Department of Cell Biology & Neuroscience, University of California, Riverside, CA 92521, USA.
Crit Rev Toxicol. 2013 Sep;43(8):611-31. doi: 10.3109/10408444.2013.822844.
The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53⁺/⁻, Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program's conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals.
利用基因修饰（GM）小鼠评估致癌性在化学品安全性评价中发挥着越来越重要的作用。虽然在开发和评估 Trp53⁺/⁻、Tg.AC 和 rasH2 等小鼠模型方面已经取得了进展，但这些模型作为传统啮齿动物癌症生物测定的替代品以及评估人类健康风险的适用性仍然不确定。本研究旨在评估使用 GM 小鼠进行加速癌症生物测定，以评估与接触致癌剂相关的潜在健康风险。我们将 GM 生物测定的已发表结果与国家毒理学计划（National Toxicology Program）常规慢性小鼠生物测定的结果进行了比较，以评估其在风险评估中的潜在用途。我们的分析表明，GM 模型在检测致癌剂方面效率较低，但在识别非致癌剂方面更一致。我们确定了与加速生物测定设计相关的几个问题（例如，样本量、研究持续时间、遗传稳定性和可重复性），以及 GM 和非 GM 小鼠中效应的途径依赖性和不同的致癌机制。GM 模型用于剂量反应评估尤其成问题，因为这些模型有时比传统的啮齿动物癌症生物测定更敏感或更不敏感。因此，现有的 GM 小鼠模型可能有助于危害识别，但对于剂量反应评估的用途有限。因此，在使用 GM 小鼠模型评估化学物质的致癌风险时应谨慎。
