基准剂量在燃煤砷暴露人群肝损害研究中的应用及其意义探讨

Application of benchmark dose on the study of people＇s liver dysfunction induced by arsenic-coal burning and its significance

目的探讨燃煤砷暴露人群肝损害的生物接触限值，筛选监测砷致肝损害的敏感生物学标志。方法以燃煤污染型地方性砷中毒病区118例砷暴露者为砷暴露组．非砷污染区50例居民为对照组。以尿砷、发砷（Ag—DDC法测定）作为接触指标；总胆汁酸（TBA，酶循环法测定）、谷胱甘肽硫转移酶（Gsrrs，化学比色法测定）和γ-谷氨酰转肽酶（γ-GT，重氮试剂比色法测定）作为肝细胞损害效应指标；血清透明质酸（HA）、Ⅲ型前胶原（PC—Ⅲ）和Ⅳ型胶原（Ⅳ·C）作为肝纤维化效应指标（均用放射免疫法测定）。运用基准剂量（BMD）法计算各效应指标对应的尿砷和发砷的BMD及其95％可信区间下限值（BMDL），并根据BMD和BMDL大小判断各效应指标的敏感性。结果砷暴露组的砷接触指标尿砷（98．50mg／kgCr）、发砷（7．42mg／kg）和肝损害效应指标TBA、GSTs、γ-GT、HA、PC—Ⅲ、Ⅳ·c的几何均数（6．78μmol／L、22．05U／L、48．04U／L、85．19μg／L、89．76μg／L、86．85μg／L）均明显高于对照组的尿砷（22．98mg／kgCr）、发砷（1．28mg／kg）和肝损害效应指标（4．63μmol／L、13．76U／L、36．45U／L、54．62μg／L、74．45μg／L、54．81μg/L，P〈0．01），尿砷、发砷与肝损害效应指标间存在剂量-效应关系（P〈0．05或〈0．01）。尿砷的BMD和BMDL范围分别为49．53～101．96、39．02～70．15mg／kgCr，发砷的BMD和BMDL范围分别为3．04～5．02、2.36～3．25mg／kg。肝细胞损害指标的敏感顺序均为GSTs〉TBA〉γ-GT；而肝纤维化指标的敏感顺序均为HA〉Ⅳ·C〉PC—Ⅲ。结论根据肝损害生物学标志的最低尿砷、发砷BMDL值，结合当地健康人群尿砷、发砷平均值，建议燃煤砷暴露者肝损害的生物接触限值尿砷为35．00mg／kgCr，发砷为2．50mg／kg。GSTs、TBA、γ-GT和HA、Ⅳ·C、PC—Ⅲ分别能不同程度地反映燃煤砷污染对人体的肝细胞损害和肝纤维化情况；GSTs、HA分别是其相对最敏感的生物学标志。

Objective To explore the biological exposure limit of liver dysfunction induced by arseniccoal burning, and screen sensitive biomarkers for its＇ liver dysfunction monitoring. Methods One hundred and eighteen subjects from the exposed area and 50 control from non-pollution area were studied. Their urinary and hair contents of arsenic were tested as exposure biomarkers by Ag-DDC assay. Total bile acid （TBA, detected by enzymatic cycling method）, glutathione S-transferase （GSTs, detected by chemical colorimetry） and γ-glutamyl transpeptidase （γ-GT, detected by colorimetry of diazotization reagent） were used as biomarkers indicating liver cell damage. Hyaluronic acid （HA）, Procollagen Type Ⅲ （PC- Ⅲ ） and Collagen Type Ⅳ （ Ⅳ.C ）, all detected by radioimmunoassay, were used as liver fibrosis biomarkers. The benchmark dose（BMD）and the lower confidence limit of benchmark dose（BMDL） of urinary and hair arsenic were calculated. Sensitivity of each biomarker was estimated according to the BMD and BMDL value. Results The geometric mean of urinary and hair arsenic（98.50 mg/kg Cr, 7.42 mg/kg） and TBA, GSTs, γ-GT, HA, PC-Ⅲ, Ⅳ.C （6.78 μmol/L,22.05 U/L,48.04 U/L,85.19μg/L,89.76 μg/L,86.85 μg/L） in the exposed group were significantly higher than urinary and hair arsenic（22.98 mg/kg Cr, 1.28 mg/kg） and each biomarker in the control group（4.63 μmol/L, 13.76 U/L,36.45 U/L,54.62 μg/L,74.45 μg/L,54.81μg/L, P 〈 0.01 ）. Significant dose-effect relationship existed between urinary and hair arsenic contents and each biomarker. BMD and BMDL value of urinary arsenic was 49.53 - 101.96 mg/kg Cr and 39.02 - 70.15 mg/kg Cr, respectively. Those of hair arsenic were 3.04 - 5.02 mg/kg and 2.36 - 3.25 mg/kg, respectively. According to BMD and BMDL value of urinary and hair arsenic, the sensitivity of biomarkers decreased in the order of GSTs, TBA and γ-GT for liver cell damage. As for liver fibrosis, the sensitivity reduced in an order of HA, Ⅳ.C and PC-Ⅲ. Conclusions According to the lowest BMD and BMDL of urinary and hair arsenic, averaged reference value of urinary and hair arsenic in the local normal population, we suggest urinary 35.0 mg/kg Cr and hair 2.5 mg/kg as their biological exposure limits for those with liver dysfunction induced by arsenic-coal burning. GSTs, TBA, γ-GT and HA, Ⅳ. C, PC-Ⅲ can respectively reflect liver cell damage and liver fibrosis caused by arsenic-coal burning in different degrees, among which, GSTs and HA are the most sensitive biomarkers respectively for liver cell damage and liver fibrosis.