Boobis Alan R, Cohen Samuel M, Doerrer Nancy G, Galloway Sheila M, Haley Patrick J, Hard Gordon C, Hess Frederick G, Macdonald James S, Thibault Stéphane, Wolf Douglas C, Wright Jayne
Imperial College London, London, United Kingdom.
Toxicol Pathol. 2009 Oct;37(6):714-32. doi: 10.1177/0192623309343779. Epub 2009 Aug 21.
The two-year cancer bioassay in rodents remains the primary testing strategy for in-life screening of compounds that might pose a potential cancer hazard. Yet experimental evidence shows that cancer is often secondary to a biological precursor effect, the mode of action is sometimes not relevant to humans, and key events leading to cancer in rodents from nongenotoxic agents usually occur well before tumorigenesis and at the same or lower doses than those producing tumors. The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) hypothesized that the signals of importance for human cancer hazard identification can be detected in shorter-term studies. Using the National Toxicology Program (NTP) database, a retrospective analysis was conducted on sixteen chemicals with liver, lung, or kidney tumors in two-year rodent cancer bioassays, and for which short-term data were also available. For nongenotoxic compounds, results showed that cellular changes indicative of a tumorigenic endpoint can be identified for many, but not all, of the chemicals producing tumors in two-year studies after thirteen weeks utilizing conventional endpoints. Additional endpoints are needed to identify some signals not detected with routine evaluation. This effort defined critical questions that should be explored to improve the predictivity of human carcinogenic risk.
啮齿动物的两年期癌症生物测定法仍然是对可能构成潜在癌症危害的化合物进行活体筛查的主要测试策略。然而，实验证据表明，癌症往往继发于生物前体效应，其作用模式有时与人类无关，并且非遗传毒性剂导致啮齿动物患癌的关键事件通常在肿瘤发生之前很久就已发生，且发生剂量与产生肿瘤的剂量相同或更低。国际生命科学研究所（ILSI）健康与环境科学研究所（HESI）推测，在短期研究中可以检测到对识别人类癌症危害具有重要意义的信号。利用国家毒理学计划（NTP）数据库，对在两年期啮齿动物癌症生物测定中出现肝脏、肺部或肾脏肿瘤且也有短期数据的16种化学物质进行了回顾性分析。对于非遗传毒性化合物，结果表明，在利用常规终点进行13周的研究后，对于两年期研究中产生肿瘤的许多（但并非全部）化学物质，可以识别出指示致癌终点的细胞变化。需要额外的终点来识别一些常规评估未检测到的信号。这项工作确定了为提高人类致癌风险预测能力而应探索的关键问题。
