【作者】 翁少凡；

【导师】 陈卫红；

【作者基本信息】 华中科技大学 ， 劳动卫生与环境卫生学， 2012， 博士

【摘要】 尘肺是由于长期接触生产性粉尘引起的以肺组织纤维化为主要病理特征的疾病,是我国以及很多其他发展中国家发病最多、危害最严重的职业病。卫生部发布的年度职业病报告显示,2010年我国报告新发职业病27240例,其中尘肺病23812例,占总数的87.42%。2009年和2010年,我国报告的新发尘肺病例分别比前一年上升了33.85%和64.28%,并且群体性病例报告不断出现,严重影响社会和谐和经济的可持续发展,因此,防治尘肺是我国职业病防治的重中之重。生产性粉尘存在于很多行业,如矿山开采,公路桥梁建设、陶瓷生产等。其中矿山开采是生产性粉尘危害最严重的行业之一,在生产过程中的诸多环节如风钻、爆破、采矿、破碎、运输等产生的生产性粉尘浓度都很高。矿工长期吸入生产性粉尘可以引起肺泡炎症,肺间质增生,胶原沉积,最终发展为以纤维化为主要病理表现的尘肺病。既往研究显示,在累积粉尘暴露量和粉尘中游离二氧化硅含量接近的情况下,不同工人的尘肺发病情况不尽相同,提示尘肺的发生不仅与接触生产性粉尘有关,还受到其他因素如吸烟、患其他呼吸系统疾病、遗传易感性等的影响。本课题组前期研究时,选择湖北某大型国有铁矿1960年1月1日到1974年12月31日之间登记在册,并且在该铁矿工作过一年以上的所有工人建立了研究队列。1986年以前为回顾性资料收集,1986年以后为前瞻性随访,本研究在前期研究的基础上继续随访队列人群到2011年底。本研究目的是分析该铁矿尘肺发病规律及其影响因素,以期为铁矿及类似行业尘肺防治工作提供参考依据。同时,收集了死亡队列成员的死亡相关信息,分析生产性粉尘接触对从业工人疾病死亡率的影响,为促进工人健康,减少死亡提供指导。本研究共包括三部分：第一部分铁矿接尘工人尘肺发病规律及其影响因素研究在前期研究的基础上,本研究随访铁矿队列人群至2011年底,完成了95.93%的队列成员的终身职业史随访。尘肺病例均由具有资质的职业病诊断机构进行确诊。同时,通过铁矿历年各工作岗位粉尘浓度监测资料建立了工种-年代-总粉尘浓度矩阵,结合个人的职业史计算每个队列成员的累积粉尘接触量(cumulative dust exposure,CDE),分析铁矿接尘工人尘肺的发病规律和影响因素。本研究队列共7666人,男性6543人,女性1123人,到2011年底,共随访332609.88人年。其中接尘工人3658人,共随访150216.02人年,诊断尘肺328例,人年发病率0.22%。78.05%的尘肺发病年龄在40-60岁之间。50年代建矿之初主要接尘工作点的平均总粉尘浓度超过11mg/m3,合格率只有33%左右。随着生产工艺的改进和防尘降尘措施的采用,铁矿的总粉尘浓度迅速下降,2000年以来平均1.92 mg/m3(1.54 mg/m3-2.47 mg/m3),合格率达到90%以上。不同年代开始接尘的工人接尘量和尘肺发病有显著差异。1960年之前开始接尘的1818名工人平均累积接尘量为95.41±56.68 mg/m3-y,其中有285人被诊断为尘肺,占该铁矿诊断尘肺病例总数的86.89%；1970年之后开始接尘的865名工人的平均累积接尘量为45.51±22.84 mg/m3-y,有11人被诊断为尘肺。该铁矿尘肺的平均潜伏期为22.68年(6.92年-50.92年),其中71.34%的病例在10-30年之间。尘肺的发病危险性随着接尘量的增大而升高,呈现剂量反应关系,按累积接尘量将接尘工人分为高接尘组(CDE≥100 mg/m3-y)、中接尘组(50mg/m3-y≤CDE＜100mg/m3-y)和低接尘组(CDE<50 mg/m3-y)后,高、中、低接尘组的尘肺累积发病率分别为22.26%、7.32%和2.92%。调整性别、吸烟、患肺结核等因素之后,高、中接尘组相对于低接尘组的危险度分别为4.83(95%CI：3.97-7.76)和2.18(95%CI：1.36-3.39)。校正接尘量、性别等因素后,接尘工人中吸烟者尘肺发病危险度是不吸烟者的1.74倍(p<0.01),患有结核的接尘工人尘肺发病危险度是未患结核者的12.78倍(p<0.01)。本部分研究结果表明,尘肺的发病危险随着累积接尘量的增加而升高,吸烟和患肺结核等也会增加尘肺发病危险度。第二部分铁矿尘肺发病与遗传易感性的关联研究显示,接尘情况类似的工人,尘肺发病存在很大差异,说明尘肺发病可能受到遗传易感性的影响。矽尘进入机体后被肺泡巨噬细胞识别和吞噬,引起活性氧(Reactive oxygen species, ROS),自由基的产生和释放,溶酶体裂解,促进Nalp3炎性体的形成和成熟,从而促进细胞凋亡蛋白酶1 (Caspase-1)的活化,活化的Caspase-1可以刺激前炎性因子如白细胞介素(interleukin, IL)-1β等前体的分化成熟,从而促进纤维化的发生发展。研究对象包括铁矿的182名尘肺病例、214名非尘肺接尘工人和180名不接尘工人。由经过培训的调查人员对研究对象进行问卷调查,并在空腹时采集外周静脉血5m1,肝素抗凝,用于提取基因组DNA。采用TaqMan技术测定在生产性粉尘的免疫识别和诱发炎性反应中具有重要作用的Nalp3-Caspase-1-IL-1β通路上选定的五个SNP位点的基因型,采用Logistic多元回归分析基因型与铁矿尘肺发病之间的关联。本研究得到同济医学院伦理道德委员会批准。调整出生年月、性别、吸烟和接尘情况等因素后,Nalp3基因SNP位点rs34298345G/-型接尘工人相对于G/G型工人的尘肺发病危险度是2.96(95%CI：1.39-6.28)；Caspase-1基因SNP位点rs1042743 G/A型接尘工人相对于G/G型工人的尘肺发病危险度是3.61(95%CI：1.60-8.13)。Nalp3基因SNP位点rs1539019以及IL-1β基因SNP位点rs1143627和rs1143634突变频率与尘肺发病危险呈现负相关趋势,但差异没有统计学意义(p>0.05)。本部分研究表明rs34298345和rs1042743位点的突变型可能增加尘肺发病危险性,应该加强对这类工人的健康监护,减少尘肺发生。第三部分铁矿接尘工人死因分析本课题组对铁矿接尘工人队列进行了长达43.07年的随访,通过职工医院病历等收集了队列中死者的详细死亡资料,分析接尘对接尘工人死因的影响。根据累积粉尘接触量将接尘工人分成高、中、低接尘组,通过计算相对危险度(relative risk, RR)比较不同接尘量工人死因的差异,同时以全国城市居民年龄别疾病别死亡率为参考,计算主要疾病的标化死亡比(standardized mortality rates, SMRs)及其95%可信区间。铁矿共有接尘工人3658人,共随访150216.02人年,死亡1581人,累积死亡率43.22%,人年死亡率为1052.48/10万人年。铁矿接尘工人的前6位主要死因依次为恶性肿瘤、呼吸系统疾病、心血管疾病、脑血管疾病、意外事故和消化系统疾病。高、中、低接尘组的全死因累积死亡率依次为57.12%、43.92%和33.97%。调整性别,开始工作年龄,吸烟情况等因素后,高接尘组和中接尘组相对于低接尘组的死亡危险度分别为2.07(95%CI：1.69-2.55)和1.32(95%CI：1.11-1.56)。全死因、恶性肿瘤及其中的肺癌、心血管疾病、脑血管疾病、呼吸系统疾病及其中的COPD和尘肺的死亡率均随着接尘量的增加而升高,呈现剂量反应关系。诊断的328名尘肺病人中有248人死亡,累积死亡率75.61%,明显高于非尘肺接尘工人的40.03%。尘肺病人的肺癌、呼吸系统疾病和心血管疾病的死亡率分别为非尘肺接尘工人的2.01、4.81和1.49倍,差异有统计学意义(p<0.05)。与同期全国城市居民的平均水平相比,铁矿接尘工人死亡率升高的有全死因、肺癌、心血管疾病、脑血管疾病、呼吸系统疾病、尘肺和意外事故。本部分研究显示铁矿接尘工人的死亡率高于全国城市居民的平均水平,并且与接尘呈现剂量-反应关系。尘肺病人的死亡率高于非尘肺接尘工人。综上所述,铁矿尘肺的发病率随着接尘量的增加而升高,同时也受到吸烟、肺结核、基因多态性等的影响。加强对生产性粉尘的控制,不仅可以减少尘肺的发生,也可以降低与粉尘接触相关的疾病死亡率。更多还原

