Marriage of Surrogate Markers with Medium Term Tests for Carcinogenicity and Modification Potential

Given the immense variety of compounds being developed for introduction into the human environment, reliable medium term alternatives to traditional long term rodent test protocols for carcinogen risk assessment are a high priority. In vivo models are necessary because it has been well established that there is a lack of complete correlation between mutagenicity and carcinogenicity. Optimally, they should be able to detect not only complete carcinogenic or promoting potential, but also any ability to inhibit neoplasia. In order to be effective, they must take into account the detailed available knowledge on mechanisms of action of carcinogens and modulating agents. To allow shortening of the time period, attention must be concentrated on preneoplaqstic lesions and other surrogate For the liver, a uniquely comprehensive set of background data have already been accumulated with the Ito model, for which, has a solid scientific basis, with quantitation of glutathione S transferase positive foci as the preneoplasia-based surrogate endpoint (PSE). A very practical candidate for routine application, its predictive power, flexibility and capacity to incorporate a range of mechanism-based surrogate endpoints (MSEs) can also provide a powerful tool for attainment of the twin goals of detecting carcinogenic agents and identifying promising chemopreventors.