Indium concentration in serum is an excellent predictor for assessing accumulated indium concentration in the lungs.

OBJECTIVE: To clarify whether indium in serum (In-S) is an appropriate parameter for assessing accumulated indium concentration in the lungs (In-L). METHODS: During our approximately 15-year Japanese cohort follow-up, five male indium-tin oxide (ITO) or/and indium trioxide-exposed workers underwent lung surgical procedures to treat lung diseases or to confirm a diagnosis of lung impairments. We measured In-L of these Cases 1-5 and were able to assess the relationship between In-L and the most recent In-S. Another 1 Japanese case (Case 6) exposed to indium trioxide and indium hydroxide was referred from an article. RESULTS: Cases 1 and 3 had lung cancer, Case 2 suffered from recurrent pneumothorax, and Case 4 had interstitial pneumonia with mild emphysema. Case 5 had severe emphysema with pulmonary hypertension and underwent bilateral lung transplantation. In Cases 1-5, In-L and In-S ranged from 3.4 to 161.2 µg/g wet weight and 0.7 to 60.4 ng/mL, respectively, and In-L/In-S ratios ranged from 2484 to 4857. The slope of the single regression equation with zero intercept was 2767 and the correlation coefficient was 0.995. In contrast, Case 6 was extraordinarily outlying, but the reason is unclear. CONCLUSIONS: In-S is an excellent predictor for assessing indium load in the lungs in ITO or/and indium trioxide-exposed workers. However, number of cases was only five and not enough to authorize definite conclusion. It is desirable to add more cases to confirm our conclusion.

Indium kinetics in an indium exposed worker before and after bilateral lung transplantation.

BACKGROUND: A male worker with indium-tin oxide (ITO)-induced pneumoconiosis underwent bilateral lung transplantation (LT). METHODS: Post-LT histopathological investigations of the isolated lungs and hilar lymph nodes were performed and indium concentration in serum (In-S) and serum Krebs von den Lungen-6 (KL-6) were tracked for 122 weeks. RESULTS: He has attained the ultimate treatment goal of > 2-year survival. The main histopathological characteristics were pan-lobular emphysematous change, interstitial fibrosis, and lymphocytic infiltration in the peribronchiolar/perivascular portions, and numerous cholesterol clefts and giant cells containing brown particles. These findings support the conclusion that the lung injury was caused by the inhalation of ITO. Metal element mapping and indium in the isolated lungs revealed that inhaled ITO particles in humans migrate to the lymph nodes. In-S remained at remarkably high levels (≥30 ng/mL) and showed wide fluctuation with bimodality until 46 weeks after LT, but KL-6 remained in the normal range for almost the entire period. The indium concentration in the donor's resection lung at 10 weeks after LT was 143.5 ng/g wet-weight, which was only one one-thousandth of the recipient's lung (161 µg/g wet-weight). After 48 weeks of LT, the recipient's In-S had gradually decreased; the biological half-life was 1.2 years. These results clearly suggest that indium remaining in the recipient's tissues did not adversely influence the transplant donor's lungs. CONCLUSIONS: The transplanted donor's lungs were not influenced by indium in the recipient's organs. Bilateral LT is thus an effective treatment option in severe indium lung disease cases.

Possibility of lung cancer risk in indium-exposed workers: An 11-year multicenter cohort study.

BACKGROUND: We established a causal relationship between indium exposure and lung interstitial and emphysematous effects. Lung cancer has been clearly demonstrated in rats and mice exposed to indium phosphide and in rats exposed to indium tin oxide. However, no information is available on human indium-related lung cancer. METHODS: The baseline studies were conducted on 381 indium-exposed and 150 referent workers in 11 factories from 2003 to 2006. Items examined included indium concentration in serum (In-S), occupational history, Krebs von den Lungen-6 (KL-6), chest high-resolution computed tomography (HRCT), medical history, smoking habits, and subjective symptoms. Subjects received follow-up health checkups, and a total of 220 indium-exposed and 26 nonexposed workers were examined at least once with chest HRCT from 2013 to 2018. RESULTS: Four lung cancer cases were identified only in indium-exposed workers. Two were prevalent cases and two were incident cases. The averages (range) of age (years), exposure duration (years), In-S (µg/L), and KL-6 (U/mL) at the baseline survey were 58 (50-74), 1.7 (0.3-4.8), 3.1 (0.3-9.7), and 663 (414-942). The mean (range) latency from initial indium exposure was 5.3 (0.4-11) years. The HRCT findings in two incident cases were mild interstitial/emphysematous change and mild interstitial change. The standardized incidence ratio (SIR) of the incident cases was 1.89 (95%CI 0.52-6.88). CONCLUSIONS: Although the SIR was not statistically significant, there was an undeniable possibility of indium-related lung cancer due to the short follow-up duration being insufficient to disclose lung cancer and the small number of lung cancer cases. Further follow-up is necessary.

