Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Hirata Miyuki Last modified date:2019.06.28

Assistant Professor / Social Medicine / Center for Cohort Studies / Faculty of Medical Sciences


Papers
1. Satoko Iwasawa, Makiko Nakano, Hiroyuki Miyauchi, Shigeru Tanaka, Yaeko Kawasumi, Ichiro Higashikubo, Akiyo Tanaka, Miyuki Hirata, Kazuyuki Omae, Personal indium exposure concentration in respirable dusts and serum indium level, Industrial Health, 10.2486/indhealth.2016-0015, 55, 1, 87-90, 2017.01.
2. Makiko Nakano, Akiyo Tanaka, Miyuki Hirata, Hiroyuki Kumazoe, Kentaro Wakamatsu, Dan Kamada, Kazuyuki Omae, An advanced case of indium lung disease with progressive emphysema, Jounal of Occupational Health, 10.1539/joh.16-0076-CS, 58, 5, 477-481, 2016.09.
3. Takaaki Amano, Thapanut Sarinont, Kazunori Koga, Miyuki Hirata, Akiyo Tanaka, Masaharu Shiratani, Production of In, Au, and Pt nanoparticles by discharge plasmas in water for assessment of their bio-compatibility and toxicity, MRS Advances, 10.1557/adv.2016.41, 1, 18, 1301-1306, 2016.01, Nanoparticles have great potential for biomedical applications such as early detection, accurate diagnosis, and personalized treatment of cancer. Assessment of bio-compatibility and toxicity of nanoparticles body is an emerging topic for these applications. To study kinetics of nanoparticles in body, we synthesized indium, gold and platinum nanoparticles in aqueous suspension using pulsed electrical discharge plasmas in water. The average size of synthesized primary nanoparticles for indium, gold, and platinum are 6.2 nm, 6.7 nm, and 5.4 nm, whereas the average size of secondary nanoparticles for indium, gold, and platinum are 315 nm, 72.3 nm, and 151 nm, respectively. Synthesized indium nanoparticles are transported from subcutaneous to serum and brain. The indium content in serum for the synthesized nanoparticles is much higher than that for the In2O3 nanoparticles of 150 nm in primary size. For gold and platinum nanoparticles, preliminary examination of intratracheal administration revealed that administration of synthesized nanoparticles with 10 mg/kg BW (body weight) may cause bleedings and/or emphysema in lung..
4. Takaaki Amano, Thapanut Sarinont, Kazunori Koga, Miyuki Hirata, Akiyo Tanaka, Masaharu Shiratani, Synthesis of indium-containing nanoparticles in aqueous suspension using plasmas in water for evaluating their kinetics in living body, Journal of Nanoscience and Nanotechnology, 10.1166/jnn.2015.11427, 15, 11, 9298-9302, 2015.11, 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..
5. Makiko Nakano, Akiyo Tanaka, Miyuki Hirata, Iwasawa Satoko, Kazuyuki Omae, Pulmonary effects in workers exposed to indium metal: a cross-sectional study, Jounal of Occupational Health, 10.1539/joh.4-0262-OA, 57, 4, 346-352, 2015.04.
6. Akiyo Tanaka, Miyuki Hirata, Nagisa Matsumura, Yutaka Kiyohara, Tissue distribution of indium after repeated intratrachal instillations of indium-tin oxide into the lungs of hamsters, Jounal of Occupational Health, 10.1539/joh.14-0123-BR, 57, 2, 189-192, 2015.02.
7. Akiyo Tanaka, Miyuki Hirata, Nagisa Matsumura, Kazunori Koga, Masaharu Shiratani, Yutaka Kiyohara, Comparative study on the pulmonary toxicity of indium hydroxide, indium-tin oxide, and indium oxide following intratracheal instillations into the lungs of rats., MRS Symposium Proceedings/MRS Online Proceeding Library CAMBRIDGE UNIVERSITY PRESS, 1723, 1, 2015.01.
8. Akiyo Tanaka, Miyuki Hirata, Nagisa Matsumura, Kazunori Koga, Masaharu Shiratani, Yutaka Kiyohara, Comparative study on the pulmonary toxicity of indium hydroxide, indium-tin oxide, and indium oxide following intratracheal instillations into the lungs of rats, 2014 MRS Fall Meeting Plasma Processing and Diagnostics for Life Sciences, 10.1557/opl.2015.21, 1723, 8-13, 2015.01, We studied the pulmonary toxicity of indium hydroxide (In(OH)3), which is produced during a recycling process of indium-tin oxide (ITO), in comparison with that of ITO or indium oxide (In2O3), two raw materials of flat panel displays. One hundred and forty-four male Wistar rats were intratracheally given equivalent doses of 10 mg/kg indium as In(OH)3, ITO, or In2O3particles, twice a week, for a total of 5 times for 2 weeks. Control rats were given distilled water as a vehicle. After 3 weeks, these rats were serially euthanized, and toxicological effects were determined. Body weight gain was significantly suppressed in the In(OH)3-treated rats compared to that in the control group, but not in the ITO-or In2O3-treated rats. Relative lung weights in all the indium-treated groups significantly increased compared to those in the control group throughout the observation period. Furthermore, lung weights in the In(OH)3 group were significantly higher than those in either the ITO or In2O3 group. Blood indium levels in the In(OH)3-treated rats were much higher, 70-to 200-fold, than those in the In2O3- or ITO-treated rats at each time point. Although the lung indium content decreased gradually during the observation periods, the content in the In(OH)3 group was significantly higher than that in either the ITO or In2O3 group. A histopathological analysis revealed foci indicating a slight to severe pulmonary inflammatory response, including exudation to alveolar spaces, were present in all the indium-treated groups. Interstitial fibrotic proliferation was seen only in the In(OH)3-treated rats. The severity of these lesions in the In(OH)3-treated rats was greater than that in either the ITO-or In203-treated rats. The results of our study clearly demonstrated that In(OH)3 particles caused severe pulmonary toxicity when repeated intratracheal instillations were performed in rats. Furthermore, the toxic potency of In(OH)3 in the lung was much higher than that of ITO and In2O3. Accordingly, the toxicity of In(OH)3 particles should be considered in addition to that of ITO and In2O3 particles when indium exposure occurs..
