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.

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.

Biological monitoring of o-toluidine in urine pretreated by an enzymatic deconjugation method.

OBJECTIVES: To establish an enzymatic deconjugation method to separately quantify urinary o-toluidine (OT), its six metabolites, another six chemicals present in an OT-processing plant, and one metabolite of p-toluidine, and to propose optimal urinary biological monitoring items of OT exposure. METHODS: Thirty-six urine samples of an OT-processing plant's workers were obtained and pretreated by an enzymatic deconjugation method employing ß-glucuronidase/arylsulfatase for 3 hours at 37°C and measured by liquid chromatograph-mass spectrometry (LC-MS). An alkaline hydrolytic pretreatment and 1-chlorobutane extraction procedure was also examined as a widely used urinary OT measurement method. RESULTS: The 14 chemicals were separated by LC-MS condition set by us and 13 chemicals other than 2-chloroaniline showed satisfiable linearity and limits of determination. Standard substances of six OT metabolites decomposed after the alkaline heating. In the 36 urine samples, OT, N-(4-hydroxy-2-methylphenyl) acetamide (NHM), and 4-amino-m-cresol (ACR) accounted for approx. 90% of the total OT and OT metabolites, but inter-individual variation of the three substance excretion seemed to be wide. Time course of urinary excretion revealed that concentration of the three substances was higher 24 hours after the work shift's end rather than just after the work shift. CONCLUSIONS: OT and its six metabolites can each be determined with LC-MS. The alkaline method is not so optimal for exact biological monitoring. Rather, the sum of urinary OT, NHM, and ACR measured by the enzymatic method is a better index, and "end of the workweek" is a good urine-sampling time for the biological monitoring of OT exposure.

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.

[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.

Microorganism levels in spray from warm-water bidet toilet seats: factors affecting total viable and heterotrophic plate counts, and examination of the fluctuations and origins of Pseudomonas aeruginosa.

The objectives of this study were to conduct an appropriate microbial evaluation of warm-water bidet toilet seats. Health-related advantages and disadvantages have been associated with using warm-water bidet toilet seats, which are classified according to the tank type, including tanks equipped with reservoir water heaters and on-demand tankless systems equipped with an instantaneous water heater. However, related bacterial research is sparse. Here, we performed a long-term survey of the behavior of microorganisms (i.e., the total viable count (TVC), heterotrophic plate counts (HPCs), and Pseudomonas aeruginosa count) in a university campus. We also examined the differences between the tank and on-demand types, and the origins of P. aeruginosa. A low TVC (≤1/mL) in the spray waters from both on-demand and tank-type warm-water bidet toilet seats showed low bacterial contamination, although there was an increase in HPC, i.e., growth of biofilms, inside in the warm-water bidet toilet seats. When P. aeruginosa was detected in spray water over an extended duration, the P. aeruginosa origin was considered as either from feces or tap water. Collectively our findings demonstrate that hygienic safety of warm-water bidet toilet seats is being maintained overall.

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.

Influence of sulfur dioxide on the respiratory system of Miyakejima adult residents 6 years after returning to the island.

BACKGROUND: Mount Oyama, on the Japanese island of Miyakejima, began erupting in June 2000, necessitating the evacuation of 3,000 island residents. Volcanic gas emissions, primarily consisting of sulfur dioxide (SO2), gradually decreased and residents returned to the island after the evacuation order was lifted in February 2005. OBJECTIVES: To assess the exposure-effect and exposure-response relationships between SO2 exposure and effects on respiratory system in adult Miyakejima residents. METHOD: Health checkups focusing on pulmonary function and respiratory/irritative symptoms were conducted six times every November from 2006 to 2011. The study population comprised 168 subjects who underwent all health checkups. SO2 concentrations were measured at six fixed monitoring stations in inhabitable areas. RESULT: Based on the annual mean SO2 concentration, inhabitable areas were classified into three categories; namely, lower (L), higher (H-1), and highest (H-2) areas. Average SO2 concentrations (ppb) during 3 months prior to each health checkup dropped from 11.3 to 3.29, 32.2 to 13.4 and 75.1 to 12.6 from 2006 to 2010/2011 in L, H-1, and H-2. No significant declines in pulmonary function were observed in all areas. However, prevalence of subjective symptoms such as "Cough," "Irritation and/or pain in throat," "Irritation, runny nose, and/or nasal sniffles," and "Irritation and/or pain in the eyes," dependently increased on SO2 concentration. Odds ratios were statistically significant at approximately 70 ppb of SO2 or above. CONCLUSION: Adult residents of Miyakejima island showed no deterioration in pulmonary function at SO2 levels, but complained of respiratory/irritative symptoms in an SO2 concentration-dependent manner.

