Anderson D, Sorsa M, Waters M D
BIBRA Toxicology International, Carshalton, UK.
Mutat Res. 1994 Oct-Dec;313(2-3):101-15. doi: 10.1016/0165-1161(94)90042-6.
Over the past two decades mutagenicity tests have been used for the identification of potential human mutagens and have had an ancillary role, as supportive evidence in the assessment of human carcinogens. The demonstration of human germinal mutagens has been beyond the main scope of short-term testing strategies. However, just as mutagenicity tests have been useful in detecting potential carcinogens so should carcinogenicity tests assist the identification of presumptive germ cell mutagens. Cancer is an easily observable phenotype of mutation for genotoxic carcinogens and multi-site carcinogens or gonadal carcinogens logically could be germ cell mutagens. Thus carcinogenicity and mutagenicity data for a given genotoxic chemical should be considered together in the identification of putative germinal mutagens. Clearly, most classified human carcinogens are genotoxic thus helping to build the case for human germ cell mutagenicity. This paper describes the issues involved in such thinking and suggests an enhanced parallelogram approach incorporating the cancer endpoint. The enhanced parallelogram is explored using 1,3-butadiene and ethylene oxide as examples. The obvious lack of data for extrapolations using the parallelogram method suggests the need for targeted studies specifically designed for use in this approach.
在过去二十年中，致突变性测试已被用于识别潜在的人类诱变剂，并在评估人类致癌物时起到辅助作用，作为支持性证据。人类生殖细胞诱变剂的证明超出了短期测试策略的主要范围。然而，正如致突变性测试在检测潜在致癌物方面很有用一样，致癌性测试也应有助于识别推定的生殖细胞诱变剂。癌症是遗传毒性致癌物突变的一种易于观察的表型，多部位致癌物或性腺致癌物从逻辑上讲可能是生殖细胞诱变剂。因此，在识别推定的生殖细胞诱变剂时，应将给定遗传毒性化学物质的致癌性和致突变性数据综合考虑。显然，大多数已分类的人类致癌物具有遗传毒性，因此有助于证明人类生殖细胞的致突变性。本文描述了这种思路中涉及的问题，并提出了一种纳入癌症终点的增强平行四边形方法。以1,3 - 丁二烯和环氧乙烷为例探讨了增强平行四边形方法。使用平行四边形方法进行外推时明显缺乏数据表明需要专门为此方法设计的针对性研究。
