Defining the molecular and cellular basis of toxicity using comparative models.

A critical element of any experimental design is the selection of the model that will be used to test the hypothesis. As Claude Bernard proposed over 100 years ago "the solution of a physiological or pathological problem often depends solely on the appropriate choice of the animal for the experiment so as to make the result clear and searching." Likewise, the Danish physiologist August Krogh in 1929 wrote that "For a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied." This scientific principle has been validated repeatedly in the intervening years as investigators have described unique models that exploit natural differences in chemical and molecular structure, biochemical function, or physiological response between different cells, tissues, and organisms to address specific hypotheses. Despite the power of this comparative approach, investigators have generally been reluctant to utilize nonmammalian or nonclassical experimental models to address questions of human biology. The perception has been that studies in relatively simple or evolutionarily ancient organisms would provide little insight into "complex" human biology. This perception, although always somewhat misguided, is now even less tenable given the results of the genome sequencing projects, which demonstrate that the human genome is remarkably similar to that of evolutionarily ancient organisms. Thus, the various life forms on Earth share much more in common then anyone had previously envisioned. This realization provides additional rationale for the use of nonclassical experimental models and provides perhaps the strongest validation of Bernard's and Krogh's assertions. This overview emphasizes some of the special attributes of alternative animal models that may be exploited to define the molecular and cellular basis of toxicity. For each attribute, selected examples of animal models and experimental approaches are presented. It focuses on the areas of neurotoxicology, reproductive and developmental toxicology, organ systems toxicology, carcinogenesis, and functional genomics/toxicogenomics and highlights the use of fish, avian, Drosophila, Caenorhabditis elegans, and yeast models in such studies.