Occupational exposure to crystalline silica in a sample of the French general population.

OBJECTIVE: To describe the proportions of subjects exposed to crystalline silica and the sectors of activity concerned between 1965 and 2010 in a sample of the general French population. METHODS: We included 2942 participants aged 40 to 65 years, recruited at random from electoral rolls, from the French general population in the cross-sectional ELISABET study between 2011 and 2013. The proportions of subjects exposed to crystalline silica and their sectors of activity were determined on the basis of their career history and the use of the Matgéné job-exposure matrix. RESULTS: In the total sample, occupational exposure to crystalline silica was found for 291 subjects (9.9%) between 1965 and 2010, with a predominance of men (20.2% of exposed subjects among men (282 out of 1394) versus 0.6% among women (9 out of 1548)). The highest proportion of participants exposed to crystalline silica was reached in 1980 with 6.1% and then decreases to 4.4% in 2010. Among men, the most frequently exposed sectors of activity were manufacture of basic metals (41.5% of exposed men (117 out of 282)), specialised construction activities (23.1% of exposed men (65 out of 282)) and construction of buildings (14.2% of exposed men (40 out of 282)). CONCLUSIONS: Although the proportion of workers exposed to crystalline silica has been decreasing since the 1980s, it is still significant at least until 2010, particularly in the construction sector, and further research is needed to improve the monitoring of workers who are or have been exposed to crystalline silica.

Assessment of lung hyperinflation in occupational chronic obstructive pulmonary disease: a multicentric cross-sectional study.

Occupational exposure is associated with elevated morbidity and lower quality of life in patients with chronic obstructive pulmonary disease (COPD). Static hyperinflation is an independent risk factor for all-cause mortality in COPD and for COPD exacerbation. In a multicentre, cross-sectional study (BPROFETIO), we sought to analyse the relationship between static hyperinflation and occupational exposure in patients with COPD with or without occupational exposure. MATERIAL AND METHODS: An overall 'whole working life' cumulative exposure index was calculated for occupational patients with COPD. Spirometry indices and lung volumes were measured according to the 2005 American Thoracic Society/European Respiratory Society guidelines. RESULTS: After adjustment for age, sex, height, body mass index, smoking and coexposure, the analysis for each occupational hazard showed a higher risk for hyperinflation and FEV1 decline or progression of COPD or GOLD stage for patients with COPD exposed to non-metallic inorganic dusts. CONCLUSION: Occupational exposures should be more investigated in clinical practice and studies as they contribute to the COPD heterogeneity and are associated for some with the development of a static hyperinflation; a condition that is known to have a negative impact on quality of life and survival.

The impact of occupational exposure to crystalline silica dust on respiratory function (airway obstruction and FEF25-75) in the French general population.

INTRODUCTION: Although several studies have studied the relationship between occupational exposure to crystalline silica dust and respiratory mortality, few have examined the relationship with impairments in respiratory function and the exposure threshold triggering spirometric monitoring in exposed workers. The objective of the present study was to evaluate the impact of exposure to crystalline silica dust on respiratory function. METHODS: We included 1428 male participants (aged 40 to 65) recruited from the French general population, at random from electoral rolls, in the cross-sectional ELISABET study and for whom data on forced expiratory flow-volume curve indices z-scores (calculated using the Global Lung Function Initiative 2012 equations) and exposure (via a questionnaire) were available. A cumulative exposure index (CEI) for crystalline silica dust (CEIsilica, expressed in mg.m-3.year) was calculated using the Matgéné occupational exposure matrix. RESULTS: 293 of the 1428 participants (20.52%) reported exposure to silica dust. We found that the adjusted z-scores for the forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) ratio decreased significantly as CEIsilica increased. After adjustment, the adjusted z-scores for FEV1/FVC (ß: -0.426 (95% confidence interval (CI): -0.792, -0.060) per 1 mg m-3.year increment) and the mean forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25-75) (ß: -0.552 (95% CI: -0.947, -0.157)) were significantly lower in the participants with CEIsilica ≥1 mg m-3.year than in non-exposed participants. The likelihoods of having airway obstruction (odds ratio (OR): 3.056 (95% CI: 1.107, 7.626)) or having an impaired FEF25-75 (OR: 4.305 (95% CI: 1.393, 11.79)) were also significantly higher in participants with CEIsilica ≥1 mg m-3.year. CONCLUSION: Our results emphasize the importance of spirometry-based monitoring in workers exposed to more than 1 mg m-3.year of crystalline silica dust, in order to identify small airway obstruction or airway obstruction as early as possible.

Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set.

BACKGROUND: The single-breath diffusing capacity of the lung for carbon monoxide (DLCO) interpretation needs the comparison of measured values to reference values. In 2017, the Global Lung Function Initiative published new reference values (GLI-2017) for DLCO, alveolar volume (VA) and transfer coefficient of the lung for carbon monoxide (KCO). We aimed to assess the applicability of GLI-2017 reference values for DLCO on a large population by comparing them to the European Community of Steel and Coal equations of 1993 (ECSC-93) widely used. METHODS: In this retrospective study, spirometric indices, total lung capacity, DLCO, VA and KCO were measured in adults classified in 5 groups (controls, asthma, chronic bronchitis, cystic fibrosis, and interstitial lung diseases (ILD)). Statistical analysis comparing the 2 equations sets were stratified by sex. RESULTS: 4180 tests were included. GLI-2017 z-scores of the 3 DLCO indices of the controls (n = 150) are nearer to 0 (expected value in a normal population) than ECSC-93 z-scores. All groups combined, in both genders, DLCO GLI-2017 z-scores and %predicted are significantly higher than ECSC z-scores and %predicted. In the ILD group, differences between the 2 equation sets depend on the DLCO impairment severity: GLI-2017 z-scores are higher than ECSC z-scores in patients with no or "mild" decrease in DLCO, but are lower in "moderate" or "severe" decrease. CONCLUSION: GLI-2017 reference values for DLCO are more suitable to our population and influence the diagnostic criteria and severity definition of several lung diseases.

Extracellular vesicles as actors in the air pollution related cardiopulmonary diseases.

Many associations were reported between air pollution and daily mortality rates for cardiopulmonary diseases. Humans are exposed to a mixture of oxidizing gases and particles, both anthropogenic and natural. Exposure to air toxics causes or exacerbates cardiovascular damages and respiratory diseases. Numerous studies have identified the induction of oxidative stress and sustained inflammatory response as among the main known underlying pathophysiological mechanisms of air pollutants. More recently, the relationship between these mechanisms of action and the secretion of extracellular vesicles (EVs) by lung cells has been revealed. EVs have been shown to be important mediators of cellular communication in the body. The purpose of this review is to first recall the main air pollutants. Then, the cardiopulmonary diseases caused by exposure to air pollution and the pathophysiological mechanisms are presented before showing, through an exhaustive review of the literature, the involvement of EVs in the toxicity of air pollutants and the initiation of cardiopulmonary diseases.

The association between blood cadmium and glycated haemoglobin among never-, former, and current smokers: A cross-sectional study in France.

