Genetically Modified Models
The conventional rodent bioassay has been used for over three decades and is accorded credibility in identifying carcinogens thought to pose risks for human health. An ongoing goal of the NTP is to seek other model systems for toxicology and carcinogenesis studies, especially those that can provide mechanistic information relative to understanding an agent's mode of action. The use of genetically modified models holds promise for improving both the accuracy and efficacy of experimental assessment of the carcinogenic potential of chemicals. Genetically altered or "transgenic" mouse models carry activated oncogenes or inactivated tumor suppressor genes known to be involved in neoplastic processes both in humans and rodents. This trait may allow them to respond to carcinogens more quickly than conventional rodent strains. In addition, the neoplastic effects of agents can be observed in transgenic models within a time frame in which few, if any, spontaneous tumors would arise. The high incidences of spontaneous or background tumors, which occur most often late in the two-year rodent cancer studies, are among the most confounding factors for interpreting the findings of chemical carcinogenesis and their implications for human health. The use of target or reporter genes also allows for direct molecular and cellular analysis of a chemical's effects in these models and can provide additional mechanistic information about mode of action.
Over the past few years, the NIEHS/NIH and NTP have been actively evaluating transgenic strains in toxicological testing strategies. Based on completed evaluations, two models, the p53 deficient (p53+/- heterozygous) and Tg.AC (v-Ha-ras transgene), have shown potential usefulness in identifying carcinogens and mechanisms of action. Data from studies with these two models were presented to the NTP Board of Scientific Counselors (BSC) for their review and comment together with plans for future NTP studies with genetically manipulated animal models. The BSC recommended continued evaluation of the Tg.AC and p53 deficient models and encouraged the evaluation of new models as they are developed.
Aspartame was one of the test agents selected for the continued evaluation of the genetically manipulated mouse strains, Tg.AC, and p53 and for initial evaluations of the p16model. Aspartame has been evaluated in conventional rodent cancer studies (non NTP studies) and is considered negative. However, it has been argued that the studies showed a slight increase in brain tumors. Therefore, it was of interest to evaluate aspartame in the p16 model which has been proposed to be susceptible to glial cell tumors of the brain. Learn more about the NTP studies of Aspartame.
