National Center for Environmental Assessment (NCEA), Office of Research and Development (ORD), U.S. Environmental Protection Agency (U.S.EPA), Washington, DC, USA.
Environ Mol Mutagen. 2013 Jan;54(1):19-35. doi: 10.1002/em.21737. Epub 2012 Sep 26.
Mutagenic agents have long been inferred to act through low-dose linear, nonthreshold processes. However, there is debate about this assumption, with various studies interpreting datasets as showing thresholds for DNA damage and mutation. We have applied rigorous statistical analyses to investigate the shape of dose-response relationships for a series of in vitro and in vivo genotoxicity studies using potassium bromate (KBrO(3) ), a water ozonation byproduct that is bioactivated to a reactive species causing oxidative damage to DNA. We analyzed studies of KBrO(3) genotoxicity where no-effect/threshold levels were reported as well as other representative datasets. In all cases, the data were consistent with low-dose linear models. In the majority of cases, the data were fit either by a linear (straight line) model or a model which was linear at low doses and showed a saturation-like downward curvature at high doses. Other datasets with apparent upward curvature were still adequately represented by models that were linear at low dose. Sensitivity analysis of datasets showing upward curvature revealed that both low-dose linear and nonlinear models provide adequate fits. Additionally, a simple biochemical model of selected key processes in bromate-induced DNA damage was developed and illustrated a situation where response for early primary events suggested an apparent threshold while downstream events were linear. Overall, the statistical analyses of DNA damage and mutations induced by KBrO(3) are consistent with a low-dose linear response and do not provide convincing evidence for the presence of a threshold.
诱变剂长期以来被认为是通过低剂量线性、无阈值的过程起作用的。然而，对于这一假设存在争议，各种研究对数据集的解释表明 DNA 损伤和突变存在阈值。我们应用严格的统计分析方法，研究了一系列使用溴酸钾（KBrO3）的体外和体内遗传毒性研究的剂量-反应关系的形状，KBrO3是水臭氧化的副产物，被生物激活成一种活性物质，导致 DNA 氧化损伤。我们分析了报告无作用/阈值水平的 KBrO3遗传毒性研究以及其他具有代表性的数据集。在所有情况下，数据都与低剂量线性模型一致。在大多数情况下，数据要么符合线性（直线）模型，要么在低剂量下符合线性模型，在高剂量下显示出类似饱和的向下曲率。其他表现出明显上凸曲率的数据集仍然可以通过低剂量线性模型来很好地表示。对表现出上凸曲率的数据集的敏感性分析表明，低剂量线性和非线性模型都能提供良好的拟合。此外，还开发了一个溴酸盐诱导 DNA 损伤中选定关键过程的简单生化模型，并说明了一种情况，即早期原发性事件的反应表明存在一个明显的阈值，而下游事件则呈线性。总的来说，KBrO3诱导的 DNA 损伤和突变的统计分析与低剂量线性反应一致，并没有提供令人信服的证据表明存在阈值。
