Abstract
Objectives
To describe the characteristics of incident cases and calculate the standardized incidence ratio (SIR) of kidney cancer in a multicenter cohort study.
Methods
Baseline studies included 601 individuals across 12 factories manufacturing or recycling indium compounds between 2003 and 2006. In total, 341 individuals had undergone at least 1 follow-up health checkup by 2022. Of these, 128 individuals were examined from 2019 to 2022, with a mean follow-up duration of 17.1 years (range 13.3-18.4). The overall SIRs of kidney cancer were calculated.
Results
One female and 2 male incident cases of kidney cancer were identified at 3 different factories. The mean age was 55 years, and they were either smokers or secondhand smokers. The mean duration of indium exposure was 14.6 years, and the mean serum indium concentration at baseline was 2.3 μg/L (range <0.1-4.3 μg/L). One case consistently exhibited undetectable indium concentrations in both serum and kidney tissue. Another case involved double primary cancers of the lung and kidney. The expected number of kidney cancer cases based on the Japanese general population was 0.505. The overall SIR was 5.95 (95% CI, 2.02-17.47). Even after excluding the case with undetectable In-S and In-K levels, the overall and female SIRs remained significantly elevated (overall SIR 3.96; 95% CI, 1.09-14.44; female SIR 56.86; 95% CI, 9.80-314.69).
Conclusions
Indium exposure may contribute to the development of not only lung cancer but also kidney cancer in humans. Continued follow-up in the cohort study is warranted.
Keywords: indium, indium tin oxide, kidney cancer, carcinogenicity
Key points
What is already known on this topic
Indium compounds are classified as Group 2A carcinogens by the Japan Society for Occupational Health, and indium tin oxide (ITO) as Group 2B by the International Agency for Research on Cancer (IARC). Our previous study demonstrated that the standardized incidence ratio (SIR) for lung cancer was 1.89 (95% CI, 0.52-6.88); however, the association between indium compounds and lung cancer remained inconclusive.
What this study adds
A female patient exposed to ITO, with a serum indium concentration <3 μg/L, was diagnosed with double primary cancers: lung and kidney cancer. In this multicenter cohort study, the overall SIR for kidney cancer was 3.96 (95% CI, 1.09-14.44). However, the findings are limited by the small number of cases and the absence of a dose–response relationship.
How this study might affect research, practice, or policy
Evidence suggesting that indium compounds may accumulate in both the lung and kidney, potential target organs, underscores the need for ongoing health surveillance of workers exposed to indium compounds, with particular attention to the risks of lung and kidney cancer.
1. Introduction
Indium lung disease,1 including interstitial pneumonia, emphysema, and pneumothorax, is a recently recognized occupational lung disease affecting workers exposed to indium compounds such as indium tin oxide (ITO), which is used in manufacturing electrodes for flat panel displays, as well as to indium oxide, indium hydroxide, and indium chloride, which are involved in the production or reclamation of ITO. Emphysematous changes can progress to long-term pulmonary impairment even after exposure levels decline.1 With respect to human carcinogenicity, we previously reported a standardized incidence ratio (SIR) of 1.89 (95% CI, 0.52-6.88) for lung cancer in an 11-year multicenter cohort study.2 However, the causal relationship between indium exposure and lung cancer remains uncertain.
Recently, a case of double primary cancers of the lung and kidney was identified in a worker exposed to ITO who participated in an 18-year follow-up cohort study. Therefore, the objective of this study was to describe the characteristics of incident cases and to calculate the SIR for kidney cancer in this multicenter cohort.
2. Methods
This study was approved by the Ethics Committee of the School of Medicine at Keio University (approval number 20110268) and the National Institute of Occupational Safety and Health in Japan (approval number 2023 N10). Written informed consent for participation and reporting was obtained from the patients.
2.1. SIR of kidney cancer
2.1.1. Study population
Our previous 11-year multicenter cohort study2 included participants from 11 facilities; 1 additional laboratory that was not included in the previous study2 was added for this analysis, resulting in a total of 12 facilities. Baseline assessments were conducted on 601 individuals exposed and unexposed to indium between 2003 and 2006 who had measured serum indium concentrations (In-S) and serum levels of Krebs von den Lungen 6 (KL-6). After excluding 45 nonconsenting, 151 unexposed, and 55 lost-to-follow-up workers, 341 indium-exposed individuals underwent at least 1 follow-up health checkup by 2022 (Figure 1). The follow-up rate for the exposed group was 86%. Of these, 128 individuals were examined from 2019 to 2022, with a mean follow-up duration of 17.1 years (range 13.3-18.4 years). Kidney cancer diagnoses were confirmed through medical certification.
