生殖和发育毒性筛选试验中基准剂量法的应用

发布时间：2018-03-28 11:45

本文选题：基准剂量　切入点：生殖和发育毒性　出处：《卫生研究》2017年02期

【摘要】：目的应用基准剂量(BMD)法对生殖和发育毒性筛选试验的常规数据和生殖数据进行分析,并与传统的非致癌危险度评价无明显有害作用剂量(NOAEL)法进行比较。方法将120只SPF级健康成年SD大鼠随机分为对照组及低、中、高剂量染毒组,雌性大鼠染毒剂量为0、12.5、50和200 mg/kg BW,雄性大鼠染毒剂量为0、10、40和150 mg/kg,每天1次经口灌胃给予一种腈类化合物,染毒周期54天。记录各组大鼠体重、摄食量、中毒体征,仔鼠数量、窝重、性别、死产、活胎和外观畸形,孕鼠着床数和黄体数,计算生殖器官脏器系数,并进行病理组织学检查。确定关键临界毒性效应的剂量作为NOAEL的参考剂量。利用EPA开发的BMDS 2.6软件分析所有符合条件的毒性效应数据,选择敏感性最高的毒效应指标,取其最佳BMD的95%CI下限(BMDL)作为风险评估基准参考剂量。结果高剂量组染毒后第1、2、5及6周,雌鼠每日平均摄食量[(16.39±0.75)、(16.57±0.24)、(43.65±1.94)和(31.18±6.93)g]与对照组[(20.79±0.11)、(18.30±0.87)、(46.20±1.90)和(43.57±10.67)g]比较均明显减少(P0.01)。高剂量组20天孕鼠体重[(353.67±29.73)g]较对照组[(389.83±29.46)g]明显降低(P0.01),仔鼠0天和4天窝重[(64.97±37.75)和(108.66±62.67)g]较对照组[(94.39±23.00)和(156.37±29.06)g]降低(P0.05)。低、中、高剂量组母鼠的着床损失率分别为15.2%、19.6%和47.0%,与对照组(5.7%)比较明显升高,中、高剂量组差异有统计学意义(P0.01)。NOAEL方法判断试验关键效应为母鼠着床损失,NOAEL水平设为12.5 mg/kg BW。BMD软件筛选生殖数据敏感性最高的毒效应为母鼠着床损失,17.8 mg/kg BW为最佳BMDL值。结论该生殖和发育毒性筛选试验中,采用BMD方法得到BMDL参考剂量为17.8 mg/kg BW。
[Abstract]:Objective to analyze the routine data and reproductive data of reproductive and developmental toxicity screening test by the method of BMD. Methods 120 healthy adult SD rats of SPF grade were randomly divided into control group, low dose group, middle dose group and high dose group. Female rats were given 0 ~ 12.5U ~ (50) and 200 mg/kg BWs, male rats were given a nitrile compound by oral administration once a day for 54 days, and male rats were given 0 ~ 1040 and 150 mg / kg. Body weight, food intake, toxic signs and the number of young rats were recorded. Litter weight, sex, stillbirth, live fetus and appearance malformation, number of implantation and corpus luteum of pregnant rats, coefficient of organs of reproductive organs were calculated. Histopathological examination was carried out to determine the dose of critical toxicity effect as the reference dose of NOAEL. All eligible toxic effect data were analyzed by BMDS 2.6 software developed by EPA, and the most sensitive toxic effect index was selected. The 95%CI lower limit of the optimal BMD was used as the reference dose for risk assessment. The average daily intake of female rats [16.39 卤0.75, 16.57 卤0.24, 43.65 卤1.94) and 31.18 卤6.93g] was significantly lower than that of the control group [20.79 卤0.111.30 卤0.117.20 卤1.90) and 43.57 卤10.67g]. The body weight of pregnant rats in the high dose group of 20 days [353.67 卤29.73g] was significantly lower than that of the control group [389.83 卤29.46g], and the litter weight of the young rats [64.97 卤37.97] and 108.66 卤62.67g were significantly lower than that of the control group [94.23.39 00g and 156.37 卤29.37 g], and the body weight of the young mice was lower than that of the control group [94.23.39 00g and 156.37 卤29.73 g], and the litter weight of the young mice was lower than that of the control group [64.97 卤37.97 卤6.67 g]. In the high dose group, the rate of bed loss was 15.20.96% and 47.0%, respectively, which was significantly higher than that of the control group (5.7%). There was significant difference in high dose group. P0.01U. NOAEL method was used to judge that the key effect of the test was that the maternal implantation loss was the most sensitive to screening reproductive data using 12.5 mg/kg BW.BMD software. The best BMDL value was 17.8 mg/kg BW. Conclusion in this reproductive and developmental toxicity screening test, The reference dose of BMDL was 17.8 mg/kg BW by BMD method.
【作者单位】：中国疾病预防控制中心职业卫生与中毒控制所;
【分类号】：R114

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