该研究的主要目标是在大鼠多终点遗传毒性评估平台中研究低剂量N-乙基-N-亚硝基脲(ENU)和甲磺酸乙酯(EMS)的遗传毒性反应,并得出潜在阈值和相关指标。雄性Sprague-Dawley大鼠每天口服灌胃ENU(0.25~8mg/kgbw)和EMS(5~160mg/kgbw),连续28天,两者都有六个紧密间隔的剂量水平。猪-基因突变检测,微核试验,和彗星测定在几个时间点进行。然后,使用没有观察到的基因毒性效应水平和具有不同临界效应大小的基准剂量(BMD)方案(CES,0.05、0.1、0.5和1SD)。总的来说,对于ENU和EMS,所有研究终点均呈剂量依赖性增加.PoDs在不同的基因终点,时间点,和统计方法,而选择合适的95%的BMD置信下限,则需要综合考虑化学品的作用方式,测试的特点,以及模型拟合方法。在实验条件下,ENU和EMS的PoDs分别为0.0036mg/kgbw和1.7mg/kgbw,分别。
The main goal of the study was to investigate the genotoxic response of N-ethyl-N-nitrosourea (ENU) and ethyl methanesulfonate (EMS) at low doses in a multi-endpoint genotoxicity assessment platform in rats and to derive potential thresholds and related metrics. Male Sprague-Dawley rats were treated by daily oral gavage for 28 consecutive days with ENU (0.25 ~ 8 mg/kg bw) and EMS (5 ~ 160 mg/kg bw), both with six closely spaced dose levels. Pig-a gene mutation assay, micronucleus test, and comet assay were performed in several timepoints. Then, the dose-response relationships were analyzed for possible points of departure (PoD) using the no observed genotoxic effect level and benchmark dose (BMD) protocols with different critical effect sizes (CES, 0.05, 0.1, 0.5, and 1SD). Overall, dose-dependent increases in all investigated endpoints were found for ENU and EMS. PoDs varied across genetic endpoints, timepoints, and statistical methods, and selecting an appropriate lower 95% confidence limit of BMD needs a comprehensive consideration of the mode of action of chemicals, the characteristics of tests, and the model fitting methods. Under the experimental conditions, the PoDs of ENU and EMS were 0.0036 mg/kg bw and 1.7 mg/kg bw, respectively.