[Study on the Establishment of a Specific Similar Exposure Group (SEG) in Personal Exposure Monitoring: A Case Report of Indium Tin Oxide Target Surface Grinding Process].

Surface grinding workers of Indium Tin Oxide target material are exposed to an indium compound with high toxicity. We divided individual exposure workers into similar exposure groups (SEG) and examined the effectiveness of the classification of SEG. Sampling was carried out twice a day for a total of 10 times, in 9 of which a work environment measurement in unit work area was performed at the same time. The classification examined two methods. One method was to set all the workers in the work place as one group (SEG1), and the other was to classify them depending on whether the workers handled the target material contained indium or not (SEG2). The group handled indium-contained material was SEG2(+) n=9, and the other was SEG2(-) n=9. Only the arithmetic mean value (AM) of four groups 2.8-27.4 µg/m3 in the SEG2(+) was lower than the measurement B value of the work environment measurement, but the AM of all the groups in SEG2(+) 2.8-276.8 µg/m3 was higher than the geometric mean value of measurement A 0.4-12.3 µg/m3. The concentration range of 100 µg/m3 or more of SEG2(+) AM was 20% of the total. This range was not recognized in the other items, and the variation of SEG2(+) was small. Even though the evaluation of SEG1 is control class 2, if revaluated on SEG2(+), 50% of the SEG2(+) were evaluated as control class 3. It is possible to efficiently manage chemical substances by establishing specific SEG properly stratified.

Personal indium exposure concentration in respirable dusts and serum indium level.

The aim of this study was to assess the relationship between indium exposure concentration in the respirable dust fraction (In-E) and indium in serum (In-S) in workers. METHODS: A total of 39 workers were studied. The study subjects were categorized into 3 groups, namely, smelting workers (n=7), ITO workers (n=6) in an ITO grinding plant, and other workers (n=26). In-E and In-S ranged from 0.004-24.0 µg/m3 and 0.1-8.50 µg/L, respectively. The simple regression equation was log(In-S)=0.322×log(In-E)-0.443. The simple correlation coefficients for the smelting workers, ITO workers and other workers were 0.489, 0.812 and 0.163, respectively. The differences in the relationships among the three groups suggest that In-S may vary with the chemical form to which the workers were exposed. In-E and In-S seem to be positively correlated. The correlation coefficient was higher for both smelting and ITO workers than for other workers.

An advanced case of indium lung disease with progressive emphysema.

OBJECTIVES: To report the occurrence of an advanced case of indium lung disease with severely progressive emphysema in an indium-exposed worker. CASE REPORT: A healthy 42-year-old male smoker was employed to primarily grind indium-tin oxide (ITO) target plates, exposing him to indium for 9 years (1998-2008). In 2004, an epidemiological study was conducted on indium-exposed workers at the factory in which he worked. The subject's serum indium concentration (In-S) was 99.7 µg/l, while his serum Krebs von den Lungen-6 level was 2,350 U/ml. Pulmonary function tests showed forced vital capacity (FVC) of 4.17 l (91.5% of the JRS predicted value), forced expiratory volume in 1 s (FEV1) of 3.19 l (80.8% of predicted), and an FEV1-to-FVC ratio of 76.5%. A high-resolution chest computed tomography (HRCT) scan showed mild interlobular septal thickening and mild emphysematous changes. In 2008, he was transferred from the ITO grinding workplace to an inspection work section, where indium concentrations in total dusts had a range of 0.001-0.002 mg/m3. In 2009, the subject's In-S had increased to 132.1 µg/l, and pulmonary function tests revealed obstructive changes. In addition, HRCT scan showed clear evidence of progressive lung destruction with accompanying severe centrilobular emphysema and interlobular septal thickening in both lung fields. The subject's condition gradually worsened, and in 2015, he was registered with the Japan Organ Transplant Network for lung transplantation (LTx). CONCLUSIONS: Heavy indium exposure is a risk factor for emphysema, which can lead to a severity level that requires LTx as the final therapeutic option.

