Risk of bladder cancer in male Japanese workers exposed to ortho-toluidine and other aromatic amines.

PURPOSE: Nine bladder cancer (BCa) cases were reported among aromatic amine-exposed male workers at a factory manufacturing organic dye/pigment intermediates in Japan. We aimed to evaluate the characteristics of aromatic amine-exposed workers by cross-sectional observation, and the risk of BCa by assessing the standardized incidence ratio (SIR). METHODS: In the cross-sectional study, our subjects were: 9 BCa patients, 36 aromatic amine-exposed non-patients, and 79 non-exposed workers from 3 factories. We evaluated the subjects' medical history, urinalysis, qualitative determination of nuclear matrix protein 22, and urinary cytology. For SIR assessment, 98 aromatic amine-exposed workers from 1 factory were included, and the Japanese general male population was used as a referent population. Since no direct aromatic amine-exposure data were available, we calculated surrogate exposure levels using information on job sites, exposure potency, and duration. RESULTS: Coexistent aromatic amines were ortho-toluidine (OT), aniline, para-toluidine, ortho-anisidine, 2,4-xylidine, and ortho-chloroaniline. The prevalence rates of cystitis and bladder lesion-related symptoms in both BCa patients and aromatic amine-exposed non-patient workers were significantly higher than those of non-exposed workers. Overall, the SIR for BCa in OT-exposed workers was 56.8 (95% CI 27.7-104.3) and apparent dose-response relationships were revealed between the SIR and the surrogate exposure level in the 0-10-year lagged analyses. Overall, SIRs in other aromatic amine-exposed workers were also significantly high but no or unclear dose-response relationships were observed. CONCLUSIONS: We conclude that OT may be responsible for the increased risk of BCa. Regular monitoring of bladder lesion-related symptoms is essential for the early identification of BCa.

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.

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.

Update of occupational lung disease.

OBJECTIVE: Occupational Lung Disease is an oldest but still a biggest problem in occupational health. METHODS: Steering Committee members of the Japan Society for Occupational Health (JSOH) Occupational Lung Disease Study Group selected and summarized current topics on occupational lung diseases based on expert opinion, as informed by governmental regulation, public health concerns, and frequently discussed in related academic conferences. RESULTS: The topics included in this review are professional education in medical screening skills, 2014 update of Helsinki Criteria, respiratory diseases found in the earthquake and tsunami affected regions, newly recognized occupational lung diseases, and potential respiratory health hazards. DISCUSSIONS: Although occupational lung diseases seem to stay as one of the major concerns in occupational health, screening tools and control measures are standardized for the better prevention of the diseases. As this health problem usually occurs in where the most actively economically developing area is, the patients tend to increase in emerging economic powers with huge population.

An epidemic of bladder cancer: ten cases of bladder cancer in male Japanese workers exposed to ortho-toluidine.

BACKGROUND: ortho-Toluidine (OT) was listed as a Group 1 carcinogen by the International Agency for Research on Cancer in 2012 based on epidemiological observations of workers co-exposed to OT and aromatic amines. From 2014 to 2017, several cases of bladder cancer (BCa) secondary to occupational exposure, primarily to OT, were detected in Japan. OBJECTIVE: To describe 10 cases of BCa in male Japanese workers exposed primarily to OT at two plants that produce organic dye and pigment intermediates. METHODS: Details of the 10 cases were obtained from company records and through a questionnaire and interview. The surrogate level of exposure to each aromatic amine was calculated as the total job-weight/month for each process for each job-year. RESULTS: No quantitative exposure data were available. In most cases the surrogate level of exposure to OT was higher than to other amines. All 10 cases were exposed primarily to OT and co-exposed to para-toluidine, ortho-anisidine, aniline, 2,4-xylidine or ortho-chloroaniline. The age range at diagnosis was 41-71 years (mean 56). The duration of OT exposure was 7-28 years (mean 16.5). Disease latency was 16-28 years (mean 21.9). Eight patients were smokers. The main symptom at diagnosis was hematuria (70%). CONCLUSIONS: The characteristics of BCa cases were associated with a high surrogate level of OT exposure and a disease latency of more than 20 years from the initial OT exposure. The main route of OT exposure was likely through the skin. It is necessary to continue health examinations in these target groups.

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.

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.

Indium lung disease.

