本文選題：隊列研究　切入點：塵肺　出處：《華中科技大學》2012年博士論文

【摘要】：塵肺是由于長期接觸生產(chǎn)性粉塵引起的以肺組織纖維化為主要病理特征的疾病,是我國以及很多其他發(fā)展中國家發(fā)病最多、危害最嚴重的職業(yè)病。衛(wèi)生部發(fā)布的年度職業(yè)病報告顯示,2010年我國報告新發(fā)職業(yè)病27240例,其中塵肺病23812例,占總數(shù)的87.42%。2009年和2010年,我國報告的新發(fā)塵肺病例分別比前一年上升了33.85%和64.28%,并且群體性病例報告不斷出現(xiàn),嚴重影響社會和諧和經(jīng)濟的可持續(xù)發(fā)展,因此,防治塵肺是我國職業(yè)病防治的重中之重。 生產(chǎn)性粉塵存在于很多行業(yè),如礦山開采,公路橋梁建設、陶瓷生產(chǎn)等。其中礦山開采是生產(chǎn)性粉塵危害最嚴重的行業(yè)之一,在生產(chǎn)過程中的諸多環(huán)節(jié)如風鉆、爆破、采礦、破碎、運輸?shù)犬a(chǎn)生的生產(chǎn)性粉塵濃度都很高。礦工長期吸入生產(chǎn)性粉塵可以引起肺泡炎癥,肺間質(zhì)增生,膠原沉積,最終發(fā)展為以纖維化為主要病理表現(xiàn)的塵肺病。 既往研究顯示,在累積粉塵暴露量和粉塵中游離二氧化硅含量接近的情況下,不同工人的塵肺發(fā)病情況不盡相同,提示塵肺的發(fā)生不僅與接觸生產(chǎn)性粉塵有關,還受到其他因素如吸煙、患其他呼吸系統(tǒng)疾病、遺傳易感性等的影響。 本課題組前期研究時,選擇湖北某大型國有鐵礦1960年1月1日到1974年12月31日之間登記在冊,并且在該鐵礦工作過一年以上的所有工人建立了研究隊列。1986年以前為回顧性資料收集,1986年以后為前瞻性隨訪,本研究在前期研究的基礎上繼續(xù)隨訪隊列人群到2011年底。 本研究目的是分析該鐵礦塵肺發(fā)病規(guī)律及其影響因素,以期為鐵礦及類似行業(yè)塵肺防治工作提供參考依據(jù)。同時,收集了死亡隊列成員的死亡相關信息,分析生產(chǎn)性粉塵接觸對從業(yè)工人疾病死亡率的影響,為促進工人健康,減少死亡提供指導。本研究共包括三部分： 第一部分鐵礦接塵工人塵肺發(fā)病規(guī)律及其影響因素研究 在前期研究的基礎上,本研究隨訪鐵礦隊列人群至2011年底,完成了95.93%的隊列成員的終身職業(yè)史隨訪。塵肺病例均由具有資質(zhì)的職業(yè)病診斷機構(gòu)進行確診。同時,通過鐵礦歷年各工作崗位粉塵濃度監(jiān)測資料建立了工種-年代-總粉塵濃度矩陣,結(jié)合個人的職業(yè)史計算每個隊列成員的累積粉塵接觸量(cumulative dust exposure,CDE),分析鐵礦接塵工人塵肺的發(fā)病規(guī)律和影響因素。 本研究隊列共7666人,男性6543人,女性1123人,到2011年底,共隨訪332609.88人年。其中接塵工人3658人,共隨訪150216.02人年,診斷塵肺328例,人年發(fā)病率0.22%。78.05%的塵肺發(fā)病年齡在40-60歲之間。 50年代建礦之初主要接塵工作點的平均總粉塵濃度超過11mg/m3,合格率只有33%左右。隨著生產(chǎn)工藝的改進和防塵降塵措施的采用,鐵礦的總粉塵濃度迅速下降,2000年以來平均1.92 mg/m3(1.54 mg/m3-2.47 mg/m3),合格率達到90%以上。不同年代開始接塵的工人接塵量和塵肺發(fā)病有顯著差異。1960年之前開始接塵的1818名工人平均累積接塵量為95.41±56.68 mg/m3-y,其中有285人被診斷為塵肺,占該鐵礦診斷塵肺病例總數(shù)的86.89%；1970年之后開始接塵的865名工人的平均累積接塵量為45.51±22.84 mg/m3-y,有11人被診斷為塵肺。該鐵礦塵肺的平均潛伏期為22.68年(6.92年-50.92年),其中71.34%的病例在10-30年之間。 塵肺的發(fā)病危險性隨著接塵量的增大而升高,呈現(xiàn)劑量反應關系,按累積接塵量將接塵工人分為高接塵組(CDE≥100 mg/m3-y)、中接塵組(50mg/m3-y≤CDE＜100mg/m3-y)和低接塵組(CDE50 mg/m3-y)后,高、中、低接塵組的塵肺累積發(fā)病率分別為22.26%、7.32%和2.92%。調(diào)整性別、吸煙、患肺結(jié)核等因素之后,高、中接塵組相對于低接塵組的危險度分別為4.83(95%CI：3.97-7.76)和2.18(95%CI：1.36-3.39)。 校正接塵量、性別等因素后,接塵工人中吸煙者塵肺發(fā)病危險度是不吸煙者的1.74倍(p0.01),患有結(jié)核的接塵工人塵肺發(fā)病危險度是未患結(jié)核者的12.78倍(p0.01)。 本部分研究結(jié)果表明,塵肺的發(fā)病危險隨著累積接塵量的增加而升高,吸煙和患肺結(jié)核等也會增加塵肺發(fā)病危險度。 第二部分鐵礦塵肺發(fā)病與遺傳易感性的關聯(lián) 研究顯示,接塵情況類似的工人,塵肺發(fā)病存在很大差異,說明塵肺發(fā)病可能受到遺傳易感性的影響。矽塵進入機體后被肺泡巨噬細胞識別和吞噬,引起活性氧(Reactive oxygen species, ROS),自由基的產(chǎn)生和釋放,溶酶體裂解,促進Nalp3炎性體的形成和成熟,從而促進細胞凋亡蛋白酶1 (Caspase-1)的活化,活化的Caspase-1可以刺激前炎性因子如白細胞介素(interleukin, IL)-1β等前體的分化成熟,從而促進纖維化的發(fā)生發(fā)展。 研究對象包括鐵礦的182名塵肺病例、214名非塵肺接塵工人和180名不接塵工人。由經(jīng)過培訓的調(diào)查人員對研究對象進行問卷調(diào)查,并在空腹時采集外周靜脈血5m1,肝素抗凝,用于提取基因組DNA。采用TaqMan技術測定在生產(chǎn)性粉塵的免疫識別和誘發(fā)炎性反應中具有重要作用的Nalp3-Caspase-1-IL-1β通路上選定的五個SNP位點的基因型,采用Logistic多元回歸分析基因型與鐵礦塵肺發(fā)病之間的關聯(lián)。