张林, 陈诗奇, 马文彦, 吕懿, 郭艳琳, 仇玉兰. 基准剂量法评估低剂量氯乙烯亚慢性染毒致肝毒性的生物接触限值[J]. 环境与职业医学, 2018, 35(5): 384-388. DOI: 10.13213/j.cnki.jeom.2018.17690
引用本文: 张林, 陈诗奇, 马文彦, 吕懿, 郭艳琳, 仇玉兰. 基准剂量法评估低剂量氯乙烯亚慢性染毒致肝毒性的生物接触限值[J]. 环境与职业医学, 2018, 35(5): 384-388. DOI: 10.13213/j.cnki.jeom.2018.17690
ZHANG Lin, CHEN Shi-qi, MA Wen-yan, LÜ Yi, GUO Yanlin, QIU Yu-lan. Estimating biological exposure limits of sub-chronic hepatotoxicity induced by low-concentration vinyl chloride using benchmark dose method[J]. Journal of Environmental and Occupational Medicine, 2018, 35(5): 384-388. DOI: 10.13213/j.cnki.jeom.2018.17690
Citation: ZHANG Lin, CHEN Shi-qi, MA Wen-yan, LÜ Yi, GUO Yanlin, QIU Yu-lan. Estimating biological exposure limits of sub-chronic hepatotoxicity induced by low-concentration vinyl chloride using benchmark dose method[J]. Journal of Environmental and Occupational Medicine, 2018, 35(5): 384-388. DOI: 10.13213/j.cnki.jeom.2018.17690

基准剂量法评估低剂量氯乙烯亚慢性染毒致肝毒性的生物接触限值

Estimating biological exposure limits of sub-chronic hepatotoxicity induced by low-concentration vinyl chloride using benchmark dose method

  • 摘要: 目的 应用基准剂量(BMD)法分析氯乙烯低剂量亚慢性染毒的肝脏毒效应,估算其BMD、基准剂量下限值(BMDL),为低剂量氯乙烯的亚慢性肝毒性的风险评估提供资料。

    方法 48只ICR雄性小鼠分为氯乙烯高浓度组(160 mg/m3)、中浓度组(80 mg/m3)、低浓度组(40 mg/m3)和阴性对照组,每组12只,静式吸入染毒10周,每周染毒5次,每次2 h。观察记录小鼠体重变化,行肝脏病理学检查,测定肝脏系数、血清丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)、肝脏三酰甘油(TG)及胆固醇(CHO)含量。根据BMD法筛选肝脏毒性效应数据,采用BMDS 2.7软件中连续型变量的4种剂量-效应关系模型(Hill、Linear、Polynomial和Power模型)对筛选后的实验数据进行拟合,选择最佳拟合模型,得出BMD和BMDL值。

    结果 对照组和低浓度组小鼠肝脏病理学检查未观察到异常改变,中、高浓度组出现明显的肝细胞水肿、嗜酸性改变及炎细胞浸润。与对照组相比,染毒组的起始体重、终末体重、肝脏系数、血清ALT、AST及肝脏TG差异均无统计学意义(P>0.05);高、中浓度组肝脏CHO含量(1 836.86±179.89)、(1 944.20±213.45)mmol/g均高于低浓度组及对照组(1 176.65±73.91)、(1 085.10±211.95)mmol/g,且差异具有统计学意义(P < 0.05)。将肝脏CHO含量采用BMD法进行分析,选择最敏感模型Hill模型计算得出BMD和BMDL分别为38.96、16.48 mg/m3。氯乙烯的未观察到有害作用水平(NOAEL)为40 mg/m3

    结论 低浓度氯乙烯亚慢性染毒导致小鼠肝脏脂质代谢紊乱,且BMD和BMDL值均低于NOAEL。

     

    Abstract: Objective To calculate benchmark dose (BMD) and benchmark dose lower limit (BMDL) of sub-chronic hepatotoxicity in mouse induced by vinyl chloride at low concentrations, and provide data for related risk assessment.

    Methods Forty-eight ICR male mice were randomly classified into three exposed groups160 (high concentration), 80 (medium concentration), and 40 (low concentration) mg/m3 of vinyl chloride and one negative control group, with 12 mice in each group. All mice received static inhalation of designated dosages of vinyl chloride for 10 weeks, 5 episodes per week and 2 hours per episode. Body weight change, liver histopathology, liver coefficient, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and liver triglyceride (TG) and cholesterol (CHO) were evaluated and recorded. All data were screened for the requirement of BMD method and fitted into four dose-effect models (including Hill, Linear, Polynomial, and Power models) as continuous variables using the BMDS 2.7 software. BMD and BMDL were obtained from the optimal model.

    Results Compared with the control and the low concentration groups without abnormal liver histopathological change, the medium and high concentration groups showed obvious hepatocyte edema, eosinophilic change, and inflammatory cell infiltration. There were no differences in initial body weight, terminal body weight, liver coefficient, serum ALT, serum AST, and liver TG between the exposed groups and the control group (P>0.05). Intrahepatic CHO level was significantly elevated in both the high concentration group(1 836.86±179.89) mmol/g and the medium concentration group(1 944.20±213.45) mmol/g compared with the low concentration group(1 176.65±73.91) mmol/g and the control group(1 085.10±211.95) mmol/g (P < 0.05). The BMD and BMDL were 38.96 mg/m3 and 16.48 mg/m3 respectively by the optimal Hill model. No observed adverse effect level (NOAEL) was 40 mg/m3.

    Conclusion Lipometabolic disturbance is induced in mouse by low-concentration sub-chronic vinyl chloride exposure, and the related BMD and BMDL are lower than the NOAEL.

     

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