BACKGROUND: Reports of pulmonary fibrosis, emphysema, and, more recently, pulmonary alveolar proteinosis (PAP) in indium workers suggested that workplace exposure to indium compounds caused several different lung diseases. METHODS: To better understand the pathogenesis and natural history of indium lung disease, a detailed, systematic, multidisciplinary analysis of clinical, histopathologic, radiologic, and epidemiologic data for all reported cases and workplaces was undertaken. RESULTS: Ten men (median age, 35 years) who produced, used, or reclaimed indium compounds were diagnosed with interstitial lung disease 4-13 years after first exposure (n = 7) or PAP 1-2 years after first exposure (n = 3). Common pulmonary histopathologic features in these patients included intraalveolar exudate typical of alveolar proteinosis (n = 9), cholesterol clefts and granulomas (n = 10), and fibrosis (n = 9). Two patients with interstitial lung disease had pneumothoraces. Lung disease progressed following cessation of exposure in most patients and was fatal in two. Radiographic data revealed that two patients with PAP subsequently developed fibrosis and one also developed emphysematous changes. Epidemiologic investigations demonstrated the potential for exposure to respirable particles and an excess of lung abnormalities among coworkers. CONCLUSIONS: Occupational exposure to indium compounds was associated with PAP, cholesterol ester crystals and granulomas, pulmonary fibrosis, emphysema, and pneumothoraces. The available evidence suggests exposure to indium compounds causes a novel lung disease that may begin with PAP and progress to include fibrosis and emphysema, and, in some cases, premature death. Prospective studies are needed to better define the natural history and prognosis of this emerging lung disease and identify effective prevention strategies.

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.

Lifestyle factors and visible skin aging in a population of Japanese elders.

BACKGROUND: The number of studies that use objective and quantitative methods to evaluate facial skin aging in elderly people is extremely limited, especially in Japan. Therefore, in this cross-sectional study we attempted to characterize the condition of facial skin (hyperpigmentation, pores, texture, and wrinkling) in Japanese adults aged 65 years or older by using objective and quantitative imaging methods. In addition, we aimed to identify lifestyle factors significantly associated with these visible signs of aging. METHODS: The study subjects were 802 community-dwelling Japanese men and women aged at least 65 years and living in the town of Kurabuchi (Takasaki City, Gunma Prefecture, Japan), a mountain community with a population of approximately 4800. The facial skin condition of subjects was assessed quantitatively using a standardized facial imaging system and subsequent computer image analysis. Lifestyle information was collected using a structured questionnaire. The association between skin condition and lifestyle factors was examined using multivariable regression analysis. RESULTS: Among women, the mean values for facial texture, hyperpigmentation, and pores were generally lower than those among age-matched men. There was no significant difference between sexes in the severity of facial wrinkling. Older age was associated with worse skin condition among women only. After adjusting for age, smoking status and topical sun protection were significantly associated with skin condition among both men and women. CONCLUSIONS: Our study revealed significant differences between sexes in the severity of hyperpigmentation, texture, and pores, but not wrinkling. Smoking status and topical sun protection were significantly associated with signs of visible skin aging in this study population.

Serum antioxidants and age-related macular degeneration among older Japanese.

From the perspective of human nutrition, the prevention of age-related macular degeneration (AMD) through diet control is feasible and desirable. We investigated the relationship between serum antioxidants and AMD in the community-dwelling older Japanese eating a typical Japanese diet. In this study, 722 subjects aged 65 years or older (297 males and 425 females) who had gradable fundus photographs were included. The subjects were divided into three groups of early or late AMD or non-maculopathy. Serum antioxidants (alpha-, gamma-tocopherols, retinol, beta-cryptoxanthin, alpha-, beta-carotenes, lycopene, and lutein and zeaxanthin) were measured with high-performance liquid chromatography. To clarify the combined effect as the group of the antioxidants, we defined the carotene family (alpha-, beta-carotenes and lycopene) and carotenoid family (beta-cryptoxanthin, alpha-, beta-carotenes, lycopene, lutein and zeaxanthin). Tertiles of each serum antioxidant were obtained and the prevalence of early or late AMD was compared with univariate or multivariate analysis. The overall prevalence of early AMD was 4.4% (95% confidence interval: 3.1-6.2) and late AMD was 1.1% (0.5-2.2). Only alpha-tocopherol and beta-cryptoxanthin were related to late AMD as single antioxidants. On the other hand, the carotene and carotenoid families as a combination of antioxidants were protectively associated with late AMD. No relationship was found between serum antioxidants and early AMD. Our findings support the hypothesis that a combination of serum antioxidants obtained from the traditional Japanese diet is protective for late AMD, but not for early AMD.

Effects of SO2 on respiratory system of adult Miyakejima resident 2 years after returning to the island.