INTRODUCTION: The association between cadmium levels in the body and diabetes has been extensively studied, with sometimes contrasting results. Smoking is the primary non-occupational source of cadmium, and constitutes a risk factor for diabetes. One can therefore hypothesize that the putative association with cadmium is actually explained by tobacco. To fully control for this confounding factor, we studied the relationship between blood cadmium and glycated haemoglobin (HbA1c) levels separately in never-, former and current smokers. METHODS: We studied a sample of 2749 middle-aged adults from the cross-sectional ELISABET survey in and around the cities of Lille and Dunkirk; none had chronic kidney disease or a history of haematological disorders, and none were taking antidiabetic medication. The blood cadmium level-HbA1c associations in never-, former and current smokers were studied in separate multivariate models. The covariables included age, sex, city, educational level, tobacco consumption (or passive smoking, for the never-smokers), body mass index, estimated glomerular filtration rate, and (to take account of the within-batch effect) the cadmium batch number. RESULTS: In the multivariate analysis, a significant association between cadmium and HbA1c levels was found in all three smoking status subgroups. A 0.1 µg/L increment in blood cadmium was associated with an HbA1c increase [95% confidence interval] of 0.016% [0.003; 0.029] among never-smokers, 0.024% [0.010; 0.037] among former smokers, and 0.020% [0.012; 0.029] among current smokers. CONCLUSIONS: The observation of a significant association between the blood cadmium concentration and HbA1c levels in a group of never-smokers strengthens the hypothesis whereby diabetes is associated with cadmium per se and not solely with tobacco use. The small effect size observed in our population of never smokers with low levels of exposure to cadmium suggested that the risk attributable to this metal is not high. However, the impact of exposure to high cadmium levels (such as occupational exposure) on the risk of diabetes might be of concern.

Early Effect Markers and Exposure Determinants of Metalworking Fluids Among Metal Industry Workers: Protocol for a Field Study.

BACKGROUND: Exposure to aerosols from metalworking fluids (MWF) has previously been related to a series of adverse health outcomes (eg, cancer, respiratory diseases). Our present epidemiological study focuses on occupational exposures to MWF and a panel of exposure and effect biomarkers. We hypothesize that these health outcomes are caused by particle exposure that generates oxidative stress, leading to airway inflammation and ultimately to chronic respiratory diseases. We aimed to assess whether MWF exposure, in particular as characterized by its oxidative potential, is associated with biomarkers of oxidative stress and inflammation as well as genotoxic effects. OBJECTIVE: The ultimate goal is to develop exposure reduction strategies based on exposure determinants that best predict MWF-related health outcomes. The following relationships will be explored: (1) exposure determinants and measured exposure; (2) occupational exposure and preclinical and clinical effect markers; (3) exposure biomarkers and biomarkers of effect in both exhaled breath condensate and urine; and (4) biomarkers of effect, genotoxic effects and respiratory symptoms. METHODS: At least 90 workers from France and Switzerland (30 controls, 30 exposed to straight MWF and 30 to aqueous MWF) were followed over three consecutive days after a nonexposed period of at least two days. The exposure assessment is based on MWF, metal, aldehyde, and ultrafine particle number concentrations, as well as the intrinsic oxidative potential of aerosols. Furthermore, exposure biomarkers such as metals, metabolites of polycyclic aromatic hydrocarbons and nitrosamine are measured in exhaled breath condensate and urine. Oxidative stress biomarkers (malondialdehyde, 8-isoprostane, 8-hydroxy-2'-deoxyguanosine, nitrates, and nitrites) and exhaled nitric oxide, an airway inflammation marker, are repeatedly measured in exhaled breath condensate and urine. Genotoxic effects are assessed using the buccal micronucleus cytome assay. The statistical analyses will include modelling exposure as a function of exposure determinants, modelling the evolution of the biomarkers of exposure and effect as a function of the measured exposure, and modelling respiratory symptoms and genotoxic effects as a function of the assessed long-term exposure. RESULTS: Data collection, which occurred from January 2018 until June 2019, included 20 companies. At the date of writing, the study included 100 subjects and 29 nonoccupationally exposed controls. CONCLUSIONS: This study is unique as it comprises human biological samples, questionnaires, and MWF exposure measurement. The biomarkers collected in our study are all noninvasive and are useful in monitoring MWF exposed workers. The aim is to develop preventative strategies based on exposure determinants related to health outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13744.

Short-term exposure to air pollution: Associations with lung function and inflammatory markers in non-smoking, healthy adults.