【Abstract】 Pneumoconiosis is a fibrotic disease of lungs caused by the inhalation and deposition of occupational dust for long time. It is the most serious occupational disease in China and many other developing countries. Chinese national annual occupational disease reports which are issued by the Ministry of Health showed that, there were 27240 new occupational disease cases reported in China in 2010, including 23812 new pneumoconiosis cases, which account for 87.42% of total new occupational disease, In China, the number of new pneumoconiosis cases was reported to be increased rapidly in the past several years. It is increased 33.85% and 64.28% respectively in 2009 and 2010 compared with previous year. And group pneumoconiosis cases were reported frequently in recent years. It influent the building of harmonious society and sustainable development of economic. Therefore, pneumoconiosis prevention is very important in China.Exposure to occupational dust occurs in a variety of industries, such as metal mining, constructing of highway and bridge, ceramics making. Metal mining of is one of industries which have high concentration of occupational dust in workplaces. A lot of job in the process of mining can produce occupational dust, such as drilling, mining, crushing, blasting, transporting. The workers in mine industry, who have long-term exposure to occupational dust can occur inflammation in alveolar, and sustained inflammation will cause pulmonary interstitial hyperplasia and collagen deposition, and finally developed into fibrosis, which is the main pathological features of pneumoconiosis.Many previous studies have shown that the incidence of pneumoconiosis varied among individuals while have similar cumulative dust exposure and free silica content in dust. Researches have suggested that the development of pneumoconiosis not only affected by dust exposure, but also by other factors such as smoking status, combining other respiratory diseases, and genetic susceptibility.In the preliminary study, a cohort of silica-exposed workers was established in a large state-owned iron mine located in Hubei province. The cohort included all workers registered and worked at least one year between January 1,1960 and December 31,1974 in the iron mine. Retrospective data collection before 1986 and prospectively followed up after 1986. In this study, we followed up to December 31,2011 on the basis of preliminary study.The objects of this study were to analyze the characteristic and influencing factors of pneumoconiosis in iron mine, and to provide reference to the prevention and treatment of pneumoconiosis in iron mine or