An Increase in Plasma Adipsin Levels Is Associated With Higher Cumulative Dust Exposure and Airway Obstruction in Foundry Workers.

OBJECTIVE: The aim of the study was to assess whether plasma adipokine levels (adipsin, adiponectin, leptin, and resistin) are associated with pulmonary function in foundry workers. METHODS: We examined 65 dust-exposed foundry workers and 40 nonexposed controls and analyzed their lung function and plasma adipokine levels at baseline and after approximately 7 years of follow-up. RESULTS: A higher increase in plasma adipsin was associated with the development of airway obstruction in exposed subjects during follow-up after adjusting for body mass index changes during the follow-up period. Furthermore, the increase in adipsin levels was positively associated with cumulative dust exposure even after adjusting for smoking and body mass index changes during follow-up ( P = 0.015). CONCLUSION: The results suggest that plasma adipsin is involved in the pathogenesis of subclinical airway inflammation and the development of chronic obstruction and is induced by occupational dust exposure.

High alveolar nitric oxide is associated with steeper lung function decline in foundry workers.

Occupational dust exposure induces inflammatory responses that often precede the onset of clinical disease. Inflammation in the peripheral part of the lung can be demonstrated by measuring the alveolar NO concentration (CANO) in exhaled breath. The aim of the study was to assess whether cumulative dust exposure affects the change in CANO during follow-up and whether baseline CANO can predict an impairment in lung function during follow-up in foundry workers. We examined 74 dust-exposed and 42 nonexposed foundry workers and measured CANO and lung function at baseline and after 7 years of follow-up. An increase in CANO during the follow-up period was positively associated with cumulative dust exposure in foundry work (p= 0.035). Furthermore, a higher baseline CANO was associated with an accelerated decline in the forced vital capacity (FVC) during the follow-up period (absolute decrease in FVCp= 0.021, relative decrease in FVCp= 0.017). Higher cumulative dust exposure in foundry work is associated with a greater increase in CANO during follow-up, suggesting ongoing pulmonary inflammation in these subjects. Importantly, a high baseline CANO is associated with an accelerated decline in lung function, suggesting that CANO measurements might serve as a screening tool for high-risk workers.

Trends in occupational diseases in Finland, 1975-2013: a register study.

OBJECTIVES: The objective was to investigate trends in the incidence of recognized and suspected cases of occupational diseases in Finland from 1975 to 2013, including variations by industry - and describe and recognize factors affecting variations in incidence. DESIGN: A register study. SETTING: The data consisted of recognized and suspected cases of occupational diseases recorded in the Finnish Registry of Occupational Diseases (FROD) in 1975-2013. PARTICIPANTS: Altogether 240 000 cases of suspected and recognized ODs were analysed. PRIMARY AND SECONDARY OUTCOME MEASURES: From the annual workforce statistics and FROD data, we calculated the incidence of ODs and suspected ODs per 10 000 employees. For time trends by industrial sector, we used a 5-year moving average and a Poisson regression analysis. RESULTS: Annual average rates of ODs have varied from year to year. The total number was 25.0/10 000 employees in 1975 and 20.1/10 000 employees in 2013. Screening campaigns and legislative changes have caused temporary increases. When the financial sector was the reference (1.0), the highest incidence rates according to industrial sector were in mining and quarrying (9.87; 95% CI 8.65 to 11.30), construction (9.11; 95% CI 9.98 to 10.43), manufacturing (9.04; 95% CI 7.93 to 10.36) and agriculture (8.78; 95% CI 7.69 to 10.06). There is a distinct decreasing trend from 2005 onwards: the average annual change in incidence was, for example, -9.2% in agriculture, -10.3% in transportation and -4.7% in construction. The average annual decline was greatest in upper limb strain injuries (-11.1%). CONCLUSION: This study provides a useful overview of the status of ODs in Finland over several decades. These data are a valuable resource for determining which occupations are at an increased risk and where preventive actions should be targeted. It is important to study long-term trends in the statistics of ODs to see beyond the year-to-year fluctuations.

