[Show abstract][Hide abstract] ABSTRACT: Indium-tin oxide (ITO) is used to make transparent conductive coatings for touch-screen and liquid crystal display electronics. Occupational exposures to potentially toxic particles generated during ITO production have increased in recent years as the demand for consumer electronics continues to rise. Previous studies have demonstrated cytotoxicity in vitro and animal models have shown pulmonary inflammation and injury in response to various indium-containing particles. In humans, pulmonary alveolar proteinosis (PAP) and fibrotic interstitial lung disease have been observed in ITO facility workers. However, which indium materials or specific processes in the workplace may be the most toxic to workers is unknown. Here we examined the pulmonary toxicity of three different particle samples that represent real-life worker exposures, as they were collected at various production stages throughout an ITO facility. Indium oxide (In2 O3 ), sintered ITO (SITO) and ventilation dust (VD) particles each caused pulmonary inflammation and damage in rats over a time course (1, 7 and 90 days post-intratracheal instillation), but SITO and VD appeared to induce greater toxicity in rat lungs than In2 O3 at a dose of 1 mg per rat. Downstream pathological changes such as PAP and fibrosis were observed in response to all three particles 90 days after treatment, with a trend towards greatest severity in animals exposed to VD when comparing animals that received the same dose. These findings may inform workplace exposure reduction efforts and provide a better understanding of the pathogenesis of an emerging occupational health issue. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
Journal of Applied Toxicology 10/2015; DOI:10.1002/jat.3253 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Occupational and environmental causes of bronchiolar disorders are recognized on the basis of case reports, case series, and, less commonly, epidemiologic investigations. Pathology may be limited to the bronchioles or also involve other components of the respiratory tract, including the alveoli. A range of clinical, functional, and radiographic findings, including symptomatic disease lacking abnormalities on noninvasive testing, poses a diagnostic challenge and highlights the value of surgical biopsy. Disease clusters in workplaces and communities have identified new etiologies, drawn attention to indolent disease that may otherwise have been categorized as idiopathic, and expanded the spectrum of histopathologic responses to an exposure. More sensitive noninvasive diagnostic tools, evidence-based therapies, and ongoing epidemiologic investigation of at-risk populations are needed to identify, treat, and prevent exposure-related bronchiolar disorders.
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Seminars in Respiratory and Critical Care Medicine 06/2015; 36(3):366-378. DOI:10.1055/s-0035-1549452 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Work-related asthma is asthma that is caused or exacerbated by exposure to specific substances in the workplace. Approximately 10%-16% of adult-onset asthma cases are attributable to occupational factors, and estimates of asthma exacerbated by work range from 13% to 58%. During 2008-2012, the Massachusetts Department of Public Health received nine reports of work-related asthma among workers at a facility that manufactured syntactic foam used for flotation in the offshore oil and gas industry. These reports and a request from facility employees led to a CDC health hazard evaluation during 2012-2013 in which CDC reviewed records, toured the facility, and administered a questionnaire to current employees. Investigators found that workers' risk for asthma increased substantially after hire, possibly because of known asthma triggers (i.e., asthmagens) used in production. The company has since initiated efforts to reduce employee exposures to these substances. This cluster of work-related asthma was identified through CDC-funded, state-based surveillance and demonstrates complementary state and federal investigations.
MMWR. Morbidity and mortality weekly report 04/2015; 64(15):411-4.
[Show abstract][Hide abstract] ABSTRACT: Indium-tin oxide (ITO) is used to make transparent conductive coatings for touch-screen and liquid crystal display electronics. As the demand for consumer electronics continues to increase, so does the concern for occupational exposures to particles containing these potentially toxic metal oxides. Indium-containing particles have been shown to be cytotoxic in cultured cells and pro-inflammatory in pulmonary animal models. In humans, pulmonary alveolar proteinosis and fibrotic interstitial lung disease have been observed in ITO facility workers. However, which ITO production materials may be the most toxic to workers and how they initiate pulmonary inflammation remain poorly understood. Here we examined four different particle samples collected from an ITO production facility for their ability to induce pro-inflammatory responses in vitro. Tin oxide, sintered ITO (SITO), and ventilation dust particles activated nuclear factor kappa B (NFκB) within 3 h of treatment. However, only SITO induced robust cytokine production (IL-1β, IL-6, TNFα, and IL-8) within 24 h in both RAW 264.7 mouse macrophages and BEAS-2B human bronchial epithelial cells. Our lab and others have previously demonstrated SITO-induced cytotoxicity as well. These findings suggest that SITO particles activate the NLRP3 inflammasome, which has been implicated in several immune-mediated diseases via its ability to induce IL-1β release and cause subsequent cell death. Inflammasome activation by SITO was confirmed, but it required the presence of endotoxin. Further, a phagocytosis assay revealed that pre-uptake of SITO or ventilation dust impaired proper macrophage phagocytosis of E. coli. Our results suggest that adverse inflammatory responses to SITO particles by both macrophage and epithelial cells may initiate and propagate indium lung disease. These findings will provide a better understanding of the molecular mechanisms behind an emerging occupational health issue.
