Cytotoxicity and chromosome aberrations in vitro: Experience in industry and the case for an upper limit on toxicity in the aberration assay
Cytotoxicity and chromosome aberrations in vitro: Experience in industry and the case for an upper limit on toxicity in the aberration assay
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DOI：
10.1002/(sici)1098-2280(2000)35:3
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发表时间：
2000-01-01
影响因子：
2.8
通讯作者：
Galloway, SM
中科院分区：
文献类型：
--
作者：
Galloway, SM
体外染色体畸变试验是一种有效、灵敏的基因毒素检测方法。然而，畸变可能继发于毒性，化合物不与DNA反应，在体内没有遗传毒性。因此，体外畸变试验的一些阳性结果与人类风险无关。为了帮助评估毒性的影响，从27家制药和化学公司以及合同实验室收集了数据。当细胞毒性通过细胞计数或汇合测量时，预计会破坏DNA的化合物（第1类）通常会引起畸变，而不会伴随严重的细胞毒性，即在细胞生长的60%或更多。毒性更大的核苷类似物、拓扑异构酶抑制剂、氟喹诺酮类抗生素、抗叶酸盐和活性氧产生物仍然呈阳性，细胞生长比对照组高50%或更多。相比之下，当有证据表明这些化合物不具有DNA损伤性（第2类）时，毒性相关的致癌物的比例更高，在不到50%的对照细胞生长中呈阳性结果。当使用有丝分裂指数（MI）作为细胞毒性指标时，模式不太清楚，尽管第2类化合物有更多的有丝分裂抑制趋势。总的来说，数据表明，毒性限制和更准确的估计毒性的方法将通过减少具有阈值型剂量关系的不相关阳性结果的频率来提高测定的准确性。讨论了评估体外畸变测定阳性结果的基本原理，特别是与毒性相关的结果，以及统一监管方法的必要性。(C) 2000 Wiley-Liss, Inc。
The chromosome aberration assay in vitro is a useful and sensitive test For detection of genotoxins. However, aberrations can occur secondary to toxicity, with compounds that do not react with DNA and are not genotoxic in vivo. Thus, some positive results in the in vitro aberration assay are not relevant to human risk. To help evaluate the influence of toxicity, data were collected from 27 pharmaceutical and chemical companies and contract laboratories. When cytotoxicity was measured by cell counts or confluence, compounds expected to damage DNA (Category 1) generally induced aberrations without severe concomitant cytotoxicity, i.e., at cell growth 60% or more of control. The more toxic nucleoside analogues, topoisomerase inhibitors, Fluoroquinolone antibiotics, antifolates, and producers of reactive oxygen were still positive with cell growth 50% or more of control. In contrast, when there was evidence that the compounds were not DNA damaging (Category 2), there was a higher proportion of toxicity-associated clastogens, with positive results at less than 50% of control cell growth. When mitotic index (MI) was used as an indicator of cytotoxicity, the pattern was less clear, although there was a tendency to more mitotic suppression with the Category 2 compounds. Overall the data indicate that a limit on toxicity, and a more accurate way of estimating it, would increase the accuracy of the assay by reducing the frequency of nonrelevant positive results with a threshold-type of dose relation. The rationale For evaluating positive results in the in vitro aberration assay, especially those associated with toxicity, is discussed, as is the need For a harmonized regulatory approach. (C) 2000 Wiley-Liss, Inc.