Glycoprotein YKL-40 Levels in Plasma Are Associated with Fibrotic Changes on HRCT in Asbestos-Exposed Subjects.

YKL-40 is a chitinase-like glycoprotein produced by alternatively activated macrophages that are associated with wound healing and fibrosis. Asbestosis is a chronic asbestos-induced lung disease, in which injury of epithelial cells and activation of alveolar macrophages lead to enhanced collagen production and fibrosis. We studied if YKL-40 is related to inflammation, fibrosis, and/or lung function in subjects exposed to asbestosis. Venous blood samples were collected from 85 men with moderate or heavy occupational asbestos exposure and from 28 healthy, age-matched controls. Levels of plasma YKL-40, CRP, IL-6, adipsin, and MMP-9 were measured with enzyme-linked immunosorbent assay (ELISA). Plasma YKL-40 levels were significantly higher in subjects with asbestosis (n = 19) than in those with no fibrotic findings in HRCT following asbestos exposure (n = 66) or in unexposed healthy controls. In asbestos-exposed subjects, plasma YKL-40 correlated negatively with lung function capacity parameters FVC (Pearson's r -0.259, p = 0.018) and FEV1 (Pearson's r -0.240, p = 0.028) and positively with CRP (Spearman's rho 0.371, p < 0.001), IL-6 (Spearman's rho 0.314, p = 0.003), adipsin (Spearman's rho 0.459, p < 0.001), and MMP-9 (Spearman's rho 0.243, p = 0.025). The present finding suggests YKL-40 as a biomarker associated with fibrosis and inflammation in asbestos-exposed subjects.

Cancer Incidence in Asbestos-Exposed Workers: An Update on Four Finnish Cohorts.

BACKGROUND: We assessed the cancer risks of four different Finnish asbestos-exposed cohorts. We also explored if the cohorts with varying profiles of asbestos exposure exhibited varying relative risks of cancer. METHODS: The incident cancer cases for the asbestos-exposed worker cohorts were updated to the end of 2012 using the files of the Finnish Cancer Registry. The previously formed cohorts consisted of asbestos mine workers, asbestosis patients, asbestos sprayers, and workers who had taken part in a screening study based on asbestos exposure at work. RESULTS: The standardized incidence ratio (SIR) for mesothelioma varied from about threefold to > 100-fold in the different cohorts. In the screening cohort the SIR for mesothelioma was highest in 2003-2007, In other cohorts it was more constant in 5-year period inspection. The SIR for lung cancer was about twofold to tenfold in all except the screening cohort. Asbestos sprayers were at the highest risk of mesothelioma and lung cancer. CONCLUSION: The SIR for mesothelioma is high in all of the cohorts that represent different kinds of asbestos exposure. The smaller SIR for mesothelioma in the screening cohort with lowest level of asbestos exposure might suggest dose-responsiveness between asbestos exposure and mesothelioma. It does seem that the highest risk of lung cancer in these cohorts except in the youngest of the cohorts, the screening cohort, is over. The highest SIR for lung cancer of the asbestosis patient and sprayers cohort is explained by their heavy asbestos exposure.

Cancer incidence among Finnish male cobalt production workers in 1969-2013: a cohort study.

BACKGROUND: There is inadequate evidence for the carcinogenicity of cobalt and cobalt compounds in humans. Consequently, the International Agency for Research on Cancer (IARC) has evaluated cobalt metal without tungsten carbide as possibly carcinogenic to humans (Group 2B). The aim of the study was to assess the risk of cancer among workers employed in a Finnish cobalt plant since the beginning of production in 1968. METHODS: The study cohort consisted of all males employed by the Finnish cobalt plant for at least a year during 1968-2004. The follow-up for cancer was performed by studying the files of the Finnish Cancer Registry, using personal identity codes as a key. The cohort was divided into subcohorts by exposure levels. Standardised incidence ratios (SIRs) and 95% confidence intervals (95% CIs) were calculated as ratios of the observed numbers of cancer cases and the numbers expected on the basis of incidence rates in the population of the same region. RESULTS: The follow-up cohort consisted of 995 men with 26,083 person-years. During the follow-up period, 92 cases of cancer were diagnosed (SIR 1.00, 95% CI 0.81-1.22), six of which were lung cancer cases (SIR 0.50; 95% CI 0.18-1.08). The only cancer type with increased incidence was tongue cancer (three cases, SIR 7.39; 95% CI 1.52-21.6). We observed no dose-response effect across the different exposure levels and the incidence of any cancer type. CONCLUSIONS: The results suggest that occupational exposure to cobalt is not associated with an increased overall cancer risk or lung cancer risk among cobalt workers. Because of the small number of cancer cases the results must be interpreted with caution.