9. Makiko Nakano, Akiyo Tanaka, Miyuki Hirata, Satoko Iwasawa, Kazuyuki Omae, Pulmonary effects in workers exposed to indium metal
A cross-sectional study, Journal of Occupational Health, 10.1539/joh.14-0262-OA, 57, 4, 346-352, 2015.01, 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/m3, 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..
10. Makiko Nakano, Kazuyuki Omae, Akiyo Tanaka, Miyuki Hirata, Kazuhiko Uchikawa, Takehiro Michikawa, Five-year cohort study : emphysematous progression of indium-exposed workers, Chest, 10.1378/chest.13-2484, 146, 11, 1166-1175, 2014.11.
11. Makiko Nakano, Kazuyuki Omae, Akiyo Tanaka, Hirata Miyuki, KL-6 is not ineffective biomarker of indiumu lung., Int Arch Occup Environ Health, 10.1007/s00420-013-0873-x, 86, 7, 845-846, 2013.04, 中国製のKL-6キットを用いたインジウム作業者の血清KL-6では血清インジウム濃度との相関は低い。.
12. Akiyo Tanaka, Miyuki Hirata, [Health effects of solar cell component material. Toxicity of indium compounds to laboratory animals determined by intratracheal instillations]., Japanese Journal of Hygiene, 10.1265/jjh.68.83, 68, 2, 83-87, 2013.01, 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..
13. Akiyo Tanaka, Miyuki Hirata, Kazunori Koga, Makiko Nakano, Kazuyuki Omae, Yutaka Kiyohara, Pulmonary toxicity of indium tin oxide and copper indium gallium diselenide, 2012 MRS Spring Meeting Plasma Processing and Diagnostics for Life Sciences, 10.1557/opl.2012.1074, 1469, 125-136, 2012.12, The aim of this review is to introduce the adverse health effects of indium compounds. This review consists of 2 parts: (1) a study of the toxic effects of indium compounds in humans, and (2) a study of the toxic effects of indium tin oxide (ITO) and copper indium gallium diselenide (CIGS) in animals. To date, 4 epidemiological surveys have been conducted of indium-handling workers in Japan, and all who were studied showed that exposure to indium compounds caused pulmonary interstitial and emphysematous changes. There were clear dose-response and dose-effect relationships between the serum indium levels and the levels of Krebs von den Lungen-6 (KL-6), which is a serological indicator of interstitial pneumonia. Up until 2011, 8 cases of interstitial pneumonia in Japanese indium-exposed workers, 2 cases of pulmonary alveolar proteinosis (PAP) in US indium-exposed workers, and 1 case of PAP in a Chinese indium-exposed worker have been reported. In animal studies, it has been clearly demonstrated that ITO and CIGS particles cause pulmonary toxicity and that the dissolution of ITO and CIGS particles in the lungs is considerably slow when repeated intratracheal instillations were given to experimental animals. Thus, more studies are needed on the effects of human exposure to indium compounds..
14. Hiroyuki Miyauchi, Aoi Minozoe, Shigeru Tanaka, Akiyo Tanaka, Miyuki Hirata, Masahiro Nakaza, Heihachiro Arito, Yoko Eitaki, Makiko Nakano, Kazuyuki Omae, Assessment of workplace air concentrations of indium dust in an indium-recycling plant, Journal of Occupational Health, 10.1539/joh.11-0233-OA, 54, 2, 103-111, 2012.08, 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/m3. 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/m3 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..
15. Akiyo Tanaka, Miyuki Hirata, Masaharu Shiratani, Kazunori Koga, Yutaka Kiyohara, Subacute pulmonary toxicity of copper indium gallium diselenide following intratracheal instillations into the lungs of rats, Journal of Occupational Health, 10.1539/joh.11-0164-OA, 54, 3, 187-195, 2012.08, 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 demon-strate 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..
16. Akiyo Tanaka, Miyuki Hirata, Masaharu Shiratani, Kazunori Koga and Yutaka Kiyohara, Subacute pulmonary toxicity of copper indium gallium diselenide following intratracheal instillations into the lungs of rats, Journal of Occupational Health, 10.1539, 54, 3, 187-195, 2012.03.
17. Hiyoyuki Miyauchi, Aoi Minozoe, Shigeru Tanaka, Miyuki Hirata, Masahiro Nakaza, Heihachiro Arito, Yoko Eitaki, Makiko Nakano and Kazuyuki Omae, Assessment of workplace air concentrations of indium dust in an indium-recycling plant, Journal of occupational Health, 10.1539, 54, 2, 103-111, 2012.02.
18. Kazuyuki Omae, Makiko Nakano, Akiyo Tanaka, Miyuki Hirata, Tsutahiro Hamaguchi, Tatsuya Chonan, Indium lung-case reports and epidemiology, International Archives of Occupational and Environmental Health, 10.1007/s00420-010-0575-6, 84, 5, 471-477, 2011.06, 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..
19. Makiko Nakano, Akiyo Tanaka, Miyuki Hirata, Kazuyuki Omae, [Validity of serum surfactant protein D measurements in a cross-sectional study]., Rinsho byori. The Japanese journal of clinical pathology, 59, 4, 337-344, 2011.04, 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. 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. 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..