Bidet toilet use and incidence of hemorrhoids or urogenital infections: A one-year follow-up web survey.

Although bidet toilets are widely used in Japan, the relationship between habitual bidet toilet use and the incidence of hemorrhoids or urogenital infections has not been prospectively studied. We performed a web survey and followed bidet toilets users and non-users to assess the incidence of hemorrhoids or urogenital infections from 2013 to 2014. Study subjects were randomly selected from a research company's (Macromill, Inc.) web panel. The baseline survey inquired about toilet use and confounding parameters, and the follow-up survey examined outcome parameters. A total of 7637 subjects were analyzed using single or multiple logistic regression models. The prevalence odds ratios (ORs) between bidet toilet users and non-users for hemorrhoids, urological infections, and vulval pruritus were significantly > 1.0 but their incidence ORs were not significant. The adjusted incidence OR for bacterial vaginitis symptoms was significant (2.662, 95% confidence interval [CI] [1.315-5.520]). These findings suggest that positive relations between habitual bidet toilet use and hemorrhoids and urogenital symptoms, except bacterial vaginitis, were due to reverse causation. The incidence of bacterial vaginitis might be caused by bidet toilet use, but the incidence rates were too small to make a definite conclusion, and further studies are needed.

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.

Bidet toilet seats with warm-water tanks: residual chlorine, microbial community, and structural analyses.

Despite the reported health-related advantages of the use of warm water in bidets, there are health-related disadvantages associated with the use of these toilet seats, and the bacterial research is sparse. We conducted a survey on the hygienic conditions of 127 warm-water bidet toilet seats in restrooms on a university campus. The spray water from the toilet seats had less residual chlorine than their tap water sources. However, the total viable microbial count was below the water-quality standard for tap water. In addition, the heat of the toilet seats' warm-water tanks caused heterotrophic bacteria in the source tap water to proliferate inside the nozzle pipes and the warm-water tanks. Escherichia coli was detected on the spray nozzles of about 5% of the toilet seats, indicating that the self-cleaning mechanism of the spray nozzles was largely functioning properly. However, Pseudomonas aeruginosa was detected on about 2% of the toilet seats. P. aeruginosa was found to remain for long durations in biofilms that formed inside warm-water tanks. Infection-prevention measures aimed at P. aeruginosa should receive full consideration when managing warm-water bidet toilet seats in hospitals in order to prevent opportunistic infections in intensive care units, hematology wards, and other hospital locations.

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.

Effects of sulfur dioxide on the respiratory system of Miyakejima child residents 6 years after returning to the island.

OBJECTIVES: This study investigated the health effects of volcanic gas, mainly sulfur dioxide (SO2), exposure on the children of Miyakejima Island. METHODS: Health checkups were conducted in November from 2006 to 2011. Health effects were evaluated through a self-administered questionnaire on respiratory and irritative symptoms, and spirometry. SO2 was measured continuously from February 2005 onward at six fixed monitoring stations in inhabitable areas. Based on mean SO2 concentration during 3 months before each health checkup, inhabitable areas were classified into three categories: (1) lower (area L); (2) higher (area H-1); and (3) highest (area H-2). RESULTS: Average concentrations (ppb) of SO2 decreased year-by-year and ranged from 11.3 to 2.47 in area L, from 32.2 to 12.2 in area H-1, and from 75.1 to 12.1 in area H-2, respectively. In general, prevalence of respiratory and irritative symptoms was higher in area H-2, and the prevalence decreased year-by-year in all three areas by Cochran-Armitage test for trend. We defined a study population in area L in 2008 as a reference population because we had no unexposed population. Applying a logistic regression model, age-, sex-, and hypersusceptibility-adjusted prevalence odds ratios to the reference population showed clear exposure-dependent increases in some irritative symptoms such as "Irritation and/or pain in throat" and "in eyes," and approximately 30 ppb seemed to be the threshold concentration. Spirometry did not show any significant differences. CONCLUSIONS: Though no pulmonary functions were affected, some subjective symptoms were detected dose-dependently by SO2 exposure concentration in child residents during the 6 years after the eruption.

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.