Evaluation of Selected Transgenic Mouse Models as Altern

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We are bringing to culmination several years effort to develop and evaluate alternative short-term models for identifying potential environmental carcinogens based upon the use of genetically modified mouse lines. The hypothesis underlying this work was that introduction or alteration of selected genes known to be involved in critical pathways of tumorigenicity could result in a truncation of the neoplastic process when such animals were exposed to chemicals. The principle models focus upon in this laboratory were the p53 deficient line and a v-Ha-ras zetaglobin promoted line (Tg.AC). The results of work published from our studies have helped to catalyze an international effort to evaluate these and other short-term models that was organized by the International Life Sciences Institute and involved over 50 organizations representing private sector pharmaceutical and chemical companies, and government research and regulatory agencies. The culmination of this project has verified the value of selected transgenic models and has resulted in the implementation of the use of the models, particularly within the US pharmaceutical industry under the guidance of the Food and Drug Administration. In addition, we have proposed a strategy through which transgenic models could be implemented in conventional carcinogenicity studies during the subchronic toxicological characterization of chemicals that would result in informative data being available that could preclude the necessity to conduct a long-term two year bioassay or to be able to modify the conduct of long-term studies. This would result in reducing costs, decreasing the time in which the chemical is characterized and in reducing the number of animals necessary to characterize the toxicologic in carcinogenic properties of chemicals.