A case report of Indium lung with progressive emphysema and fibrosis underwent lung unilateral transplantation 20 years after the end of the exposure.

BACKGROUND: Indium lung is characterized by interstitial pneumonia and/or emphysema which occurs in indium-tin oxide (ITO) workers. Indium lung is now known to progress after stopping exposure to ITO, but the long-term influences of ITO remain unclear. CASE PRESENTATION: Forty seven years old, a never-smoker, who had been engaged in an ITO manufacturing process for 8 years. Emphysema was indicated by the medical check-up for ex-ITO workers, and he was diagnosed with indium lung. He underwent partial lung resections for pneumothorax two times, and obstructive pulmonary dysfunction had progressed through the years. He underwent right single lung transplant 20 years after ITO exposure. Pathologically, his lung showed severe distal acinar emphysema and honeycomb change. Fibrosis and destruction of the lung tissue significantly progressed compared to the previous partial resections. Scanning electron microscopy combined with energy dispersive spectroscopy revealed that the deposited particles contained indium and tin. After the transplantation, his respiratory function was improved. CONCLUSIONS: In this case, ITO resided in the lung tissue for 20 years, and lung tissue destruction kept progressing. Careful medical follow-up is recommended for ITO-workers even if they are asymptomatic.

Two-year follow-up of exposure, engineering controls, respiratory protection and respiratory health among workers at an indium-tin oxide (ITO) production and reclamation facility.

OBJECTIVES: To determine whether engineering controls and respiratory protection had measurable short-term impact on indium exposure and respiratory health among current indium-tin oxide production and reclamation facility workers. METHODS: We documented engineering controls implemented following our 2012 evaluation and recorded respirator use in 2012 and 2014. We measured respirable indium (Inresp) and plasma indium (InP) in 2012 and 2014, and calculated change in Inresp (∆Inresp) and InP (∆InP) by the 13 departments. We assessed symptoms, lung function, serum biomarkers of interstitial lung disease (Krebs von den Lungen (KL)-6 and surfactant protein (SP)-D) and chest high-resolution CT at both time points and evaluated workers who participated in both 2012 and 2014 for changes in health outcomes (new, worsened or improved). RESULTS: Engineering controls included installation of local exhaust ventilation in both grinding departments (Rotary and Planar) and isolation of the Reclaim department. Respiratory protection increased in most (77%) departments. ∆InP and ∆Inresp often changed in parallel by department. Among 62 workers participating in both 2012 and 2014, 18 (29%) had new or worsening chest symptoms and 2 (3%) had functional decline in lung function or radiographic progression, but average KL-6 and SP-D concentrations decreased, and no cases of clinical indium lung disease were recognised. CONCLUSIONS: Increased engineering controls and respiratory protection can lead to decreased Inresp, InP and biomarkers of interstitial lung disease among workers in 2 years. Ongoing medical monitoring of indium-exposed workers to confirm the longer-term effectiveness of preventive measures is warranted.

Response to pembrolizumab in a patient with primary lung adenocarcinoma originated from indium lung.

BACKGROUND: Indium is a metal used as a compound called indium-tin oxide for liquid crystal display. Its inhalation causes lung toxicity, resulting in a new occupational lung disease called indium lung. Although the carcinogenicity of indium has been reported in an animal model, its carcinogenicity in humans is unknown. CASE PRESENTATION: This is the first reported case of a primary lung cancer originating from indium lung. In this report, we describe a 46-year-old man with interstitial pneumonia-type indium lung diagnosed 16 years ago. The initial symptom was left chest pain, and computed tomography showed a mass adjacent to the aorta with left pleural effusion. Specimens collected using video-assisted thoracoscopy revealed an adenocarcinoma with a high expression of programmed cell death-ligand 1 (cT4N0M1a stage IVA). Although the lesions showed a remarkable aggressive nature, the patient benefited from pembrolizumab, a monoclonal antibody against programmed cell death 1, which was used as second-line therapy for 2 years. CONCLUSIONS: It is important for clinicians to be aware of lung cancer development in indium-exposed workers or in patients with indium lung, as this could have an aggressive behavior. Treatment with immune checkpoint inhibitors is an option even in patients with interstitial pneumonia-type indium lung.

Biomonitorization of concentrations of 28 elements in serum and urine among workers exposed to indium compounds.

