低浓度苯系物作业人员尿中反-反式黏糠酸和苯巯基尿酸与8-羟基脱氧鸟苷的关系

目的 以低浓度苯系物职业接触人群为研究对象,分析低浓度苯接触剂量与尿中反-反式黏糠酸(ttMA)、苯巯基尿酸(S-PMA)、8-羟基脱氧鸟苷(8-OHdG)水平关系.方法 以7家企业120名苯系物接触工人为研究对象(接触组),对照组为同企业共84名不接触苯系物的行政和后勤工作人员.热解析气相色谱法测定工作环境中苯、甲苯和二甲苯浓度,高效液相色谱三重串联四级杆质谱(HPLC-MS-MS)测定职业接触人群尿中ttMA、S-PMA和8-OHdG含量,并进行统计分析.结果 在作业场所苯平均加权浓度(CTWA)0.25～5.98 mg/m3时,尿中ttMA、S-PMA与空气中苯浓度均呈相关性(r2＝0.8759,r2=0.7497).低浓度苯系物(CTWA＜6 mg/m3)、甚至低于3.25 mg/m3的苯也对职业苯接触人员造成遗传损伤,且损伤程度有随苯浓度的增高而增强的趋势;尿中8-OHdG含量与苯接触浓度呈一定的剂量-反应关系(r2=0.181、P＜0.01).结论 尿中ttMA、S-PMA与空气中苯浓度均具有较高的相关性,可作为低浓度苯职业性接触生物监测的接触标记物;低浓度苯具有遗传损伤效应,尿中8-OHdG可作为苯致遗传损伤的效应标志物.未发现混杂接触限值以内的甲苯、二甲苯(CTWA＜50 mg/m3)对苯遗传损伤产生协同或拮抗作用.     

苯暴露大鼠尿中反-反式黏糠酸变化研究

目的观察苯动态染毒大鼠模型尿中反-反式黏糠酸(t,t-MA)的变化情况,探讨尿t,t-MA作为苯职业暴露水平生物标志物的可行性。方法48只成年Wistar大鼠,随机分为对照组、低浓度组、中浓度组和高浓度组,每组数量相同,雌雄各半;纯苯动态染毒28d(分4个时段,每时段染毒5d后停2d)。监测苯浓度,每个时段染毒后立即取5h尿,反相高效液相色谱-紫外检测法检测大鼠尿中t,t-MA浓度,并用尿肌酐校正。结果在不同染毒时段内,对照组、低、中、高浓度组间尿t,t-MA含量差异有统计学意义(P<0.05),鼠尿中t,t-MA浓度随着环境中苯浓度增高而升高,且没有随染毒时间延长而变化(P>0.05)。结论动物模型研究说明尿中t,t-MA是反映苯接触水平比较敏感的生物标志物。     

低苯暴露与职业暴露人群尿中t,t-MA及S-PMA的相关性

目的探讨低苯暴露与职业暴露人群尿中反-反式粘糠酸(t,t-MA)及苯巯基尿酸(S-PMA)的相关性。方法选择2015年1-2月某制鞋厂职业苯接触工人42例作为职业暴露组,该厂非职业接触办公人员28例作为低暴露组,分别检测工作环境中苯浓度和尿样中t,t-MA、S-PMA浓度,并分析二者间的相关性。结果低暴露组空气中苯浓度低于职业暴露组,差异有统计学意义(P0.05);低暴露组班前班后t,t-MA、S-PMA浓度比较差异无统计学意义(均P0.05)。职业暴露组班后t,t-MA、S-PMA浓度均高于班前,差异有统计学意义(均P0.05);职业暴露组t,t-MA、S-PMA浓度在班前和班后均高于低暴露组,差异有统计学意义(均P0.05)。低暴露组S-PMA班前、班后浓度与空气中苯浓度呈正相关(P0.05),t,t-MA与空气中苯浓度没有明显相关性(P0.05);职业暴露组班前、班后t,t-MA、S-PMA浓度与空气中苯浓度均呈正相关(P0.05)。结论低苯暴露人群t,t-MA和S-PMA浓度低于职业苯接触人群,且S-PMA浓度与空气中苯浓度密切相关。     

