The role of transgenic mouse models in carcinogen identification.

Abstract

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.

Biological, cellular, and molecular characteristics of an inducible transgenic skin tumor model: a review

“…With the ILSI initiative and individual lab testing, a wide variety of chemicals have been tested on Tg.AC mice in an effort to validate the model Spalding et al, 1999Spalding et al, , 2000. An extensive analysis of those chemical tests has recently been performed (reviewed in Pritchard et al, 2003;Sistare et al, 2002) and a compilation of tests and references can be found on the Tg.AC website at http://dir.niehs.nih.gov/dirlecm/TgAC/TgAC_Home.htm. The data from these studies show that a variety of chemical carcinogens can generate a tumorigenic response in Tg.AC mice, including both genotoxic and nongenotoxic carcinogens.…”

Induction of mesothelioma in p53+/- mouse by intraperitoneal application of multi-wall carbon nanotube

“…Here, we adopted a short-term bioassay, i.e., the p53 heterozygous mouse intraperitoneal exposure model reported to be sensitive to asbestos and develop mesotheliomas fast (Marsella et al, 1997;Vaslet et al, 2002). This mouse model has been reported to be sensitive not only to genotoxic carcinogens (Pritchard et al, 2003) but also to reactive oxygen species (ROS)-related carcinogenesis (Tazawa et al, 2007) and therefore fits with the postulated carcinogenesis mechanisms of asbestos and asbestos-like particles (Marsella et al, 1997;Vaslet et al, 2002).…”

Mechanisms of SEPA 0009-Induced Tumorigenesis in v-rasHa Transgenic Tg.AC Mice

“…The Tg.AC mouse has been proposed to be a good predictor of human carcinogens applied topically and responds with sensitivity to both mutagenic and nonmutagenic carcinogens (Spalding et al, 1993;Pritchard et al, 2003). However, the sensitivity of this model to wounding and chronic irritation may also be its greatest weakness.…”