Many studies have documented the abnormal concentrations of metals/metalloids in serum or urine of occupational workers, but no works systematically analysed the concentrations of elements in serum or urine of indium-exposed workers. This study was aimed to assess 28 elements in serum and urine from 57 individuals with occupational exposure to indium and its compounds. Control subjects were 63 workers without metal exposure. We collected information on occupation and lifestyle habits by questionnaire. Biological samples were collected to quantify elements by inductive coupled plasma-mass spectrometer. Air in the breathing zones was drawn at flow rates of 1.5-3 L/min for a sampling period of 6 to 8 h, using a Model BFC-35 pump. The average ambient indium level was 0.078 mg/m3. Serum/urine Indium levels were significantly higher in indium-exposed workers than in controls (P < 0.01). Moreover, serum/urine indium concentrations in the group with 6-14 years and ≥15 years of employment were significantly higher than those with ≤5 employment years(P < 0.05). Ten of the other 27 elements/metals measured were higher in serum/urine in indium-exposed workers compared to the controls (aluminum, beryllium, cadmium, cesium, chromium, lithium, manganese, magnesium, molybdenum and vanadium). Zinc levels in serum/urine were significantly decreased in the indium-exposed workers. Additionally, other elements/metals were higher in one specimen (serum or urine) but lower in the other (Selenium was lower in serum but higher in urine in the indium-exposed workers compared with the controls; likewise Thallium and Rubidium were higher in serum but lower in urine). Linear regression analyses, revealed significant correlations between serum and urine for indium, aluminum, arsenic, barium, cadmium, cesium, cobalt, selenium, silver, and zinc (P < 0.05). These data suggest that occupational exposure to indium and its compounds may disturb the homeostasis of trace elements in systemic circulation, indium concentrations in serum or urine appear reflective of workers' exposure to ambient indium and their years of working, respectively. The serum/urine levels of essential metals are modified by exposure to indium in occupationally exposed workers. Further studies including larger sample size and more kinds of biological sample are needed to validate our findings.

Indium and iridium: Two rare metals with a high rate of contact sensitization.

BACKGROUND: Humans are exposed to a variety of metals on a daily basis, and nickel is the most frequent contact allergen. Little is known about the frequency of sensitization to indium and iridium. OBJECTIVES: Study the prevalence of indium and iridium sensitization and evaluate the optimal patch test conditions. METHODS: A total of 364 patients were patch tested at the allergy unit of the University Hospital of Basel. Pure metals, metal chlorides, and metal sulfates were applied in petrolatum or water in Inert Quadrate (IQ) test chambers for 2 days and read twice at day (D) 2, and between D4 and D7. RESULTS: Eleven patients reacted to indium salts (3.0%), 13 to iridium salts (3.6%), and one reacted to both salts. None of the patients reacted to pure metals. Nineteen of the 23 patients who reacted either to indium or iridium showed concomitant positive reactions to other metals, mainly nickel and palladium. CONCLUSION: This retrospective clinical study provides insight into the prevalence and test conditions of two rarely tested metal allergens in a large patient cohort. A considerable number of indium- or iridium-positive subjects had co-sensitization to other metals.

Work Tasks as Determinants of Respirable and Inhalable Indium Exposure among Workers at an Indium-Tin Oxide Production and Reclamation Facility.

Increased global demand for touch screens, photovoltaics, and optoelectronics has resulted in an increase in the production of indium-tin oxide (ITO). Occupational exposure to indium compounds is associated with the development of indium lung disease. Although many previous epidemiologic investigations highlight an excess of lung abnormalities in workplaces where ITO is produced, few assessments of occupational exposure to respirable and inhalable indium are reported to date. The objective of this study was to identify the determinants of respirable and inhalable indium at an ITO production facility to target exposure interventions. In 2012 and 2014, we conducted exposure assessments at an ITO production facility and collected full-shift personal respirable (n = 159) and inhalable (n = 57) indium samples. We also observed workers and recorded information on task duration and location, materials used, and use of personal protective equipment (PPE). Tasks (n = 121) recorded in task diaries were categorized into 40 similar task groups using the Advanced REACH Tool and process-related information. Mixed-effects models were fit separately for log-transformed respirable and inhalable indium, with random effect of subject and fixed effects of task groups. Overall, respirable and inhalable indium measurements ranged from 0.1 to 796.6 µg m-3 and 1.6 to 10 585.7 µg m-3, respectively, and were highly correlated with Spearman correlation coefficient of 0.90. The final model for respirable indium explained 36.3% of total variance and identified sanding, powder transfer tasks in reclaim, powder transfer tasks in refinery, handling indium materials, and liquid transfer tasks in ITO production as tasks associated with increased respirable indium exposure. The final model for inhalable indium explained 24.6% of total variance and included powder transfer tasks in ITO production, cleaning cylinder or tile, and handling indium material tasks. Tasks identified as strong predictors of full-shift exposure to respirable and inhalable indium can guide the use of engineering, administrative, and PPE controls designed to mitigate occupational exposure to indium. Moreover, since the tasks were aligned with REACH activities, results from this study can also be used to inform REACH activity scenarios.