低苯暴露人群尿中t，t-MA及S-PMA的生物监测

目的分析职业低苯和环境低苯接触与人体尿液中t,t-MA和S-PMA浓度的相关性。方法选取广州市某制鞋厂钳帮和刷胶工人等苯职业接触人员作为职业低苯暴露人群（职业组）,选取非职业苯接触且家庭1年内装修过并已入住半年以上的人员作为环境低苯接触人群（环境组）。采用超高效液相串联质谱联用（UPLC—MS／MS）内标法测定尿中t,t-反式粘糠酸（t,t-MA）及苯巯基尿酸（S-PMA）含量,采用气相色谱法检测空气中苯浓度。结果职业组个体空气暴露的苯浓度（均值±标准差）为（0．16±0．06）mg／m^3,尿中t,t-MA及S-PMA含量分别为（42．7±39．2）和（0．28±0．19）μg／gCr;环境组个体空气暴露的苯浓度中位数（四分位间距）为0．01（0．02）mg／m^3,尿中t,t-MA及S-PMA含量的中位数（四分位间距）分别为20．5（16．2）和0．03（0．04）μg/gCr;经非参数Mann—WhitneyU—test检验分析发现：职业组的个体空气暴露苯浓度及尿中t,t-MA、S-PMA含量均高于环境组（均P〈0．01）。相关性分析结果显示,当空气中苯浓度为0．16mg／m^3时,尿中t,t—MA和S-PMA与空气中苯浓度存在良好的相关性（r=0．499、0．715）。结论t,t-MA及S-PMA可作为生物标记物用于职业低苯和环境低苯暴露的生物监测。     

苯暴露对β2-微球蛋白和尿视黄醇蛋白的影响

为了解苯对职业人群肾损伤的影响,寻找作业工人健康监护的早期指标,对某石化公司170名苯接触工人尿中β2-微球蛋白(β2-MG)和尿视黄醇蛋白(RBP)的含量进行了检测。结果显示,低浓度接触组尿β2-MG含量(322.6±235.8pg/L)高于对照组(P<0.05),高浓度接触组尿β2-MG含量(412.9±331.3pg/L)高于对照组(P<0.01)。低浓度接触组尿RBP含量(292.7±172.9pg/L)高于对照组(P<0.05)。提示苯暴露会影响肾小管功能导致尿中β2-MG和RBP含量升高,且尿β-MG含量升高较为显著。建议将尿β-微球蛋白含量作为苯职业人群的健康监护指标。     

长期低浓度苯暴露对职工健康的影响

目的探讨长期低浓度苯暴露对职工各职业健康检查指标的影响以及接触指标与损伤指标的关系。方法采用横断面调查,选择2018-2020年某汽车生产企业进行职业健康检查的135名低浓度苯暴露工人为接触组,149名不接苯工人为对照组,收集其健康检查资料及外周血和尿液样本。以质谱仪检测尿中以尿肌酐校正后的苯巯基尿酸（S-PMA）含量作为内暴露指标,采用比色法检测血清中脂质过氧化物丙二醛（MDA）、尿中8-羟基脱氧鸟苷（8-OHdG）水平,比较两组人员检查指标的差异,分析接触组S-PMA与8-OHdG的相关性。结果该企业苯主要存在于搅拌调漆、底漆和面漆喷涂、烘干、补漆等工序,C_TWA为<0.3～0.25 mg/m³,C_STEL为<0.3～0.40 mg/m³。接触组血压偏高检出率为18.12%～22.46%,对照组为11.41%～18.12%;接触组红细胞、血红蛋白量均值均低于对照组（t=-4.135,-2.386,P<0.05）,且红细胞偏低检出率高于对照组（χ²=7.62...     