PLoS ONE 04/2015; 10(4):e0124368. DOI:10.1371/journal.pone.0124368 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rationale: Occupational exposure to indium compounds including indium-tin oxide (ITO) can result in potentially fatal indium lung disease. However, the early effects of exposure on the lungs are not well understood. Objectives: To determine the relationship between short-term occupational exposures to indium compounds and development of early lung abnormalities. Methods: Among ITO production and reclamation facility workers, we measured plasma indium, respiratory symptoms, pulmonary function, chest computed tomography, and serum biomarkers of lung disease. The relationships between plasma indium concentration and health outcome variables were evaluated using restricted cubic spline and linear regression models. Measurements and Main Results: Eighty-seven (93%) of 94 ITO facility workers (median tenure=2 years; median plasma indium=1.0 mcg/L) participated in the study. Spirometric abnormalities were not in excess and few had radiographic evidence of alveolar proteinosis (n=0), fibrosis (n=2), or emphysema (n=4). Compared to participants with plasma indium concentrations <1.0 mcg/L, those with values ≥1.0 mcg/L had more dyspnea, lower mean FEV1% and FVC%, and higher median serum KL-6 and SP-D levels. Spline regression demonstrated non-linear exposure-response, with significant differences occurring at plasma indium concentrations as low as 1.0 mcg/L for FEV1%, FVC%, KL-6, and SP-D compared to the reference. Associations between health outcomes and plasma indium were evident in linear regression models and not explained by age, smoking status, or facility tenure. Conclusions: In ITO facility workers with short-term, low-level exposure, plasma indium concentrations lower than previously reported were associated with lung symptoms, abnormal spirometry, and increased serum biomarkers of lung disease.
[Show abstract][Hide abstract] ABSTRACT: Occupational exposure to indium compound particles has recently been associated with lung disease among workers in the indium-tin oxide (ITO) industry. Previous studies suggested that excessive alveolar surfactant and reactive oxygen species (ROS) may play a role in the development of pulmonary lesions following exposure to indium compounds. However, toxicity at the cellular level has not been comprehensively evaluated. Thus, the aim of this study was to assess which, if any, compounds encountered during ITO production are toxic to cultured cells and ultimately contribute to the pathogenesis of indium lung disease. The compounds used in this study were collected from eight different processing stages at an ITO production facility. Enhanced dark field imaging showed 5 of the compounds significantly associated with cells within 1 h, suggesting that cellular reactions to the compound particles may be occurring rapidly. To examine the potential cytotoxic effects of these associations, ROS generation, cell viability, and apoptosis were evaluated following exposures in RAW 264.7 mouse monocyte macrophage and BEAS-2B human bronchial epithelial cell lines. Both exhibited reduced viability with exposures, while apoptosis only occurred in RAW 264.7 cells. Our results suggested that excessive ROS production is likely not the predominant mechanism underlying indium-induced lung disease. However, the effects on cell viability reveal that several of the compounds are cytotoxic, and therefore, exposures need to be carefully monitored in the industrial setting.
Journal of Toxicology and Environmental Health Part A 09/2014; 77(20):1193-209. DOI:10.1080/15287394.2014.920757 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives:
To better understand respiratory symptoms and lung function in flavouring manufacturing workers.
We offered a questionnaire and lung function testing to the current workforce of a flavouring manufacturing facility that had transitioned away from diacetyl and towards substitutes in recent years. We examined symptoms, spirometric parameters and diffusing capacity measurements by exposure variables, including facility tenure and time spent daily in production areas. We used linear and logistic regression to develop final models adjusted for age and smoking status.
A total of 367 (93%) current workers participated. Shortness of breath was twice as common in those with tenure ≥ 7 years (OR 2.0, 95% CI 1.1 to 3.6). Other chest symptoms were associated with time spent daily in production. Participants who spent ≥ 1 h daily in production areas had twice the odds of any spirometric abnormality (OR 2.3; 95% CI 1.1 to 5.3) and three times the odds of low diffusing capacity (OR 2.8; 95% CI 0.9 to 9.4) than other participants. Mean spirometric parameters were significantly lower in those with tenure ≥ 7 years and those who spent ≥ 1 h daily in production. Mean diffusing capacity parameters were significantly lower in those with tenure ≥ 7 years. Differences in symptoms and lung function could not be explained by age, smoking status or employment at another flavouring plant.
Symptoms and lung function findings were consistent with undiagnosed or subclinical obliterative bronchiolitis and associated with workplace exposures. Further efforts to lower exposures to flavouring chemicals, including diacetyl substitutes, are warranted.