Indium Lung: Discovery, Pathophysiology and Prevention.

Indium is mainly used as indium-tin oxide (ITO), which has a unique character of transparency, and is a requisite in making liquid crystal displays. Pulmonary toxicity of indium compounds in humans were not recognized until the last 2 decades. Several initial human cases of indium-related lung disease, named indium lung, were reported in Japan, with their main pathologic findings being interstitial pneumonia, emphysema and cholesterol crystals-containing granulomas. In 2010, three cases with alveolar proteinosis were reported from the United States and China. As of March 2019, more than 10 cases of interstitial pneumonia-dominant indium lung have been reported. Cross-sectional studies in indium workers indicate that the serum indium concentration (sIn) is closely related to the exposure period, the extent of interstitial as well as emphysematous changes of the lung on high-resolution computed tomography (HRCT) and serum biomarkers of interstitial pneumonia, including KL-6 and surfactant protein-D (SP-D). Longitudinal studies have shown it is possible to reduce the sIn as well as the interstitial shadows on HRCT; however, emphysematous lesions increased progressively in heavily exposed workers, even after cessation of exposure. Early detection is required to prevent irreversible changes. The first case of lung cancer associated with indium lung developed in a nonsmoking ex-worker. He had been diagnosed with indium lung and stopped working in indium processing 17 years before. This suggested there is a need for appropriate screening to detect for complications of lung cancer at early stages for those with indium lung.

Indium (III) induces isolated mitochondrial permeability transition by inhibiting proton influx and triggering oxidative stress.

While Indium's toxicity to organs is realized, its effects on mitochondria are still under investigation. Mitochondrial permeability transition (MPT) is widely accepted in mitochondrial dysfunction approaches and its importance in metal-induced mitochondrial degradation has been proposed. Since mitochondria are respiratory organelles, their interaction with free In3+ is analyzed to access structural and functional changes. Spectral methods and multimode plate reader was used to detect mitochondrial swelling, membrane potential, membrane fluidity, and inner membrane permeability. Flow cytometry was employed to detect mitochondrial reactive oxygen species (ROS) generation and transmission electron microscopy to image mitochondria. And oxygen electrode was used to measure respiratory rate, microcalorimetry to monitor long-term real-time mitochondrial metabolism. In3+ at a concentration up to 1mM induces mitochondrial swelling, membrane depolarization and inhibits the protons transportation. In3+-induced mitochondrial swelling and membrane depolarization is protected by MPT inhibitors and -SH protectors, but the influence on protons transportation is not protected. In addition, In3+ is able to accelerate the ROS production and inhibit the electron transition and respiratory chain while it stimulates long-term metabolism. Our findings show that In3+ induces MPT by inhibiting the proton channels located in the inner mitochondrial membrane and by stimulating mitochondrial oxidative stress.

Toxicological and efficacy assessment of post-transition metal (Indium) phthalocyanine for photodynamic therapy in neuroblastoma.

Metallo-phthalocyanines due to their photophysical characteristics as high yield of triplet state and long lifetimes, appear to be good candidates for photodynamic therapy (PDT). Complexes with diamagnetic metals such as Zn2+, Al3+ Ga3+ and In3+meet such requirements and are recognized as potential PDT agents. Clinically, Photofrin® PDT in neuroblastoma therapy proved in pediatric subjects diagnosed with progressive/recurrent malignant brain tumors increased progression free survival and overall survival outcome. Our study focuses on the dark toxicity testing of a Chloro-Indium-phthalocyanine photosensitizer (In-Pc) upon SH-SY5Y neuroblastoma cell line and its experimental in vitro PDT. Upon testing, In-Pc has shown a relatively high singlet oxygen quantum yield within the cells subjected to PDT (0.553), and 50 µg/mL IC50. Classical toxicological and efficacy assessment were completed with dynamic cellular impedance measurement methodology. Using this technology we have shown that long time incubation of neuroblastoma cell lines in In-Pc (over 5 days) does not significantly hinder cell proliferation when concentration are ≤ 10 µg/mL. When irradiating neuroblastoma cells loaded with non-toxic concentration of In-Pc, 50% of cells entered apoptosis. Transmission electron microscopy has confirmed apoptotic characteristics of cells. Investigating the proliferative capacity of the in vitro treated cells we have shown that cells that "escape" the irradiation protocol, present a reduced proliferative capacity. In conclusion, In-Pc represents another photosensitizer that can display sound PDT properties enhancing neuroblastoma therapy armentarium.