基于生物监测指标评估的低浓度苯暴露职业健康风险

目的通过流行病学调查资料和苯接触生物标志物的检测资料,初步建立基于生物监测指标的低浓度苯暴露致癌风险评价方法。方法根据苯的流行病学调查资料,基于多阶模型推导出低浓度苯职业暴露下的致癌风险模型。利用贝叶斯线性回归和马尔科夫链蒙特卡洛方法,采用R语言、JARG软件包和水晶球软件建立苯空气浓度与苯代谢物浓度函数关系并进行不确定性分析,并利用尿中苯巯基尿酸(S-phenylmercapturic acid,S-PMA)和反-反式黏糠酸(trans,trans-muconic acid,tt-MA)的浓度预测苯的致癌风险。结果考虑适用低浓度苯暴露的情况,建立了二项式的多阶模型用于表征致癌风险。基于建立的致癌风险模型,我国现行的职业接触限值[空气中苯的时间加权平均容许浓度6 mg/m^(3),工作班后尿S-PMA浓度100μg/g(以Cr校正),班后尿tt-MA浓度3.0 mg/g(以Cr校正)]下的致癌风险分别为5.64×10^(-4)、2.31×10^(-4)、1.52×10^(-4),均高于美国环境保护署(EPA)和疾病预防控制中心(CDC)提出的职业人群致癌风险可接受水平(10^(-4))。结论利用苯的代谢产物预测致癌风险,显示在空气中苯浓度低于职业接触限值的情况下,苯的致癌影响仍然存在。需要采取工程控制及个体防护等措施,尽可能降低苯的致癌风险。目前我国苯职业接触限值存在尽可能降低的必要性。     

低浓度苯暴露对大鼠神经行为的影响

摘要:目的　研究低浓度气态苯吸入对大鼠学习记忆等神经行为的影响,并探讨低浓度苯吸入对大鼠血象的改变。方法　SD雄性大鼠随机分4组,每组10只,低、中、高剂量组苯染毒浓度分别为4 mg/m3、6 mg/m3和10 mg/m3,对照组吸入空气。采用静式吸入染毒法,4 h/d,5 d/w,持续染毒4 w,染毒结束后进行学习记忆等神经行为学测试、血象、嗜多染红细胞微核实验。结果　Morris水迷宫定位航行实验,高剂量组大鼠d 3、d 4的逃避潜伏期明显高于对照组（P＜0.05）,空间探索实验的目标象限时间明显低于对照组（P＜0.05）。高剂量组大鼠的后肢撑力指数明显高于对照组（P＜0.05）。低、中、高剂量组白细胞计数明显低于对照组（P＜0.05）。结论　低剂量、短时间暴露苯可损害大鼠学习记忆及运动功能,引起外周血白细胞计数降低。     

苯并(a)芘对大鼠睾丸胰岛素样因子3基因表达的影响

目的 观察青春期大鼠苯并(a)芘(BaP)亚慢性染毒对睾丸间质细胞功能标志物胰岛素样因子3(Ins13)mRNA表达水平的影响.方法 72只青春期健康雄性SD大鼠随机分为溶剂对照组(玉米油)、1、5mg/kgBaP染毒组,每组24只.隔日染毒,等体积灌胃,连续染毒90d.分别于染毒后30、60和90 d,每组各随机选取8只大鼠处死.取睾丸、附睾、心、肝、脾、肾称重并计算脏器系数,放免法检测血清睾酮含量,实时荧光定量PCR法检测睾丸Ins13 mRNA表达差异.结果 60dBaP各染毒组以及90 d5 mg/kg组附睾系数显著低于对照组(P＜0.05);染毒30 d5 mg/kg组肝脏系数显著大于对照组(P＜0.05),90d时显著小于对照组(P＜0.05);血清睾酮水平30 d和60 d 5 mg/kg染毒组明显高于对照组(P＜0.05),90 d 5 mg/kg组明显低于1 mg/kg组(P＜0.05);BaP处理组睾丸Ins13 mRNA表达水平各时相点比对照组显著下调(P＜0.01),染毒60 d比30 d显著下调(P＜0.05),尤其是5mg/kg组(P＜0.01).结论 青春期大鼠BaP亚慢性暴露可以干扰血清睾酮及睾丸Ins13基因表达水平,对附睾、肝脏可能有潜在毒性.     

苯接触人群的生物标志物研究进展

苯是应用广泛的化工原料.接触苯可引起急、慢性苯中毒,甚至白血病.研究苯接触人群的生物标志物在了解苯致病机制、接触苯人群的健康筛查等方面有重要价值,下面就国内外关于苯接触人群的生物标志物的研究进行综述. 1 苯的接触标志物 接触标志物是指进入机体内的外源性物质、代谢产物和它们与靶分子交互作用的产物.苯进入人体后多储留在脂肪组织内,在肝脏氧化成苯环氧化物,环氧化物与谷胱甘肽结合,形成苯巯基尿酸(S-PMA),其半减期为12.8 h[1].PACI等[2]利用高效液相色谱-串联质谱联用(HPLC/MS/MS)对S-PMA进行了研究,得到了尿S-PMA与苯的时间加权平均浓度直线相关,且不受性别、年龄、吸烟习惯的影响.     

