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Causal Relationship Between Indium Compound Inhalation and Effects on the Lungs

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Causal Relationship Between Indium Compound Inhalation and Effects on the Lungs Journal of J Occup Health 2009; 51: 513–521 Occupational Health Causal Relationship between Indium Compound Inhalation and Effects on the Lungs Makiko NAKANO1, Kazuyuki OMAE1, Akiyo TANAKA2, Miyuki HIRATA2, Takehiro MICHIKAWA1, Yuriko KIKUCHI1, Noriyuki YOSHIOKA1, Yuji NISHIWAKI1 and Tatsuya CHONAN3 1Department of Preventive Medicine and Public Health, School of Medicine, Keio University, 2Department of Hygiene, Graduate School of Medical Sciences, Kyushu University and 3Department of Medicine, Nikko Memorial Hospital, Japan Abstract: Causal Relationship between Indium SP-D and SP-A, respectively. Conclusion: Dose- Compound Inhalation and Effects on the Lungs: dependent lung effects due to indium exposure were Makiko NAKANO, et al. Department of Preventive shown, and a decrease of indium exposure reduced Medicine and Public Health, School of Medicine, the lung effects. An In-S value of 3 ng/ml may be a Keio University—Background: Recent case reports cut-off value which could be used to prevent early and epidemiological studies suggest that inhalation of effects on the lungs. indium dust induces lung damage. Objectives: To (J Occup Health 2009; 51: 513–521) elucidate the dose-dependent effects of indium on the lungs and to prove a causal relationship more clearly. Key words: Cross-sectional study, Indium, Interstitial Methods: A baseline observation was conducted on pneumonitis, KL-6, HRCT, SP-D 465 workers currently exposed to indium, 127 workers formerly exposed to indium and 169 workers without Due to the rapid expansion of flat panel displays and indium exposure in 12 factories and 1 research solar cells, indium demand has increased every year, and laboratory from 2003 to 2006. Indium in serum (In-S) in 2007, Japan consumed over 90% of the indium in the was determined as an exposure parameter, and its world1). effects on the lungs were examined. Results: The Until the early 1990’s, there was little information on the means of In-S in the current, former and no exposure toxic effects of indium on humans or animals. In the mid workers were 8.35, 9.63 and 0.56 ng/ml, respectively. 1990’s, intra-tracheal instillation studies of particles of The current and former exposure workers had compound semiconductors such as indium phosphide, significantly higher levels of KL-6, and showed significant dose-dependent increases in KL-6, SP-D, indium arsenide and indium trichloride revealed that metal and SP-A. Current exposure workers with In-S of 3 compounds containing indium had a strong potential to 2–6) 7) ng/ml or above demonstrated a significant increase of induce severe lung damage . In 2003, Homma et al. KL-6 in both GM and prevalence exceeding the disclosed a case of interstitial pneumonia in a 27-yr-old male reference value. Approximately a quarter of the former worker engaged in the wet surface polishing process of exposure workers had interstitial changes as seen on indium-tin oxide (ITO) target plates, high-density plates chest HRCT. In-S of exposed workers who had been made of very hard ceramics composed of indium oxide and working before improvements of the working tin oxide, which are used to laminate transparent electro- environment (Group Bef) and those who started conductive thin-film on flat displays and solar cells. The working after improvements (Group Aft) were 12.29 and worker started this job in 1994, and at the beginning of 1998 0.81 ng/ml, respectively. Adjusted odds ratios indicated was admitted to a hospital with the complaint of increasing 87%, 71% and 44% reductions among Group Aft workers who exceeded the reference values of KL-6, dry cough and breathlessness. After a detailed medical examination, he was diagnosed with interstitial pneumonia, possibly caused by the inhalation of ITO particles. Up to Received May 25, 2009; Accepted Aug 26, 2009 the end of 2008, seven indium-induced cases of lung injury Published online in J-STAGE Oct 16, 2009 7–11) Correspondence to: M. Nakano, Department of Preventive were disclosed . After the first case was found, two Medicine and Public Health, School of Medicine, Keio University, epidemiological studies were performed in two different 12, 13) 35 Shinano-machi, Shinjuku, Tokyo 160-8582, Japan (e-mail: populations of indium-exposed workers . Both studies [email protected]) suggested strong relationships between indium in serum 514 J Occup Health, Vol. 51, 2009 Table 1. Characteristics of study population and concentrations of indium in serum No exposure Former exposure Current exposure n 169 127 465 Male (%) 81.9 91.1** 91.6** Age (yr): Mean ± SD 40.9 ± 10.89 39.1 ± 9.61 35.9 ± 11.30** Smokers (%) 116 (67.8) 76 (60.8) 278 (72.8) In-S (ng/ml): Mean (range ) 0.56 (n.d.