本研究得到同濟醫(yī)學院倫理道德委員會批準。 調(diào)整出生年月、性別、吸煙和接塵情況等因素后,Nalp3基因SNP位點rs34298345G/-型接塵工人相對于G/G型工人的塵肺發(fā)病危險度是2.96(95%CI：1.39-6.28)；Caspase-1基因SNP位點rs1042743 G/A型接塵工人相對于G/G型工人的塵肺發(fā)病危險度是3.61(95%CI：1.60-8.13)。Nalp3基因SNP位點rs1539019以及IL-1β基因SNP位點rs1143627和rs1143634突變頻率與塵肺發(fā)病危險呈現(xiàn)負相關趨勢,但差異沒有統(tǒng)計學意義(p0.05)。 本部分研究表明rs34298345和rs1042743位點的突變型可能增加塵肺發(fā)病危險性,應該加強對這類工人的健康監(jiān)護,減少塵肺發(fā)生。 第三部分鐵礦接塵工人死因分析 本課題組對鐵礦接塵工人隊列進行了長達43.07年的隨訪,通過職工醫(yī)院病歷等收集了隊列中死者的詳細死亡資料,分析接塵對接塵工人死因的影響。 根據(jù)累積粉塵接觸量將接塵工人分成高、中、低接塵組,通過計算相對危險度(relative risk, RR)比較不同接塵量工人死因的差異,同時以全國城市居民年齡別疾病別死亡率為參考,計算主要疾病的標化死亡比(standardized mortality rates, SMRs)及其95%可信區(qū)間。 鐵礦共有接塵工人3658人,共隨訪150216.02人年,死亡1581人,累積死亡率43.22%,人年死亡率為1052.48/10萬人年。鐵礦接塵工人的前6位主要死因依次為惡性腫瘤、呼吸系統(tǒng)疾病、心血管疾病、腦血管疾病、意外事故和消化系統(tǒng)疾病。 高、中、低接塵組的全死因累積死亡率依次為57.12%、43.92%和33.97%。調(diào)整性別,開始工作年齡,吸煙情況等因素后,高接塵組和中接塵組相對于低接塵組的死亡危險度分別為2.07(95%CI：1.69-2.55)和1.32(95%CI：1.11-1.56)。全死因、惡性腫瘤及其中的肺癌、心血管疾病、腦血管疾病、呼吸系統(tǒng)疾病及其中的COPD和塵肺的死亡率均隨著接塵量的增加而升高,呈現(xiàn)劑量反應關系。 診斷的328名塵肺病人中有248人死亡,累積死亡率75.61%,明顯高于非塵肺接塵工人的40.03%。塵肺病人的肺癌、呼吸系統(tǒng)疾病和心血管疾病的死亡率分別為非塵肺接塵工人的2.01、4.81和1.49倍,差異有統(tǒng)計學意義(p0.05)。 與同期全國城市居民的平均水平相比,鐵礦接塵工人死亡率升高的有全死因、肺癌、心血管疾病、腦血管疾病、呼吸系統(tǒng)疾病、塵肺和意外事故。 本部分研究顯示鐵礦接塵工人的死亡率高于全國城市居民的平均水平,并且與接塵呈現(xiàn)劑量-反應關系。塵肺病人的死亡率高于非塵肺接塵工人。 綜上所述,鐵礦塵肺的發(fā)病率隨著接塵量的增加而升高,同時也受到吸煙、肺結(jié)核、基因多態(tài)性等的影響。加強對生產(chǎn)性粉塵的控制,不僅可以減少塵肺的發(fā)生,也可以降低與粉塵接觸相關的疾病死亡率。
[Abstract]:According to the annual occupational disease report released by the Ministry of Health , there are 27240 new cases of occupational disease reported in China in 2010 . Among them , there are 2,812 cases of new occupational diseases reported in China in 2010 , accounting for 87.42 % of the total . In 2009 and 2010 , the new cases reported in China increased by 33.85 % and 64.28 % respectively compared with the previous year .
Production dust exists in many industries , such as mine exploitation , highway bridge construction , ceramic production , etc . Among them , mining is one of the most serious industries in productive dust .
Previous studies have shown that in cases where the cumulative dust exposure and the free silicon dioxide content in the dust are close to each other , the occurrence of dust - lungs of different workers is different , suggesting that the occurrence of dust - lungs is not only related to the contact with the production dust , but also affected by other factors such as smoking , other respiratory diseases , genetic susceptibility , and the like .