Biological monitoring of exposure to benzene: a comparison between S-phenylmercapturic acid, trans,trans-muconic acid, and phenol.

OBJECTIVES--Comparison of the suitability of two minor urinary metabolites of benzene, trans,trans-muconic acid (tt-MA) and S-phenylmercapturic acid (S-PMA), as biomarkers for low levels of benzene exposure. METHODS--The sensitivity of analytical methods of measuring tt-MA and S-PMA were improved and applied to 434 urine samples collected from 188 workers in 12 studies in different petrochemical industries and from 52 control workers with no occupational exposure to benzene. In nine studies airborne benzene concentrations were assessed by personal air monitoring. RESULTS--Strong correlations were found between tt-MA and S-PMA concentrations in samples from the end of the shift and between either of these variables and airborne benzene concentrations. It was calculated that exposure to 1 ppm (8 hour time weighted average (TWA)) benzene leads to an average concentration of 1.7 mg tt-MA and 47 micrograms S-PMA/g creatinine in samples from the end of the shift. It was estimated that, on average, 3.9% (range 1.9%-7.3%) of an inhaled dose of benzene was excreted as tt-MA with an apparent elimination half life of 5.0 (SD 2.3) hours and 0.11% (range 0.05%-0.26%) as S-PMA with a half life of 9.1 (SD 3.7) hours. The mean urinary S-PMA in 14 moderate smokers and 38 non-smokers was 3.61 and 1.99 micrograms/g creatinine, respectively and the mean urinary tt-MA was 0.058 and 0.037 mg/g creatinine, respectively. S-PMA proved to be more specific and more sensitive (P = 0.030, Fisher's exact test) than tt-MA. S-PMA, but not tt-MA, was always detectable in the urine of smokers who were not occupationally exposed. S-PMA was also detectable in 20 of the 38 non-smokers from the control group whereas tt-MA was detectable in only nine of these samples. The inferior specificity of tt-MA is due to relatively high background values (up to 0.71 mg/g creatinine in this study) that may be found in non-occupationally exposed people. CONCLUSIONS--Although both tt-MA and S-PMA are sensitive biomarkers, only S-PMA allows reliable determination of benzene exposures down to 0.3 ppm (8 h TWA) due to its superior specificity. Because it has a longer elimination half life S-PMA is also a more reliable biomarker than tt-MA for benzene exposures during 12 hour shifts. For biological monitoring of exposure to benzene concentrations higher than 1 ppm (8 h TWA) tt-MA is also suitable and may even be preferred due to its greater ease of measurement.     

Validation of biomarkers in humans exposed to benzene: urine metabolites

BACKGROUND: The present study was conducted among Chinese workers employed in glue- and shoe-making factories who had an average daily personal benzene exposure of 31+/-26 ppm (mean+/-SD). The metabolites monitored were S-phenylmercapturic acid (S-PMA), trans, trans-muconic acid (t,t-MA), hydroquinone (HQ), catechol (CAT), 1,2, 4-trihydroxybenzene (benzene triol, BT), and phenol. METHODS: S-PMA, t,t-MA, HQ, CAT, and BT were quantified by HPLC-tandem mass spectrometry. Phenol was measured by GC-MS. RESULTS: Levels of benzene metabolites (except BT) measured in urine samples collected from exposed workers at the end of workshift were significantly higher than those measured in unexposed subjects (P < 0.0001). The large increases in urinary metabolites from before to after work strongly correlated with benzene exposure. Concentrations of these metabolites in urine samples collected from exposed workers before work were also significantly higher than those from unexposed subjects. The half-lives of S-PMA, t,t-MA, HQ, CAT, and phenol were estimated from a time course study to be 12.8, 13.7, 12.7, 15.0, and 16.3 h, respectively. CONCLUSIONS: All metabolites, except BT, are good markers for benzene exposure at the observed levels; however, due to their high background, HQ, CAT, and phenol may not distinguish unexposed subjects from workers exposed to benzene at low ambient levels. S-PMA and t,t-MA are the most sensitive markers for low level benzene exposure.     