similar industries. At the same time, in order to promote workers’health and reduce death, detailed information about deaths was collected to analyze the relation between occupational dust exposure and cause-specific mortalities in workers. This study includes three parts:Part I The characteristics and influencing factors of pneumoconiosis among dust exposure workers in iron mineOn the basis of preliminary studies, we followed up the subjects to December 31,2011, and completed lifelong occupational history for 95.93 %of the subjects in this study. All pneumoconiosis cases were diagnosed by qualified occupational disease diagnosis group. Meanwhile, we established the job-year-total dust concentration matrix using the monitoring data of dust concentration in every job over years, and calculated cumulative dust exposure (CDE) for each worker. The characteristics and influencing factors of pneumoconiosis in iron mine were analyzed.There are 7666 subjects in the cohort, including 6453 men and 1123 women, and 332,609.88 person-years were followed up till December 31,2011. There were 3658 workers have been exposed to occupational dust in workplace in this study, and followed up 150,216.02 person-years in total. A total of 328 pneumoconiosis cases were diagnosed during the period of follow up. The cumulative incidence of pneumoconiosis was 8.97% and morbidity was 0.22%. Among the pneumoconiosis cases in the iron mine,78.05% cases were diagnosed between 40 to 60 years old.The total dust concentration in the iron mine decreased gradually. In the 1950s, when the iron mine just rebuilt, the average total dust concentration was higher than llmg/m3 and only 33% monitor point did not exceed the national occupational standard. With the improvement of production process and the adoption of more dust controlling measures, the total dust concentration decreased dramatically. From 2000 to 2011, the average total dust concentration was 1.92 mg/m3 (1.54 mg/m3～2.47 mg/m3) and dust concentration of more than 90% monitor points were lower than the national occupational standard. There had significant difference in cumulative dust exposure and incidence of pneumoconiosis among workers began to dust exposure at different era. The average cumulative dust exposure was 95.41±56.68 mg/m3-y for 1818 workers who started dust exposure before 1960. There were 285 workers were diagnosed with pneumoconiosis in those people, accounting for 86.89% of the total pneumoconiosis cases. While the average cumulative dust exposure was 45.51±22.84 mg/m3-y for 865 workers who started dust exposure after 1970. There were only 11 workers were diagnosed with pneumoconiosis in those people. The average latency of all pneumoconiosis cases was 22.68 years (6.92years-50.92years) in the iron mine, and the latencies of 71.34% cases were between 10 to 30 years.The incidence of pneumoconiosis in iron miners increased with cumulative dust exposure, and there was a dose-response relationship. When classified dust exposure workers into three group, high dust exposure group (CDE≥100 mg/m3-y), median dust