Pulmonary inflammation in foundry workers.

OBJECTIVE: To assess whether cumulative dust exposure in foundry work is associated with airway inflammation measured by the analysis of fractionated exhaled nitric oxide (NO) concentration, or by inflammatory markers in exhaled breath condensate or serum. METHODS: We examined 476 dust-exposed and nonexposed foundry workers, and assessed the individual cumulative exposure to dusts and respirable quartz. Bronchial and alveolar NO production and inflammatory markers in exhaled breath condensate and in serum samples were also analyzed. RESULTS: After adjusting for pack-years of smoking, increased levels of alveolar NO, serum C-reactive protein, and interleukin-8 were associated with a higher level of cumulative exposure to dust. The referents had higher serum myeloperoxidase levels, bronchial NO output, and 8-isoprostane levels in exhaled breath condensate than in the dust-exposed groups. CONCLUSIONS: Dust exposure in foundry work may induce both systemic and alveolar inflammation.

Chest HRCT signs predict deaths in long-term follow-up among asbestos exposed workers.

OBJECTIVES: To study associations between chest HRCT signs and subsequent deaths in long-term follow-up. METHODS: Lung and pleural signs of 633 asbestos exposed workers (age 45-86, mean 65) screened with HRCT were recorded by using the International Classification of Occupational and Environmental Respiratory Diseases (ICOERD) system, which contains detailed instructions for use and reference images. Subsequent mortality was checked from the national register. Cox regression adjusted for covariates (age, sex, BMI, asbestos exposure, pack-years) was used to explore the relations between HRCT signs and all-cause deaths, cardiovascular and benign respiratory deaths, and deaths from neoplasms - all according to the ICD-10 diagnostic system. RESULTS: The follow-up totalled 5271.9 person-years (mean 8.3 y/person, range .04-10.3). 119 deaths were reported. Irregular/linear opacities, honeycombing, emphysema, large opacities, visceral pleural abnormalities and bronchial wall thickening were all significantly related to all-cause deaths. Most of these signs were associated also with deaths from neoplasms and benign respiratory disease. Deaths from cardiovascular disease were predicted by emphysema and visceral pleural abnormalities. CONCLUSIONS: Several HRCT signs predicted deaths. Careful attention should be paid on subjects with radiological signs predictive of deaths and new secondary preventive strategies developed. This calls for further focused studies among different populations.

Muscular, cardiorespiratory and thermal strain of mast and pole workers.

This field study evaluated the level of muscular, cardiorespiratory and thermal strain of mast and pole workers. We measured the muscular strain using electromyography (EMG), expressed as a percentage in relation to maximal EMG activity (%MEMG). Oxygen consumption (VO2) was indirectly estimated from HR measured during work and expressed as a percentage of maximum VO2 (%VO2max). Skin and deep body temperatures were measured to quantify thermal strain. The highest average muscular strain was found in the wrist flexor (24 ± 1.5%MEMG) and extensor (21 ± 1.0%MEMG) muscles, exceeding the recommendation of 14%MEMG. Average cardiorespiratory strain was 48 ± 3%VO2max. Nearly half (40%) of the participants exceeded the recommended 50%VO2max level. The core body temperature varied between 36.8°C and 37.6°C and mean skin temperature between 28.6°C and 33.4°C indicating possible occasional superficial cooling. Both muscular and cardiorespiratory strain may pose a risk of local and systemic overloading and thus reduced work efficiency. Thermal strain remained at a tolerable level.