INTRODUCTION: Air pollution impacts health by increasing mortality and the incidence of acute events in unhealthy individuals. In contrast, the acute effects of pollution in healthy individuals are less obvious. The present study was designed to evaluate the associations between short-term exposure to air pollution on one hand and lung function, and inflammatory markers on the other in middle-aged, non-smoking adults with no respiratory disease, in two urban areas in northern France. METHODS: A sample of 1506 non-smoking adults (aged from 40 to 65) with no respiratory disease was selected from the participants in the 2011-2013 cross-sectional Enquête Littoral Souffle Air Biologie Environnement (ELISABET) survey in two urban areas in the northern France. We evaluated the associations between (i) mean levels of particulate matter with aerodynamic diameter < 10 µm (PM10), nitrogen dioxide (NO2) and ozone (O3) exposure on the day and the day before the study examination for each participant, and (ii) spirometry data and levels of inflammatory markers. Coefficients of multiple linear regression models were expressed (except for the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio) as the percentage change [95% confidence interval] per 10 µg increment in each pollutant. RESULTS: Levels of PM10, NO2 and O3 exposure were below or only close to the World Health Organization's recommended limits in our two study areas. An increment in NO2 levels was significantly associated with a lower FEV1/FVC ratio (-0.38 [-0.64; -0.12]), a lower forced expiratory flow between 25% and 75% of FVC (FEF25-75%) (-1.70 [-3.15; -0.23]), and a lower forced expiratory flow measured at 75% of FVC (FEF75%) (-3.07 [-4.92; -1.18]). An increment in PM10 levels was associated with lower FEF75% (-1.41 [-2.79; -0.01]) and a non-significant elevation in serum levels of high-sensitivity C-reactive protein (+3.48 [-0.25; 7.36], p = 0.07). Lastly, an increment in O3 levels was associated with a significantly higher blood eosinophil count (+2.41 [0.10; 4.77]) and a non-significant elevation in fractional exhaled nitric oxide (+2.93 [-0.16; 6.13], p = 0.06). CONCLUSION: A short-term exposure to air pollution was associated with a subclinical decrement in distal lung function and increment in inflammatory markers in healthy inhabitants of two urban areas in France. If these exploratory results are confirmed, this could suggest that even moderate levels of air pollution could have an impact on respiratory health on the general population, and not solely on susceptible individuals.

Exhaled breath NOx levels in a middle-aged adults population-based study: reference values and association with the smoking status.

BACKGROUND: Biomarkers in exhaled breath condensate (EBC) are potentially sensitive indicators of early biochemical changes in airways following exposure to pneumotoxic substances, particularly in susceptible subjects. NOx are the stable end products of the nitrite-nitrate-NO oxidative stress pathway and can be used to monitor airway inflammatory diseases, especially in asthma. Nevertheless, population-based surveys are needed to better interpret EBC NOx levels in clinical studies. The aim of this study was to establish reference values of EBC NOx in a large group of middle-aged, healthy adults of a sample of the general population with particular focus on the smoking status. METHODS: The EBC NOx levels were analysed from 2872 subjects among the ELISABET population-based cross sectional study including a representative sample of men and women aged from 40 to 66 years olds conducted in northern France, which included comprehensive questionnaires by interview and spirometry data. Healthy participants were defined as participants with no self-reported respiratory disease. RESULTS: For the healthy subjects (n = 1251), the median NOx concentration (IQR) was equal to 7.2  µM (3.12) and concentrations of NOx in EBC did not differ significantly according to smoking status. The upper fifth percentile (95%) (ULN) of NOx concentrations among healthy subjects was equal to 13.6  µM, ranging from 12.7  µM (smokers) to 14.4  µM (ex smokers). Among subjects with EBC NOx values higher than the ULN and compared with subjects that had EBC NOx values lower than the ULN, we found a significant higher proportion of subjects with current asthma (10.5% vs 6.5%) or with chronic bronchitis symptoms (7.6% vs 3.3%). CONCLUSION: This population-based study has provided the distribution and the upper limit reference value of a nitrosative stress biomarker (NOx) in EBC of middle aged, healthy adults. EBC NOx levels were not associated with smoking status.

