parison will be accelerated by the availability of mouse and human genome data. Proteins involved in chemical uptake across the gut, distribution in the fluid space, multidrug transport of chemicals in and out of cells, and excretion from the body are less well known and should also be characterized and compared.

Moreover, once the differences are recognized, test animals such as mice can perhaps be modified genetically to reduce their differences from humans. Thus, cross-species extrapolations could be improved in this respect. It may not be feasible to eliminate all toxicokinetic differences between the mouse and human, however, the differences will be better known with such approaches when extrapolations are invoked.

In level 2 assays involving nonmammalian organisms, such as Drosophila, C. elegans, and zebrafish, it is also important to know the differences between humans and rodents in terms of drug metabolism to increase the accuracy of extrapolations to mammals. Transgenesis and mutagenesis can be done at high frequency in these animals to make them less different from mammals in their drug metabolism.

2.4. Quantitative risk assessment: toxicodynamic differences of test animals and humans should be characterized to improve extrapolations.

The differences in development of various organisms mostly reflect differences in the time, place, order, and combinations of use of conserved developmental components, such as those of the signaling pathways and genetic regulatory circuits. The committee’s recommendation to make more use of nonmammalian model animals in developmental toxicology is based on the recognition of the conservation, although with the caveat that the scoring of toxicant effects is done in these animals at the molecular level of conserved components, and not at the diversified tissue and organ levels, which are obviously not conserved across phyla.

The extent to which developmental components of different animals differ in their interactions with toxicants is not known. Some components can be exchanged between flies and mice without loss of function, but most have not been tested for interchangeability. Vertebrates also have large genomes containing two or more duplicated and slightly diversified genes for many components for which nonvertebrates have a single gene. These diversified components might differ in their toxicant interactions. The recognition of differences will be aided by the genome databases and by further genetic substitutions in test animals. Once toxicokinetic differences are minimized between mice and humans, modified mice should be tested with a battery of toxicants known to affect humans in order to make sure that equivalent developmental outcomes are obtained. If equivalent outcomes are not obtained, the difference is grounds for further analysis of toxicodynamic comparisons.

Current research in developmental biology, which includes mouse development as the exemplar of mammalian development, will increasingly use compari-



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement