ucts) have been tested. Chemicals are usually assessed for effects on growth, morphology, and viability of the newborn rodent but not for functional (e.g., behavioral), molecular (e.g., toxicant metabolism or transcriptional changes), or cellular (e.g., mitosis defects and apoptosis) effects. Because the validity of extrapolation from animal results to humans is often assumed, as is the relevance of some of the animal exposure conditions, risk assessment often includes large default corrections in the extrapolation to “safe” human exposure concentrations.

To improve qualitative risk assessment, a better understanding of the mechanisms of toxicity of a reference set of compounds would provide predictions for related, but less well-tested, compounds. Toxicity information on a wider range of compounds would also help qualitatively. Results from current developmental toxicity assessments reveal both qualitative and quantitative differences in animal responses to toxicants. A complete understanding of these species differences is not known, particularly, the proportion of these differences that is due to toxicokinetic versus toxicodynamic differences. Thus, to improve quantitative risk assessment, a better understanding of the differences and similarities between test animals and humans with regard to toxicokinetics and toxicodynamics would allow better extrapolations to be made. Use of default corrections could be limited or be made on the basis of knowledge rather than assumptions. An understanding of genetic differences (polymorphisms) among test animals, and a deliberate effort to control the differences, would reduce and rationalize the wide range of responses of test animals to a toxicant. An understanding of human polymorphisms of molecular components of toxicokinetic and toxicodynamic importance would allow better estimation of safe exposures of individuals over the whole range of human susceptibility to a toxicant. Finally, an understanding of toxicity mechanisms, including toxicant effects on cell division and cell function, as reflected in molecular-stress and cell-cycle checkpoint pathways, and an understanding of the polymorphisms of toxicokinetic and toxicodynamic components, would allow better estimation of low-dose exposure effects, as extrapolated from high-dose results. The committee believes that the possibilities for improvements in data for risk assessment are great.

To date, little of the new information has been brought to bear on the tests and interpretations needed for qualitative and quantitative risk assessment, simply because the problems are difficult and it takes time and resources to do so. The committee believes the new information can be incorporated extensively in the next decade.

Because molecular components and processes of development are best understood in genetically modifiable model organisms, such as Drosophila, C. elegans, the zebrafish, and the mouse, and because the conservation of components is so pervasive that it extends to humans, the committee recommends that these organisms be used more effectively for analyzing mechanisms of developmental toxicity at the molecular level and for assaying the developmental toxicity of the numerous never-tested chemicals and chemical combinations. These or-



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