Association of genes of protease-antiprotease balance pathway to lung function and emphysema subtypes.

BACKGROUND: The imbalance between proteases and antiproteases has been proposed to participate to the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. Gene level variation in different metalloproteinases, metalloproteinase inhibitors, and cytokines affecting them may contribute to this imbalance and destruction of the lung parenchyma. We investigated whether polymorphisms in selected protease-antiprotease balance pathway genes predispose to different emphysema subtypes (centrilobular, paraseptal, panlobular, and bullae) and airflow limitation among Finnish construction workers. METHODS: Eleven single nucleotide polymorphisms (SNPs) from seven genes (GC: rs7041 and rs4588; MMP1: rs1799750; MMP9: rs3918242; MMP12: rs652438; TIMP2: rs2277698; TNF: rs1799724 and rs1800629; TGFB1: rs1800469, rs1800470, and rs2241718) were analyzed from 951 clinically and radiologically characterized construction workers. The genotype and haplotype data was compared to different emphysematous signs confirmed with high resolution computed tomography (HRCT), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and maximal expiratory flow at 50% of FVC (MEF50) by using linear and logistic regression analyses, adjusted for potential confounders. RESULTS: The TIMP2 rs2277698 SNP was associated with overall (p = 0.022) and paraseptal (p = 0.010) emphysema, as well as with FEV1/FVC ratio (p = 0.035) and MEF50 (p = 0.008). The TGFB1 rs2241718 and MMP9 rs3918242 SNPs were associated with centrilobular emphysema (p = 0.022 and p = 0.008), and the TNF rs1800629 SNP with paraseptal emphysema (p = 0.017). In stratified analysis, individuals with at least one TIMP2 rs2277698 or TNF rs1800629 variant allele were found to be at around two-fold risk for pathological paraseptal changes (OR 1.94, 95% CI 1.14-3.30; OR 2.10, 95% CI 1.24-3.56). On the contrary, the risk for pathological centrilobular changes was halved for individuals with at least one MMP9 rs3918242 (OR 0.51, 95% CI 0.30-0.86) or TGFB1 rs2241718 (OR 0.53, 95% CI 0.30-0.90) variant allele, or TGFB1 rs1800469-rs1800470 AT-haplotype (OR 0.55, 95% CI 0.33-0.93). MEF50, in turn, was significantly reduced among individuals with at least one TIMP2 rs2277698 variant allele (p = 0.011). CONCLUSION: Our findings strengthen the hypothesis of the importance of protease-antiprotease balance in pathogenesis of emphysema and shed light on the aetiology of different emphysema subtypes by associating MMP9 and TGFB1 to centrilobular emphysema, and TIMP2 and TNF to paraseptal emphysema and/or airflow obstruction.

Adipokine adipsin is associated with the degree of lung fibrosis in asbestos-exposed workers.

OBJECTIVES: Asbestos-exposure causes an inflammatory response driven by alveolar macrophages that can lead to pulmonary fibrosis. In addition to classical inflammatory cytokines, macrophages produce adipokines which regulate the inflammatory response. We studied if adipokines are related to the degree of parenchymal fibrosis, impaired lung function and inflammation in asbestos-exposed subjects. METHODS: Eighty-five males with moderate to heavy occupational exposure to asbestos and unexposed controls were studied. We measured plasma levels of adipokines adiponectin, adipsin, leptin and resistin, IL-6, IL-8, erythrocyte sedimentation rate (ERS), spirometry and D(L,CO). Degree of interstitial lung fibrosis (septal thickening, subpleural lines, parenchymal bands or honeycombing) was scored in classes 0-5 according to a validated scoring system. The subjects were divided into three groups: normal parenchymal finding (fibrosis class 0), borderline changes (classes 0.5-1.5) and fibrosis (i.e. asbestosis; classes 2-5). RESULTS: Adipsin correlated positively with parenchymal fibrosis (rho=0.412, p<0.001) and there was a linear increasing trend of mean plasma adipsin levels among the three groups of asbestos-exposed subjects (from normal parenchymal finding to borderline changes and to fibrosis) (p<0.0001). Accordingly, plasma adipsin levels correlated positively with the extent of pleural plaques (r=0.245, p=0.043), and negatively with D(L,CO) (r=-0.246, p=0.023). Also, a positive correlation was found between adipsin and inflammatory markers ESR (r=0.315, p=0.008) and IL-6 (r=0.256, p=0.018). CONCLUSIONS: Adipsin was associated with the degree of parenchymal fibrosis, impairment of pulmonary diffusing capacity and with inflammatory activity in asbestos-exposed subjects suggesting that adipsin may have a role in the pathogenesis or as a biomarker in asbestos-induced lung disease.