20. Omae K, Nakano M, Tanaka A, Hirata M, Hamaguchi T, Chonan T, Indium lung - Case reports and epidemiology, Int Arch Occup Environ Health, online 01 October 2010, 2010.10.
21. Indium lung.
22. Akiyo Tanaka, Miyuki Hirata, Yutaka Kiyohara, Makiko Nakano, Kazuyuki Omae, Masaharu Shiratani, Kazunori Koga, Review of pulmonary toxicity of indium compounds to animals and humans, Thin Solid Films, 10.1016/j.tsf.2009.10.123, 518, 11, 2934-2936, 2010.03, Due to the increased production of ITO, the potential health hazards arising from occupational exposure to this material have attracted much attention. This review consists of three parts: 1) toxic effects of indium compounds on animals, 2) toxic effects of indium compounds on humans, and 3) recommendations for preventing exposure to indium compounds in the workplace. Available data have indicated that insoluble form of indium compounds, such as ITO, indium arsenide (InAs) and indium phosphide (InP), can be toxic to animals. Furthermore, InP has demonstrated clear evidence of carcinogenic potential in long-term inhalation studies using experimental animals. As for the dangers to humans, some data are available concerning adverse health effects to workers who have been exposed to indium-containing particles. The Japan Society for Occupational Health recommended the value of 3 μg/L of indium in serum as the occupational exposure limit based on biological monitoring to preventing adverse health effects in workers resulting from occupational exposure to indium compounds. Accordingly, it is essential that much greater attention is focused on human exposure to indium compounds, and precautions against possible exposure to indium compounds are most important with regard to health management among indium-handling workers..
23. Akiyo Tanaka, Miyuki Hirata, Toshiaki Homma, Yutaka Kiyohara, Chronic pulmonary toxicity study of indium-tin oxide and indium oxide following intratracheal instillations into the lungs of hamsters, Journal of Occupational Health, 10.1539/joh.L9097, 52, 1, 14-22, 2010.01, Objectives: The aim of this study was to clarify the chronic toxicological effects of indium-tin oxide (ITO) and indium oxide (In 2O3) 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 2O3 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 2O3-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 2O3 particles caused chronic pulmonary toxicity when repeated intratracheal instillations were given to hamsters..
24. Makiko Nakano, Kazuyuki Omae, Akiyo Tanaka, Miyuki Hirata, Takehiro Michikawa, Yuriko Kikuchi, Noriyuki Yoshioka, Yuji Nishiwaki, Tatsuya Chonan, Causal relationship between indium compound inhalation and effects on the lungs, Journal of Occupational Health, 10.1539/joh.L9077, 51, 6, 513-521, 2009.11, Department of Preventive Medicine and Public Health, School of Medicine, Keio University-Background: Recent case reports and epidemiological studies suggest that inhalation of indium dust induces lung damage. Objectives: To elucidate the dose-dependent effects of indium on the lungs and to prove a causal relationship more clearly. Methods: A baseline observation was conducted on 465 workers currently exposed to indium, 127 workers formerly exposed to indium and 169 workers without indium exposure in 12 factories and 1 research laboratory from 2003 to 2006. Indium in serum (In-S) was determined as an exposure parameter, and its effects on the lungs were examined. Results: The means of In-S in the current, former and no exposure workers were 8.35, 9.63 and 0.56 ng/ml, respectively. The current and former exposure workers had significantly higher levels of KL-6, and showed significant dose-dependent increases in KL-6, SP-D, and SP-A. Current exposure workers with In-S of 3 ng/ml or above demonstrated a significant increase of KL-6 in both GM and prevalence exceeding the reference value. Approximately a quarter of the former exposure workers had interstitial changes as seen on chest HRCT. In-S of exposed workers who had been working before improvements of the working environment (Group Bef) and those who started working after improvements (Group Aft) were 12.29 and 0.81 ng/ml, respectively. Adjusted odds ratios indicated 87%, 71% and 44% reductions among Group Aft workers who exceeded the reference values of KL-6, SP-D and SP-A, respectively. Conclusion: Dose-dependent lung effects due to indium exposure were shown, and a decrease of indium exposure reduced the lung effects. An In-S value of 3 ng/ml may be a cut-off value which could be used to prevent early effects on the lungs..
25. Health effect and control of indium .
26. T Hamaguchi, K Omae, T Takebayashi, Y Kikuchi, N Yoshioka, Y Nishiwaki, A Tanaka, M Hirata, O Taguchi, T Chonan, Exposure to hardly soluble indiumn compounds in ITO production and recycling plants is a new risk for interstitial lung damage, Occup Environ Med, 65, 51-55, 2008.01.
27. T. Hamaguchi, K. Omae, T. Takebayashi, Y. Kikuchi, N. Yoshioka, Y. Nishiwaki, Akiyo Tanaka, Miyuki Hirata, O. Taguchi, T. Chonan, Exposure to hardly soluble indium compounds in ITO production and recycling plants is a new risk for interstitial lung damage, Occupational and Environmental Medicine, 10.1136/oem.2006.029124, 65, 1, 51-55, 2008.01, Objectives: To identify the effects of indium on the lung and to assess exposure-effect and exposure-response relations between indium exposure and effects on the lungs. Methods: Ninety three male indium exposed and 93 male non-exposed workers from four ITO manufacturing or ITO recycling plants were analysed in a cross-sectional study. Indium in serum (In-S) was determined as a biological exposure index. Geometric means (GSD) of In-S were 8.25 ng/ml (4.55) in the exposed workers and 0.25 (2.64) in the non-exposed workers. The maximum concentration of In-S was 116.9 ng/ml. A questionnaire for respiratory symptoms and job histories, spirometry, high-resolution computerised tomography (HRCT) of the chest, serum KL-6, serum SP-A, serum SP-D and serum CRP were measured as the effect indices. Results: Spirometry, subjective symptoms and the prevalence of interstitial or emphysematous changes on lung HRCT showed no differences between exposed and non-exposed workers. Geometric means (GSD) of KL-6, SP-D and SP-A in the exposed workers were 495.4 U/ml (2.26), 85.2 ng/ml (2.02) and 39.6 ng/ml (1.57), and were significantly higher than those in the non-exposed workers. The prevalence (%) of the exposed and non-exposed workers exceeding the reference values were also significantly higher in KL-6 (41.9 vs 2.2), SP-D (39.8 vs 7.5), and SP-A (43.0 vs 24.7). Very sharp exposure-effect and exposure-response relations were discovered between In-S and KL-6 and between In-S and SP-D when the exposed workers were classified into seven groups by In-S. Conclusions: The study outcomes with regard to the basis of serum immunochemistry biomarkers and HRCT indicate that exposure to hardly soluble indium compound dust may represent a risk for interstitial lung damage..