Respirable indium exposures, plasma indium, and respiratory health among indium-tin oxide (ITO) workers.

BACKGROUND: Workers manufacturing indium-tin oxide (ITO) are at risk of elevated indium concentration in blood and indium lung disease, but relationships between respirable indium exposures and biomarkers of exposure and disease are unknown. METHODS: For 87 (93%) current ITO workers, we determined correlations between respirable and plasma indium and evaluated associations between exposures and health outcomes. RESULTS: Current respirable indium exposure ranged from 0.4 to 108 µg/m(3) and cumulative respirable indium exposure from 0.4 to 923 µg-yr/m(3) . Plasma indium better correlated with cumulative (rs = 0.77) than current exposure (rs = 0.54) overall and with tenure ≥1.9 years. Higher cumulative respirable indium exposures were associated with more dyspnea, lower spirometric parameters, and higher serum biomarkers of lung disease (KL-6 and SP-D), with significant effects starting at 22 µg-yr/m(3) , reached by 46% of participants. CONCLUSIONS: Plasma indium concentration reflected cumulative respirable indium exposure, which was associated with clinical, functional, and serum biomarkers of lung disease. Am. J. Ind. Med. 59:522-531, 2016. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Effects of a powered air-purifying respirator intervention on indium exposure reduction and indium related biomarkers among ITO sputter target manufacturing workers.

This study aimed to evaluate the efficacy of powered air-purifying respirators (PAPRs) worn by the workers, and to investigate the effect of this application on exposure and preclinical effects in terms of workplace measuring and biomarker monitoring in ITO sputter target manufacturing plants and workers, respectively. Fifty-four workers were recruited and investigated from 2010-2012, during which PAPRs were provided to on-site workers in September 2011. Each worker completed questionnaires and provided blood and urine samples for analysis of biomarkers of indium exposure and preclinical effects. Area and personal indium air samples were randomly collected from selected worksites and from participants. The penetration percentage of the respirator (concentration inside respirator divided by concentration outside respirator) was 6.6%. Some biomarkers, such as S-In, SOD, GPx, GST, MDA, and TMOM, reflected the decrease in exposure and showed lower levels, after implementation of PAPRs. This study is the first to investigate the efficacy of PAPRs for reducing indium exposure. The measurement results clearly showed that the implementation of PAPRs reduces levels of indium-related biomarkers. These findings have practical applications for minimizing occupational exposure to indium and for managing the health of workers exposed to indium.

High levels of indium exposure relate to progressive emphysematous changes: a 9-year longitudinal surveillance of indium workers.

BACKGROUND: During the last decade it has been clarified that the inhalation of indium compounds can evoke alveolar proteinosis, cholesterol granuloma, pulmonary fibrosis and emphysema. In this study, we aimed to elucidate the characteristics and time course of pulmonary disorders among indium workers using comprehensive pulmonary examinations at an indium-processing factory. METHODS: Data for 84 male workers who underwent the examinations for nine consecutive years from 2002 to 2010 were analysed regarding their symptoms, serum indium concentration (sIn), serum markers of interstitial pneumonia, pulmonary function test parameters and high-resolution CT (HRCT) findings of the lungs. RESULTS: In association with improvements in the work environment and work practice, the sIn levels decreased with significant reductions in the KL-6 and surfactant protein D (SP-D) levels. Regarding the HRCT findings, the interstitial lesions regressed partially, whereas emphysematous lesions increased progressively in the workers with high sIn values. FEV1/FVC decreased with the years and the rate of decrease was significantly greater in those with high sIn. The biological half-life of sIn was estimated to be 8.09 years. CONCLUSIONS: The present findings suggest that the sIn, SP-D, KL-6 levels and radiological interstitial changes can be reduced in indium workers by alleviating exposure to indium, whereas emphysematous lesions can progress among those with a history of heavy exposure.

Pulmonary effects in workers exposed to indium metal: A cross-sectional study.

