磷酸三(1,3-二氯异丙基)酯对大鼠的急性和亚慢性毒性作用

Acute and sub-chronic toxicity of tris(1,3-dichloroisopropyl)phosphate in rats

目的:研究磷酸三(1,3-二氯异丙基)酯(TDCIPP)对大鼠的急性和亚慢性毒性作用。方法:急性毒性试验中,将50只SPF级SD大鼠随机分为5组,每组10只,雌雄各半,按照TDCIPP剂量464、1000、2150、4640和10000 mg/kg分别进行单次经口灌胃染毒,观察14 d。在亚慢性毒性试验中,将80只SPF级SD大鼠随机分为4组,每组20只,雌雄各半,TDCIPP按照0、13.3、40、120 mg/(kg·d)的剂量,每天1次,连续灌胃112 d。于试验结束当天分别称取大鼠体质量;腹主静脉取血进行血常规、血液生化指标的检测;处死大鼠后收集脑、心、肝、脾、肺、肾并称取质量,计算脏器系数,并对这些组织进行HE染色分析组织病理变化。选择具有代表性的指标为毒性效应,使用基准剂量法(BMD)评估在特定风险水平下的暴露水平,与无可见有害作用法(NOAEL)参考值进行比较,分析相对更具体和敏感的剂量限值。结果:在急性经口毒性试验中,TDCIPP对SD大鼠的半数致死剂量(LD_(50))为2000~2300 mg/kg,属低毒物质。在亚慢性经口毒性试验中,与对照组比较,120 mg/(kg·d)染毒组显著影响雌鼠的体质量增长(P<0.05);40和120 mg/(kg·d)染毒组大鼠肝和肾的脏器系数明显升高(P<0.05);40 mg/(kg·d)染毒组雄鼠白细胞计数、淋巴细胞计数、单核细胞计数、嗜酸性粒细胞计数均升高(P<0.05);120 mg/(kg·d)染毒组雌鼠红细胞计数、红细胞压积、嗜酸性粒细胞计数、嗜酸性粒细胞百分比降低(P<0.05);40与120 mg/(kg·d)染毒组雄性大鼠AST水平降低(P<0.05);40 mg/(kg·d)染毒组雌性大鼠ALT和AST均明显降低(P<0.05);40和120 mg/(kg·d)染毒组HE染色显示明显的肾脏病理损伤。基于NOAEL评估TDCIPP最高无可见有害作用剂量为13.3 mg/(kg·d);基于BMD法以肾功能指标血肌酐作为危险度评定中计算参考剂量的基础,其限值为2.696 mg/(kg·d)。结论:TDCIPP急性和亚慢性染毒对大鼠具有毒性作用,肝和肾可能是TDCIPP毒性主要的靶器官。

OBJECTIVE:To investigate the acute and sub-chronic toxicity of tris(1,3-dichloro-2-propyl)phosphate(TDCIPP)in rats.METHODS:In the acute toxicity test,50 SD rats at SPF level were randomly divided into 5 groups,with 10 rats per group,equally male and female,and given a single oral dose of 464,1000,2150,4640,and 10000 mg/kg.In the sub-chronic toxicity test,80 SD rats at the SPF level were randomly divided into 4 groups of 20 rats per group,equally divided between males and females,and orally administered a dose of 0,13.3,40,and 120(high dose)mg/kg per day for 112 consecutive days.Organs were harvested and weighed,and the organ coefficient was calculated.Blood routine and blood biochemical indices were examined.HE staining was performed to analyze histopathological changes.Representative indicators were selected for toxic effects using the baseline dose BMD method to assess exposure levels at specific risk levels,compared with the NOAEL method reference values to analyze relatively more specific and sensitive dose limits.RESULTS:The LD_(50) of TDCIPP in acute oral toxicity test in SD rats was 2000-2300 mg/kg.Compared with the control group,the 120 mg/(kg·d)sub-chronic exposure dose significantly affected the body mass growth of female rats;the organ coefficients of the liver and kidney of rats in the 40 and 120 mg/(kg·d)dose of TDCIPP group were significantly elevated(P<0.05);and the leukocyte counts,lymphocyte counts,and monocyte counts of male rats in the 40 mg/(kg·d)dose of TDCIPP group were significantly elevated(P<0.05).The mean values of white blood cell count,lymphocyte count,monocyte count and eosinophil count in male rats dosed with 40 mg/(kg·d)were significantly higher than those in the control group(P<0.05).The mean values of AST in male rats were significantly lower than those in the control group in the 40 mg/(kg·d)dose group;the mean values of ALT and AST in female rats in the 40 mg/(kg·d)dose group were significantly lower than those in the control group(P<0.05);and HE staining of the 40 and 120 mg/(kg·d)dose groups showed significant renal pathology damage.The highest NOAEL of 13.3 mg/(kg·d)was assessed based on the no-observed-adverse-effects level(NOAEL).The benchmark dose method(BMD),which uses blood creatinine as an indicator of renal function,determined the reference dose in the risk assessment with a limit of 2.696 mg/(kg·d).CONCLUSION:The livers and kidneys were the main target organs of TDCIPP in rats.