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1 Dept of Medicine, Nikko Memorial Hospital, Hitachi, and 2 Dept of Preventive Medicine and Public Health, School of Medicine, Keio University, Tokyo, Japan.
CORRESPONDENCE: T. Chonan, Dept of Medicine, Nikko Memorial Hospital, 2-12-8 Kamine-cho, Hitachi, Ibaraki 317-0064, Japan. Fax: 81 294241216. E-mail: ttchonan{at}mbd.ocn.ne.jp
Keywords: Indium-tin oxide, interstitial pneumonia, occupational lung disease, semiconductor industry, sialylated carbohydrate antigen KL-6
Received: February 10, 2006
Accepted September 20, 2006
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ABSTRACT |
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 TOP ABSTRACT METHODS AND MATERIALSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The study was carried out in 108 male workers in the indium plant where the two interstitial pneumonia patients mentioned above were employed, and included high-resolution computed tomography (HRCT) of the lungs, pulmonary function tests and analysis of serum sialylated carbohydrate antigen KL-6 and the serum indium concentration.
Significant interstitial changes were observed in 23 indium workers on HRCT and serum KL-6 was abnormally high (>500 U·mL-1) in 40 workers. Workers with serum indium concentrations in the highest quartile had significantly longer exposure periods, greater HRCT changes, lower diffusing capacity of the lung for carbon monoxide and higher KL-6 levels compared with those in the lowest quartile. The serum indium concentration was positively correlated with the KL-6 level and with the degree of HRCT changes.
In conclusion, the results of the present study indicated that serum KL-6 and high-resolution computed tomography abnormalities were prevalent among indium workers and that these abnormalities increased with the indium burden, suggesting that inhaled indium could be a potential cause of occupational lung disease.
Indium-tin oxide (ITO), a sintered material consisting of 90% indium oxide and 10% tin oxide, is used to make flat-panel displays such as liquid-crystal displays and plasma display panels. Its production has been increasing during the 10 yrs, particularly in east Asia. However, indium compounds, either when inhaled as an aerosol or instilled into the trachea, have been reported to exhibit pulmonary toxicity in animal experiments 1–3. The US National Toxicology Program 4 performed indium phosphide inhalation experiments in rats and mice for 2 yrs and concluded that there was clear evidence of an increase in pulmonary inflammation and carcinogenesis.
Recently, Homma et al. 5 reported a case of severe interstitial pneumonia accompanied by bilateral pneumothorax in a 27-yr-old male whose occupation was surface grinding of ITO. This report was followed by another milder case of pulmonary fibrosis in a 30-yr-old male who worked at the same plant 6. Therefore, the current authors conducted a comprehensive study to detect pulmonary disorders in workers employed at the indium processing plant in Japan where the two individuals were employed.
The present study included high-resolution computed tomography (HRCT) of the lungs, pulmonary function tests and measurement of the serum indium concentration. The level of serum sialylated carbohydrate antigen KL-6 was also measured. KL-6 is a high molecular weight glycoprotein mainly produced by alveolar type II cells and it has been reported that KL-6 is, like surfactant protein (SP)-A and SP-D, a sensitive marker of interstitial lung disease 7–9. Some of the results of the present study have been reported previously in the form of an abstract 10.
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METHODS AND MATERIALS |
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TOPABSTRACTMETHODS AND MATERIALSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The study was carried out in October and November 2002 in a total of 108 male workers, including 81 current and 27 former workers (median (range) post-exposure period 4.6 yrs (0.3–12.4)), aged 20–60 yrs (mean±SD 34.0±9.2 yrs), who had engaged in indium processing in the plant for 3.6 yrs (0.8–17.2). Of these, 23 workers were nonsmokers and 85 workers were former or current smokers; the median smoking history of the latter group was 9 pack-yrs (0.3–49.5). The serum indium concentration was measured in 105 workers and all other parameters were obtained from all 108 workers. A total of 38 healthy volunteers (aged 41.7±7.9 yrs) were recruited from non-indium workers and administrative personnel in the same plant to obtain reference HRCT (n = 24) and serum indium concentrations (n = 27). These volunteers consisted of 10 nonsmokers and 28 former or current smokers; the smoking history of the latter was 15.5 pack-yrs (0.2–49.5). Written informed consent was obtained from all the subjects.
The working duration, respiratory symptoms and signs were examined according to the Japanese Pneumoconiosis Questionnaire 11. Most workers had rotated among various ITO processing sections so it was difficult to analyse the relationship between specific job sites and the prevalence of disorders. However, since the reported fatal case 5 was engaged in wet-surface grinding of ITO targets, special care was taken to see whether there were any differences between workers who had mainly been engaged in surface grinding (n = 30) and those who had mainly been engaged in other tasks (n = 78).