Occupational and Environmental Medicine 06/2014; 71(8). DOI:10.1136/oemed-2013-101927 · 3.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vocal cord dysfunction (VCD) is the intermittent paradoxical adduction of the vocal cords during respiration, resulting in variable upper airway obstruction. Exposure to damp indoor environments is associated with adverse respiratory health outcomes, including asthma, but its role in the development of VCD is not well described.
We describe the spectrum of respiratory illness in occupants of 2 water-damaged office buildings.
The National Institute for Occupational Safety and Health conducted a health hazard evaluation that included interviews with managers, a maintenance officer, a remediation specialist who had evaluated the 2 buildings, employees, and consulting physicians. In addition, medical records and reports of building evaluations were reviewed. Diagnostic evaluations for VCD had been conducted at the Asthma and Allergy Center of the Medical College of Wisconsin.
Two cases of VCD were temporally related to occupancy of water-damaged buildings. The patients experienced cough, chest tightness, dyspnea, wheezing, and hoarseness when in the buildings. Spirometry was normal. Methacholine challenge did not show bronchial hyperreactivity but did elicit symptoms of VCD and inspiratory flow-volume loop truncation. Direct laryngoscopy revealed vocal cord adduction during inspiration. Coworkers developed upper and lower respiratory symptoms; their diagnoses included sinusitis and asthma, consistent with recognized effects of exposure to indoor dampness. Building evaluations provided evidence of water damage and mold growth.
VCD can occur with exposure to water-damaged buildings and should be considered in exposed patients with asthma-like symptoms.
[Show abstract][Hide abstract] ABSTRACT: To explore factors associated with fatal accidents among contractors and operators by using the Mine Safety and Health Administration database.
Cross-sectional data on 157,410 miners employed by operators or contractors during 1998-2007 were analyzed using logistic regression and multiple imputation.
Univariate odds of fatal versus nonfatal accident were 2.8 (95% confidence interval, 2.3 to 3.4) times higher for contractors than operators. In a multivariable model, fatality was associated with contractor, less experience at the current mine, and occurrence at more than 8 hours into the workday (P < 0.05 for each). Differences in odds of fatality by employment type were more pronounced in surface mines.
Contractors had a higher proportion of fatal injuries. Fatality also varied by mine experience, the number of hours worked before injury, work location, and mine type.
Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 10/2013; 55(11). DOI:10.1097/JOM.0b013e3182a2a5a2 · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
We evaluated the effectiveness of workplace changes to prevent indium lung disease, using 2002-2010 surveillance data collected by an indium-tin oxide production facility.
We assessed pulmonary function using lower limits of normal. Blood indium concentration and personal air sampling data were used to estimate exposure.
Abnormalities were uncommon at hire. After hire, prevalence of spirometric restriction was 31% (n = 14/45), about fourfold higher than expected. Excessive decline in FEV1 was elevated at 29% (n = 12/41). Half (n = 21/42) had blood indium ≥5 µg/l. More recent hires had fewer abnormalities. There was a suggestion that abnormalities were more common among workers with blood indium ≥5 µg/l, but otherwise an exposure-response relationship was not evident. Peak dust concentrations were obscured by time averaging.
Evolving lung function abnormalities consistent with subclinical indium lung disease appeared common and merit systematic investigation. Traditional measures of exposure and response were not illustrative, suggesting fresh approaches will be needed. Workplace changes seemed to have had a positive though incomplete impact; novel preventive interventions are warranted.
American Journal of Industrial Medicine 03/2013; 56(3). DOI:10.1002/ajim.22125 · 1.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reports of pulmonary fibrosis, emphysema, and, more recently, pulmonary alveolar proteinosis (PAP) in indium workers suggested that workplace exposure to indium compounds caused several different lung diseases.
To better understand the pathogenesis and natural history of indium lung disease, a detailed, systematic, multidisciplinary analysis of clinical, histopathologic, radiologic, and epidemiologic data for all reported cases and workplaces was undertaken.
Ten men (median age, 35 years) who produced, used, or reclaimed indium compounds were diagnosed with interstitial lung disease 4-13 years after first exposure (n = 7) or PAP 1-2 years after first exposure (n = 3). Common pulmonary histopathologic features in these patients included intraalveolar exudate typical of alveolar proteinosis (n = 9), cholesterol clefts and granulomas (n = 10), and fibrosis (n = 9). Two patients with interstitial lung disease had pneumothoraces. Lung disease progressed following cessation of exposure in most patients and was fatal in two. Radiographic data revealed that two patients with PAP subsequently developed fibrosis and one also developed emphysematous changes. Epidemiologic investigations demonstrated the potential for exposure to respirable particles and an excess of lung abnormalities among coworkers.
Occupational exposure to indium compounds was associated with PAP, cholesterol ester crystals and granulomas, pulmonary fibrosis, emphysema, and pneumothoraces. The available evidence suggests exposure to indium compounds causes a novel lung disease that may begin with PAP and progress to include fibrosis and emphysema, and, in some cases, premature death. Prospective studies are needed to better define the natural history and prognosis of this emerging lung disease and identify effective prevention strategies.