铬酸盐低水平长期职业接触与劳动者早期健康效应
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摘要
目的:从肺功能、免疫毒性及遗传损伤方面综合探讨铬酸盐长期低水平职业接触对劳动者健康的影响,以期发现潜在的早期健康效应标志物。方法:以内蒙古某职业卫生环境监测下长期符合国家标准的电镀企业22名铬酸盐接触工人和44名非铬酸盐接触工人为研究对象,问卷调查收集工人基本情况、吸烟饮酒史、疾病史等信息;分别采用便携式肺功能仪、电感耦合等离子体质谱法和胞滞分裂阻滞微核试验测定铬酸盐接触工人肺功能、全血铬(whole blood Cr,WB-Cr)和外周血淋巴细胞微核率(micronuclei frequency,MNF);采用流式微球阵列法检测两组工人血清细胞因子IL-1β、IL-6、IL-8、IL-10、IL-12P70和TNFα含量,分析铬酸盐接触对上述生物内暴露、肺功能、免疫应答、遗传损伤各指标的影响及不同损伤效应间的相关性。结果:(1)铬酸盐接触工人平均工龄为31年,WBCr浓度为1.11~4.19μg/L,按中位数1.72μg/L将铬酸盐接触者分为高暴露组和低暴露组,高暴露组平均WB-Cr水平(2.17μg/L)高于低暴露组(1.58μg/L)和健康人群参考值(1.74μg/L,P<0.05);(2)肺功能检测发现10名(45.45%)铬酸盐接触工人出现单个或多个肺功能指标异常情况,其中大气道损伤指标呼气流量峰值(peak expiratory flow,PEF)与小气道损伤指标每分钟最大通气量(maximum ventilation volume,MVV)和FEF25%~75%分别与WB-Cr呈负相关(r=-0.53,P<0.05;r=-0.52,P<0.05;r=-0.44,P<0.05);(3)铬酸盐接触工人血清IL-1β,IL-6,IL-8和TNFα均高于对照人群(P<0.05),且TNFα与WB-Cr间存在正相关,各细胞因子之间两两正相关(P<0.05);(4)铬酸盐接触工人淋巴细胞MNF平均为1.341%,高于一般人群参考值0.436%(P<0.01),Poisson多元回归结果显示高暴露工人MNF高于低暴露工人,OR(95%CI)值为1.323(1.049,1.669);(5)多元线性回归结果显示肺功能指标用力呼气中段流量(forced expiratory flow rate 25%~75%,FEF25%~75%)随TNFα升高而降低(P<0.05),未发现其他细胞因子、MNF、肺功能指标之间存在有统计学意义的相关性。结论:长期低水平铬酸盐职业接触引起劳动者肺功能下降、免疫炎症反应、遗传损伤的发生,其中局部或全身炎症反应与肺功能下降有关。肺功能指标PEF、FEF25%~75%、MVV,血清细胞因子IL-1β、IL-6、IL-8、TNFα水平和外周血淋巴细胞微核率可能作为铬酸盐暴露的早期健康效应标志物。
Objective: To explore the effects of low-level long-term occupational exposure to chromate on the health of workers,and the potential biomarkers of early health effects in terms of lung function,immune toxicity and genetic damage. Methods: A total of 22 chromate contact workers and 44 non-chromate contact workers from an electroplating enterprise with long-term occupational environment monitoring in line with the national standards in Inner Mongolia were investigated. The questionnaire survey was conducted to collect the basic situation,the history of smoking,drinking,diseases and so on. The portable lung function instrument,inductively coupled plasma mass spectrometry and cytokinesis-blocked micronucleus test were performed to measure the chromate contact workers' lung function,whole blood Cr( WBCr) and micronuclei frequency( MNF) of peripheral blood lymphocytes respectively. The cytometric bead array was used to detect the levels of IL-1β,IL-6,IL-8,IL-10,IL-12 P70 and TNFα in the serum among the two groups. The effects of chromate exposure on the above-mentioned indexes involved biological exposure,lung function,immune response and genetic damage,and their correlation were analyzed with different statistical methods. Results:( 1) the average length of service for chromate contact workers was 31 years,and their concentration of WB-Cr was 1. 11-4. 19 μg/L. They were divided into high and low exposure groups according to the median of 1. 72 μg/L. The WB-Cr in the high exposure group( 2. 17 μg/L) was higher than that in the low exposure group( 1. 58 μg/L) as well as the reference value of the healthy population( 1. 74 μg/L,P < 0. 05);( 2) the lung function test showed 10( 45. 45%)chromate exposure workers had single or multiple abnormal lung function indexes,among which large airway injury index PEF,and small airway injury indexes MVV and FEF25%-75% were all negatively correlated with WB-Cr( r =-0. 53,P < 0. 05; r =-0. 52,P < 0. 05; r =-0. 44,P < 0. 05);( 3) IL-1β,IL-6,IL-8 and TNFα in the serum of chromate contact workers were higher than those in the control group( P < 0. 05),and there was a positive correlation between TNFα and WB-Cr,and among these cytokines( P < 0. 05);( 4) the average lymphocyte MNF in chromate contact workers was 1. 341%,higher than the reference value of the general population( 0. 436%,P < 0. 01). Poisson regression analysis showed MNF in thehigh exposure group was higher than that in the low exposure group,OR( 95% CI) =1. 323( 1. 049,1. 