Chest radiography and HRCT of the lung
Chest radiographs were taken to evaluate abnormal shadows in the lung fields, especially those that were reticulonodular or ground glass-like.
HRCT of the lungs was obtained at three levels: upper lung field, at the vicinity of the aortic arch; middle lung field, at the vicinity of the tracheal bifurcation; and lower lung field, 1–3 cm above the right hemidiaphragm. These are basically the same levels used to assess low-attenuation areas in patients with emphysema 12. Thin-section (1-mm) slices were obtained from each bilateral lung field at a deep inspiratory level and the degrees of interstitial (ground-glass opacity or reticulonodular shadow) and emphysematous changes (low-attenuation areas) were scored visually based on the area involved: 0, none; 1, 1–10%; 2, 11–25%; 3, 26–50%; 4, 51–75%; and 5, >75% of the lung field. Two pulmonologists who were naïve to the patients’ histories scored the HRCT films independently and the average total score was adopted for those that differed. Spearman’s rank correlations between the scores of the two examiners were 0.598 and 0.422 for interstitial and emphysematous changes, respectively (p<0.0001). The difference in scores between the two examiners was 0 or 1 in 88% of subjects for the interstitial ratings and in 91% for the emphysematous ratings. The average total score that exceeded the 90th percentile of that of normal volunteers was adopted to be significant for interstitial and emphysematous changes.
Pulmonary function tests
Spirometry was performed using a respirometer (DISCOM-21FX; Chest MI, Tokyo, Japan) to obtain vital capacity (VC), forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). Diffusing capacity of the lung for carbon monoxide (DL,CO) was measured by the single-breath method (Chestac-8800; Chest MI). Functional residual capacity (FRC) was obtained by the helium dilution method and residual volume (RV) and total lung capacity (TLC) were calculated by concomitantly performed spirometry. Per cent predicted values of VC, DL,CO, FRC, RV and TLC were calculated according to predictive literature data 13–17.
Measurement of serum KL-6 and serum indium
Serum KL-6 levels were measured by an electrochemiluminescence immunoassay (Special Reference Laboratory, Tokyo, Japan). The concentration of serum indium was measured by Japan Industrial Safety and Health Association (JISHA) using inductively coupled plasma mass spectrometry (ICP-MS; Agilent Technologies, Santa Clara, CA, USA).
Measurement of indium in the working environment
In the plant presently studied, the processing of ITO includes the mixing of indium oxide (average diameter 2.0 µm) and tin oxide powder (1.9 µm), pulverisation, press moulding, sintering, surface grinding and sawing; all the working rooms were equipped with an exhaust ventilation system and the workers were required to use dust respirators (DR80L2W; Shigematsu, Tokyo, Japan) compatible with the standard of Ministry of Health, Labour and Welfare (filter efficiency >95%). Although pulverisation, surface grinding and sawing were performed in wet systems, it was recognised that ITO-containing droplets and waste water splashed around the machines could dry, resulting in ITO dust suspended in the air, particularly in the surface-grinding room. The diameter of the dust particles ranged 0.1–11 µm (average 2.5 µm).
The indium in the air of eight working areas was measured by JISHA in November 2002 according to the Work Environment Measurement Law: area sampling of at least six sampling points in a work site (cross-points of 3-m mesh line), using a low volume air sampling pump (Airchek HV30; SKC Gulf Coast Inc., Houston, TX, USA) with an appropriate filter (Fiberfilm Filter T60A20; Tokyo Dylec, Tokyo, Japan), and a sampling time of 
10 min was adopted at each sampling point.
Statistical analysis
For continuous data, the data distribution was examined and an appropriate transformation was performed to approximate a normal distribution before the analysis. An unpaired t-test, Welch method or one way ANOVA followed by Dunnett’s test was applied to compare the differences in means. When an appropriate transformation was not valid, Wilcoxon’s nonparametric test or Kruskal–Wallis rank-sum test was employed. The dose-dependent trend was assessed by applying a multiple regression model. For prevalence data, proportions were compared by Chi-squared test or Fisher’s exact method. The dose-dependent trend of the proportions was examined by applying a multiple logistic regression model. Pearson’s product–moment correlation coefficient or Spearman’s rank correlation coefficient was used to assess the relationship between two sets of data.
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RESULTS |
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TOPABSTRACTMETHODS AND MATERIALSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Radiological findings
Fine reticulonodular shadows were recognised on chest radiographs in seven indium workers; four of them had chronic cough and/or sputum and one of them was a nonsmoker.