28. A case report of indium lung injury found by clinical examination of indium.
29. Fukai Y, Hirata M, Ueno M, Ichikawa N, kobayashi H, Saitoh H, Sakurai T, Kinoshita K, Kaise T, Clinical pharmacokinetic study of arsenic trioxide in an acute promyelocytic luekemia(APL) patient: Speciation of arsenic metabolites in serum and urine, Biol Parm. Bull, 29(5), 1022-1027, 2006.05.
30. Yasuomi Fukai, Miyuki Hirata, Mayumi Ueno, Naoaki Ichikawa, Hikaru Kobayashi, Hiroshi Saitoh, Teruaki Sakurai, Kenji Kinoshita, Toshikazu Kaise, Shin Ohta, Clinical pharmacokinetic study of arsenic trioxide in an acute promyelocytic leukemia (APL) patient
Speciation of arsenic metabolites in serum and urine, Biological and Pharmaceutical Bulletin, 10.1248/bpb.29.1022, 29, 5, 1022-1027, 2006.05, The pharmacokinetics of arsenic species in a Japanese patient with relapsed acute promyelocytic leukemia (APL) treated with arsenic trioxide at a daily dose of 0.08 mg/kg was investigated. After achieving complete remission on Day 35 during the induction therapy of arsenic trioxide, we collected the serum and urine samples on Days 4 and 5 during the consolidation therapy of arsenic trioxide. The concentrations of inorganic arsenic and the methylated metabolites in serum and urine were measured by HPLC/ICP-MS. The patient restricted taking the seafood for 3 d before the start of administration and during the sampling period in order to avoid the influence of arsenic derived from seafood. Arsenite (AsIII), methylarsonic acid (MMAsV), and dimethylarsinic acid (DMAsV) were detected in serum and urine. The total concentration of AsIII, MMAsV and DMAsV in serum ranged from 18 to 41 μg/l (240-547 nM) during 24 h on Day 4. The amount of total arsenic (AsIII+MMAsV+DMAsV) in urine was 4464 μg/d on Day 4. These results suggest that not the micro-molar but the nano-molar order of arsenic in serum is sufficient to produce the therapeutic effect on APL cells..
31. Lung damage caused by occupational exposure og indium. Leasion and diagnosis.
32. Occurrences of arsenic in the surface and ground water of farm villages near Hanoi, Vietnam, and factors relating to it.
33. Minoru Omura, Yohei Shimasaki, Yuji Oshima, Kei Nakayama, Kazuhiko Kubo, Shuji Aou, Rika Ogata, Miyuki Hirata, Naohide Inoue, Distribution of tributyltin, dibutyltin and monobutyltin in the liver, brain and fat of rats
two-generation toxicity study of tributyltin chloride., Environmental sciences : an international journal of environmental physiology and toxicology., 11, 2, 123-132, 2004.01, The distribution of tributyltin (TBT) and its metabolites, dibutyltin (DBT) and monobutyltin (MBT), was examined in the liver, brain and fat tissues in a two-generation reproductive toxicity study of tributyltin chloride (TBTCl) in rats using dietary supplementation at concentrations of 5, 25 and 125 ppm. In the liver, irrespective of TBTCl dietary concentration, gender or generation, the highest concentration of metabolite was consistently MBT, followed by DBT, and then TBT. In contrast, TBT was consistently present at the highest concentration in the brain, nearly always followed by DBT and MBT. In fat tissues, the concentrations of the three butyltin compounds showed similar relationships to those observed in the brain, although the concentrations were much lower. In the liver, the concentration of TBT was higher in females, and those of DBT and MBT were higher in males. Factorial ANOVA also suggested the effect of gender on the concentrations of the three butyltin compounds in the liver. The results of this study suggest tissue-dependent distribution of TBT, DBT and MBT and gender-dependent distribution of the three metabolites in the liver of rats..
34. Akiyo Tanaka, Miyuki Hirata, Minoru Omura, Pulmonary Squamous Cyst Induced by Exposure to Indium Arsenide in Hamsters, Journal of Occupational Health, 10.1539/joh.45.405, 45, 6, 405-407, 2003.11.
35. Koichi Miyaki, Kanae Hosoda, Miyuki Hirata, Akiyo Tanaka, Yuji Nishiwaki, Toru Takebayashi, Naohide Inoue, Kazuyuki Omae, Biological monitoring of indium by means of graphite furnace atomic absorption spectrophotometry in workers exposed to particles of indium compounds, Journal of Occupational Health, 10.1539/joh.45.228, 45, 4, 228-230, 2003.07.
