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High Levels of Indium Exposure Relate to Progressive Occupational lung disease Thorax: first published as 10.1136/thoraxjnl-2014-206380 on 18 August 2015. Downloaded from ORIGINAL ARTICLE High levels of indium exposure relate to progressive emphysematous changes: a 9-year longitudinal Editor’s choice Scan to access more free content surveillance of indium workers Atsuko Amata,1,2 Tatsuya Chonan,1 Kazuyuki Omae,3 Hiroshi Nodera,1 Jiro Terada,2 Koichiro Tatsumi2 ▸ Additional material is ABSTRACT published online only. To view Background During the last decade it has been Key messages please visit the journal online fi (http://dx.doi.org/10.1136/ clari ed that the inhalation of indium compounds can thoraxjnl-2014-206380). evoke alveolar proteinosis, cholesterol granuloma, pulmonary fibrosis and emphysema. In this study, we 1Department of Medicine, What is the key question? Nikko Memorial Hospital, aimed to elucidate the characteristics and time course of ▸ Does the progress of interstitial and/or Hitachi, Japan pulmonary disorders among indium workers using emphysematous lesion in indium workers 2 Department of Respirology, comprehensive pulmonary examinations at an indium- change by alleviating exposure to indium? Graduate School of Medicine, processing factory. Chiba University, Chiba, Japan 3 Methods Data for 84 male workers who underwent What is the bottom line? Department of Preventive ▸ Because permanent emphysematous changes Medicine and Public Health, the examinations for nine consecutive years from 2002 School of Medicine, Keio to 2010 were analysed regarding their symptoms, serum may be evoked under heavy exposure to indium University, Tokyo, Japan indium concentration (sIn), serum markers of interstitial compounds, it is necessary to reduce exposure pneumonia, pulmonary function test parameters and to indium-containing particles and detect lung Correspondence to fi disorders caused by indium as early as possible. Dr Jiro Terada, Department of high-resolution CT (HRCT) ndings of the lungs. Respirology, Graduate School Results In association with improvements in the work Why read on? of Medicine, Chiba University, environment and work practice, the sIn levels decreased ▸ This comprehensive study, for the first time, 1-8-1 Inohana Chuoku Chiba with significant reductions in the KL-6 and surfactant city, Chiba 2608670, Japan; fi examined the same workers in an indium plant [email protected] protein D (SP-D) levels. Regarding the HRCT ndings, for nine consecutive years, showing different the interstitial lesions regressed partially, whereas longitudinal patterns of interstitial and Received 1 October 2014 emphysematous lesions increased progressively in the Revised 29 June 2015 emphysematous lesions in patients with indium workers with high sIn values. FEV1/FVC decreased with lung after stopping or decreasing the exposure http://thorax.bmj.com/ Accepted 22 July 2015 the years and the rate of decrease was significantly Published Online First to the inhaled indium compounds. 18 August 2015 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 observed in a significant number of indium- can be reduced in indium workers by alleviating processing workers.3 Furthermore, workers with exposure to indium, whereas emphysematous lesions can serum indium (sIn) concentrations in the highest progress among those with a history of heavy exposure. fi quartile had a history of signi cantly longer on September 29, 2021 by guest. Protected copyright. periods of exposure, greater HRCT changes, lower diffusing capacity of the lung for carbon monoxide (DLCO) and higher KL-6 levels compared with INTRODUCTION those with sIn concentrations in the lowest quartile. Indium is a rare metal that is primarily used in the According to these findings, we proposed that form of indium-tin oxide (ITO), a sintered material inhaled indium compound may be a potential new consisting of 90% indium oxide (In2O3) and 10% cause of occupational lung disease (‘indium 13 tin oxide (SnO2), to produce flat panel displays, lung’). This hypothesis was subsequently con- such as liquid-crystal displays. Recently, indium use firmed in different populations of indium workers.4 has sharply increased; the world demand for Combining the data obtained from 12 factories, indium in 2007 was approximately four times including ours, and one research laboratory, higher than in 1999.1 Nakano et al5 reported a strong dose–response In 2001, a 29-year-old man who was an ITO relationship between the sIn level and effects on surface grinder died of interstitial pneumonia with the lungs. bilateral pneumothorax,2 constituting the first As of May 2013, nine cases of interstitial lung – reported case of indium-related lung disease. In disease