Figure 1
shows an example of a HRCT, which indicates fine reticulonodular shadows and sparse ground-glass-like areas scattered throughout the lower lung fields. Significant interstitial changes were observed in 23 (21%) indium workers. All of the seven workers who had abnormalities on chest radiographs were found to have significant interstitial shadows on HRCT.
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shows an example of the emphysematous changes on HRCT; in this case, low-attenuation areas are observed in addition to interstitial changes in the left upper lung field. There were significant emphysematous changes in 14 (13%) indium workers and among them two were nonsmokers and five had chronic cough and/or sputum.
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Serum KL-6 and indium levels
The serum KL-6 level was abnormally high (>500 U·mL-1) in 40 (37%) indium workers. The geometric mean (GM)±geometric SD of serum indium in the indium workers was 7.9±4.3 ng·mL-1, which was significantly higher than the level of 0.3±2.6 ng·mL-1 found in the healthy volunteers (p<0.001).
Analysis of working environment
According to JISHA, the GM of indium in the eight working areas ranged 0.01–0.05 mg·m-3. The GM indium concentrations were similar between the surface-grinding room (0.05±3.96 mg·m-3) and other rooms (0.01±1.36–0.05±4.16 mg·m-3) and the maximum concentrations were 0.24 and 0.36 mg·m-3, respectively. However, both interstitial and emphysematous HRCT changes were more prevalent among surface-grinding workers than other workers (interstitial changes: 40% versus 14%; emphysematous changes: 27% versus 8%; p<0.01). Other parameters including the serum indium concentration and KL-6 were not significantly different between the two groups.
Comparison among currently indium-exposed, formerly indium-exposed and non-indium-exposed workers
The serum indium concentration was significantly higher in both formerly and currently exposed workers than in nonexposed workers, but it did not differ between former and current workers (table 1). The exposure period was also not different between current and former workers.
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Quartile analysis according to serum indium level
The combined currently and formerly exposed indium workers were classified into four groups according to the serum indium concentration: 0.2–2.9, 3.2–8.0, 8.3–21.7, and 22.2–126.8 ng·mL-1 (table 2). The percentage of smokers was not different nor was there any difference in smoking history among the quartiles. All of the four workers with clubbed fingers belonged to the fourth quartile of the serum indium concentration.
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Comparison according to HRCT changes
A comparison was made between the indium workers with significant changes on HRCT and those without HRCT changes based on the criteria described in the Methods and materials section (table 3). The smoking index and the prevalence of smokers were not different between the two groups. In contrast, those with positive HRCT changes had experienced longer exposure to indium and had higher serum indium levels than those without HRCT changes. Similarly, those who showed HRCT changes had higher rates of KL-6 abnormalities and greater mean KL-6 values as compared with those who did not. Those with interstitial changes had a higher prevalence of significant emphysematous changes as well as greater emphysematous scores, and vice versa.
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Correlation analysis
The correlations between the variables among the indium workers are shown in table 4. A significant correlation was found between the log serum indium concentration and the log KL-6 among the indium workers. The serum indium concentration was also correlated with the interstitial and emphysematous scores on HRCT. Diffusing capacity was inversely correlated with the degrees of both interstitial and emphysematous changes on HRCT. Per cent predicted values of TLC and RV were negatively correlated with the interstitial score on HRCT.
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DISCUSSION |
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TOPABSTRACTMETHODS AND MATERIALSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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KL-6 is mainly produced by alveolar type II cells and its level increases in the serum in the presence of lung injury through the rise in alveolar-capillary permeability and the production is augmented by regenerated alveolar type II cells 8, 9. It appeared that ITO particles deposited in the alveoli evoked persistent lung injury and an increase in the serum KL-6 levels in many indium workers in the present study.
Kazerooni et al. 18 have reported that a limited thin-section computed tomography scoring system like the one adopted in the present study correlates well with the pathological changes of idiopathic pulmonary fibrosis. A similar scoring method has been reported to assess the low-attenuation areas in patients with pulmonary emphysema 12. Furthermore, these scores appeared to express the extent of the disease in so far as the degree of HRCT changes assessed with the method used had a dose–response relationship with the serum indium level and it was correlated with other indices of interstitial lung disease such as the serum KL-6 level and DL,CO.
The functional impairments were mild in subjects of the present study; TLC and DL,CO showed a dose-dependent reduction with the serum indium level but the mean % pred values of TLC and DL,CO were within normal ranges, even in the highest quartile of the serum indium level. Although the predicted values may be inappropriate for DL,CO, RV, FRC and TLC because these reference values were not obtained from the Japanese population, the mixed disorder, comprising interstitial and emphysematous lesions, may in part have minimised the lung volume changes.