36. Yuji Makita, Toshiaki Matsuura, Rika Ogata, Yesid Romero, Minoru Omura, Akiyo Tanaka, Miyuki Hirata, Naohide Inoue, Systemic effects of orally administered p, p′-DDE on immature male Wistar rats during pubertal period, Journal of Occupational Health, 10.1539/joh.45.223, 45, 4, 223-227, 2003.07, Systemic effects of p, p′-DDE (1, 1-dichloro-2, 2 bis (p-chlorophenyl) ethylene; DDE) on immature male rats were investigated in pubertal Wistar rats after oral administration of DDE. Special rat chow containing 125 ppm DDE (approximately 10 mg/kg DDE) had been administered daily for 42 d since 6 wk of age and its effects had been observed until 12 wk of age. The administration of DDE did not produce any overt signs of toxicity. Neither physical development nor sexual maturation was affected, and serum biochemistry was not impaired at the dose used in this experiment. Moreover, the male reproductive organs and epididymal sperm count were not affected by the administration of DDE during the pubertal period. Our results showed that even immature male rats were resistant to DDE exposure at the daily dose of ca. 10 mg/kg, but metabolic and immunological changes still remained uncertain. Further investigation should be conducted to reveal all the effects of DDE on immature male rats..
37. Toshiaki Homma, Takahiro Ueno, Kiyohisa Sekizawa, Akiyo Tanaka, Miyuki Hirata, Interstitial pneumonia developed in a worker dealing with particles containing indium-tin oxide, Journal of Occupational Health, 10.1539/joh.45.137, 45, 3, 137-139, 2003.05.
38. Yuji Makita, Toshiaki Matsuura, Rika Ogata, Minoru Omura, Akiyo Tanaka, Miyuki Hirata, Naohide Inoue, Systemic toxicity of p,p'-DDE in aged male Wistar rats following oral administration., Fukuoka Acta Medica, 94, 4, 59-65, 2003.04, Systemic toxicity of p,p'-DDE (DDE) in aged male rats was investigated in Wistar rats by oral administration of DDE. About 10 mg/kg DDE had been daily administered for 28 days from 48 weeks to 52 weeks of age and its effects were observed subsequently. The administration of DDE did not give rise to any overt signs of toxicity. Male reproductive organs were not affected and serum biochemistry was not impaired at the dose of this experiment. Organ weights of the liver and spleen slightly increased and the thymus weight reduced with DDE administration. Serum total cholesterol and free T4 levels slightly decreased with DDE administration, albeit statistically insignificant. Our results indicated that even aged male rats were resistant to DDE exposure at the daily dose of ca. 10 mg/kg. However, metabolic and immunological changes still remained uncertain. Further investigation should be performed to reveal the entire effects of DDE on aged male rats..
39. Akiyo Tanaka, Miyuki Hirata, Minoru Omura, Naohide Inoue, Takahiro Ueno, Toshiaki Homma, Kiyohisa Sekizawa, Pulmonary toxicity of indium-tin oxide and indium phosphide after intratracheal instillations into the Lung of hamsters, Journal of Occupational Health, 10.1539/joh.44.99, 44, 2, 99-102, 2002.05.
40. Minoru Omura, Akiyo Tanaka, Miyuki Hirata, Naohide Inoue, Testicular toxicity evaluation of two antimony compounds, antimony trioxide and antimony potassium tartrate, in rats and mice, Environmental Health and Preventive Medicine, 10.1265/ehpm.2002.15, 7, 1, 15-18, 2002.04, Objectives: Testicular toxicities of antimony compounds were evaluated in rats and mice. The slightly water-soluble antimony compound antimony trioxide (ATO) and the highly water-soluble antimony compound antimony potassium tartrate (APT) were examined. Methods: Daily doses of the compounds were 27.4, 12.0 and 1,200 mg/kg body weight in the APT group, low-ATO group and high-ATO group, respectively. The corresponding daily doses of antimony were 10, 10 and 1,000 mg/kg body weight, in the APT group, low-ATO group and high-ATO group, respectively. Both compounds were administered by garage gavage: rats, 3 days per week for 4 weeks; mice, 5 days per week for 4 weeks. Results: Neither compound reduced the weights of reproductive organs or accessory sex organs nor affected sperm parameters. Few marked histopathologic changes were found in the testes of the treated animals. Even at 1,200 mg/kg body weight, which is greater than the LD50 of APT, ATO produced no effects. Conclusions: In this study, it was found that ATO and APT are not toxic to testes in rodents..
41. Minoru Omura, Akiyo Tanaka, Miyuki Hirata, Naohide Inoue, Takahiro Ueno, Toshiaki Homma, Kiyohisa Sekizawa, Testicular toxicity evaluation of indium-tin oxide, Journal of Occupational Health, 10.1539/joh.44.105, 44, 2, 105-107, 2002.
42. Minoru Omura, Rika Ogata, Kazuhiko Kubo, Yohei Shimasaki, Shuji Aou, Yuji Oshima, Akiyo Tanaka, Miyuki Hirata, Yuji Makita, Naohide Inoue, Two-generation reproductive toxicity study of tributyltin chloride in male rats, Toxicological Sciences, 10.1093/toxsci/64.2.224, 64, 2, 224-232, 2001.12, A 2-generation reproductive toxicity study of tributyltin chloride (TBTCl) was conducted in male rats using dietary concentrations of 5, 25, and 125 ppm TBTCl to evaluate its effect on sexual development and the reproductive system. F1 males were killed on postnatal day 119 and F2 males were killed on postnatal day 91. TBTCl affected the male reproductive system of rats. The weights of the testis and epididymis were decreased and homogenization-resistant spermatid and sperm count were reduced mainly in the 125 ppm TBTCl group. Histopathologic changes were also observed in the testis of this group and included vacuolization of the seminiferous epithelium, spermatid retention, and delayed spermiation. However, the changes were minimal in nature. The weight of the ventral prostate was decreased to 84% of the control value in the 125 ppm group in the F1 generation and decreased to 84 and 69% of the control value in the 25 ppm and 125 ppm TBTCl groups, respectively, in the F2 generation. The serum 17 β-estradiol concentration was also decreased to 55% of the control value in the 125 ppm group in the F1 generation and decreased to 78 and 57% of the control value in the 25 ppm and 125 ppm TBTCl groups, respectively, in the F2 generation. However, the serum concentrations of luteinizing hormone (LH) and testosterone were not decreased in these groups. These changes corresponded with those caused by aromatase inhibition and therefore TBTCl might be a weak aromatase inhibitor in male rats..