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.

Two new isoflavanones from the roots of Erythrina variegata.

Two new isoflavanones, eryvarins Y (1) and Z (2), together with three known compounds (3-5) were isolated from the roots of Erythrina variegata. The structures of 1 and.2 were established on the basis of spectroscopic data. The new compounds are peculiar isoflavanones, possessing both a 3-methylbut-2-en- 1-yl group and a 2-hydroxy-3-methylbut-3-en-1-yl group. Among the isolates, orientanol E (5) exhibited potent antibacterial activity against methicillin- resistant Staphylococcus aureus (MRSA) strains.

Tissue distribution of indium after repeated intratracheal instillations of indium-tin oxide into the lungs of hamsters.

OBJECTIVES: The aim of this study was to analyze the tissue distribution of indium after intratracheally instilling indium-tin oxide (ITO) into the lungs of hamsters. METHODS: Male Syrian hamsters received an intratracheal dose of 3 mg/kg or 6 mg/kg of ITO particles containing 2.2 mg/kg or 4.5 mg/kg of indium, twice weekly for 8 weeks. In parallel, control hamsters received only an intratracheal dose of distilled water. A subset of hamsters was euthanized periodically throughout the study from 8 up to 78 weeks after the final instillation. The distribution of indium in the lungs, liver, kidneys and spleen, as well as pathological changes in the liver, kidneys, and spleen, was determined. RESULTS: The contents of indium in the lungs in the two ITO groups gradually decreased over the 78-week observation period, with elimination half-lives of approximately 142 weeks for the 3 mg/kg ITO group and 124 weeks for the 6 mg/kg ITO. The indium concentrations in the liver, kidneys, and spleen gradually increased throughout the observation period. Although foci of the lesions were observed histopathologically in the extrapulmonary organs among the two ITO groups, the control group showed similar lesions. CONCLUSIONS: The results clearly demonstrate that the clearance of indium from the body is extremely slow after intratracheal instillation in hamsters.

Synthesis of Indium-Containing Nanoparticles in Aqueous Suspension Using Plasmas in Water for Evaluating Their Kinetics in Living Body.

Nanoparticles have great potential for medical applications such as cancer therapy, whereas their toxic effects on human body are pointed out. To study kinetics and toxicity of nanoparticles in living body, we synthesized indium-containing nanoparticles in aqueous suspension using pulsed electrical discharge plasmas in water, because no indium compounds exist in the living body in the normal situation and hence indium-containing nanoparticles are useful tracer materials for analyzing kinetics of nanoparticles in living body. The mean size of synthesized primary nanoparticles is 7 nm, whereas the mean size of secondary nanoparticles is 315 nm. EDX and XRD analysis reveal that nanoparticles are indium crystalline and indium hydroxide crystalline with the mass ratio of 8:2. Preliminary subcutaneous administration of nanoparticles to mice shows that indium is transported from subcutaneous to blood. These results show that synthesized indium-containing nanoparticles are useful for analyzing kinetics of nanoparticles in living body.

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.

Phenolic constituents from stem bark of Erythrina poeppigiana and their inhibitory activity on human glyoxalase I.

A novel isoflavone, erythgianin A (1), along with nine known compounds 2-10, was isolated from the stem bark of Erythrina poeppigiana (Leguminosae). The unusual isoflavone structure of 1, possessing a highly oxidized 3″,4″-dihydroxy-2″-hydroxymethyl-2″-methyl-2″,3″-dihydropyrano substituent, was determined on the basis of spectroscopic analyses. All of the isolated compounds were evaluated for their in vitro inhibitory activity toward human glyoxalase I. Among the isolates, isolupalbigenin (10) with two prenyl groups showed the highest inhibitory activity.