Effects of occupational exposure to poorly soluble forms of beryllium on biomarkers of pulmonary response in exhaled breath of workers in machining industries.

OBJECTIVE: To analyze the effects of occupational exposure to poorly soluble forms of beryllium (Be) on biomarkers of pulmonary inflammation using exhaled breath condensate (EBC) in workers employed in machining industries. METHODS: Twenty machining operators were compared to 16 controls. The individual exposure to Be was assessed from the work history with several indices of exposure calculated on the basis of task-exposures matrices developed for each plant using historical air measurements. Clinical evaluation consisted in a medical questionnaire, measurements of biomarkers in EBC (tumor necrosis factor alpha (TNF-α), total nitrogen oxides (NOx)), measurement of the fraction of exhaled nitric oxide (FeNO) and resting spirometry. Adjusted multiple linear regressions were used to study the effect of the exposure to Be on inflammatory biomarkers. RESULTS: Levels of TNF-α and NOx in EBC were not statistically different between exposed and controls. We found a statistically significant relationship between levels of TNF-α in EBC and both index of cumulative exposure and duration of exposure to Be. No other statistically significant relationships were found between exposure to Be and pulmonary response. CONCLUSION: Our results suggest that machining-related exposure to Be is related to pulmonary inflammation involving TNF-α. These findings must be confirmed by larger studies.

Beryllium in exhaled breath condensate as a biomarker of occupational exposure in a primary aluminum production plant.

OBJECTIVE: Low beryllium exposure can induce pulmonary granulomatosis, so called berylliosis. For occupational health monitoring, it is more relevant to assess the internal dose of Be received by the lungs than urinary or atmospheric Be. Exhaled breath condensate (EBC) is a matrix collected non-invasively that derives from the airway lining fluid. EBC beryllium (Be) levels were evaluated as a marker of occupational exposure in a primary aluminum production plant. METHODS: We collected urine and EBC from controls and workers recently exposed to beryllium in the pot room and the anode repair sectors, and calculated a cumulative beryllium exposure index (CBEI) summing the number of years of employment in each task and multiplying by the estimated average beryllium exposure for the task. Concentrations of beryllium and aluminum were measured in EBC (Be-EBC and Al-EBC) and in urine (Be-U and Al-U) by ICP-MS. RESULTS AND CONCLUSION: We have shown that it was possible to measure Be and Al in workers' EBC. Compared with controls and after adjustment for smoking status, levels of Be-EBC and Al-EBC were higher in pot room workers and exposed subjects, respectively. Due to its relationship with CBEI, but not with Be-U, it appears that Be-EBC could be a promising marker of occupational exposure and provide additional toxicokinetic information in occupational health studies.

Manganese in exhaled breath condensate: a new marker of exposure to welding fumes.

OBJECTIVE: To evaluate manganese in exhaled breath condensate (Mn-EBC) as an indicator of exposure to fumes from metal inert gas welding process. METHODS: We collected EBC and urine from 17 welders and 16 unexposed control subjects after 5 days exposure. Concentrations of manganese (Mn), nickel (Ni), iron (Fe) and chromium (Cr) were measured in EBC and urine samples and correlated with cumulative exposure indices for the working week (CIW) and for the total welding years (WY), based on duration of welding activity and atmospheric metal measurements. RESULTS: Concentrations of Mn and Ni in EBC were significantly higher among welders than controls whereas this difference was not significant for Mn in urine. Levels of Mn and Ni in EBC were not correlated with their respective levels in urine. The linear regressions found significant positive coefficients between Mn-EBC, Ni-EBC, Ni-U and Cr-U concentrations and the cumulative exposure indices. Taking into account tobacco use, statistical analysis showed the same trends except for the relationship between Mn-U and CIW. CONCLUSION: This pilot study showed that Mn-EBC, as well as Ni-EBC, can serve as reliable indices of occupational exposure to welding fumes and provide complimentary toxicokinetic information to that provided by urine analyses.