43. Akiyo Tanaka, Miyuki Hirata, M. Omura, M. Zhao, Y. Makita, K. Yamazaki, N. Inoue, K. Gotoh, Comparative study of the toxic effects of gallium arsenide, indium arsenide and arsenic trioxide following intratracheal instillations to the lung of syrian golden hamsters, Fukuoka Acta Medica, 91, 1, 21-33, 2000.03, Toxic effects of gallium arsenide (GaAs), indium arsenide (InAs) and arsenic trioxide (As2O3) were studied in male Syrian golden hamsters. GaAs (7.7 mg/kg) and As2O3 (1.3 mg/kg) particles were instilled intratracheally twice a week a total of 16 times, while InAs (7.7 mg/kg) was instilled a total of 14 times. As a control, hamsters were treated with the vehicle, phosphate buffer solution. During the instillation period, the cumulative body weight gain of the InAs-, but not the GaAs- or As2O3-treated hamsters was suppressed significantly, when compared with the control group. Slight to severe inflammatory responses were observed in the lung for all treatment groups. The most severe inflammatory change, characterized by an accumulation of neutrophils and macrophages, exudation, thickness of the pleura and fibrotic proliferation was found in the InAs-treated hamsters. Extensive alveolar or bronchiolar cell hyperplasia with or without keratinizing squamous cell metaplasia was observed in almost all the InAs-treated hamsters. Furthermore, squamous cell metaplasia or squamous cell hyperplasia developed in some of the InAs-treated hamsters, but not in the GaAs- or As2O3-treated hamsters. Slight to mild lesions were found in the convoluted tubules of the kidney in both the GaAs and InAs groups. From the present study, the toxic potency of these particles was provisionally estimated to be in the following order: InAs>GaAs>As2O3, at the dosage level used in this study. Furthermore, there was evidence that InAs particles could induce pulmonary, renal or systemic toxicity, and as such, InAs particles may produce pulmonary precancerous change when instilled intratracheally into hamsters..
44. M. Omura, K. Yamazaki, Akiyo Tanaka, Miyuki Hirata, Y. Makita, N. Inoue, Changes in the testicular damage caused by indium arsenide and indium phosphide in hamsters during two years after intratracheal instillations, Journal of Occupational Health, 10.1539/joh.42.196, 42, 4, 196-204, 2000.01, Changes in the testicular damage caused by indium arsenide (InAs) and indium phosphide (InP) was examined during two yr after repetitive intratracheal instillations in hamsters. In this study, 4.0 mg/kg body weight/day of InAs or 3.0 mg/kg body weight/day of InP was instilled intratracheally twice weekly for eight wk. A single instillation dose of indium was 2.4 mg/kg body weight in both groups. Testicular damage was evaluated 0, 8, 16, 40, 64 and 88 wk after the last instillation. Both InAs and InP were proved to be definite testicular toxicants. Both materials decreased reproductive organ weight and caudal sperm count, and caused severe histopathologic changes in the testes. InAs-induced testicular damage was always more serious than InP-induced testicular damage. The serum indium concentration in the InAs group was always higher than that in the InP group, and indium was probably a toxic element in both materials. In the histopathologic examination, vacuolization of seminiferous epithelium was frequently observed as an early histopathologic change and spermatogonia remained in general even in the seminiferous tubules with severe histopathologic changes in both groups. It is therefore estimated that Sertoli cells, not stem cell spermatogonia, were the target cells of these indium-containing compound semiconductor materials. The threat of InAs and InP to male reproduction was proved in this study. We concluded that male reproductive disorders should not be overlooked when severe exposure to indium-containing compound semiconductor materials is apparent in human subjects..
45. K. Yamazaki, Akiyo Tanaka, Miyuki Hirata, M. Omura, Y. Makita, N. Inoue, K. Sugio, K. Sugimachi, Long term pulmonary toxicity of indium arsenide and indium phosphide instilled intratracheally in hamsters, Journal of Occupational Health, 10.1539/joh.42.169, 42, 4, 169-178, 2000.01, We examined the long-term toxicological effects of III-V semiconductor particles on laboratory animals. Eight-week-old male Syrian golden hamsters were given 4 mg/kg indium arsenide (InAs) or 3 mg/kg indium phosphide (InP) particles, both containing 2.4 mg/kg as indium, intratracheally twice a week for 8 weeks. Control hamsters were given only a vehicle, phosphate buffer solution. Over a 2-yr period, these animals were euthanized serially and the biological effects were determined. Weight gain was significantly suppressed in both InAs and InP groups, compared to the control group, with greater suppression in the InAs group. The serum indium concentration in the InAs group was about twice as high as that in the InP group, in each period. Histopathologically, severe pulmonary inflammation and localized lesions with bronchiolo-alveolar cell hyperplasia were present in both InAs and InP groups from just after the last administration. The localized lesions gradually transformed to proteinosis-like lesions with periodic acid Schiff reagent positive exudation after 16 wk. By means of immunostaining of proliferating cell nuclear antigen and argyrophilic proteins associated with nucleolar organizer regions staining, proliferative activities were evidenced in the localized lesions at each time and were noticeable in their early stage. K-ras, a known oncogene, was not mutated in association with these lesions. In conclusion, InAs and InP particles caused severe systemic toxicity and pulmonary localized hyperplastic lesions with proliferative activity were derived via the respiratory route. Neoplastic change was nil even in a 2-yr observation period..
