The role of transgenic mouse models in carcinogen identification.
In this article, we examine existing data on the use of transgenic mouse models for identification of human carcinogens. We focus on the three most extensively studied of these mice, Trp53+/-, Tg/AC, and RasH2, and compare their performance with the traditional 2-year rodent bioassay. Data on 99 chemicals were evaluated. Using the International Agency for Research on Cancer/Report on Carcinogens determinations for the carcinogenicity of these chemicals to humans as the standard for comparison, we evaluated a variety of potential testing strategies ranging from individual transgenic models to combinations of these three models with each other and with traditional rodent assays. The individual transgenic models made the "correct" determinations (positive for carcinogens; negative for noncarcinogens) for 74-81% of the chemicals, with an increase to as much as 83% using combined strategies (e.g., Trp53+/- for genotoxic chemicals and RasH2 for all chemicals). For comparison, identical analysis of chemicals in this data set that were tested in the 2-year, two-species rodent bioassay yielded correct determinations for 69% of the chemicals. However, although the transgenic models had a high percentage of correct determinations, they did miss a number of known or probable human carcinogens, whereas the bioassay missed none of these chemicals. Therefore, we also evaluated mixed strategies using transgenic models and the rat bioassay. These strategies yielded approximately 85% correct determinations, missed no carcinogens, and cut the number of positive determinations for human noncarcinogens in half. Overall, the transgenic models performed well, but important issues of validation and standardization need further attention to permit their regulatory acceptance and use in human risk assessment.
Pritchard
John B
JB
Laboratory of Pharmacology and Chemistry, Environmental Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. pritchard@niehs.nih.gov
French
John E
JE
Davis
Barbara J
BJ
Haseman
Joseph K
JK
D000818:Animals; D001681:Biological Assay / Q000379:methods; D002273:Carcinogens / Q000009:adverse effects*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009152:Mutagenicity Tests; D009369:Neoplasms / Q000139:chemically induced; D012016:Reference Values; D018570:Risk Assessment; D012680:Sensitivity and Specificity
D002273:Carcinogens