Ashby J, Paton D
ICI Central Toxicological Laboratory, Macclesfield, Ches., UK.
Mutat Res. 1993 Mar;286(1):3-74. doi: 10.1016/0027-5107(93)90003-x.
Gold and her colleagues have tabulated the results of rodent bioassays on 522 chemicals and have analysed the data. The present study complements those analyses by providing a perspective from the viewpoint of the chemical structure of the carcinogens. The chemical structure of each of the carcinogens is displayed and the Gold database is represented with the test agents as the primary variable. The carcinogens are gathered into six chemical classes and each chemical is assessed for structural alerts to DNA reactivity. The database is then analysed using an integration of the following parameters: bioassay in rat, mouse or both; structural alert status; chemical class; sites and multiplicity of carcinogenesis, and trans-species carcinogenicity. A series of Figures is presented that enables rapid acquaintance with what represents the core database of rodent carcinogenicity. The several analyses presented combine in endorsing the reality of two broad classes of rodent carcinogen--presumed DNA-reactive and others (putative genotoxic and non-genotoxic carcinogens, but semantics have been largely avoided). Vainio and his colleagues have tabulated 55 situations in which humans have succumbed to chemically induced cancer, and have listed the tissues affected. This database of human carcinogens has been analysed in the present study as done for the rodent carcinogen database, and comparisons made between the two. The predominance of putative genotoxic carcinogens in the human database was confirmed, as was the reality of putative non-genotoxic carcinogenicity in humans. It is concluded that putative genotoxic rodent carcinogenesis can be correlated both with chemical structure and the extent and nature of the induced effect, and that it is of clear relevance to humans. In contrast, it is concluded that putative non-genotoxic rodent carcinogenesis is more closely related to the test species than to the test chemical, and that it is essentially unpredictable in the absence of mechanistic models. In the absence of such models nongenotoxic carcinogenic effects should be extrapolated to humans with caution. Progress in the accurate prediction and extrapolation of rodent carcinogenicity will be helped by a common, if only temporary, enabling acceptance that not all carcinogens are intrinsically genotoxic.
戈尔德及其同事已将522种化学物质的啮齿动物生物测定结果制成表格，并对数据进行了分析。本研究从致癌物化学结构的角度提供了一个视角，对这些分析进行了补充。展示了每种致癌物的化学结构，并以测试剂作为主要变量来呈现戈尔德数据库。致癌物被归为六个化学类别，并对每种化学物质进行DNA反应性结构警示评估。然后使用以下参数的综合分析数据库：大鼠、小鼠或两者的生物测定；结构警示状态；化学类别；致癌作用的部位和多样性，以及跨物种致癌性。给出了一系列图表，使人能够快速了解啮齿动物致癌性核心数据库的内容。所呈现的几项分析共同支持了两类宽泛的啮齿动物致癌物的真实性——假定的DNA反应性致癌物和其他致癌物（推定的遗传毒性和非遗传毒性致癌物，但在很大程度上避免了语义学问题）。瓦尼奥及其同事已将人类因化学诱导癌症而死亡的55种情况制成表格，并列出了受影响的组织。本研究对该人类致癌物数据库进行了与啮齿动物致癌物数据库相同的分析，并对两者进行了比较。确认了人类数据库中推定的遗传毒性致癌物占主导地位，以及人类中推定的非遗传毒性致癌性的真实性。得出的结论是，推定的遗传毒性啮齿动物致癌作用可以与化学结构以及诱导效应的程度和性质相关联，并且与人类明显相关。相比之下，得出的结论是，推定的非遗传毒性啮齿动物致癌作用与测试物种的关系比与测试化学物质的关系更密切，并且在没有机制模型的情况下基本上是不可预测的。在没有此类模型的情况下，非遗传毒性致癌作用应谨慎地外推至人类。如果能够达成一个共同的（哪怕只是暂时的）共识，即并非所有致癌物本质上都是遗传毒性的，将有助于在准确预测和外推啮齿动物致癌性方面取得进展。