OBJECTIVES: Indium was added to the list of substances regulated by the Ordinance on Prevention of Hazards due to Specified Chemical Substances (OPHSCS) in 2013. Indium metal (IM), however, is not regulated by the OPHSCS due to insufficient information on pulmonary effects following exposure. METHODS: From 2011 to 2013, a cross-sectional study was conducted on 141 IM-exposed workers at 11 factories. Subjective symptoms were assessed, including levels of serum biomarkers, spirometry readings and total and diffuse lung capacity. Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) were selected as biomarkers of interstitial pneumonia. Indium serum concentration (In-S) and personal air sampling data were used to estimate exposure. Subjects were categorized into 5 groups based on occupation and type of exposure: smelting, soldering, dental technician, bonding and other. RESULTS: The highest level of In-S was 25.4 µg/l, and the mean In-S level was significantly higher in the smelting group than in other groups. In the smelting group, the prevalence of increased In-S levels was 9.1%, while that of abnormal KL-6 was 15.2%. A significant dose-effect relationship was observed between the In-S and KL-6 levels. No marked differences were observed between any of the groups in SP-D values, pulmonary symptoms, or pulmonary function test results. A total of 31% of the subjects worked in an environment with IM levels exceeding 0.3 µg/m(3), which requires a protective mask to be worn. CONCLUSIONS: For workers exposed to IM, work environments should be monitored, appropriate protective masks should be worn, and medical monitoring should be conducted according to the OPHSCS.

Interstitial lung disorders in the indium workers of Korea: an update study for the relationship with biological exposure indices.

BACKGROUND: Korea is one of the highest indium-consuming countries worldwide. The present study aims to determine the relationship between interstitial lung disorders and indium exposure in Korea. METHODS: In 50 indium workers from seven plants, the effect of serum indium on the lungs was determined using laboratory tests, spirometry, and high-resolution computed tomography (HRCT). RESULTS: Higher serum indium and Krebs von den Lungen-6 (KL-6) levels were associated with HRCT-detected interstitial lung changes. Workers with high serum indium levels (≥3 µg/L) had longer exposure durations and a higher prevalence of HRCT-detected interstitial lung changes. KL-6 and surfactant protein-D (SP-D) levels were significantly higher in the highest serum indium quartile than the lowest quartile. Significant dose-effect relationships existed between serum indium levels and KL-6, SP-D levels and the prevalence of HRCT-detected interstitial lung changes. CONCLUSIONS: Workforce medical surveillance should be established to prevent indium-induced interstitial lung disease in Korea.

Five-year cohort study: emphysematous progression of indium-exposed workers.

BACKGROUND: Dose-dependent adverse lung effects due to indium exposure have been reported in a cross-sectional study. This is a 5-year longitudinal cohort study of indium-exposed and unexposed workers, assessing indium exposure levels and its clinical lung effects. METHODS: From 2008 to 2011, a 5-year follow-up study was conducted on 40 unexposed and 240 workers formerly or currently exposed to indium at 11 factories. Indium exposure was assessed by serum indium (In-S) (µg/L). Lung effects were assessed by subjective symptoms, serum biomarkers, spirometry, and chest high-resolution CT scan. Effect biomarkers used were Krebs von den Lungen and surfactant protein D. RESULTS: Mean values of In-S, Krebs von den Lungen, and surfactant protein D among the workers exposed to indium at baseline declined during the 5-year follow-up by 29.8%, 27.2%, and 27.5%, respectively. Of the exposed subjects with In-S levels > 20 µg/L, 26.3% experienced emphysematous progression on high-resolution CT scan. Ninety percent (18 of 20) of workers with emphysematous progression during follow-up were current smokers at baseline, and a trend of increasing incidence of emphysematous progression at higher In-S levels was observed among the smokers (P = .005). Emphysematous changes among subjects with In-S levels > 20 µg/L were likely to progress, after adjusting for age, mean duration since initial indium exposure, and smoking history (OR = 10.49, 95% CI = 1.54-71.36). CONCLUSIONS: Long-term adverse effects on emphysematous changes were observed. The results suggest workers exposed to indium with In-S levels > 20 µg/L should be immediately removed from exposure.

[Indium lung disease].

"Indium lung" is a new occupational lung disease. The global demand for indium, the major material used in manufacturing flat-screen display panels, has skyrocketed since the 1990s (Japan comprises 85% of the worldwide demand). The first case was reported in Japan in 2003, followed by seven cases (interstitial pneumonia and emphysema) in Japan. Two pulmonary alveolar proteinosis (PAP) cases in the USA followed in 2011. Indium lung has been described as interstitial pneumonia, pneumothorax, emphysema, and PAP. In 2013, The Japan Ministry of Health, Labor and Welfare issued an "Ordinance on the Prevention of Hazards Due to Specified Chemical Substances" requiring employers to provide regular health checks for employees and measurements of work environment concentrations of respirable indium dust.