Figure 1.
Study participant flow diagram.
2.1.2. SIR calculation
Using national cancer statistics3 and national estimates of cancer incidence based on cancer registries in Japan (2003-2015) and the national cancer registry in Japan (2016-2020),4 we calculated mean age-specific 5-year incidence rates for kidney cancer by sex from 2003 to 2020. The observation period was calculated from the day of initial exposure to any indium compound to the time of examination at the latest health check. The endpoint of the observation period was July 6, 2022. Time was censored as follows: (1) the latest date on which subjects confirmed their health status through our examination, and (2) the day of diagnosis for patients with kidney cancer.
2.2. Smoking adjustment
Tobacco smoking status at the initial study of each worker was used. Using the age-specific distribution in the study population, we calculated the age-adjusted smoking rates in the general Japanese population using an indirect method. Following the study by Carreon et al,5 we used national data to estimate the bias factor of smoking and to investigate the effect of differences in smoking status by sex between the general Japanese population and this study population on the SIR calculation. When the smoking status of 4204 Japanese males and 4906 Japanese females was assessed in 2003 via the National Nutrition Survey, the distribution among males was 32.3% nonsmokers, 20.9% former smokers, and 46.8% current smokers, and that among females was 85.1% nonsmokers, 3.6% former smokers, and 11.3% current smokers.6 In the Japanese population, the hazard of smoking and kidney cancer is not as clear as in Western countries, and it has been suggested that only heavy current smokers have an increased risk of renal cell carcinoma.7–9 Because there were no data showing the hazard in current smokers by level of exposure, marginal data were used. The hazard ratios (HRs) for kidney cancer in the Japanese population were reported to be 1.09 (95% CI, 0.49-2.39) among former smokers, 1.79 (95% CI, 0.92-3.48) among current smokers, and 1 among nonsmokers.7
The bias factor was calculated as follows:
 |
where PNW is the proportion of nonsmokers among the workers, PFW is the proportion of former smokers among the workers, PCW is the proportion of current smokers among the workers, PNJ is the proportion of nonsmokers in the general Japanese population, PFJ is the proportion of former smokers in the general Japanese population, PCJ is the proportion of current smokers in the general Japanese population, HRF is the hazard ratio for kidney cancer in former smokers, and HRC is the hazard ratio for kidney cancer in current smokers.
2.3. Statistical analysis
The Mann-Whitney U test was used to compare continuous variables between the lost-to-follow-up and follow-up groups. The χ2 test or Fisher exact test was used to compare proportions and prevalence. Statistical significance was assessed by 2-tailed analysis, and P < .05 was considered significant. All statistical analyses were performed using SPSS v.29 (IBM Corporation, Armonk, NY, USA).
2.4. Indium concentration in the serum and the kidney
In-S (μg/L) and kidney tissue indium (In-K, ng/g) were measured by inductively coupled plasma mass spectrometry at the Center of Advanced Instrumental Analysis, Kyushu University. In-K for Case 3 was analyzed by the Japan Industrial Safety and Health Association. Detailed methods have been reported previously.10 Prior to analysis, measurement accuracy between the 2 institutions was verified via a blinded study. Noncancerous kidney tissue was used for the In-K analysis.
3. Results
3.1. Baseline characteristics of the lost-to-follow-up and follow-up groups
Table 1 shows the baseline characteristics compared between the lost-to-follow-up group and the follow-up group. The lost-to-follow-up group had a significantly higher proportion of formerly exposed workers compared with the follow-up group. In contrast, the lost-to-follow-up group had significantly lower values of In-S, KL-6, and SP-D compared with the follow-up group. In contrast, age, sex, duration after initial exposure and cessation of exposure in formerly exposed workers, smoking status, and lung functions were not significantly different between the 2 groups.
Table 1.
