicodynamic differences from humans, hence improving extrapolation, and they can be genetically modified to reduce some of the differences. Finally, the suspected genotype-environment source of many human developmental defects can initially be explored in model organisms for which the genotype can be controlled.

At the same time, human individual differences in drug-metabolism components and developmental components are being identified and quantified. As polymorphisms are related to individual susceptibility to toxicants, the difficult domain of human genotype-environment interactions will be entered. The knowledge of human variation will improve quantitative risk assessment.

Charge 4: Develop recommendations for future research in developmental biology and developmental toxicology; focus on those areas most likely to assist in risk assessment for developmental effects.

The committee concludes that recent advances in the fields of developmental biology and genomics provide unprecedented opportunities to understand the molecular mechanisms of action of toxicants, the differences in the developmental responses of test animals and humans to toxicants, the extrapolation of high-dose effects to low-dose effects, and the differences in the individual human susceptibility effects of toxicants on development. These advances can lead to improved animal tests for toxicants, improved extrapolation of animal results to humans, and through the means of better data, improved risk assessment.

A multilevel, multidisciplinary approach to toxicity assessment involves the use of genetically tractable model organisms for which development is well understood and the genome is completely sequenced (or soon will be), namely, C. elegans, Drosophila, zebrafish, and mouse. Because some of these animals are inexpensive to use, testing could be expanded to cover a larger number of chemicals, chemical combinations, and testing conditions, including various genotypic backgrounds of the test organism and scoring of toxic effects at developmental stages before organogenesis. The validity of extrapolation of test results can be tested as well. Risk assessors would benefit, the committee believes, from the use of a variety of toxicity data, combined with human exposure and susceptibility information. The recommendations in the next section are summarized in a text box.

RECOMMENDATIONS

Recommendation 1. To improve the understanding of the mechanisms of action of toxicants, the committee recommends that critical molecular targets of toxicants be identified among the components of developmental processes.



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