Analysis of urinary S-phenylmercapturic acid and trans, trans-muconic acid as exposure biomarkers of benzene in petrochemical and industrial areas of Korea

OBJECTIVES: Recently, S-phenylmercapturic acid (S-PMA) and trans,trans-muconic acid (t,t-MA) in urine have been proposed as reliable biomarkers for monitoring occupational exposure to benzene. The aim of this study was to test the applicability of S-PMA and t,t-MA as exposure biomarkers and to monitor the occupational exposure level and the extent of environmental contamination from benzene in Korea. METHODS: The urinary excretion of S-PMA and t,t-MA in rats after the intraperitoneal administration of benzene (0.88-800 mg/kg body weight, 7 days) was examined. These biomarkers were also validated in human urine samples collected from elementary schoolchildren in several industrial areas including chemical manufacturing plants, oil refineries, and natural gas-producing installations in Korea. Urine was collected from elementary schoolchildren in a mountain village with no known occupational exposure to benzene and air pollution as the reference group. RESULTS: In rats, there was a significant relationship between the benzene concentration and the excretion of the urinary S-PMA and t,t-MA as a function of concentration, and the excretion of benzene metabolites peaked on the first day after intraperitoneal administration. In human urine, higher levels of S-PMA and t,t-MA were detected more frequently in petrochemical industrial areas than in areas with no known occupational exposure to benzene. CONCLUSIONS: These results show that the quantitative determination of S-PMA and t,t-MA in urine can be used as a reliable exposure biomarker for benzene, and they also suggest that extensive attention to benzene exposure is needed for maintaining the health of the population in Korea.     

Application of the urinary S-phenylmercapturic acid test as a biomarker for low levels of exposure to benzene in industry.

Recently, the determination of S-phenylmercapturic acid (S-PMA) in urine has been proposed as a suitable biomarker for the monitoring of low level exposures to benzene. In the study reported here, the test has been validated in 12 separate studies in chemical manufacturing plants, oil refineries, and natural gas production plants. Parameters studied were the urinary excretion characteristics of S-PMA, the specificity and the sensitivity of the assay, and the relations between exposures to airborne benzene and urinary S-PMA concentrations and between urinary phenol and S-PMA concentrations. The range of exposures to benzene was highest in workers in chemical manufacturing plants and in workers cleaning tanks or installations containing benzene as a component of natural gas condensate. Urinary S-PMA concentrations were measured up to 543 micrograms/g creatinine. Workers' exposures to benzene were lowest in oil refineries and S-PMA concentrations were comparable with those in smoking or nonsmoking control persons (most below the detection limit of 1 to 5 micrograms/g creatinine). In most workers S-PMA was excreted in a single phase and the highest S-PMA concentrations were at the end of an eight hour shift. The average half life of elimination was 9.0 (SD 4.5) hours (31 workers). Tentatively, in five workers a second phase of elimination was found with an average half life of 45 (SD 4) hours. A strong correlation was found between eight hour exposure to airborne benzene of 1 mg/m3 (0.3 ppm) and higher and urinary S-PMA concentrations in end of shift samples. It was calculated that an eight hour benzene exposure of 3.25 mg/m3 (1 ppm) corresponds to an average S-PMA concentration of 46 micrograms/g creatinine (95% confidence interval 41-50 micrograms/g creatinine). A strong correlation was also found between urinary phenol and S-PMA concentrations. At a urinary phenol concentration of 50 mg/g creatinine, corresponding to an eight hour benzene exposure of 32.5 mg/m3 (10 ppm), the average urinary S-PMA concentration was 383 micrograms/g creatinine. In conclusion, with the current sensitivity of the test, eight hour time weighted average benzene exposures of 1 mg/m3 (0.3 ppm) and higher can be measured.     