[Health effects of solar cell component material. Toxicity of indium compounds to laboratory animals determined by intratracheal instillations].

Owing to the increasing interest being paid to the issue of the global environment, the production of solar cells has increased rapidly in recent years. Copper indium gallium diselenide (CIGS) is a new efficient thin film used in some types of solar cell. Indium is a constitutive element of CIGS thin-film solar cells. It was thought that indium compounds were not harmful until the beginning of the 1990s because there was little information regarding the adverse health effects on humans or animals arising from exposure to indium compounds. After the mid-1990s, data became available indicating that indium compounds can be toxic to animals. In animal studies, it has been clearly demonstrated that indium compounds cause pulmonary toxicity and that the dissolution of indium compounds in the lungs is considerably slow, as shown by repeated intratracheal instillations in experimental animals. Thus, it is necessary to pay much greater attention to human exposure to indium compounds, and precautions against possible exposure to indium compounds are paramount with regard to health management.

Subacute pulmonary toxicity of copper indium gallium diselenide following intratracheal instillations into the lungs of rats.

OBJECTIVES: The aim of this study was to clarify the pulmonary toxicity of copper indium gallium diselenide (CIGS) solar cells on 62 8-wk-old rats. METHODS: Male Wistar rats were given 0.5, 5 or 50 mg/kg of CIGS particles, intratracheally, 3 times for a week. Control rats were given vehicle, distilled water, only. These rats were euthanized 0, 1 or 3 wk after the final instillation serially, and toxicological effects were determined. RESULTS: None of the CIGS-treated groups exhibited suppression of body weight gain compared with the control group. The relative lung weight in the CIGS 5 mg/kg-treated and 50 mg/kg-treated groups were significantly increased compared with that in the control group throughout the observation period. Although serum copper (Cu) and selenium (Se) concentrations were not affected by instillations of CIGS particles, the indium (In) levels increased with the passage of time in the CIGS 5 mg/kg-treated and 50 mg/kg-treated groups. However, the serum gallium (Ga) levels decreased in the CIGS 50 mg/kg-treated group from 0 to 3 wk. The content of each metal in the lung increased depending on the dose instilled and was constant during observation periods. Histopathologically, foci of slight to severe pulmonary inflammatory response and exudation were present among all the CIGS-treated groups, and the severity of these lesions worsened with the passage of time. CONCLUSION: The present results clearly demonstrate that CIGS particles caused subacute pulmonary toxicity and that dissolution of CIGS particles in the lung was considerably slow when repeated intratracheal instillations were given to rats.

Assessment of workplace air concentrations of indium dust in an indium-recycling plant.

OBJECTIVES: Suspended indium dust in an indium-recycling plant was quantified, in order to improve the work environment and to reduce workers' exposure to the dust. METHODS: Assessment of indium dust in the workplace air by multipoint area sampling and personal breathing zone sampling was conducted twice in 2004 and 2008. RESULTS: In 2004, all recycling processes except for purity analysis were classified into control class III according to the 2004 Notification. Two out of 5 workers were exposed to total dust with indium concentrations exceeding the ACGIH's TLV-TWA of 0.1 mg In/m(3). In 2008, the indium-contaminated workplace air was improved by local exhaust ventilation systems installed in some processes, resulting in control class I. According to the 2010 Technical Guideline, however, all the processes were classified into stage II or III, indicating that the first assessment value or Measurement B-based concentrations exceeded the acceptable exposure concentration limit of 0.0003 mg In/m(3) of respirabe dust. Exposure of almost all the workers to indium dust was below the TLV-TWA. CONCLUSIONS: The first field survey showed that almost all workplaces were classified into control class III, and that some workers were exposed to dust with indium concentrations exceeding the TLV-TWA. It was found in the second survey that workplace air contamination was improved by the local exhaust ventilation system, but was not reduced sufficiently to a level that meets the new Guideline.

[Validity of serum surfactant protein D measurements in a cross-sectional study].

