Pritchard John B, French John E, Davis Barbara J, Haseman Joseph K
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.
Environ Health Perspect. 2003 Apr;111(4):444-54. doi: 10.1289/ehp.5778.
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.
在本文中，我们研究了关于使用转基因小鼠模型鉴定人类致癌物的现有数据。我们重点关注其中研究最为广泛的三种小鼠，即Trp53+/-、Tg/AC和RasH2，并将它们的表现与传统的两年期啮齿动物生物测定法进行比较。对99种化学物质的数据进行了评估。以国际癌症研究机构/致癌物报告中对这些化学物质对人类致癌性的判定作为比较标准，我们评估了从单个转基因模型到这三种模型相互组合以及与传统啮齿动物试验组合的各种潜在测试策略。单个转基因模型对74% - 81%的化学物质做出了“正确”判定（致癌物为阳性；非致癌物为阴性），采用联合策略（例如，对遗传毒性化学物质使用Trp53+/-，对所有化学物质使用RasH2）时，这一比例可提高至83%。相比之下，对在两年期两种物种啮齿动物生物测定中测试的该数据集中的化学物质进行相同分析时，对69%的化学物质做出了正确判定。然而，尽管转基因模型的正确判定比例很高，但它们确实遗漏了一些已知或可能的人类致癌物，而生物测定法没有遗漏这些化学物质中的任何一种。因此，我们还评估了使用转基因模型和大鼠生物测定的混合策略。这些策略的正确判定率约为85%，没有遗漏致癌物，并且将人类非致癌物的阳性判定数量减半。总体而言，转基因模型表现良好，但验证和标准化的重要问题需要进一步关注，以使其能被监管机构接受并用于人类风险评估。