669);( 5) multiple linear regression analysis showed that the lung function index FEF25%-75% decreased with the increase of TNFα( P < 0. 05),no significant correlation was found between other cytokines,MNF and lung function indexes. Conclusion: Long-term low-level occupational exposure to chromate can cause the decline of lung function,immune inflammatory reaction and genetic damage in workers,in which local or systemic inflammatory response is associated with decreased lung function. Lung function indexes PEF,FEF25%-75% and MVV,serum cytokines IL-1β,IL-6,IL-8,and TNFα,and peripheral blood lymphocyte MNF may be used as early health effects biomarkers of chromate exposure.
Objective: To explore the effects of low-level long-term occupational exposure to chromate on the health of workers,and the potential biomarkers of early health effects in terms of lung function,immune toxicity and genetic damage. Methods: A total of 22 chromate contact workers and 44 non-chromate contact workers from an electroplating enterprise with long-term occupational environment monitoring in line with the national standards in Inner Mongolia were investigated. The questionnaire survey was conducted to collect the basic situation,the history of smoking,drinking,diseases and so on. The portable lung function instrument,inductively coupled plasma mass spectrometry and cytokinesis-blocked micronucleus test were performed to measure the chromate contact workers' lung function,whole blood Cr( WBCr) and micronuclei frequency( MNF) of peripheral blood lymphocytes respectively. The cytometric bead array was used to detect the levels of IL-1β,IL-6,IL-8,IL-10,IL-12 P70 and TNFα in the serum among the two groups. The effects of chromate exposure on the above-mentioned indexes involved biological exposure,lung function,immune response and genetic damage,and their correlation were analyzed with different statistical methods. Results:( 1) the average length of service for chromate contact workers was 31 years,and their concentration of WB-Cr was 1. 11-4. 19 μg/L. They were divided into high and low exposure groups according to the median of 1. 72 μg/L. The WB-Cr in the high exposure group( 2. 17 μg/L) was higher than that in the low exposure group( 1. 58 μg/L) as well as the reference value of the healthy population( 1. 74 μg/L,P < 0. 05);( 2) the lung function test showed 10( 45. 45%)chromate exposure workers had single or multiple abnormal lung function indexes,among which large airway injury index PEF,and small airway injury indexes MVV and FEF25%-75% were all negatively correlated with WB-Cr( r =-0. 53,P < 0. 05; r =-0. 52,P < 0. 05; r =-0. 44,P < 0. 05);( 3) IL-1β,IL-6,IL-8 and TNFα in the serum of chromate contact workers were higher than those in the control group( P < 0. 05),and there was a positive correlation between TNFα and WB-Cr,and among these cytokines( P < 0. 05);( 4) the average lymphocyte MNF in chromate contact workers was 1. 341%,higher than the reference value of the general population( 0. 436%,P < 0. 01). Poisson regression analysis showed MNF in thehigh exposure group was higher than that in the low exposure group,OR( 95% CI) =1. 323( 1. 049,1. 669);( 5) multiple linear regression analysis showed that the lung function index FEF25%-75% decreased with the increase of TNFα( P < 0. 05),no significant correlation was found between other cytokines,MNF and lung function indexes. Conclusion: Long-term low-level occupational exposure to chromate can cause the decline of lung function,immune inflammatory reaction and genetic damage in workers,in which local or systemic inflammatory response is associated with decreased lung function. Lung function indexes PEF,FEF25%-75% and MVV,serum cytokines IL-1β,IL-6,IL-8,and TNFα,and peripheral blood lymphocyte MNF may be used as early health effects biomarkers of chromate exposure.
