Focus On: Genetically Altered Mouse Cancer Models Testing Compounds in Genetically Altered Mice

ABSTRAC~ National Institute of Environmental Health Sciences researchers are exploring the utility of genetically altered mice to study mechanisms of carcinogenesis. Two of these mouse models, the Tg.AC (carrier of an activated mouse H-ms oncogene) and the p53+ (heterozygous for the wild-type tumor suppressor gene Trp53), have genetic alterations that appear to hasten their expression of chemically induced tumors. These 2 models have been proposed as a basis for new strategies for identifying chemical carcinogens and for assessing risk. The National Toxicology Program (NTP) is conducting a series of studies with these 2 genetically altered strains to further examine their strengths and weaknesses for identification of documented rodent and human carcinogens. In this first evaluation, candidates for study were drawn from the NTP historical database of 2-yr rodent carcinogenicity studies and the open literature (primarily for drugs). Results with this first set of 11 chemicals tested in genetically altered mice, compared with previous findings in the traditional 2-yr rodent assays and literature on human tumor findings, appear to support the premise advanced by Tennant et a1 that these models have the potential to serve as more rapid and less expensive test systems to identify carcinogens. INTRODUCTION Regulatory agencies evaluate all available toxicity and carcinogenicity data on specific chemicals or drugs to establish potential human risk through their use or their exposure. Two sources of the more critical data are human epidemiological studies and long-term rodent bio-assays. The most directly relevant data come from epidemiology studies, because they associate human health effects with environmental conditions. When a single environmental agent can be shown to be directly related to a specific health problem in an exposed population, the risk to humans for that agent is clear. Two fundamental limitations of epidemiology are that 1) it is difficult to relate a health problem to 1 environmental agent, since most exposures are poorly characterized and are mixtures of agents and that 2) there is an inherently low power to detect an effect. In addition, these studies are retrospective evaluations of hazards that may have already adversely impacted public health (1).