BACKGROUND: In October, 2008, the method for enzyme-linked immunoassay for serum surfactant protein D (SP-D) was changed from SP-D kit (Yamasa) EIA to SP-D kit (Yamasa) EIA2 in Japan. In our follow-up survey on 144 indium-exposed workers from December, 2008 to June, 2009, SP-D showed systematically higher values compared to the first survey from March to July, 2008. Geometric means (prevalence rate) of serum SP-D of the first and follow-up study were 52.1 ng/mL (4.1%) and 72.1 ng/mL (14.6%), respectively, though serum KL-6 and SP-A were stable. Thus, we examined the validity of the old and new methods. METHOD AND RESULTS: As a result of examining about 200 subjects, the correlation between the two methods was good. However, as a reproducibility examination of about another 300 subjects between the post-measured and the pre-measured values with the same new method at Laboratory A, the differences between vales in each observation are not acceptable. Especially, examinations performed using the lot 804, 805, and 105 at laboratory A showed systematic higher values than others. CONCLUSION: Various factors might have caused the large measurement bias; in particular, the new method lacks sufficient reproducibility between lots. When observing the chronological change of SP-D, attention must be given in comparisons of serum SP-D after October, 2008 to before that because of the metrology-dependent measurement bias.

Indium lung--case reports and epidemiology.

PURPOSE: The present review is aimed to introduce an new occupational lung disease, Indium Lung. METHODS: We searched case reports and epidemiological studies concerning indium-related lung diseases and reviewed. RESULTS: Up to March, 2010, 7 cases of interstitial pneumonia in Japanese indium-exposed workers, two cases of pulmonary alveolar proteinosis (PAP) in US indium-exposed workers, one case of PAP in a Chinese indium-exposed worker, and 4 cross-sectional surveys in Japan had been published. All cases and epidemiological studies in Japan indicate that exposure to hardly soluble indium compounds causes interstitial as well as emphysematous lung damages, which we call "Indium Lung". Based on the epidemiological studies, the Japan Society for Occupational Health proposed 3 µg/l of indium in serum as an occupational exposure limit based on biological monitoring to prevent significant increase of KL-6. COMMENTS: Long-term follow-up of currently and formerly indium-exposed workers is essential not only to clarify the natural history of indium lung but also to trace the incidence of lung cancer. It is also necessary to elucidate the mechanism of indium lung and difference in clinical manifestations between Japanese and US cases.

Chronic pulmonary toxicity study of indium-tin oxide and indium oxide following intratracheal instillations into the lungs of hamsters.

OBJECTIVES: The aim of this study was to clarify the chronic toxicological effects of indium-tin oxide (ITO) and indium oxide (In(2)O(3)) on laboratory animals. METHODS: Male Syrian golden hamsters were intratracheally administered 3 mg/kg or 6 mg/kg of ITO particles, or 2.7 mg/kg or 5.4 mg/kg of In(2)O(3) particles, containing 2.2 mg/kg or 4.5 mg/kg of indium, twice a week, for 8 wk. Control hamsters were given vehicle of distilled water only. The hamsters were euthanized serially up to 78 wk after the final instillation and the toxicological effects were determined. RESULTS: Body weight gain was significantly suppressed in the ITO 6 mg/kg-treated hamsters compared with the control group, but not in the ITO 3 mg/kg-treated or In(2)O(3)-treated hamsters. Relative lung weights among all the indium-treated groups were significantly increased compared to that in the control group throughout the observation period. The serum indium concentration among all the indium-treated groups gradually increased up to the end of the observation period. Histopathologically, foci of slight to severe pulmonary inflammatory response with diffuse alveolar or bronchiolar cell hyperplasia, expansion of the alveolar spaces and interstitial fibrotic proliferation were present in all the indium-treated hamsters and the severity of these lesions worsened with the passage of time. Lung benign adenomas were only manifest in 3 out of 15 of the ITO 6 mg/kg-treated hamsters. CONCLUSIONS: The present results clearly demonstrate that ITO and In(2)O(3) particles caused chronic pulmonary toxicity when repeated intratracheal instillations were given to hamsters.