引文
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[3]Salama A,Hegazy R,Hassan A.Intranasal chromium induces acute brain and lung injuries in rats:assessment of different potential hazardous effects of environmental and occupational exposure to chromium and introduction of a novel pharmacological and toxicological animal model[J].PLo S One,2016,11(12):e168688.
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[5]Honda A,Tsuji K,Matsuda Y,et al.Effects of air pollutionrelated heavy metals on the viability and inflammatory responses of human airway epithelial cells[J].Int J Toxicol,2015,34(2):195-203.
[6]李苹,李阳,张济,等.工作场所可溶性铬酸盐职业接触限值的探讨[J].中华预防医学杂志,2014,48(3):222-224.
[7]Shrivastava R,Upreti RK,Seth PK,et al.Effects of chromium on the immune system[J].FEMS Immunol Med Microbiol,2002,34(1):1-7.
[8]Hu G,Li P,Cui X,et al.Cr(Ⅵ)-induced methylation and down-regulation of DNA repair genes and its association with markers of genetic damage in workers and 16HBE cells[J].Environ Pollut,2018,238:833-843.
[9]Xu J,Zhao M,Pei L,et al.Oxidative stress and DNA damage in a long-term hexavalent chromium-exposed population in North China:a cross-sectional study[J].BMJ Open,2018,8(6):e21470.
[10]Azad N,Rojanasakul Y,Vallyathan V.Inflammation and lung cancer:roles of reactive oxygen/nitrogen species[J].J Toxicol Environ Health B Crit Rev,2008,11(1):1-15.
[11]贾光,李阳,于善法,等.职业人群铬酸盐危害新证据及其健康监护建议[C].广州:第6届全国毒理大会,2013:1.
[12]GBZ2.2-2007,工作场所有害因素职业接触限值第二部分[S].
[13]Thomas P,Fenech M.Cytokinesis-block micronucleus cytome assay in lymphocytes[J].Methods Mol Biol,2011,682(5):217-234.
[14]Qian Q,Li P,Wang T,et al.Alteration of Th1/Th2/Th17 cytokine profile and humoralimmune responses associated with chromate exposure[J].Occup Environ Med,2013,70(10):697-702.
[15]滕晶晶.中国一般人群外周血淋巴细胞胞质分裂阻滞法微核率基准值研究[D].北京:中国疾病预防控制中心,2016.
[16]Li P,Gu Y,Yu S,et al.Assessing the suitability of 8-OHd G and micronuclei as genotoxic biomarkers in chromate-exposed workers:a cross-sectional study[J].BMJ Open,2014,4(10):e5979.
[17]杜仙梅,张济,马衍辉,等.呼吸系统损伤与铬盐职业接触水平评价指标间的相关性研究[J].中国职业医学,2009,36(2):91-94.
[18]李阳,贾光.用职业暴露矩阵综合分析环境暴露评价和生物暴露评价:以职业性铬酸盐接触为例[C].山东泰安:第十三次全国劳动卫生与职业病学术会议,2014:52-61.