Peroxiredoxins and tropomyosins as plasma biomarkers for lung cancer and asbestos exposure.

The prognosis of lung cancer is poor due to late diagnosis, the lack of established screening programs, and the paucity of early biomarkers for high-risk populations. Plasma proteome analysis was used to identify novel biomarkers for diagnosing lung cancer, and to unravel the mechanisms of underlying pathogenesis. Plasma proteins obtained from asbestos-exposed lung cancer cases detected by CT screening, asbestos-exposed subjects, clinical lung cancer patients, and healthy tobacco smokers, 5-6 cases in each group, were separated by two-dimensional gel electrophoresis, and identified with tandem mass spectrometry (LC-MS/MS). Nine proteins were selected for immunological confirmation in a test or validation set of plasma samples from an additional 49 clinical lung cancer cases, 66 asbestos-exposed patients, and 107 healthy tobacco smokers. Twenty-eight unique proteins were differentially expressed between the four study groups (p<0.05). Peroxiredoxin 1 (PRX1) was detected as a novel plasma marker for lung cancer (p=0.001). We also confirmed the previously found association of serum amyloid A with lung cancer (p<0.001). High plasma levels of tropomyosin 4 (TPM4: p<0.001) and peroxiredoxins 1 and 2 (PRX2: p<0.001) correlated with asbestos exposure or a diagnosis of asbestosis. PRX1 and PRX2 exhibited an inverse correlation with tobacco smoking (p<0.001). Plasma peroxiredoxins 1 and 2, and tropomyosin 4 were shown to associate with asbestos-exposure, and peroxiredoxin 1 with lung cancer. High plasma levels of peroxiredoxin 1 may result from genetic damage caused by reactive oxygen species. This study has identified several biomarkers worthy of further investigation in lung cancer and asbestos-related diseases.

Lung and pleural CT signs predict deaths: 10-year follow-up after lung cancer screening of asbestos-exposed workers.

PURPOSE: To work out the predictive value of pathological (HR)CT signs concerning long-term mortality among those screened for lung cancer. METHODS: Five hundred and eighty four construction workers (574 males, 10 females) were originally screened for lung cancer and found negative. Their images were also scored for several lung and pleural signs. Mortality data were checked from the National Registry of Causes of Death. Cox regression adjusted for age, sex, smoking, BMI, and asbestos exposure was used to explore the relations between the radiological signs and deaths. The mean follow-up time was 10.53 years (0.56-12.98 years) and a total of 6,150 person years were followed up. RESULTS: Altogether, 185 deaths occurred (64 cardiovascular, 51 cancer, 24 non-cancer respiratory deaths, and 46 deaths from other causes). All studied emphysema signs were significant predictors of all-cause deaths as were most fibrosis signs (subpleural nodules, septal lines, parenchymal bands, and honeycombing), ground-glass opacities, thickened bronchial walls, pleural plaque extent, and adherences. Cardiovascular deaths were significantly associated with paraseptal emphysema and bullae. Several lung/pleural signs also predicted cancer and respiratory deaths. CONCLUSION: Pathological lung/pleural CT signs found in screening seem to predict deaths in long term, which may require more careful medical surveillance of such individuals. Further studies are needed to generalize the present findings to general population.

Increased alveolar nitric oxide and systemic inflammation markers in silica-exposed workers.

