| 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.
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