Baseline characteristics, exposure levels, effect biomarkers, and lung function of indium-exposed participants.
| Exposed group at baseline (n = 396) | ||||
|---|---|---|---|---|
| Follow-up (n = 341) | Lost-to-follow-up (n = 55) | |||
| n | Mean/Prev | n | Mean/Prev | |
| Age, mean (SD), y | 341 | 37.9 (11.9) | 52 | 40.0 (12.1) |
| Male, n (%) | 341 | 312 (91.5) | 55 | 48 (87.3) |
| Exposed status | 341 | 55 | ||
| Currently, n (%) | 277 (81.2) | 33 (60.0) | ||
| Formerly, n (%) | 64 (18.8) | 22 (40.0) | ||
| Duration, mean (range), y | ||||
| After initial exposure | 334 | 4.9 (0.5-40.6) | 50 | 4.0 (0.02-21.3) |
| After cessation of exposure in formerly exposed workers | 57 | 5.3 (0.2-16.8) | 21 | 4.4 (0.6-10.3) |
| Serum indium, mean (range), μg/L | 341 | 9.3a (<0.1-117) | 55 | 2.2 (<0.1-65.4) |
| <1.0, n (%) | 120 (35.2) | 41 (74.5) | ||
| 1.0-2.9, n (%) | 58 (17.0) | 6 (10.9) | ||
| 3.0-4.9, n (%) | 31 (9.1) | 2 (3.6) | ||
| 5.0-9.9, n (%) | 44 (12.9) | 5 (9.1) | ||
| 10.0-19.9, n (%) | 46 (13.5) | 0 (0.0) | ||
| 20.0-29.9, n (%) | 12 (3.5) | 0 (0.0) | ||
| 30.0-49.9, n (%) | 16 (4.7) | 0 (0.0) | ||
| ≥50.0, n (%) | 14 (4.1) | 1 (6.7) | ||
| Smoking, n (%) | 341 | 51 | ||
| Never smokers | 103 (30.2) | 19 (37.3) | ||
| Ex-smokers | 49 (14.4) | 6 (11.8) | ||
| Current smokers | 189 (55.4) | 26 (51.0) | ||
| Biomarkers of effect, geometric mean (geometric SD) | ||||
| KL-6, U/mL | 341 | 355.4a (2.1) | 55 | 222.9 (1.7) |
| Prev of KL-6 ≥500, % | 90a (26.4) | 2 (3.6) | ||
| SP-D, ng/mL | 341 | 60.6a (2.0) | 55 | 43.7 (1.7) |
| Prev of SP-D ≥110, % | 71a (20.8) | 2 (3.6) | ||
| Lung function, mean (SD) | ||||
| FEV1.0/FVC, % | 327 | 82.7 (6.5) | 51 | 82.0 (7.4) |
| FVC, % | 328 | 100.9 (12.6) | 51 | 99.1 (11.5) |
| FEV1.0 % | 327 | 95.5 (12.0) | 51 | 93.3 (11.3) |
Abbreviations: FEV1.0, Forced expiratory volume in 1 s; FVC, Forced vital capacity; KL-6, Krebs von den Lungen 6; Prev, prevalence; SP-D, surfactant protein-D.
a P < .01 by Mann-Whitney U test, chi-squared test, and Fisher exact test.
3.2. Three incidences of kidney cancer in the cohort study
Two male and 1 female incident cases of kidney cancer were identified across 3 factories. Table 2 presents the characteristics, indium exposure levels, biomarkers for interstitial changes, In-K values, and In-K/In-S ratios for the 3 cases. The mean age was 55 years (range 46-63 years). They were either smokers or secondhand smokers. The mean duration of indium exposure was 14.6 years (range 5.5-25 years). In-S levels at baseline ranged from below the detection limit to 4.3 μg/L. Only 1 case exceeded the biological exposure limit of 3 μg/L recommended by the Japan Society for Occupational Health (JSOH). KL-6 and surfactant protein-D (SP-D), biomarkers for interstitial lung disease, remained within normal limits in all cases. The mean latency from initial exposure to diagnosis was 18.8 years (range 13.4-25 years). In Cases 1 and 2, kidney cancer was suspected during follow-up chest high-resolution chest computed tomography (HRCT); in Case 3, the diagnosis was made during a full-body examination for lung cancer staging. All cases underwent partial or total nephrectomy, and kidney cancer was confirmed histologically.
Table 2.