Mica dust and pneumoconiosis: example of a pure occupational exposure in a muscovite milling unit.

OBJECTIVE: We present pulmonary disorders of four employees who were exposed to high concentration of pure mica dust in a muscovite milling unit. METHOD: All cases underwent traditional examinations with a dual-energy chest computed tomographic scan. An analysis of exhaled breath condensate by Raman microspectrometry and of mineralogical content of a lung biopsy was performed for one case. RESULTS: All cases showed bilateral micronodular ground glass opacities and mediastinal and hilar hyperdense lymph nodes consistent with the nodal sequestration of mineral particles. Histological analysis showed giant cell granulomas without typical silicotic nodule with high concentration of birefringent particles consistent with mica. Mica particles found in the exhaled breath condensate were identical to particles in ambient air at the company. CONCLUSION: Occupational exposure to mica dust is responsible for diffuse infiltrative lung disease by overload processes.

AMP-activated protein kinase deficiency reduces ozone-induced lung injury and oxidative stress in mice.

BACKGROUND: Acute ozone exposure causes lung oxidative stress and inflammation leading to lung injury. At least one mechanism underlying the lung toxicity of ozone involves excessive production of reactive oxygen and nitrogen intermediates such as peroxynitrite. In addition and beyond its major prooxidant properties, peroxynitrite may nitrate tyrosine residues altering phosphorylation of many protein kinases involved in cell signalling. It was recently proposed that peroxynitrite activates 5'-AMP-activated kinase (AMPK), which regulates metabolic pathways and the response to cell stress. AMPK activation as a consequence of ozone exposure has not been previously evaluated. First, we tested whether acute ozone exposure in mice would impair alveolar fluid clearance, increase lung tissue peroxynitrite production and activate AMPK. Second, we tested whether loss of AMP-activated protein kinase alpha1 subunit in mouse would prevent enhanced oxidative stress and lung injury induced by ozone exposure. METHODS: Control and AMPKα1 deficient mice were exposed to ozone at a concentration of 2.0 ppm for 3 h in glass cages. Evaluation was performed 24 h after ozone exposure. Alveolar fluid clearance (AFC) was evaluated using fluorescein isothiocyanate tagged albumin. Differential cell counts, total protein levels, cytokine concentrations, myeloperoxidase activity and markers of oxidative stress, i.e. malondialdehyde and peroxynitrite, were determined in bronchoalveolar lavage (BAL) and lung homogenates (LH). Levels of AMPK-Thr172 phosphorylation and basolateral membrane Na(+)-K(+)-ATPase abundance were determined by Western blot. RESULTS: In control mice, ozone exposure induced lung inflammation as evidence by increased leukocyte count, protein concentration in BAL and myeloperoxidase activity, pro-inflammatory cytokine levels in LH. Increases in peroxynitrite levels (3 vs 4.4 nM, p = 0.02) and malondialdehyde concentrations (110 vs 230 µmole/g wet tissue) were detected in LH obtained from ozone-exposed control mice. Ozone exposure consistently increased phosphorylated AMPK-Thr172 to total AMPK ratio by 80% in control mice. Ozone exposure causes increases in AFC and basolateral membrane Na(+)-K(+)-ATPase abundance in control mice which did not occur in AMPKα1 deficient mice. CONCLUSIONS: Our results collectively suggest that AMPK activation participates in ozone-induced increases in AFC, inflammation and oxidative stress. Further studies are needed to understand how the AMPK pathway may provide a novel approach for the prevention of ozone-induced lung injury.