sive, and fast developing. Information about their development is abundant, and genetic manipulations are easy. They can be genetically optimized to contain various sensitized signaling pathways and molecular-stress pathways and can often be coupled to reporter genes for enhanced observation of effects. Also, the animals could be genetically modified to reduce their differences from humans in various ways, such as their array of drug-metabolizing enzymes. (The committee acknowledges, however, that unrecognized differences between humans and these test animals may exist and may invalidate comparison. For example, humans and test animals may differ in unknown proteins of trans-epithelial transport of the toxicant or in unknown serum proteins that bind the toxicant. Therefore, validation studies would have to be done with a set of toxicants to establish cross-species concordance.) Assays would be designed for a medium throughput of chemicals, perhaps 103-104 assays per year. Some combinations of chemicals could be tested, and various doses could be examined in some cases to discern low-concentration and threshold effects for specific developmental pathways. The fruit fly and the nematode are currently the most favorable organisms for use. The zebrafish will probably be the most favorable vertebrate for use.
Genetic modifications can include the following:
Sensitization of animals (e.g., individual signaling pathways are made rate-limiting for some aspect of development, such as eye or wing formation in Drosophila, so that a slight increase or decrease in the pathway’s function due to a chemical would give an altered phenotype). The signaling pathways would be those used repeatedly in early development and conserved across many phyla, namely, the RTK, transforming growth factor (TGF) ß, Wnt, Notch, Hedgehog, and nuclear-hormone receptor pathways.
Introduction of various reporter genes to enhance the readout of effects.
Introduction of human signaling components into the animals to reduce the extrapolation.
Introduction of human DME genes into the test organism so that, whenever possible, animals are presented with the same metabolized form of chemicals that humans would produce.
General toxicity caused by a chemical can be distinguished from specific effects on development in the animals by evaluating general lethality, growth, and developmental effects versus specific effects on the particular locally sensitized pathway of development.
An argument against the use of these model organisms is that the amount of information relevant to chemical effects on human organogenesis will be small, because the organs of model organisms, such as the fruit fly and nematode, differ substantially from those of humans. However, it is important to note that the choice of model organisms reflects the new insights about conserved processes of development, and emerging opportunities to directly assay for processes that are