Brambilla Giovanni, Martelli Antonietta
Department of Internal Medicine, Division of Clinical Pharmacology and Toxicology, University of Genoa, Viale Benedetto XV 2, I-16132 Genoa, Italy.
Toxicology. 2004 Mar 1;196(1-2):1-19. doi: 10.1016/j.tox.2003.11.003.
Theoretical reasons and experimental evidence indicate that a no-effect level generally cannot be expected for genotoxic carcinogens; as a consequence, in quantitative risk assessment the capability of distinguishing genotoxic from non-genotoxic carcinogens is of fundamental importance in order to identify relevant levels of human exposure. According to generally accepted guidelines, the standard three-test battery for the detection of genotoxic compounds consists of: (i) an in vitro test for gene mutation in bacteria; (ii) an in vitro test in mammalian cells with cytogenetic evaluation of chromosomal damage and/or a test that detects gene mutations; (iii) an in vivo test for chromosomal damage using rodent hematopoietic cells. This test battery is designed to avoid the risk of false negative results for compounds with genotoxic potential, but it cannot be taken for granted that the risk is completely eliminated. As a matter of fact there are some chemicals, classified by the International Agency for Research on Cancer (IARC) as probably or possibly carcinogenic to humans, which gave consistent negative results in this test battery, and in contrast provided positive results in other not routinely employed genotoxicity assays. The failure of the standard test battery in detecting some genotoxic carcinogens is attributable to several causes, but the principal of them are the following ones: in vitro, the artificial metabolic activity of the liver S9-mix, and the different biotransformation of chemicals in cells of different type and from different animal species; in vivo, the pharmacokinetic behaviour of the test compound, and its possible species-, sex- and tissue-specificity.
理论依据和实验证据表明，对于遗传毒性致癌物，通常无法预期其无作用水平；因此，在定量风险评估中，区分遗传毒性致癌物和非遗传毒性致癌物的能力对于确定人类相关暴露水平至关重要。根据普遍认可的指南，用于检测遗传毒性化合物的标准三项试验组合包括：（i）细菌基因突变的体外试验；（ii）对哺乳动物细胞进行染色体损伤细胞遗传学评估的体外试验和/或检测基因突变的试验；（iii）使用啮齿动物造血细胞进行染色体损伤的体内试验。该试验组合旨在避免对具有遗传毒性潜力的化合物产生假阴性结果的风险，但不能想当然地认为这种风险已完全消除。事实上，有一些被国际癌症研究机构（IARC）归类为对人类可能致癌或潜在致癌的化学物质，在该试验组合中给出了一致的阴性结果，而在其他非常规使用的遗传毒性试验中却给出了阳性结果。标准试验组合未能检测出某些遗传毒性致癌物可归因于多种原因，但其主要原因如下：在体外，肝脏S9混合物的人工代谢活性，以及不同类型和不同动物物种细胞中化学物质的不同生物转化；在体内，受试化合物的药代动力学行为及其可能的物种、性别和组织特异性。