[19]丁春光,潘亚娟,张爱华,等.2009-2010年我国一般人群全血和尿液中铬水平分布[J].中华预防医学杂志,2012,46(8):679-682.
[20]巴特,顾永恩,余善法,等.铬酸盐接触工人肺通气功能的动态观察[J].北京大学学报(医学版),2012,44(3):444-447.
[21]Li P,Li Y,Zhang J,et al.Biomarkers for lung epithelium injury in occupational hexavalent chromium-exposed workers[J].J Occup Environ Med,2015,57(4):e45-e50.
[22]Chandrasekaran V,Dilara K,Padmavathi R.Pulmonary functions in tannery workers:a cross sectional study[J].Indian J Physiol Pharmacol,2014,58(3):206-210.
[23]于素芳,于素芝,周克昌,等.铬酸盐生产工人肺功能配对分析[J].中国公共卫生,1997,13(4):46.
[24]Katiyar S,Awasthi SK,Sahu RK.Suppression of IL-6 level in human peripheral blood mononuclear cells stimulated with PHA/LPS after occupational exposure to chromium[J].Sci Total Environ,2008,390(2/3):355-361.
[25]许艳丹.氯乙烯作业工人遗传损伤与免疫功能的关系[D].上海:复旦大学,2013.
[26]Ring A,Stremmel W.The hepatic microvascular responses to sepsis[J].Semin Thromb Hemost,2000,26(5):589-594.
[27]Peters MC,Mcgrath KW,Hawkins GA,et al.Plasma interleukin-6 concentrations,metabolic dysfunction,and asthma severity:a cross-sectional analysis of two cohorts[J].Lancet Respir Med,2016,4(7):574-584.
[28]尹德刚.白细胞介素8在肺腺癌中的异常表达及其临床意义[D].杭州:浙江大学,2015.
[29]戴春.血清中炎症相关细胞因子与非小细胞肺癌关系的研究[D].昆明:昆明医科大学,2015.
[30]Bruno M,Ross J,Ge Y.Proteomic responses of BEAS-2B cells to nontoxic and toxic chromium:Protein indicators of cytotoxicity conversion[J].Toxicol Lett,2016,264:59-70.
[31]Wilbur S,Abadin H,Fay M,et al.Toxicological profile for chromium[M].Atlanta(GA):Agency for Toxic Substances and Disease Registry(US),2012:96-98.
[32]Proctor DM,Suh M,Campleman SL,et al.Assessment of the mode of action for hexavalent chromium-induced lung cancer following inhalation exposures[J].Toxicology,2014,325(6):160-179.
[33]Beaver LM,Stemmy EJ,Schwartz AM,et al.Lung inflammation,injury,and proliferative response after repetitive particulate hexavalent chromium exposure[J].Environ Health Perspect,2009,117(12):1896-1902.
[34]Pratheeshkumar P,Son YO,Divya SP,et al.Luteolin inhibits Cr(Ⅵ)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways[J].Toxicol Appl Pharmacol,2014,281(2):230-241.
[35]Barnes TC,Anderson ME,Moots RJ.The many faces of interleukin-6:the role of IL-6 in inflammation,vasculopathy,and fibrosis in systemic sclerosis[J/OL].Int J Rheumatol,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176444/pdf/IJR2011-721608.pdf.
[36]赵博,安晓琴,蒋轶文,等.异氰酸酯作业工人诱导痰炎性细胞及血清IL-8和IL-1β水平的变化[J].中国医科大学学报,2014,43(12):1117-1120.
[37]Bonassi S,El-Zein R,Bolognesi C,et al.Micronuclei frequency in peripheral blood lymphocytes and cancer risk:evidence from human studies[J].Mutagenesis,2011,26(1):93-100.
[38]Vodicka P,Musak L,Fiorito G,et al.DNA and chromosomal damage in medical workers exposed to anaesthetic gases assessed by the lymphocyte cytokinesis-block micronucleus(CBMN)assay.A critical review[J].Mutat Res,2016,770(Pt A):26-34.