In the preliminary study of the study group , a large state - owned iron mine in Hubei was selected to register between January 1 , 1960 and December 31 , 1974 , and all workers who had worked for more than one year in the iron mine set up a study cohort . In 1986 , a retrospective data collection was conducted , followed by a prospective follow - up in 1986 , and the study was followed up on the basis of previous studies to follow up the cohort population until the end of 2011 .
The purpose of this study is to analyze the pathogenesis and influencing factors of dust - dust in the iron mine , with a view to providing a reference for the prevention and treatment of dust and lung in iron ore and similar industries . At the same time , the related information of death queue members is collected , and the influence of the contact on the mortality of workers in the industry is analyzed , which provides guidance for promoting the health of workers and reducing death . The study consists of three parts :
Study on the pathogenesis and influencing factors of dust - dust in the first part of iron ore dust - collecting workers
At the end of 2011 , the follow - up iron ore cohort population of this study completed 95.93 % of the cohort member ' s lifetime career history follow - up . All cases of dust and lung were diagnosed by qualified occupational disease diagnosis organizations . Meanwhile , the cumulative dust exposure ( CDE ) of each cohort member was calculated based on the monitoring data of dust concentration in each post of iron mine . The cumulative dust exposure ( CDE ) of each cohort member was calculated based on the occupational history of the individual .
The study cohort was 7666 , male 6543 , female 1123 , by the end of 2011 , a total of 3,2609 . 88 persons were followed up . Among them , 3658 workers were followed up for a total of 150216.02 person years .
The average total dust concentration of the main dust collecting working point in the early 1950s was more than 11mg / m3 and the qualification rate was only about 33 % . With the improvement of the production process and the dust reduction measures , the total dust concentration of iron ore decreased rapidly , the qualified rate reached over 90 % .
The average cumulative exposure of 865 workers who began to dust after 1970 was 45.51 鹵 22.84 mg / m3 - y , and 11 were diagnosed with dust . The average latency of the dust - dust was 22.68 years ( 6.92 years - 50.92 years ) , among which 71.34 % were between 10 - 30 years .
The morbidity risk of dust - dust increased with the increase of dust - collecting volume . The incidence of dust - dust accumulation was 22.26 % , 7.32 % and 2.92 % in high , middle and low dust groups . The risk of dust - dust group was 4.83 ( 95 % CI : 3.97 - 7.76 ) and 2.18 ( 95 % CI : 1.36 - 3.39 ) respectively .
