mother (or child, fetus, or embryo)—keeping in mind the range of drug doses that might have been given.

During the next decade, dozens more of the DME genes (alone and in combination) are likely to be expressed in the human B-lymphoblastoid cell lines or in other similar stably transfected cell backgrounds to determine which enzymes are responsible for either detoxification or metabolic potentiation of a particular drug under study. This information will be useful in the future of developmental pharmacology and toxicology, as well as molecular epidemiology.

SUMMARY

The committee has evaluated the state of the science for elucidating mechanisms of developmental toxicity and concludes that such elucidation, although not yet realized, can be achieved in the next decade for the following simple reasons:

  1. Developmental biology has reached the molecular level of mechanistic explanations.

  2. The accumulation of new and relevant information about vertebrate development is rapid (assisted greatly by research on model organisms, such as Drosophila and C. elegans).

  3. The accumulation of genome sequence data for humans, mouse, rat, and Drosophila is rapid, adding to that already available for C. elegans, yeast, and many prokaryotes. Information on human polymorphisms and rare variants and their disease relatedness is increasing rapidly, as are data on the ever-increasing library of mouse mutants.

  4. The methods are powerful and widely applicable, and the species barriers to comparative study have been greatly reduced in the past few years.

The committee begins in this chapter, and continues in the next, the third charge to evaluate how this information can be used to improve qualitative and quantitative risk assessment. In this chapter, the committee summarizes some of the techniques for modifying model organisms, including the mouse, for effective use in assays evaluating agents for potential developmental toxicity and for elucidating mechanisms of toxicity. The committee concludes that the methods and background knowledge are at hand to make incisive comparisons of humans and model animals so that the extrapolation of results from model animals to humans can be more accurate and useful for risk assessment.



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