本文選題：基準(zhǔn)劑量　切入點(diǎn)：生殖和發(fā)育毒性　出處：《衛(wèi)生研究》2017年02期

【摘要】：目的應(yīng)用基準(zhǔn)劑量(BMD)法對(duì)生殖和發(fā)育毒性篩選試驗(yàn)的常規(guī)數(shù)據(jù)和生殖數(shù)據(jù)進(jìn)行分析,并與傳統(tǒng)的非致癌危險(xiǎn)度評(píng)價(jià)無(wú)明顯有害作用劑量(NOAEL)法進(jìn)行比較。方法將120只SPF級(jí)健康成年SD大鼠隨機(jī)分為對(duì)照組及低、中、高劑量染毒組,雌性大鼠染毒劑量為0、12.5、50和200 mg/kg BW,雄性大鼠染毒劑量為0、10、40和150 mg/kg,每天1次經(jīng)口灌胃給予一種腈類化合物,染毒周期54天。記錄各組大鼠體重、攝食量、中毒體征,仔鼠數(shù)量、窩重、性別、死產(chǎn)、活胎和外觀畸形,孕鼠著床數(shù)和黃體數(shù),計(jì)算生殖器官臟器系數(shù),并進(jìn)行病理組織學(xué)檢查。確定關(guān)鍵臨界毒性效應(yīng)的劑量作為NOAEL的參考劑量。利用EPA開(kāi)發(fā)的BMDS 2.6軟件分析所有符合條件的毒性效應(yīng)數(shù)據(jù),選擇敏感性最高的毒效應(yīng)指標(biāo),取其最佳BMD的95%CI下限(BMDL)作為風(fēng)險(xiǎn)評(píng)估基準(zhǔn)參考劑量。結(jié)果高劑量組染毒后第1、2、5及6周,雌鼠每日平均攝食量[(16.39±0.75)、(16.57±0.24)、(43.65±1.94)和(31.18±6.93)g]與對(duì)照組[(20.79±0.11)、(18.30±0.87)、(46.20±1.90)和(43.57±10.67)g]比較均明顯減少(P0.01)。高劑量組20天孕鼠體重[(353.67±29.73)g]較對(duì)照組[(389.83±29.46)g]明顯降低(P0.01),仔鼠0天和4天窩重[(64.97±37.75)和(108.66±62.67)g]較對(duì)照組[(94.39±23.00)和(156.37±29.06)g]降低(P0.05)。低、中、高劑量組母鼠的著床損失率分別為15.2%、19.6%和47.0%,與對(duì)照組(5.7%)比較明顯升高,中、高劑量組差異有統(tǒng)計(jì)學(xué)意義(P0.01)。NOAEL方法判斷試驗(yàn)關(guān)鍵效應(yīng)為母鼠著床損失,NOAEL水平設(shè)為12.5 mg/kg BW。BMD軟件篩選生殖數(shù)據(jù)敏感性最高的毒效應(yīng)為母鼠著床損失,17.8 mg/kg BW為最佳BMDL值。結(jié)論該生殖和發(fā)育毒性篩選試驗(yàn)中,采用BMD方法得到BMDL參考劑量為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 鹵0.75, 16.57 鹵0.24, 43.65 鹵1.94) and 31.18 鹵6.93g] was significantly lower than that of the control group [20.79 鹵0.111.30 鹵0.117.20 鹵1.90) and 43.57 鹵10.67g]. The body weight of pregnant rats in the high dose group of 20 days [353.67 鹵29.73g] was significantly lower than that of the control group [389.83 鹵29.46g], and the litter weight of the young rats [64.97 鹵37.97] and 108.66 鹵62.67g were significantly lower than that of the control group [94.23.39 00g and 156.37 鹵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 鹵29.73 g], and the litter weight of the young mice was lower than that of the control group [64.97 鹵37.97 鹵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.
【作者單位】： 中國(guó)疾病預(yù)防控制中心職業(yè)衛(wèi)生與中毒控制所;
【分類號(hào)】：R114

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本文編號(hào)：1676188