cally sensitized strain of the test animal can be used to identify genes for new pathway components. Because the sensitization can often be designed to affect the pathway only in a particular tissue, this approach can succeed, even if a pathway is used in many places and many stages of development and null mutations cause phenotypes too pleiotropic to be interpretable.
Such sensitized strains should also be useful for identifying toxicants that modify the activity of a pathway component. Advantages of testing on animals having a tissue-specific sensitized pathway include the following:
The chemical’s effect can be assigned to a pathway without knowing the particular target protein, or even all elements, of the pathway.
Biologically relevant thresholds of effect can be sought, because low doses should suffice.
Phenotypes are more readily and reliably assessed, because they are revealed in a tissue-specific manner.
A variety of sensitized models and other approaches to assaying effects of known and potential developmental toxicants on specific pathways should be possible in the test animals considered here. All the model animal systems provide opportunities for developing methods of toxicity assessment and for investigating toxicological mechanisms (these opportunities are discussed in greater detail in Chapter 8). (Questions will be considered below on extrapolation to humans and the differences between animals and humans in uptake and metabolism of toxicants and in developmental processes.) Although the readouts of the assays involve scoring the development of various invertebrate organs, these readouts are chosen because they are likely to reveal effects of toxicants on conserved signaling pathways, and not because the organs are like mammalian organs. A relevant point is that human polymorphisms of signaling components might sensitize certain individuals to the detrimental effects of environmental agents.
Test animals for which genetic manipulations are difficult are not mentioned in the following section. For example, the FETAX test makes use of the frog Xenopus laevis. Although much has been learned about the development of Xenopus by mRNA injections into the egg, assays of cDNA libraries, and in situ hybridization, the organism is not yet amenable to easy genetic manipulation, and transgenesis procedures are in the early stages of use (Kroll and Amaya 1996). Thus, the committee does not believe that it equals the genetic model organisms for use in sensitive and ultimately informative assays of toxicants.
Advantages of C. elegans include its low maintenance cost in the laboratory and properties mentioned above: its facility of genetic analysis, including rapid