尿邻甲酚作为接触甲苯生物监测指标的探讨

目的探讨尿邻甲酚作为接触甲苯生物监测指标的可能性。方法建立柱前衍生高效液相色谱法测定人体尿中邻甲酚,且使用该方法测定非职业及职业接触甲苯人群尿中邻甲酚水平,并进行接触评定。结果甲苯接触者尿邻甲酚水平为(2.61±1.94)mg/L,明显高于对照组[(0.32±0.23)mg/L],差异有显著性(P<0.001),且接触甲苯工人班后尿邻甲酚水平比班前明显升高,最高可达29倍。接触甲苯者尿邻甲酚水平与个体接触甲苯浓度明显相关(r=0.6295,P<0.01)。结论尿邻甲酚可以作为接触甲苯的生物监测指标。     

Biological monitoring of workers exposed to 4,4′-methylenediphenyl diisocyanate (MDI) in 19 French polyurethane industries

OBJECTIVES: To study the range of urinary levels of 4,4'-methylenedianiline (MDA), a metabolite of methylenediphenyl diisocyanate (MDI), across factories in the polyurethane industries and to evaluate the validity of this biomarker to assess MDI occupational exposure. METHODS: Workers exposed to MDI, as well as non-occupationally exposed subjects, were studied and pre- and post-shift urine samples were collected from 169 workers of 19 French factories and 120 controls. Details on work activities and practices were collected by a questionnaire and workers were classified into three job categories. The identification and quantification of the total urinary MDA were performed by high-performance liquid chromatography with electrochemical detection (HPLC/EC). RESULTS: For all the factories, MDA was detectable in 73% of the post-shift urine samples. These post-shift values, in the range of <0.10 (detection limit)-23.60 microg/l, were significantly higher than those of the pre-shift samples. Urinary MDA levels in the control group were in the range of < 0.10-0.80 microg/l. The degree of automation of the mixing operation (polyols and MDI) appears as a determinant in the extent of exposure levels. The highest amounts of MDA in urine were found in the spraying or hot processes. The excretion levels of the workers directly exposed to the hardener containing the MDI monomer were significantly higher than those of the other workers. In addition, skin exposure to MDI monomer or to polyurethane resin during the curing step were always associated with significant MDA levels in urine. CONCLUSIONS: Total MDA in post-shift urine samples is a reliable biomarker to assess occupational exposure to MDI in various industrial applications and to help factories to improve their manufacturing processes and working practices. A biological guiding value not exceeding 7 microg/l (5 microg/g creatinine) could be proposed in France.     

苯职业接触工人尿中酚和黏糠酸监测结果及意义

目的通过对苯接触工人尿中酚和反-反式黏糠酸的监测与分析,开展低苯环境下苯接触生物标志物研究,并探讨其实际应用价值。方法选取某制鞋厂员工作为研究对象,测定其尿液中酚和反-反式黏糠酸浓度,并对作业工人工作场所中苯浓度进行监测。结果接苯工人尿酚浓度与接苯浓度无显著性相关关系,尿中反-反式黏糠酸浓度与接苯浓度存在显著正相关(P0.05),接苯工人班后尿中的反-反式黏糠酸浓度显著高于班前尿(P0.05),吸烟对尿酚浓度影响较小,吸烟者尿中反-反式黏糠酸浓度显著高于非吸烟者(P0.05)。结论低浓度苯工作环境下,尿中反-反式黏糠酸可以作为一种敏感的生物标志物替代尿酚反映机体苯暴露情况。     

职业接触镉对工人胰岛素水平的影响

目的研究镉对职业暴露人群胰岛素和血糖水平的影响。方法以我国中南地区某冶炼厂98名镉作业工人为职业接触对象,同时选取该厂职工医院未接触镉的健康医生作为对照。按照研究对象镉接触工龄及血镉、尿镉分组,调查了不同接触工龄组及不同血镉、尿镉组工人血清胰岛素水平的变化,同时检测机体血锌、尿锌水平的改变,并就血镉、血锌及血胰岛素等水平之间的相关关系进行分析。结果接触工龄20-年组血糖水平[(4．9±0．6)mmol／L]明显高于对照组[(4．6±0．5) mmol／L],差异有统计学意义(P<0．01)。接触工龄10～年组血清胰岛素水平[(8．58±4．91)μIU/ml]明显低于对照组[(11．57±5．42)μIU/ml],差异有统计学意义(P<0．05);且随血镉、尿镉水平的增加,血清胰岛素水平明显降低。接触工龄20-年者尿锌水平明显增高。相关分析显示,胰岛素与血镉、尿镉呈明显的负相关关系,血糖与胰岛素、C肽水平之间呈正相关关系。结论职业接触镉可以导致血清胰岛素水平的降低,可能影响血糖水平。