exposure group (50 mg/m3-y≤CDE≤100 mg/m3-y) and low dust exposure group (CDE<50 mg/m3-y), the cumulative morbidities of pneumoconiosis were 22.26%,7.32% and 2.92% respectively. After adjusted for gender, smoking status and the prevalence of tuberculosis, the relative risk of pneumoconiosis for workers in high dust exposure group and median dust exposure group were 4.83 (95% CI:3.97-7.76) and 2.18 (95%CI: 1.36-3.39) respectively when compared with workers in low dust exposure group.The results showed that the relative risk of pneumoconiosis in smokers was 1.74 when compared with non-smokers in this study (p＜0.01), and the risk of pneumoconiosis in dust-exposed workers with tuberculosis was 12.78 time higher than those without tuberculosis (p＜0.01) after adjusted for other factors.In this part, we found that the incidence of pneumoconiosis increased with cumulative dust exposure in iron mine, and some other factors such as smoking and tuberculosis could increase the risk of pneumoconiosis.PartⅡAssociation between the risk of pneumoconiosis and genetic susceptibilitySome studies have shown that the incidence of pneumoconiosis varied greatly among workers have similar cumulative dust exposure, indicating that genetic susceptibility played roles in developing of pneumoconiosis. Silica dust was recognized and phagocytosed by alveolar macrophage after inhalation, and induce the release of reactive oxygen species and free radical, destabilization of lysosomal, and then stimulate the formation and activation of Nalp3 inflammasome. The Nalp3 inflammasome is required for caspase-1 activation, which mediated IL-1βand IL-18 secretion and maturation in response to the stimulation of dust. IL-1βplay an important role in the development of fibrosis.The subjects included 182 pneumoconiosis cases,214 non-pneumoconiosis dust exposure workers and 180 non-dust exposure workers. Basic information, medical history and occupational history information of everyone were collected by trained investigators using questionnaire. At the same time,5ml peripheral blood were collected when in the fasting and heparin is used as anticoagulant. The blood was used for genomic DNA extraction. The genotypes of five selected single nucleotide polymorphism (SNP) locus in Nalp3-Caspase-1-IL-1βpathway were determined by TaqMan technique. Multivariable unconditional logistic regression was used to analyzed the relation between incidence of pneumoconiosis and genotypes of the five SNPs among iron mine workers. This study was approved by the Tongji Medical College Institutional Review Board.The results showed that the workers with G/-genotype at rs34298345 in Nalp3 had a 2.96-fold risk of developing pneumoconiosis when compared workers with G/G genotype (95% CI:1.39-6.28); the workers with G/A genotype at rs1042743 in Caspase-1 had a 3.61-fold risk of developing pneumoconiosis when compared workers with G/G genotype (95% CI:1.60-8.13) after adjusted for birth date, sex, smoking status and cumulative dust exposure. It seems that the mutation frequency of rs1539019 in Nalp3, rs1143627 and