Characteristics and occupational history of patients with incident kidney cancer.
| Case 1 | Case 2 | Case 3 | |
|---|---|---|---|
| Information collection timing | Follow-up survey | Follow-up survey | Follow-up survey |
| Sex | Male | Male | Female |
| Smoking history | 0.9 pack—27 y | 1 pack—37 y | Secondhand smoker |
| Job type | Indium oxide handling | Research division | ITO target plate bonding/packing |
| Indium exposure duration, y | 13.4 | 5.5 | 25 |
| At the initial | |||
| In-S, μg/L | 4.3 | <0.1 | 2.4 |
| KL-6, (WNL <500), U/mL | 284 | 137 | 364 |
| SP-D, (WNL <110), ng/mL | 43.9 | 46.7 | 17.2 |
| At diagnosis | |||
| In-S, μg/L | 3.5 | <0.1 | 0.3 |
| KL-6, (<500 U/mL) | 257 | 276 | 416 |
| SP-D, (<110 ng/mL) | 29.2 | 49.9 | 18.3 |
| Latency from initial indium exposure, y | 13.4 | 18 | 25 |
| Past medical history | None | None | Sinusitis |
| Mean indium concentration in the kidneys, a ng/g | 87.8 | <1 | 15.8 |
| In-K/In-S ratio | 25 | NC | 53 |
Abbreviations: In-K, indium concentration in kidney; In-S, indium concentration in serum; KL-6, Krebs von den Lungen-6; NC, not calculated; SP-D, surfactant protein-D; WNL, within normal limits.
aKidney specimens were obtained from noncancerous tissue sites.
3.3. Cases 1 and 2
The first case was a male smoker with a 13-year latency period. His In-S level was 4.3 μg/L, and KL-6 was 284 U/mL at baseline (not reported). The second case was a male laboratory worker with consistently undetectable In-S levels (<0.1 μg/L) across all prior health checkups. In-K in the excised kidney was also below the measurement limit (<1 ng/g) following partial nephrectomy (not reported). These findings suggest that there is no significant association with indium exposure.
3.4. Case 3: double primary cancers in a female worker
Case 3 was a female secondhand smoker who worked for 8 years in a facility producing ITO target plates and then for 18 years in cleaning and packing ITO target plates. She had no history of respiratory illness or exposure to occupational dust, though she had handled toluene since 1997. At baseline, the patient had been exposed to indium for 6.4 years.
Her In-S levels were 2.4, 0.6, 0.5, and 0.3 μg/L in 2004, 2009, 2015, and 2022, respectively, showing a gradual decline over 19 years. Corresponding KL-6 levels were 364, 310, 404, and 416 U/mL. Although within normal limits, the KL-6 level at diagnosis was slightly elevated compared with baseline, exhibiting a U-shaped trend over time.
During the fourth health checkup, chest HRCT revealed a 20 mm nodule with spiculation in the right upper lung field. Pathological analysis confirmed primary lung cancer (papillary adenocarcinoma, pT1bN0M0). Concurrently, a full-body scan revealed primary renal cell carcinoma, confirmed via partial nephrectomy.
3.5. SIR of kidney cancer
Table 3 shows the incidence of kidney cancer by sex in this study, the expected cases in the general Japanese population, and the SIR. The calculated person-years for the overall cohort, males, and females in this study were 3694.8, 3414.6, and 280.2, respectively. The expected number of kidney cancer cases in the cohort, based on the overall, male, and female Japanese general population, was 0.505, 0.487, and 0.018, respectively. The overall SIR was 5.95 (3/0.505) (95% CI, 2.02-17.47). The SIR for males was 4.11 (2/0.487) (95% CI, 1.13-14.97), and the SIR for females was 56.86 (1/0.018) (95% CI, 9.80-314.7). After excluding Case 2, in which both In-S and In-K were below the detection limit, the associations remained statistically significant: overall SIR 3.96 (95% CI, 1.09-14.44), SIR for males 2.05 (95% CI, 0.36-11.63), and SIR for females 56.86 (95% CI, 9.80-314.69).
Table 3.