46. Minoru Omura, Yoshito Masuda, Miyuki Hirata, Akiyo Tanaka, Yuji Makita, Rika Ogata, Naohide Inoue, Onset of spermatogenesis is accelerated by gestational administration of 1,2,3,4,6,7-hexachlorinated naphthalene in male rat offspring, Environmental Health Perspectives, 108, 6, 539-544, 2000, We treated pregnant rats with 1 μg/kg body weight/day 1,2,3,4,6,7-hexachlorinated naphthalene (1,2,3,4,6,7-HxCN) on days 14-16 of gestation and examined the effects on the reproductive systems of their male offspring at various phases of sexual maturation. Sperm count in the cauda epididymidis did not change in 1,2,3,4,6,7-HxCN-treated rats on postnatal day 89, the age of sexual maturity, but the sperm count in the cauda epididymidis did increase to approximately 180% of the control value on postnatal day 62. In addition, homogenization-resistant testicular spermatids increased to approximately 160% of the control value on postnatal day 48, and the percent of postmeiotic tubules increased to approximately 190% of the control value on postnatal day 31 in this group. These results indicate that the onset of spermatogenesis was accelerated in the 1,2,3,4,6,7-HxCN rats. Serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) had already reached the maximum level on postnatal day 31 in the 1,2,3,4,6,7-HxCN group, suggesting that the onset of LH and FSH secretions from the pituitary gland was also accelerated and that this endocrine disruption was the cause of early onset of spermatogenesis in this group. In the fat of 1,2,3,4,6,7-HxCN-treated dams, 5.75 ± 2.81 ppb 1,2,3,4,6,7-HxCN was detected when offspring were weaned. This concentration was 5-10 times higher than that found in human adipose tissue..
47. Miyuki Hirata, A new aspect of arsenic, an old poison, Fukuoka Acta Medica, 90, 9, 347-352, 1999.09.
48. Minoru Omura, Miyuki Hirata, Akiyo Tanaka, Mangen Zhao, Yuji Makita, Naohide Inoue, Kaoru Gotoh, Noburu Ishinishi, Testicular toxicity evaluation of arsenic-containing binary compound semiconductors, gallium arsenide and indium arsenide, in hamsters, Toxicology Letters, 10.1016/S0378-4274(96)03796-4, 89, 2, 123-129, 1996.12, The testicular toxicities of gallium arsenide (GaAs), indium arsenide (InAs) and arsenic trioxide (As2O3) were examined by repetitive intratracheal instillation using hamsters. GaAs (7.7 mg/kg) and As2O3 (1.3 mg/kg) were instilled twice a week a total of 16 times and InAs (7.7 mg/kg) was instilled a total of 14 times. GaAs caused testicular spermatid retention and epididymal sperm reduction, though the degrees were less severe than those in rats shown in our previous experiment. InAs and As2O3 did not show any testicular toxicities. Serum arsenic concentration in GaAs-treated hamsters was less than half of that in As2O3-treated hamsters in which no testicular toxicities were found. Serum molar concentration of gallium was 32-times higher than that of arsenic in GaAs-treated hamsters. Therefore gallium may play a main role in the testicular toxicity of GaAs in hamsters..
49. Akiyo Tanaka, A. Hisanaga, Miyuki Hirata, M. Omura, Y. Makita, N. Inoue, N. Ishinishi, Chronic toxicity of indium arsenide and indium phosphide to the lungs of hamsters., Fukuoka Acta Medica, 87, 5, 108-115, 1996.05, Chronic toxicity of indium arsenide (InAs) and indium phosphide (InP) was studied in male Syrian golden hamsters which received InAs or InP particles containing a total dose of 7.5 mg of arsenic or phosphorus by intratracheal instillations once a week for 15 weeks. As a control, hamsters were treated with the vehicle, phosphate buffer solution. During their total life span, the cumulative body weight gain of hamsters in the InAs group was suppressed significantly compared with that in the control group, but not in the InP group when compared with that in the control group. Concerning the histopathological findings of the lung, the incidence rates of proteinosis-like lesions, alveolar or bronchiolar cell hyperplasia, pneumonia, emphysema and metaplastic ossification observed in the InAs or InP group were significantly higher than those observed in the control group. From these results, it would seem that InAs and InP produced severe damage to the lungs of hamsters..
50. Minoru Omura, Akiyo Tanaka, Miyuki Hirata, Mangen Zhao, Yuji Makita, Naohide Inoue, Kaoru Gotoh, Noburu Ishinishi, Testicular toxicity of gallium arsenide, indium arsenide, and arsenic oxide in rats by repetitive intratracheal instillation, Toxicological Sciences, 10.1006/faat.1996.0108, 32, 1, 72-78, 1996.01, The testicular toxicities of two compound semiconductor materials, gallium arsenide (GaAs) and indium arsenide (InAs), and arsenic oxide (As2O3) were examined in rats by repetitive intratracheal instillation of these substances in suspension twice a week, a total of 16 times. A single instillation dose was 7.7 mg/kg in the GaAs and the InAs groups and 1.3 mg/kg in the As2O3 group. A significant decrease in sperm count and significant increase in the proportion of morphologically abnormal sperm were found in the epididymis in the GaAs group. Especially, abnormal sperm with a straight head increased markedly in this group. In the GaAs-treated rats, there was 40-fold increase in the degenerating late elongated spermatids at the postspermiation stages, stages IX, XI, and XI. From these results, it is indicated that GaAs disturbed the spermatid head transformation at the late spermiogenic phases and caused spermiation failure. InAs caused a sperm count decrease in the epididymis, though its testicular toxicity was relatively weak compared with that of GaAs. As2O3, a probable dissolution arsenic product of GaAs and InAs in vivo, did not show any testicular toxicities in this study. It seems likely that, along with arsenics, gallium and indium play a role in the testicular toxicities of GaAs and InAs..