[39]Xiaohua L,Yanshuang S,Li W,et al.Evaluation of the correlation between genetic damage and occupational chromate exposure through BNMN frequencies[J].J Occup Environ Med,2012,54(2):166-170.
[2]Gibb HJ,Lees PS,Wang J,et al.Extended followup of a cohort of chromium production workers[J].Am J Ind Med,2015,58(8):905-913.
[3]Salama A,Hegazy R,Hassan A.Intranasal chromium induces acute brain and lung injuries in rats:assessment of different potential hazardous effects of environmental and occupational exposure to chromium and introduction of a novel pharmacological and toxicological animal model[J].PLo S One,2016,11(12):e168688.
[4]Yang Y,Liu H,Xiang X H,et al.Outline of occupational chromium poisoning in China[J].Bull Environ Contam Toxicol,2013,90(6):742-749.
[5]Honda A,Tsuji K,Matsuda Y,et al.Effects of air pollutionrelated heavy metals on the viability and inflammatory responses of human airway epithelial cells[J].Int J Toxicol,2015,34(2):195-203.
[6]李苹,李阳,张济,等.工作场所可溶性铬酸盐职业接触限值的探讨[J].中华预防医学杂志,2014,48(3):222-224.
[7]Shrivastava R,Upreti RK,Seth PK,et al.Effects of chromium on the immune system[J].FEMS Immunol Med Microbiol,2002,34(1):1-7.
[8]Hu G,Li P,Cui X,et al.Cr(Ⅵ)-induced methylation and down-regulation of DNA repair genes and its association with markers of genetic damage in workers and 16HBE cells[J].Environ Pollut,2018,238:833-843.
[9]Xu J,Zhao M,Pei L,et al.Oxidative stress and DNA damage in a long-term hexavalent chromium-exposed population in North China:a cross-sectional study[J].BMJ Open,2018,8(6):e21470.
[10]Azad N,Rojanasakul Y,Vallyathan V.Inflammation and lung cancer:roles of reactive oxygen/nitrogen species[J].J Toxicol Environ Health B Crit Rev,2008,11(1):1-15.
[11]贾光,李阳,于善法,等.职业人群铬酸盐危害新证据及其健康监护建议[C].广州:第6届全国毒理大会,2013:1.
[12]GBZ2.2-2007,工作场所有害因素职业接触限值第二部分[S].
[13]Thomas P,Fenech M.Cytokinesis-block micronucleus cytome assay in lymphocytes[J].Methods Mol Biol,2011,682(5):217-234.
[14]Qian Q,Li P,Wang T,et al.Alteration of Th1/Th2/Th17 cytokine profile and humoralimmune responses associated with chromate exposure[J].Occup Environ Med,2013,70(10):697-702.
[15]滕晶晶.中国一般人群外周血淋巴细胞胞质分裂阻滞法微核率基准值研究[D].北京:中国疾病预防控制中心,2016.
[16]Li P,Gu Y,Yu S,et al.Assessing the suitability of 8-OHd G and micronuclei as genotoxic biomarkers in chromate-exposed workers:a cross-sectional study[J].BMJ Open,2014,4(10):e5979.
[17]杜仙梅,张济,马衍辉,等.呼吸系统损伤与铬盐职业接触水平评价指标间的相关性研究[J].中国职业医学,2009,36(2):91-94.
[18]李阳,贾光.用职业暴露矩阵综合分析环境暴露评价和生物暴露评价:以职业性铬酸盐接触为例[C].山东泰安:第十三次全国劳动卫生与职业病学术会议,2014:52-61.
[19]丁春光,潘亚娟,张爱华,等.2009-2010年我国一般人群全血和尿液中铬水平分布[J].中华预防医学杂志,2012,46(8):679-682.
[20]巴特,顾永恩,余善法,等.铬酸盐接触工人肺通气功能的动态观察[J].北京大学学报(医学版),2012,44(3):444-447.