After correction of dust and sex , the risk of dust - lung disease among dust - exposed workers was 1.74 times that of non - smokers ( p0.01 ) , and the risk of dust - lung disease of dust - collecting workers with tuberculosis was 12.78 times ( p0.01 ) .
The results of this study showed that the risk of dust - dust increased with the increase of cumulative dust exposure , smoking and pulmonary tuberculosis .
Correlation between the pathogenesis and genetic susceptibility of the second part of iron - iron mine
The study shows that there is a great difference in the morbidity of dust and lungs similar to those of workers exposed to dust . It is suggested that the pathogenesis of dust may be influenced by genetic susceptibility . After entering the organism , the generation and release of reactive oxygen species ( ROS ) , free radicals production and release , lysosomal lysis , activation of Caspase - 1 can stimulate the differentiation and maturation of pro - inflammatory factors such as interleukin ( IL ) - 1尾 , and thus promote the development of fibrosis .
Two hundred and eighty - one hundred and eighty - two dust - free workers and 180 non - dust workers were investigated . The subjects were investigated by trained investigators , and peripheral venous blood ( 5m1 ) and heparin ( anticoagulant ) were collected from the trained investigators to extract genomic DNA .
After adjusting the factors such as birth date , sex , smoking and dust exposure , the risk of dust - lung morbidity among the SNP loci rs34298345G / - type workers exposed to G / G workers was 2.96 ( 95 % CI : 1.39 - 6.28 ) .
The risk of dust - lung morbidity of the SNP site rs1042743 G / A of the Caspase - 1 gene was 3.61 ( 95 % CI : 1.60 - 8.13 ) compared with the G / G workers . rs1143627 and rs1143634 SNP loci rs1143627 and rs1143634 were negatively correlated with the risk of dust and lung disease , but the difference was not statistically significant ( p . 05 ) .
This partial study shows that the mutation of rs34298345 and rs1042743 sites may increase the risk of dust and lung disease , and should strengthen the health monitoring of these workers and reduce the occurrence of dust .
Analysis on the Cause of Death of Dust - Connected Workers in the Third Part of Iron Mine
The study group conducted a follow - up of 43.07 years for iron ore dust collection workers ' queue , collected the detailed death data of the dead in the queue through the medical records of the staff and staff , and analyzed the effect of the death cause of the dust and dust collecting workers .
According to the cumulative dust exposure , the dust - collecting workers were divided into high , middle and low dust - collecting groups , and the relative risk ( RR ) was calculated to compare the causes of death among workers with different dust exposure . At the same time , the standardized mortality rates ( SMRs ) and their 95 % confidence intervals were calculated by calculating relative risk ( RR ) .
The total annual mortality rate was 43.22 % , the cumulative mortality rate was 43.22 % , and the annual mortality rate was 1052.48 / 100000 person years . The first six main causes of death were malignant tumor , respiratory system disease , cardiovascular disease , cerebrovascular disease , accident and digestive system disease .
The total death rate of the high , middle and low dust groups was 57.12 % , 43.92 % and 33.97 % , respectively . After adjusting sex , starting work age and smoking status , the risk of death in high dust collecting group and middle dust collecting group was 2.07 ( 95 % CI : 1.69 - 2.55 ) and 1.32 ( 95 % CI : 1.11 - 1.56 ) , respectively . All cause of death , malignant tumor and its lung cancer , cardiovascular disease , cerebrovascular disease , respiratory system disease and its mortality all increased with the increase of dust exposure , showing dose response relationship .
Of the 328 patients diagnosed , 248 died and the cumulative mortality rate was 75.61 % , which was significantly higher than that of non - dust - exposed workers ( 40.03 % ) . The mortality rates of lung cancer , respiratory diseases and cardiovascular diseases were 2.01 , 4.81 and 1.49 times of the non - dust - free workers , respectively , and the difference was statistically significant ( p . 05 ) .
Compared with the average of the urban residents in the same period , the death rate of the iron ore - connected workers increased , including all causes of death , lung cancer , cardiovascular diseases , cerebrovascular diseases , respiratory diseases , dust and lung and accidents .
The study shows that the mortality rate of dust - connected workers is higher than the average of urban residents in the whole country , and the dose - response relationship is related to the exposure to dust . The mortality rate of patients with dust - lung disease is higher than that of non - dust - exposed workers .
To sum up , the incidence of dust - dust in iron ore is increased with the increase of dust collecting , and it is affected by smoking , pulmonary tuberculosis , gene polymorphism and so on . The control of productive dust can not only reduce the occurrence of dust , but also reduce the mortality associated with dust exposure .

【學位授予單位】：華中科技大學
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R135.2

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