Department of Pharmacy (Faculty of Sciences), Department of Toxicology (Faculty of Medicine), Universidad Nacional de Colombia, Bogotá, D.C., Colombia; Laboratory of Neuropeptides, Institute of Pharmaceutical Research, Faculty of Pharmacy, Universidad Central de Venezuela, Caracas, Venezuela.
Department of Animal Health, Faculty of Veterinary Medicine and Zootechnics, Universidad Nacional de Colombia, Bogotá, D.C., Colombia.
J Pharmacol Toxicol Methods. 2021 Jul-Aug;110:107070. doi: 10.1016/j.vascn.2021.107070. Epub 2021 Apr 25.
For several intended uses of chemicals, the 2-year rodent bioassay (RCB) has been the benchmark method to screen the carcinogenicity to humans of substances, according to the hazard identification sphere. Despite the ongoing controversy around this traditional testing, the RCB is in force and being used by stakeholders. After assembling the RCB's ability to forecast the carcinogenicity to humans of substances, the current review aimed to provide a discussion on the RCB's (1) sensitivity and specificity; (2) utility; (3) configuration, and (4) provisional role in the regulatory policy. In general, RCBs conducted at maximum tolerated doses (MTDs) exhibited a functional ability to (1) not missing the great majority of human carcinogens, and to (2) not responding to the large majority of human non-carcinogens. There is citable evidence supporting the use of MTDs to render RCBs as sensitive as possible, particularly provided the ethically-justified small samples used in RCBs. The literature shows that rodent-specific mechanisms of chemical carcinogenesis contribute significant unspecificity to RCBs. Nonetheless, the paradox between a functional sensitivity and a significant unspecificity can be predictively resolved through the application of Bayesian forecasting. In terms of performance to forecast the carcinogenicity to humans of either genotoxic or non-genotoxic substances, 2-species-RCBs added no value over the rat-RCB. Nevertheless, there is preliminary evidence cautioning that 15% of the rodent carcinogens probably carcinogenic to humans could be missed if mouse-RCBs are indiscriminately discontinued. More than thirteen RCB-related issues relevant to regulatory pharmacology and toxicology were discussed and summarized in this review.
对于化学物质的若干预期用途，根据危害识别领域，为期两年的啮齿动物生物测定（RCB）一直是筛选物质对人类致癌性的基准方法。尽管围绕这种传统测试存在持续争议，但 RCB 仍然有效，并被利益相关者使用。在评估 RCB 预测物质对人类致癌性的能力后，本综述旨在讨论 RCB 的（1）敏感性和特异性；（2）实用性；（3）配置；以及（4）在监管政策中的临时作用。一般来说，在最大耐受剂量（MTD）下进行的 RCB 表现出以下功能能力：（1）不会错过大多数人类致癌物，并且（2）不会对大多数人类非致癌物产生反应。有可引用的证据支持使用 MTD 使 RCB 尽可能敏感，特别是考虑到 RCB 中使用的合乎道德规范的小样本。文献表明，化学致癌作用的啮齿动物特异性机制使 RCB 具有显著的非特异性。尽管如此，功能敏感性和显著非特异性之间的悖论可以通过贝叶斯预测的应用来预测解决。就预测遗传毒性或非遗传毒性物质对人类的致癌性而言，2 种物种 RCB 并没有比大鼠 RCB 增加任何价值。然而，有初步证据警告说，如果老鼠 RCB 被不加区分地停止使用，可能会错过 15%的对人类可能致癌的啮齿动物致癌物。本综述讨论并总结了与监管药理学和毒理学相关的超过 13 个 RCB 相关问题。