BACKGROUND: Mt. Oyama in Miyakejima Island erupted in June, 2000. All Miyake villagers were forced to evacuate from the island in September, 2000, due to continuous eruptions and emissions of unsafe amounts of volcanic gas, mainly SO2. From February, 2005, Miyake villagers returned to the island despite volcanic gas still being emitted. OBJECTIVES: This study examines the 2-yr changes in Miyake residents' respiratory systems from autumn 2004 to November 2006. METHODS: The study population was 823 Miyake adult residents who participated in the health check-up in 2006. Respiratory effects were evaluated by a questionnaire for respiratory symptoms and spirometry. SO2 has been continuously monitored at 7 sampling points of the inhabited area. The mean SO2 concentration from February 2005 to November 2006 was 0.031 ppm. The area was categorized into 4 areas by SO2 concentration, namely, areas L, H-1, H-2 and H-3, where average SO2 concentrations were 0.019, 0.026, 0.032, and 0.045 ppm, respectively. RESULTS: The study subjects showed no deterioration in lung function. Prevalence of cough and phlegm among all participants were significantly higher in 2006 than in 2004, and age-, sex- and smoking-adjusted odds ratios of cough and phlegm were 1.75 (95%CI 1.33-2.30) and 1.44 (1.12-1.87). Prevalence of chronic bronchitis-like symptoms among normosusceptive subjects in 2006 was 4.1% which was significantly higher than that of 2.1% in 2004 (p=0.035). Compared to area L, the frequencies of phlegm and irritation of the nose were significantly increased in areas H-2 and H-3. CONCLUSION: SO2 exposure-related respiratory symptoms were observed in adult Miyakejima residents after returning to the island.

Tegafur-uracil plus gemcitabine combination chemotherapy in patients with advanced non-small cell lung cancer previously treated with platinum.

BACKGROUND: An open-label, single-arm prospective study was conducted to evaluate the efficacy and toxicity of the combination of gemcitabine and tegafur-uracil (UFT) in patients with advanced nonsmall-cell lung cancer (NSCLC) after the failure of previous platinum-containing regimens. PATIENTS AND METHODS: Patients with advanced NSCLC received 200 mg/m2 of UFT twice daily from day 1 through 14 plus 900 mg/m2 of gemcitabine per day via intravenous injection on days 8 and 15. This regimen was repeated every 3 or 4 weeks. RESULTS: A total of 40 patients were enrolled. Eleven patients (28%; 95% confidence interval [CI], 15-44%) achieved a partial response. The median progression-free survival, median overall survival, and 1-year survival rate were 4.0 months (95% CI, 3.3-6.7 months), 12.6 months (95% CI, 7.0-22.3 months), and 51% (95% CI, 33-66%), respectively. The most common grade 3 or 4 toxicity was neutropenia (38%; 95% CI, 23-54%) and the rate of grade 3 or 4 nonhematologic toxicity remained at less than 5%. A multivariate Cox model showed that adenocarcinoma, nonsmoking history, and good performance status predicted better survival. CONCLUSIONS: Combination chemotherapy with UFT and gemcitabine showed a promising effectiveness and acceptable toxicity for patients with platinum-resistant NSCLC.

Pulmonary adenocarcinoma associated with SAPHO syndrome difficult to differentiate from multiple bone metastasis.

The patient was a 57-year-old man with a chief complaint of anterior chest pain who was diagnosed with clinical stage IV (c-T2N2M1) non-small-cell lung cancer (adenocarcinoma). Tenderness in the sternoclavicular joint, acne, periodontitis, and palmoplantar pustulosis were evident, and SAPHO syndrome was diagnosed. SAPHO syndrome is a rare disorder that results in synovitis, acne, pustulosis, hyperostosis, and osteomyelitis. Bone scintigraphy showed tracer accumulation in the costal cartilage, sternoclavicular joint, and cervical vertebrae 6-7. Although the bone lesions of SAPHO syndrome were difficult to differentiate from bone metastasis of pulmonary adenocarcinoma, metastatic bone tumors were ruled out by magnetic resonance imaging, computed tomography, and fluorodeoxyglucose positron emission tomography. There have been no previously reported cases of lung cancer with comorbid SAPHO syndrome. We report such a case and discuss the relevant literature, particularly that concerned with the evaluation of bone lesions.

A computer-aided diagnosis (CAD) system in lung cancer screening with computed tomography.

We evaluated a computer-aided diagnosis (CAD) system with automatic detection of pulmonary nodules for lung cancer screening with computed tomography (CT). Five hundred and eighteen participants were examined with low-dose helical CT during a lung cancer screening by three respiratory physicians according to the General Rule edited by the Japan Lung Cancer Society. Four cases were detected by CAD and pathologically diagnosed as lung cancer. We compared the detection capability of the physician and CAD in 301 participants. Three physicians determined 75/301 (24.9%) participants as "e" (suspicious of lung cancer) in consensus without CAD, while 3 participants were added to "e" with CAD. Three physicians did not independently judge as "e" in 14 (18.7%), 16 (21.3%) and 16 (21.3%) out of 75 participants. CAD could not identify 17 (22.7%) nodules of 75 participants, and all 17 were less than 6 mm in diameter. The CAD system offers a useful second opinion when physicians examine patients at lung cancer CT screenings.