[21]Li P,Li Y,Zhang J,et al.Biomarkers for lung epithelium injury in occupational hexavalent chromium-exposed workers[J].J Occup Environ Med,2015,57(4):e45-e50.
[22]Chandrasekaran V,Dilara K,Padmavathi R.Pulmonary functions in tannery workers:a cross sectional study[J].Indian J Physiol Pharmacol,2014,58(3):206-210.
[23]于素芳,于素芝,周克昌,等.铬酸盐生产工人肺功能配对分析[J].中国公共卫生,1997,13(4):46.
[24]Katiyar S,Awasthi SK,Sahu RK.Suppression of IL-6 level in human peripheral blood mononuclear cells stimulated with PHA/LPS after occupational exposure to chromium[J].Sci Total Environ,2008,390(2/3):355-361.
[25]许艳丹.氯乙烯作业工人遗传损伤与免疫功能的关系[D].上海:复旦大学,2013.
[26]Ring A,Stremmel W.The hepatic microvascular responses to sepsis[J].Semin Thromb Hemost,2000,26(5):589-594.
[27]Peters MC,Mcgrath KW,Hawkins GA,et al.Plasma interleukin-6 concentrations,metabolic dysfunction,and asthma severity:a cross-sectional analysis of two cohorts[J].Lancet Respir Med,2016,4(7):574-584.
[28]尹德刚.白细胞介素8在肺腺癌中的异常表达及其临床意义[D].杭州:浙江大学,2015.
[29]戴春.血清中炎症相关细胞因子与非小细胞肺癌关系的研究[D].昆明:昆明医科大学,2015.
[30]Bruno M,Ross J,Ge Y.Proteomic responses of BEAS-2B cells to nontoxic and toxic chromium:Protein indicators of cytotoxicity conversion[J].Toxicol Lett,2016,264:59-70.
[31]Wilbur S,Abadin H,Fay M,et al.Toxicological profile for chromium[M].Atlanta(GA):Agency for Toxic Substances and Disease Registry(US),2012:96-98.
[32]Proctor DM,Suh M,Campleman SL,et al.Assessment of the mode of action for hexavalent chromium-induced lung cancer following inhalation exposures[J].Toxicology,2014,325(6):160-179.
[33]Beaver LM,Stemmy EJ,Schwartz AM,et al.Lung inflammation,injury,and proliferative response after repetitive particulate hexavalent chromium exposure[J].Environ Health Perspect,2009,117(12):1896-1902.
[34]Pratheeshkumar P,Son YO,Divya SP,et al.Luteolin inhibits Cr(Ⅵ)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways[J].Toxicol Appl Pharmacol,2014,281(2):230-241.
[35]Barnes TC,Anderson ME,Moots RJ.The many faces of interleukin-6:the role of IL-6 in inflammation,vasculopathy,and fibrosis in systemic sclerosis[J/OL].Int J Rheumatol,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176444/pdf/IJR2011-721608.pdf.
[36]赵博,安晓琴,蒋轶文,等.异氰酸酯作业工人诱导痰炎性细胞及血清IL-8和IL-1β水平的变化[J].中国医科大学学报,2014,43(12):1117-1120.
[37]Bonassi S,El-Zein R,Bolognesi C,et al.Micronuclei frequency in peripheral blood lymphocytes and cancer risk:evidence from human studies[J].Mutagenesis,2011,26(1):93-100.
[38]Vodicka P,Musak L,Fiorito G,et al.DNA and chromosomal damage in medical workers exposed to anaesthetic gases assessed by the lymphocyte cytokinesis-block micronucleus(CBMN)assay.A critical review[J].Mutat Res,2016,770(Pt A):26-34.
[39]Xiaohua L,Yanshuang S,Li W,et al.Evaluation of the correlation between genetic damage and occupational chromate exposure through BNMN frequencies[J].J Occup Environ Med,2012,54(2):166-170.
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