BACKGROUND: Exposure to silica dust may cause inflammatory responses, primarily in the lungs, although systemic effects have also been reported. Alveolar inflammation can be demonstrated by increased alveolar concentration of nitric oxide (NO), but information on the effects of silica dust on exhaled NO is sparse. Inflammatory mediators including cytokines are known to take part in silica-induced processes, but the role of adipokines has not been studied previously. OBJECTIVES: The aim of the study was to investigate the pulmonary and systemic inflammatory responses to occupational exposure to silica dust. METHODS: The authors examined 94 silica-exposed workers and 35 healthy volunteers. The authors also measured alveolar NO concentration, bronchial NO flux and the plasma levels of proinflammatory cytokines, interleukin (IL)-6 and IL-8, and the adipokines, adipsin, leptin, adiponectin and resistin. RESULTS: After adjusting for age, body mass index and pack-years of tobacco smoking, silica exposure was associated with significantly higher levels of alveolar NO (p=0.001), indicating inflammatory effects of silica in the peripheral lung. In addition, increased plasma concentrations of IL-6, adiponectin, adipsin and resistin were significantly associated with silica exposure (p=0.002, p=0.034, p<0.001 and p=0.048, respectively). CONCLUSIONS: In conclusion, measurement of alveolar NO concentration and plasma cytokine and adipokine levels seems to offer a modern means to demonstrate the inflammatory effects of exposure to silica. These measures might be useful in finding subjects with a significant immune response to silica particles and thus at higher risk of developing silicosis or other immunological diseases associated with exposure to silica, but further research is needed.

[Occupational asthma in Finland]. / Ammattiastmat Suomessa rekisteritietojen valossa.

Occupational diseases have been registered since 1964 in Finland. The annual number of suspected or recognized occupational asthma cases is currently approximately 600. Allergy to cow epithelium as the cause of occupational asthma has decreased since the 1980's. Instead, microbes associated with moisture damage have emerged as frequent causes. Problems with indoor air and moisture damage in workplaces cause frequently respiratory symptoms and suspicions of occupational asthma. Long-term trends in the numbers and causes of occupational asthma reflect changes in working life. Even if the total number of occupational asthma cases is low, it is important to diagnose them. By this working conditions can be improved.

SERPINE2 haplotype as a risk factor for panlobular type of emphysema.

BACKGROUND: SERPINE2 (serpin peptidase inhibitor, clade E, member 2) has previously been identified as a positional candidate gene for chronic obstructive pulmonary disease (COPD) and has subsequently been associated to COPD and emphysema in several populations. We aimed to further examine the role of SERPINE2 polymorphisms in the development of pulmonary emphysema and different emphysema subtypes. METHODS: Four single nucleotide polymorphisms (SNPs) in SERPINE2 were analyzed from 951 clinically and radiologically examined Finnish construction workers. The genotype and haplotype data was compared to different emphysematous signs confirmed with high-resolution computed tomography (HRCT), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), diffusing capacity (DLCO), and specific diffusing capacity (DLCO/VA). RESULTS: Three of the studied SERPINE2 SNPs (rs729631, rs975278, and rs6748795) were found to be in tight linkage disequilibrium. Therefore, only one of these SNPs (rs729631) was included in the subsequent analyses, in addition to the rs840088 SNP which was in moderate linkage with the other three studied SNPs. The rs729631 SNP showed a significant association with panlobular emphysema (p = 0.003). In further analysis, the variant allele of the rs729631 SNP was found to pose over two-fold risk (OR 2.22, 95% CI 1.05-4.72) for overall panlobular changes and over four-fold risk (OR 4.37, 95% CI 1.61-11.86) for pathological panlobular changes. A haplotype consisting of variant alleles of both rs729631 and rs840088 SNPs was found to pose an almost four-fold risk for overall panlobular (OR 3.72, 95% CI 1.56-8.90) and subnormal (OR 3.98, 95% CI 1.55-10.20) emphysema. CONCLUSIONS: Our results support the previously found association between SERPINE2 polymorphisms and pulmonary emphysema. As a novel finding, our study suggests that the SERPINE2 gene may in particular be involved in the development of panlobular changes, i.e., the same type of changes that are involved in alpha-1-antitrypsin (AAT) -deficiency.