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As part of the regulatory approval process, new drugs have to be tested for their carcinogenic potential. For several decades, the two-year rodent bioassay in rats and mice has been an integral part of safety testing for the carcinogenic potential of pharmaceutical agents. Unfortunately, the two-year conventional rodent bioassay is long, expensive and frequently provides ambiguous results for human risk assessment. These limitations led to the creation of transgenic animal models, which carry genetic constructs specially designed to enhance the detection of carcinogens. The three most widely used strains of transgenic mice are the p53 knockout, the Tg.AC and the Tg.rasH2 mice. The ICH (S1B) and EMEA (CPMP/SWP/2592/02) guidelines state that the carcinogenic potential of pharmaceuticals can be evaluated from data collected from one long-term conventional rat study, as well as from data from one short-term carcinogenicity study using transgenic animals. The US FDA (CAC) recommends the use of the rasH2 mouse for non-dermal, genotoxic or non-genotoxic drugs, the p53 for non-dermal, genotoxic drugs and the Tg.AC for dermal drugs. Validation studies conducted at ITR Canada and in a number of laboratories around the world indicate that these transgenic lines provide a quicker and more cost-effective alternative to the traditional two-year mouse bioassay, in addition to being more susceptible to carcinogens in comparison to wild-type mice. ITR Canada has validated the usefulness of the Tg.rasH2 model as a quicker (capable of detecting carcinogens within six months) and more cost-effective alternative to the conventional two-year mouse bioassay. |
