Stopper H, Mueller S O, Lutz W K
Department of Toxicology, University of W]urzburg, Versbacher Strabetae 9, D-97078 W]urzburg, Germany.
Mutagenesis. 2000 May;15(3):235-8. doi: 10.1093/mutage/15.3.235.
While testing for genotoxicity is usually performed on single chemicals, exposure of humans always comprises a number of genotoxic agents. The investigation of potentially synergistic effects of combinations therefore is an important issue in toxicology. Combinations of 511 keV gamma-radiation with the chemical alkylating agent ethyl methane-sulfonate were investigated in the in vitro micronucleus test in mouse lymphoma L5178Y cells. With combinations in the low dose linear effect range for the individual agents (0. 25-2 Gy and 0.8-3.2 mM, respectively), supra-additivity by 34-86% was seen. The synergism was more pronounced at the higher dose levels. Supra-additivity was confirmed in experiments using cytochalasin B and analyzing binucleate cells only, to control for putative effects on the cell cycle. Statistical significance was shown by a 2-factor analysis of variance with interaction. The results indicate that damage to DNA by gamma-radiation and alkylation could affect different rate limiting steps in the formation of micronuclei. Further investigations will have to show whether the observations are of general validity, in particular, whether other end-points of genotoxicity produce the same results and whether the degree of supra-additivity is always dose dependent. The latter would have a strong impact on risk assessment for mixtures at low doses.
虽然遗传毒性测试通常针对单一化学物质进行，但人类接触的总是多种遗传毒性物质。因此，研究这些物质组合的潜在协同效应是毒理学中的一个重要问题。本研究在小鼠淋巴瘤L5178Y细胞的体外微核试验中，对511 keVγ射线与化学烷化剂甲磺酸乙酯的组合进行了研究。当两种物质的组合处于各自低剂量线性效应范围内（分别为0.25 - 2 Gy和0.8 - 3.2 mM）时，超相加性达34% - 86%。在较高剂量水平下，协同作用更为明显。在使用细胞松弛素B且仅分析双核细胞以控制对细胞周期假定影响的实验中，超相加性得到了证实。通过具有交互作用的双因素方差分析显示出统计学显著性。结果表明，γ射线和烷化作用对DNA的损伤可能影响微核形成过程中不同的限速步骤。进一步的研究将必须表明这些观察结果是否具有普遍有效性，特别是遗传毒性的其他终点是否会产生相同的结果，以及超相加性程度是否总是依赖于剂量。后者将对低剂量混合物的风险评估产生重大影响。
