Huff J
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Ann N Y Acad Sci. 1999;895:56-79. doi: 10.1111/j.1749-6632.1999.tb08077.x.
Long-term carcinogenesis bioassays are the most valued and predictive means for identifying potential carcinogenic hazards of various agents to humans. Agents may be chemicals, chemical mixtures, multiple chemicals, combinations of chemicals, residues and contaminants, commercial products and formulations, and various exposure circumstances. Life-styles, dietary factors, and occupational exposure circumstances are very difficult, but not totally impossible, to evaluate experimentally. Historically, the first chemical bioassay took place in the early part of this century: Yamagiwa and Ichikawa in 1915, showed that coal tar applied experimentally to rabbit ears caused skin carcinomas. Since then, nearly 1500-2000 bioassays of one sort or another have been carried out. Importantly, however, some of these bioassays must be considered inadequate for judging the absence of carcinogenicity, since there were various limitations on the way they were performed: too few animals, too short a duration, too low exposure concentrations, too limited pathology, as examples. Thus, each bioassay must be critically evaluated, especially those reported to be negative, because "false negatives" are certainly more hazardous to human health than are "false positives". Likewise, one must be careful not to discount bioassay results simply because a target organ in rodents may not have a direct counterpart in humans (e.g., Zymbal glands), or because an organ site in rodents may not be a major site of cancers in humans (e.g., mouse liver). The design and conduct of a bioassay is not simple, however, and one must be fully aware of possible pitfalls as well as viable and often necessary alternatives. Similarly, evaluating results and interpreting findings must be approached with the utmost objectivity and consistency. These and other select issues, controversies, and uncertainties possibly encountered in long-term bioassays are covered in this paper. One fact remains abundantly clear: for every known human carcinogen that has been tested adequately in laboratory animals, the findings of carcinogenicity are concordant.
长期致癌生物测定是识别各种物质对人类潜在致癌危害最有价值且具预测性的手段。这些物质可能是化学物质、化学混合物、多种化学物质、化学物质组合、残留物和污染物、商业产品及配方，以及各种暴露情况。生活方式、饮食因素和职业暴露情况很难通过实验评估，但并非完全不可能。从历史上看，首次化学生物测定发生在本世纪初：1915年，山极和市川表明，将煤焦油实验性地涂抹在兔耳上会引发皮肤癌。从那时起，已经进行了近1500 - 2000种不同类型的生物测定。然而，重要的是，其中一些生物测定在判断无致癌性方面可能被认为是不充分的，因为它们的实施方式存在各种局限性：例如动物数量太少、持续时间太短、暴露浓度太低、病理学检查太有限。因此，必须对每项生物测定进行严格评估，尤其是那些报告为阴性的测定，因为“假阴性”对人类健康肯定比“假阳性”更具危害性。同样，不能仅仅因为啮齿动物中的靶器官在人类中可能没有直接对应物（例如，津巴腺），或者因为啮齿动物中的器官部位在人类中可能不是癌症的主要部位（例如，小鼠肝脏），就轻易否定生物测定结果。然而，生物测定的设计和实施并不简单，必须充分意识到可能的陷阱以及可行且往往必要的替代方法。同样，评估结果和解释发现必须以最大程度的客观性和一致性进行。本文涵盖了长期生物测定中可能遇到的这些及其他一些特定问题、争议和不确定性。有一个事实非常清楚：对于每一种在实验动物中经过充分测试的已知人类致癌物，致癌性的发现都是一致的。