from Japan6 11 and three cases of alveolar 2002, we conducted a comprehensive study at the proteinosis from the USA12 and China13 had been To cite: Amata A, ITO plant where the above patient was employed reported. Exposure to indium compounds has been Chonan T, Omae K, et al. and reported that interstitial lung disorders charac- suggested to cause a novel lung disease consisting Thorax 2015;70: terised by abnormalities on high-resolution CT of alveolar proteinosis, cholesterol granuloma, pul- – 1040 1046. (HRCT) and the elevation of serum KL-6 were monary fibrosis and emphysema, accompanied by 1040 Amata A, et al. Thorax 2015;70:1040–1046. doi:10.1136/thoraxjnl-2014-206380 Occupational lung disease Thorax: first published as 10.1136/thoraxjnl-2014-206380 on 18 August 2015. Downloaded from pneumothorax in severe cases.14 The work environment and levels, or high sIn concentrations (2002–2006: no criteria, practice at ITO plants, where most cases have been reported, 2007–2008: >20 ng/mL, 2009–: >10 ng/mL) were transferred have considerably improved, and workplace changes have been to non-indium sections of the workplace. Thirty-seven of the 84 implemented among heavily exposed workers over the last workers had stopped working at ITO before the last year of the decade. In this study, we conducted a longitudinal surveillance present surveillance period (table 1, ‘former workers in 2010’). for nine consecutive years starting in 2002 of 84 male indium In a previous report,3 we confirmed that all variables, including workers at an indium plant, where a cross-sectional study of functional, radiological and biochemical parameters, were quali- 108 indium-processing workers was previously conducted,3 to tatively similar between the formerly and currently employed elucidate the clinical course of indium lung and the effects of indium-exposed workers with similar exposure periods; there- reduced exposure. fore, we combined the data for the former and current workers to analyse the time course of the disease. All subjects provided MATERIALS AND METHODS their informed consent prior to initiation of the analysis in this Study design and subjects study. In both the figures and tables, personal information has The present study was conducted as part of the health mainten- been carefully anonymised. ance programme for the employees and approved by the Because the severity of lung disorder caused by indium inhal- medical professional committee that oversees the health main- ation is correlated with the sIn concentration,35we classified all tenance programme of the plant. workers into four groups according to their sIn concentrations A comprehensive respiratory examination programme was measured in the first year: Group 1, <3.7; Group 2, 3.7–9.9; conducted annually from 2002 to 2010 for workers who were Group 3, 10.0–22.4; Group 4, >22.5 ng/mL. No differences formerly and/or currently engaged in indium processing. The were observed between the four groups in terms of age, preva- study design has been reported elsewhere and consisted of lence of smokers or smoking indices. We analysed chronological examinations of signs and symptoms, pulmonary function tests, changes in the variables among all participants and each of the HRCT of the lungs and measurements of the sIn concentration four groups. and serum markers of interstitial lung disease.3 Five hundred and fifteen individuals received an examination at least once, Improvements in the work environment and practice among whom 108 male workers underwent examinations in The ITO processing work environment has steadily improved in 2002 (reported as a cross-sectional study3). After excluding the addition to the introduction of various protective devices for data for 24 subjects who failed to undergo an examination for workers. As a result, the indium concentration in the air, as one or more years, we analysed the data of 84 male workers measured in accordance with the Working Environment (figure 1). The exposure period for these workers was 9.7 Measurement Law established by the Japan Industrial Safety and ±4.8 years (table 1). During the study period, workers with sig- Health Association ( JISHA), has gradually decreased (figure 2), nificant interstitial change on chest X-rays or HRCT, emphyse- and it can be assumed that the new indium burden has matous changes accompanied by elevated KL-6 and/or SP-D decreased for the study population as a whole. http://thorax.bmj.com/ on September 29, 2021 by guest. Protected copyright. Figure 1 Study flowchart. Amata A, et al. Thorax 2015;70:1040–1046. doi:10.1136/thoraxjnl-2014-206380 1041 Occupational lung disease Thorax: first published as 10.1136/thoraxjnl-2014-206380 on 18 August 2015. Downloaded from Table
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