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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(P<0.01)。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(P<0.01),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(P<0.05)。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(P<0.01)。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。
OBJECTIVE: To compare the conventional and reproductive data of reproductive and developmental toxicity screening tests with the reference dose (BMD) method and to compare with the traditional non-carcinogenic risk assessment (NOAEL) method. Methods 120 Sprague-Dawley (SD) healthy adult Sprague-Dawley rats were randomly divided into control group and low, middle and high dose exposure groups. Female rats were dosed at 0, 12.5, 50 and 200 mg / kg BW, Toxic doses of 0, 10, 40, and 150 mg / kg were administered orally once daily to a nitrile compound for a period of 54 days. The body weight, food intake, poisoning signs, number of offspring, litter weight, sex, stillbirth, live fetus and appearance deformity, implantation number and corpora luteum number of pregnant rats were recorded, and organ coefficient of reproductive organs was calculated and pathological Histological examination. The dose that determines the critical critical toxic effect is used as a reference dose for NOAEL. All eligible toxicity data were analyzed using the EPA-developed BMDS 2.6 software and the most sensitive toxic effect index was selected as the BMD of the best BMD for the risk-assessment reference dose. Results The average daily food intake of the high-dose group was (16.39 ± 0.75), (16.57 ± 0.24), (43.65 ± 1.94) and (31.18 ± 6.93) g at the 1st, 2nd, 5th and 6th week (P <0.01) compared with [(20.79 ± 0.11), (18.30 ± 0.87), (46.20 ± 1.90) and (43.57 ± 10.67) g] in control group. Compared with the control group [(389.83 ± 29.46) g] (P <0.01), the body weight of pregnant rats in the high dose group for 20 days [(353.67 ± 29.73) g] was significantly lower on day 0 and day 4 [(64.97 ± 37.75) And (108.66 ± 62.67) g] (P <0.05) compared with the control group [(94.39 ± 23.00) and (156.37 ± 29.06) g], respectively. The implantation loss rates of the low, medium and high dose groups were 15.2%, 19.6% and 47.0%, respectively, which were significantly higher than those of the control group (5.7%). There was significant difference between the medium and high dose groups (P < 0.01). NOAEL method to determine the key effect of the test for implantation loss of mother rats, NOAEL level was set to 12.5 mg / kg BW. The most sensitive toxicological effect of BMD software screening reproductive data for implantation loss of the mother rats, 17.8 mg / kg BW for the best BMDL value. Conclusion In this reproductive and developmental toxicity screening test, a BMD reference dose of 17.8 mg / kg BW was obtained using the BMD method.