Some of the affected workers were nonsmokers and neither the interstitial nor the emphysematous scores of the lung HRCT were correlated with the smoking histories, suggesting that the pulmonary disorders found in the present study were only marginally, if at all, related to the adverse effects of smoking. Conversely, the emphysematous score was correlated with the interstitial score of the lung HRCT as well as with the serum indium concentration (table 4
). The emphysematous changes may be evoked by bronchiolar obstruction due to interstitial and intra-alveolar cholesterol granulomas, as has been described previously 5, 6.
Although the HRCT changes were more prevalent in the surface-grinding workers than in other workers, this finding was not found to be related to the indium concentration in the air. The measured indium concentrations in the work sites in the present study would not necessarily correspond to the indium burden in the lungs because the biological half-life of indium in the lungs is long 4. It is likely that there was more environmental indium in the past, considering the recent efforts that have been made to improve the working conditions including semi-closure of open systems such as the wet-surface-grinding process and strict implementation of dust respirator usage. These improvements, together with the rotation of most workers among various sections of the ITO processing system, may have obscured the relationships between the environmental indium concentration and the serum indium concentration or the extent of pulmonary disorders. Therefore, no definitive conclusion can be drawn concerning the relationship between the workplace indium concentration and the respiratory effects from the results of the present study.
The contribution of tin oxide to the pathogenesis of interstitial pulmonary disease in the workers studied cannot be completely ruled out. However, it has been reported that stannosis is associated with little fibrosis 19, 20, thereby differing from the pulmonary interstitial changes and fibrosis observed in the present study and other reported cases 5, 6. Thus, it is likely that the pulmonary disorders observed in the present study were evoked mainly by indium oxide rather than by tin oxide.
Zheng et al. 21 have reported the distribution of indium following oral and intratracheal administration of indium phosphide in rats and described that indium is poorly absorbed from the gastro-intestinal tract and that indium ions are uniformly distributed among tissues once entering the circulation. It appears that the route of administration of indium was almost exclusively through the airway in subjects of the present study. In fact, there was a substantial concentration of indium particles in the working environment even at the time of the study. It has been estimated that the elimination of deposited indium from the lung is slow, and the clearance half-life is >200 days in rats 4. In the present study, there were no significant differences in the serum indium concentration or the exposure period between currently exposed and formerly exposed workers, suggesting the slow clearance of deposited indium in the body. It is also suggested that the serum indium level reflects chronic rather than acute exposure in so far as the serum indium concentration was closely related to the working duration and did not depend on whether the exposure occurred in the past or was still ongoing.
Pulmonary toxicity of various indium compounds including indium trichloride 1, 2, indium phosphide 3, 4, ITO 3 and indium arsenide 22, either inhaled or intratracheally administered, has been reported in animal experiments. However, there are little data showing whether ITO or insoluble indium metal differs from other indium compounds in terms of biological effects. The present study is the first to explore the possible pulmonary effects of indium compounds in a significant number of humans.
Homma et al. 5 reported a case of severe interstitial pneumonia that occurred in an indium worker who died of bilateral pneumothorax. The pneumothorax might have been evoked by emphysematous changes of the lung such as those described in the present report. The serum indium concentration in the case of Homma et al. 5 was 290 ng·mL-1, which is significantly higher than that of subjects of the present study; therefore, the modest pulmonary impairments found in the latter subjects may be explained by the lower degree of indium burden. However, it is noteworthy that a significant number of former workers still had elevations of KL-6 as well as changes on HRCT, suggesting the chronic persistence of these changes. Moreover, the pathological findings of some of the current authors’ subjects reported elsewhere 23 were similar to those of previously reported cases 5, 6, namely the accumulation of cholesterol-laden macrophages in the alveoli with interstitial fibrosis and cholesterol granulomas in transbronchially biopsied and/or surgically resected lung specimens. The lung interstitial as well as emphysematous changes may worsen and symptoms may become more evident in the future, considering the relatively short duration of exposure (median 3.6 yrs) and the early examination (18 yrs since the beginning of ITO processing in this plant). Therefore, careful follow-up, together with an effort to eliminate exposure to aerosolised indium, is needed.
In conclusion, the results of the present study show that interstitial pulmonary disorders occurred in a significant number of indium-processing workers, and that inhaled indium could be a potential cause of occupational lung disease.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODS AND MATERIALSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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TOPABSTRACTMETHODS AND MATERIALSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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