–3.0) 9.63 (n.d–126.8)** 8.35 (n.d.–116.9)** Exposure duration (mo): Mean (range) – 60.4 (1–252) 55.1 (0.25–455) Duration after the end of indium exposure (mo): Mean (range) – 58.3 (2–201) **: p<0.01 by Dunnett’s test (reference = no exposure workers) or χ2 test. (In-S) and effects on the lungs. exposure workers. The mean length of indium exposure After the first cross-sectional study12), we continued to was 55.1 mo (range: 0.25–455) in the current exposure make efforts to contact companies manufacturing indium workers and 60.4 mo (1–252) in the former exposure products in order to inform the results of the health risk workers. The mean duration from the end of indium of indium compounds to their indium-exposed workers exposure in the former exposure workers was 58.3 mo and to ask the workers to join our epidemiological survey. (range 2–201). There were no significant differences in By the end of 2006, 13 factories and 1 research laboratory smoking histories among the three groups. Thirty-seven had agreed to join our epidemiological study. workers (14 current exposure, 10 former exposure, and 13 no exposure workers) had a history of asthma. Subjects and Methods Study subjects Exposure assessment Among the 13 factories that participated, 1 factory Most of the current and former exposure workers were studied by Chonan et al.13) and 4 factories studied by exposed to multiple indium compound dusts such as ITO, Hamaguchi et al.12) were included. Because the results indium trioxide, indium hydroxide, indium chloride, of a pre-analysis of the remaining factories and the indium nitrate, and indium metal. Because information participating laboratory were compatible with the results about the differences in the health effects of each indium of the two studies, we combined the data and analyzed compound is very limited, and the indium concentrations all of them together. We informed all study candidates at the work sites could not be measured, we did not stratify about the health risks of indium exposure and the purpose the current and former workers by the species of indium of the epidemiological study, and obtained their informed compounds. We selected In-S as a quantitative biological consent before they participated. The study was approved marker of indium exposure14). In-S was determined by by the Ethical Committee, School of Medicine, Keio inductively coupled plasma mass spectrometry (ICP-MS) University. A total of 889 subjects gave their informed at the Center of Advanced Instrumental Analysis, Kyushu consent. We excluded one factory (n=93) from the University and the Japan Industrial Safety and Health analysis because In-S was determined by the factory’s Association. The detailed procedure has been reported laboratory using a different detection limit. We obtained elsewhere12, 13). If the level of In-S was below the detection no data from 35 workers regarding their indium exposure limit, 0.05 ng/ml was used for the statistical analysis. or In-S. In total, we exclueded 128 workers, and analyzed As shown in Table 1, the means of In-S in the current 761 workers at 5 ITO manufacturing factories, 4 indium exposure, former exposure and no exposure workers were recycling factories, 3 indium oxide manufacturing 8.35, 9.63 and 0.56 ng/ml, and the maximal factories, and 1 research laboratory consisting of 465 concentrations were 116.9, 126.8, and 3.0 ng/ml, current indium exposure workers, 127 former indium respectively. In-S in the current exposure and former exposure workers, and 169 no indium exposure workers. exposure workers was significantly higher than in the no The no exposure workers worked at a factory that did exposure workers. not process indium or were office workers in indium- To assess the dose-effect and dose-response processing factories. The participation rate was 85.6% relationships, the current and former exposure workers (761/889). were classified into 6 groups by In-S referring to Chonan Table 1 shows the characteristics of the study subjects. et al.13) and Hamaguchi et al.12); namely, workers with an The majority of the subjects were male. The current In-S of 0.9 or below were assigned to Group 1, 1.0–2.9 exposure workers were significantly younger than the no to Group 2, 3.0–4.9 to Group 3, 5.0–9.9 to Group 4, 10.0– Makiko NAKANO, et al.: Indium-Induced Respiratory Effects 515 19.9 to Group 5, 20.0 or above to Group 6. (COPD)20). Namely, a score of 0 to 5 was given to each of the 6 lung fields when the area of interstitial or Medical examinations emphysematous changes occupied 0%, 1–9%, 10–24%, Respiratory symptoms and smoking habit were 25–49%, 50–74%, or more than 75% of each lung field assessed using the Japanese version of the ATS-DLD assessed20).
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