Istituto Superiore di Sanita, Environment and Health Department, Viale Regina Elena 299, 00161 Rome, Italy.
Expert Opin Drug Metab Toxicol. 2010 Jul;6(7):809-19. doi: 10.1517/17425255.2010.486400.
Carcinogenicity and mutagenicity are toxicological end points posing considerable concern for human health. Due to the cost in animal lives, time and money, alternative approaches to the rodent bioassay were designed based on: i) identification of mutations and ii) structure-activity relationships.
Evidence on i) and ii) is summarized, covering 4 decades (1971 - 2010).
A comprehensive, state-of-the-art perspective on alternatives to the carcinogenicity bioassay.
Research to develop mutagenicity-based tests to predict carcinogenicity has generated useful results only for a limited area of the chemical space, that is, for the DNA-reactive chemicals (able to induce cancer, together with a wide spectrum of mutations). The most predictive mutagenicity-based assay is the Ames test. For non-DNA-reactive chemicals, that are Ames-negative and mutagenic in other in vitro assays (e.g., clastogenicity), no correlation with carcinogenicity is apparent. The knowledge on DNA reactivity permits the identification of genotoxic carcinogens with the same efficiency of the Ames test. Thus, a chemical mutagenic in Salmonella and/or with structural alerts should be seriously considered as a potential carcinogen. No reliable mutagenicity-based alternative tools are available to assess the risk of non-DNA-reactive chemicals.
致癌性和致突变性是对人类健康构成相当大关注的毒理学终点。由于动物生命、时间和金钱的成本，基于以下两点设计了替代啮齿动物生物测定的方法：i）鉴定突变和 ii）结构-活性关系。
总结了 i）和 ii）的证据，涵盖了 40 年（1971-2010 年）。
对致癌生物测定替代方法的全面、最先进的观点。
开发基于致突变性的测试来预测致癌性的研究仅为化学空间的有限区域产生了有用的结果，即对于 DNA 反应性化学物质（能够诱导癌症以及广泛的突变）。最具预测性的基于致突变性的测定是 Ames 测试。对于非 DNA 反应性化学物质，即 Ames 阴性且在其他体外测定中具有致突变性（例如，致裂原性），与致癌性没有明显相关性。对 DNA 反应性的了解允许用与 Ames 测试相同的效率鉴定遗传毒性致癌剂。因此，在沙门氏菌中具有致突变性和/或具有结构警报的化学物质应被认真视为潜在的致癌物质。目前尚无可靠的基于致突变性的替代工具可用于评估非 DNA 反应性化学物质的风险。
