偶氮四唑二胍的成年SD大鼠亚急性毒性实验研究

Experimental study on subacute toxicity of guanidine azotetrazolium in adult SD rats

目的了解偶氮四唑二胍(GZT)对大鼠的亚急性经口毒性效应,为职业接触人群的安全性评价提供依据。方法60只无特定病原体级健康成年SD大鼠被随机分为对照组、低剂量组、中剂量组、高剂量组和卫星组,每组10只。低、中、高剂量组大鼠分别予125 mg/kg·bw、250 mg/kg·bw和500 mg/kg·bw GZT-羧甲基纤维素混悬液经口灌胃染毒,对照组给予等体积羧甲基纤维素溶液灌胃,1次/d,连续28 d。卫星组动物染毒28 d后不再染毒,继续观察14 d。观察大鼠的毒性反应、体重、食物利用率、血常规、血清生化、脏器系数变化及组织病理学改变。采用SPSS 23.0软件进行统计分析,检验水准α=0.05。结果试验期间大鼠一般情况较好,各剂量组雌雄大鼠体重与对照组比较差异无统计学意义(P>0.05),高剂量组食物利用率低于同性别对照组(P=0.010);雌性大鼠高剂量组红细胞、血红蛋白、红细胞压积低于同性别对照组(P值分别为0.008、0.010、0.001);雄性大鼠高剂量组BUN、CREA、UA高于同性别对照组(P值分别为0.024、0.009、0.001),中、高剂量组CHOL均高于同性别对照组(P值分别为0.030、0.001);与同性别对照组比较,雌雄大鼠高剂量组肾脏脏器系数增加(P值分别为0.001、0.002)。雄性大鼠中、高剂量组胸腺脏器系数低于同性别对照组(P值分别为0.027、0.001),高剂量组脾脏脏器系数低于同性别对照组(P=0.005)。结论高剂量(500.0 mg/kg·bw)GZT可影响雌性大鼠血液系统和雄性大鼠的肾脏、免疫功能,停止受试物后影响作用是可逆的。本实验条件下,GZT的亚急性经口毒性未观察到有害作用水平(NOAEL)为125 mg/kg·bw。

Objective To explore the subacute oral toxicity of guanidine azotetrazolium(GZT)in rats,and to provide basis for the safety evaluation of occupational contact population.Methods A total of 60 healthy adult SD rats free of specific pathogens were randomly divided into control group,low dose group,medium dose group,high dose group dose and satellite group,with 10 rats in each group.Rats in the low,medium and high dose groups were given 125 mg/kg·bw,250 mg/kg·bw and 500 mg/kg·bw GZT-carboxymethyl cellulose suspension by oral gavage,respectively,while the control group was given an equal volume carboxymethyl cellulose solution by gavage once a day for 28 consecutive days.Animals in the satellite group were observed for 14 days after having been exposed for 28 days.The changes of toxic symptoms,body weight,food utilization,blood routine,serum biochemical indicators,organ coefficients and histopathology of the rats were observed.SPSS 23.0 was used for statistical analysis,and the test level wasα=0.05.Results During the experiment,animals were in good health.There were no significant differences in the body weight of male and female rats between different dose groups and the control group(P>0.05),while the food utilization rate of the high dose group was lower than that of the same sex control group(P=0.010).Red blood cell counts,hemoglobin levels,hematocrit levels of female rats in high dose group were lower than those of the same sex control group(P=0.008,P=0.010,P=0.001,respectively).Blood urea nitrogen(BUN),creatinine(CREA)and uric acid(UA)levels of male rats in high dose group were higher than those in the same sex control group(P=0.024,P=0.009,P=0.001,respectively).The cholesterol levels in medium and high dose groups were higher than that in the same sex control group(P=0.030,P=0.001,respectively).The renal organ coefficients of rats in high dose group increased when compared with the same sex(P=0.001,P=0.002,respectively).The thymus organ coefficients of male rats in medium and high dose groups were lower than those in the same sex control group(P=0.027,P=0.001,respectively).The spleen organ coefficient of the high dose group was lower than that of the same sex control group(P=0.005).Conclusions High dose(500 mg/kg·bw)of GZT could affect the blood system of female rats and the kidney and immune function of male rats.The effects were reversible after discontinued the test substance.The no observed adverse effect level(NOAEL)for subacute oral toxicity of GZT was 125 mg/kg·bw under the conditions of this experiment.