U.S. Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas.
Environ Mol Mutagen. 2014 Jun;55(5):385-99. doi: 10.1002/em.21854. Epub 2014 Feb 17.
The assumption that mutagens have linear dose-responses recently has been challenged. In particular, ethyl methanesulfonate (EMS), a DNA-reactive mutagen and carcinogen, exhibited sublinear or thresholded dose-responses for LacZ mutation in transgenic Muta™Mouse and for micronucleus (MN) frequency in CD1 mice (Gocke E and Müller L [2009]: Mutat Res 678:101-107). In order to explore variables in establishing genotoxicity dose-responses, we characterized the genotoxicity of EMS using gene mutation assays anticipated to have lower spontaneous mutant frequencies (MFs) than Muta™Mouse. Male gpt-delta transgenic mice were treated daily for 28 days with 5 to 100 mg/kg EMS, and measurements were made on: (i) gpt MFs in liver, lung, bone marrow, kidney, small intestine, and spleen; and (ii) Pig-a MFs in peripheral blood reticulocytes (RETs) and total red blood cells. MN induction also was measured in peripheral blood RETs. These data were used to calculate Points of Departure (PoDs) for the dose responses, i.e., no-observed-genotoxic-effect-levels (NOGELs), lower confidence limits of threshold effect levels (Td-LCIs), and lower confidence limits of 10% benchmark response rates (BMDL10 s). Similar PoDs were calculated from the published EMS dose-responses for LacZ mutation and CD1 MN induction. Vehicle control gpt and Pig-a MFs were 13-40-fold lower than published vehicle control LacZ MFs. In general, the EMS genotoxicity dose-responses in gpt-delta mice had lower PoDs than those calculated from the Muta™Mouse and CD1 mouse data. Our results indicate that the magnitude and possibly the shape of mutagenicity dose responses differ between in vivo models, with lower PoDs generally detected by gene mutation assays with lower backgrounds.
最近，人们对诱变剂具有线性剂量反应的假设提出了质疑。特别是，DNA 反应性诱变剂和致癌剂乙基甲磺酸（EMS）在转基因 Muta™小鼠的 LacZ 突变和 CD1 小鼠的微核（MN）频率中表现出亚线性或阈值剂量反应（Gocke E 和 Müller L [2009]：Mutat Res 678:101-107）。为了探索建立遗传毒性剂量反应的变量，我们使用预期突变频率（MF）低于 Muta™Mouse 的基因突变检测方法来表征 EMS 的遗传毒性。雄性 gpt-delta 转基因小鼠每天用 5 至 100mg/kg EMS 处理 28 天，并进行以下测量：（i）肝脏、肺、骨髓、肾脏、小肠和脾脏中的 gpt MF；（ii）外周血网织红细胞（RET）和总红细胞中的 Pig-a MF。还测量了外周血 RET 中的 MN 诱导。这些数据用于计算剂量反应的起点（PoD），即无观察到遗传毒性效应水平（NOGEL）、阈效应水平的置信下限（Td-LCI）和 10%基准反应率的置信下限（BMDL10s）。从发表的 EMS 对 LacZ 突变和 CD1 MN 诱导的剂量反应中计算出了类似的 PoD。载体对照 gpt 和 Pig-a MF 比发表的载体对照 LacZ MF 低 13-40 倍。一般来说，gpt-delta 小鼠中的 EMS 遗传毒性剂量反应的 PoD 低于从 Muta™Mouse 和 CD1 小鼠数据计算出的 PoD。我们的结果表明，体内模型之间的诱变性剂量反应的幅度和形状可能不同，具有较低背景的基因突变检测通常检测到较低的 PoD。