Incidence and standardized incidence ratio (SIR) of kidney cancer, 2013-2022.
| Kidney cancer, n | Incidence | Expected | SIR (I/E) (95% CI) | SIR excluding Case 2 a (95% CI) | |
|---|---|---|---|---|---|
| 2013-2018 | 2019-2022 | ||||
| Overall | 1 | 2 | 0.505 | 5.95 (2.02–17.47) | 3.96 (1.09–14.44) |
| Male | 1 | 1a | 0.487 | 4.11 (1.13–14.97) | 2.05 (0.36–11.63) |
| Female | 0 | 1b | 0.018 | 56.86 (9.80–314.7) | 56.86 (9.80–314.69) |
Abbreviations: E, expected number; I, incidence; In-K, indium concentration in kidney; In-S, indium concentration in serum.
aIn-S and In-K in Case 2 were below the detection limit in all previous health checks and surgical specimens.
bDouble primary cancer.
3.6. Smoking adjustment
Of the 312 male workers exposed to indium compounds for whom smoking histories were available at the initial study, 80 were nonsmokers (25.6%), 47 were former smokers (15.1%), and 185 were current smokers (59.3%). Of the 29 female workers, 23 were nonsmokers (79.3%), 2 were former smokers (6.9%), and 4 were current smokers (13.8%). The age-adjusted smoking rates of the general Japanese male population, estimated using an indirect method, were 33.5% nonsmokers, 17.4% former smokers, and 55.4% current smokers. Among general Japanese females, the rates were 79.0% nonsmokers, 3.7% former smokers, and 17.3% current smokers.
 |
 |
The calculated bias factor for each sex was 1.0. Since this result indicates that the differences in smoking status between workers exposed to indium compounds and the general Japanese population were not sufficient to affect the SIR, we did not adjust the SIR.
4. Discussion
The first female case of lung cancer and double primary cancer involving the kidney was identified in an 18-year follow-up indium cohort study, with the SIR for kidney cancer calculated accordingly. There remains insufficient evidence to classify indium compounds as human carcinogens. Indium compounds were designated as a Group 2A carcinogen by the JSOH in 2007,11 and ITO as a Group 2B carcinogen by the IARC in 2018.12 In our previous report involving 2 incident cases of lung cancer in males across 11 factories, the SIR for males was 1.89 (95% CI, 0.52-6.88), which was not statistically significant.2 In 2022, an additional incident case was reported in a secondhand smoker with a latency period of 25 years following initial indium exposure. Baseline values included an In-S of 2.4 μg/L and KL-6 of 364 U/mL. Although the In-S was low, localized concentrations of indium in the lung tissue (In-L) may have been high where ITO particles were deposited. Chronic inflammation in the lung parenchyma surrounding the opacity may lead to carcinogenesis. A previous nonsmoking case of lung cancer from the same cohort—where the first fatality occurred—showed a high In-S of 40 μg/L and elevated KL-6 of 1930 U/mL at baseline.13 These cases suggest that lung cancer may develop in indium-exposed workers even at varying exposure levels.
Three cases of kidney cancer were identified in the cohort. However, kidney cancer was not reported in 2-year ITO inhalation studies.14 In a 2-year indium phosphide inhalation study, a renal tubule carcinoma was observed in female rats exposed to the lowest dose, though no kidney tumors developed in the control group or the other 2 exposed groups.15 In a 26-week inhalation study with rats exposed to 0.1 mg/m3 ITO, the highest indium concentration was detected in the lungs, followed by the spleen, kidney, and liver. In-L/In-blood and In-K/In-blood ratios ranged from 13 000 to 25 000 and 40 to 50, respectively, indicating accumulation and distribution.14 Ionic indium binds to plasma proteins such as transferrin, is transported to the liver and kidney, accumulates in the renal cortex and medulla, and is ultimately excreted via urine.16 Indium nanoparticles and ionic indium have been shown to affect tubular epithelial cells in the kidney, leading to inflammatory cell infiltration.17 In addition, previous in vitro studies using A549 human lung epithelial cells reported that indium compounds can induce the formation of 8-nitroG through activation of the high-mobility group box-1 (HMGB1)-receptor for advanced glycation end products (RAGE)-Toll-like receptor 9 (TLR9) pathway.18 Since this pathway has also been implicated in the development of inflammatory kidney diseases19 and renal cancer,20 it is plausible that indium exposure contributes to renal carcinogenesis via mechanisms similar to those observed in the lung.