rs1143634in IL-1βwas negatively related with the incidence of pneumoconiosis, but the difference had no statistical significant (p>0.05).In this part, we found that the mutation at rs34298345 and rs 1142743 were associated with increased risk of pneumoconiosis in workers in iron mine. More attention should be paid to the workers’heath care with mutation at these two locus.PartⅢMortality study of dust exposed workers in iron mineIn this study, we followed up the dust exposed workers in iron mine for 43.07 years, and collected cause of death from medical records in the iron mine hospital. The influence on mortality of dust exposure were analyzed in dust exposed workers.We classified workers into three cumulative dust exposure groups, and then relative risks (RRs) were calculated. Standardized mortality rates (SMRs) and corresponding 95% confidential interval were calculated using national average death rate data (1970 to 2009) as reference.There were 3658 workers exposed to dust in the iron mine, and 1581 workers died during the period of followed up. The cumulative mortality was 43.22% and mortality was 1052.48 per 100,000 person-years. The first six causes of death included malignant tumors, respiratory diseases, cardiovascular diseases, cerebrovascular diseases, accidents and digestive diseases.The all-cause cumulative mortalities of high dust exposure group, median dust exposure group and low dust exposure were 57.12%,43.92% and 33.97% respectively. After adjusted for gender, start-working age and smoking status, The relative risk of death for workers in high dust exposure group and median dust exposure group were 2.07 (95%CI:1.69-2.55) and 1.32 (95%CI:1.11-1.56) respectively, when compared with workers in low dust exposure group. The mortalities from all-cause, cancer, lung cancer, cardiovascular disease, cerebrovascular disease, respiratory disease, COPD and pneumoconiosis were increased with cumulative dust exposure, and a dose-response relationship exist between the mortalities of these diseases and cumulative dust exposure. There were 248 deaths among 328 pneumoconiosis cases. The cumulative mortality rate was 75.61%, which was greatly higher than that in non-pneumoconiosis dust exposure workers (40.03%). The mortalities of lung cancer, respiratory disease and cardiovascular disease in pneumoconiosis cases were 2.01,4.81 and 1.49 times higher than those in non-pneumoconiosis dust exposure workers (p＜0.05).In this part, the study showed that the mortality of dust exposure workers in iron mine is higher than that of national average mortality. There was dose-response relationship between mortalities and cumulative dust exposure. The mortality of pneumoconiosis cases was higher than that of non-pneumoconiosis workers.In summary, the incidence of pneumoconiosis increased with increasing cumulative dust exposure. The development of pneumoconiosis was affected by smoking status, tuberculosis and gene polymorphism. Control dust concentrations in workplaces will be help to reduce pneumoconiosis and related death caused from dust exposure.更多还原