To our knowledge, this study is the first to report the SIR of kidney cancer among indium-exposed workers. The overall SIR was 5.95 (95% CI, 2.02-17.47). The SIR for males was 4.11 (95% CI, 1.13-14.97), and the SIR for females was 56.86 (95% CI, 9.80-314.7). Tobacco smoking is classified as a Group 1 carcinogen by the IARC.21 However, in the Japanese population, the risk is largely limited to heavy smokers. Among current heavy smokers, the risk of renal cell carcinoma ranges from 1.5 to 2.9,7–9 and for heavy smokers with more than 40 pack-years, it is 1.5 (95% CI, 1.01-2.25).9 Using the marginal SIR reported by Washio et al,7 the smoking bias was 1, indicating no significant difference. Therefore, we did not adjust the SIR in this study. When interpreting the results, it may be necessary to consider the potential smoking bias of 1.5 to1.68 for Japanese current heavy smokers, although interpretation is difficult for former or current light smokers.
This study has some limitations, including the small number of kidney cancer cases and the absence of a dose–response relationship, making the association between indium exposure and kidney cancer inconclusive. However, in vitro studies show that human lung epithelial cells exposed to 5-200 ng/mL of ITO and other indium compounds, including nanoparticles, exhibit a dose–response relationship with the formation of mutagenic DNA lesions (8-nitroguanine) under inflammatory conditions.18 After excluding 1 case due to undetectable In-S and In-K levels, the overall SIR for kidney cancer was 3.96 (95% CI, 1.09-14.44). These findings suggest that exposure to indium compounds may be associated with both lung and kidney cancers in humans. However, the SIR of 56.86 (95% CI, 9.80-314.69) for females should be interpreted with caution because it is based on only 1 incident case.
The follow-up rate of 86% was high, and the group lost to follow-up had lower indium exposure and fewer lung effects than the follow-up group. Nevertheless, because the dose–response relationship between In-S and kidney cancer remains unclear, it is not possible to determine whether the effect on the SIR of kidney cancer is overestimated or underestimated.
These results suggest that the inclusion of abdominal ultrasound examination may be effective in the occupational health management of workers exposed to indium compounds.
5. Conclusions
Exposure to indium compounds may be associated with an increased risk of lung cancer and kidney cancer in humans. Continued follow-up of health risks beyond pulmonary effects is necessary in the cohort study.
Acknowledgments
We thank the staff members and patients at the participating factories for their cooperation. We also thank Miyuki Hirata PhD, and Nagisa Matsumura MS, for analyzing indium concentrations in serum and kidney tissues.
Contributor Information
Makiko Nakano, Division of Epidemiological Research for Chemical Disorders, Research Center for Chemical Information and Management, National Institute of Occupational Safety and Health, 6-21-1, Nagao, Tama-ku, Kawasaki-shi, Kanagawa 2148585, Japan; Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan.
Yoko Eitaki, Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan.
Akiyo Tanaka, Center of Plasma Nanointerrace Engineering, Kyushu University, Fukuoka, Japan.
Kazuyuki Omae, Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan.
Author contributions
All authors contributed to the study’s design. Makiko Nakano, Yoko Eitaki, and Akiyo Tanaka collected specimens and coordinated with the Japan Industrial Safety and Health Association to measure indium concentrations in the kidney. Makiko Nakano and Kazuyuki Omae analyzed the data. Makiko Nakano drafted the initial manuscript. All authors critically revised and approved the final version.
Funding
This study was supported by Grants-in-aid for Scientific Research (Project Nos. 15 390 191, 17 390 179, 20 249 039, 23 249 033, 24 590 758, 19H03906) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (2003-2004, 2005-2006, 2008-2010, 2011-13, 2012-14, and 2019-2022), by Research Grants from the National Institute of Occupational Safety and Health, Japan (N-F05-08), and in part by donations for research to the Department of Preventive and Environmental Medicine, Keio University School of Medicine, from 2 of the surveyed companies. The funders did not influence the results/outcomes of the study despite author affiliations with the funder.
Conflicts of interest
Preventive and Environmental Medicine, Keio University School of Medicine, received donations for research from a surveyed company. Kyushu University received a donation for educational and academic research grants from a surveyed company. K.O. has no competing interest. The surveyed company that made the donation had no role in the study design, data collection, analysis and interpretation of data, writing of the manuscript, or the decision to submit the paper for publication.
Data availability
Access to the dataset is restricted owing to confidentiality agreements and the inclusion of sensitive corporate information that precludes public dissemination.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Access to the dataset is restricted owing to confidentiality agreements and the inclusion of sensitive corporate information that precludes public dissemination.