51. Minoru Omura, Akiyo Tanaka, Miyuki Hirata, Mangen Zhao, Yuji Makita, Naohide Inoue, Kaoru Gotoh, Noburu Ishinishi, Testicular toxicity of gallium arsenide, indium arsenide, and arsenic oxide in rats by repetitive intratracheal instillation, Toxicological Sciences, 10.1093/toxsci/32.1.72, 32, 1, 72-78, 1996.01, The testicular toxicities of two compound semiconductor materials, gallium arsenide (GaAs) and indium arsenide (InAs), and arsenic oxide (As2O3) were examined in rats by repetitive intratracheal instillation of these substances in suspension twice a week, a total of 16 times. A single instillation dose was 7.7 mg/kg in the GaAs and the InAs groups and 1.3 mg/kg in the As2O3 group. A significant decrease in sperm count and significant increase in the proportion of morphologically abnormal sperm were found in the epididymis in the GaAs group. Especially, abnormal sperm with a straight head increased markedly in this group. In the GaAs-treated rats, there was 40-fold increase in the degenerating late elongated spermatids at the postspermiation stages, stages IX, XI, and XI. From these results, it is indicated that GaAs disturbed the spermatid head transformation at the late spermiogenic phases and caused spermiation failure. InAs caused a sperm count decrease in the epididymis, though its testicular toxicity was relatively weak compared with that of GaAs. As2O3, a probable dissolution arsenic product of GaAs and InAs in vivo, did not show any testicular toxicities in this study. It seems likely that, along with arsenics, gallium and indium play a role in the testicular toxicities of GaAs and InAs..
52. N. Inoue, Miyuki Hirata, General characteristic and toxicity of VX, Fukuoka Acta Medica, 86, 11, 405-410, 1995.11.
53. M. Omura, Miyuki Hirata, M. Zhao, Akiyo Tanaka, N. Inoue, Comparative testicular toxicities of two isomers of dichloropropanol, 2,3-dichloro-1-propanol, and 1,3-dichloro-2-propanol, and their metabolites alpha-chlorohydrin and epichlorohydrin, and the potent testicular toxicant 1,2-dibromo-3-chloropropane, Bulletin of Environmental Contamination and Toxicology, 10.1007/BF00212381, 55, 1, 1-7, 1995.07.
54. Akiyo Tanaka, A. Hisanaga, Miyuki Hirata, M. Omura, Y. Makita, N. Inoue, N. Ishinishi, Chronic toxicity of tar from heavy-duty diesel exhaust following intratracheal instillations to the lungs of hamsters, Fukuoka Acta Medica, 86, 2, 65-73, 1995.01, Chronic toxicity of tar from heavy-duty diesel exhaust (HD tar) was studied in male Syrian golden hamsters which received 15 mg, 7.5 mg or 1.5 mg of HD tar as the total dosage by intratracheal instillations once a week for 15 weeks. As a control group, hamsters were treated with the 0.1 ml of Tween 60: ethanol: phosphate buffer (pH 6.88, 0.25 M) solution (5.8: 8.7: 100 by volume) once a week in the same manner. The survival rate during the instillation period in the group given 15 mg of HD tar, the high-dose group of HD tar, was the lowest, and the effect was dose-dependent. However, the survival rates during the subsequent observation period showed no marked differences among HD tar treated groups. During their total life span, one papilloma in the larynx was seen in the 44 hamsters in the group given 15 mg of HD tar, one papilloma in the larynx appeared in the 59 hamsters in the group given 1.5 mg of HD tar and one lung adenoma was developed in the 58 hamsters in the control group. There were no tumors in the respiratory tract in the group given 7.5 mg of HD tar. Concerning the histopathological findings of the lung, the incidence of alveolar cell or bronchiolar cell hyperplasia in the group given 1.5 mg of HD tar was significantly higher than that in the control group. From these results, although we could not observe any tumorigenicity or carcinogenic effect of HD tar, it would seem that HD tar caused weak but positive damage to the lungs of hamsters..
55. Minoru Omura, Akiyo Tanaka, Mangen Zhao, Miyuki Hirata, Yuji Maxita, Naohide Inoue, Kaoru Gotoh, Short Communication Toxic Effects of Gallium Arsenide on Sperm in Rats by Repeated Intratracheal Instillations, Journal of Occupational Health, 10.1539/sangyoeisei.37.3_165, 37, 3, 1995.01, Gallium arsenide (GaAs) has superior properties for making high-frequency devices and photonemitters. In the future, this is going to be extensively used in the development of super computers, telecommunication systems, light-emitting diodes, and semiconductor lasers. This will inevitably lead to an increase in the exposure of workers manufacturing these products to GaAs..
56. M. Omura, Akiyo Tanaka, K. Mori, Miyuki Hirata, M. Zao, N. Inoue, Dose-dependent testicular toxicity of propylene oxide in rats induced by repeated intraperitoneal injections, Fukuoka Acta Medica, 85, 7, 204-210, 1994.01, The dose-dependent testicular toxicity of propylene oxide (PO) was evaluated in male Wistar rats when administered by intraperitoneal injections. In 23 mg/kg, 47 mg/kg, and 93 mg/kg groups, PO was given three days a week for six weeks, while PO was given three days a week for two weeks plus once a week after the third week in a 186 mg/kg group. In the 186 mg/kg group, the epididymal weight and sperm count in the body plus tail of the epididymis decreased, while the rate of sperm with morphological abnormalities increased significantly. The number of sperm with an immature head increased slightly, although significantly, even in the 47 mg/kg group and a dose-dependent effect could be seen. The serum testosterone concentration did not change significantly and there were no apparent histopathological changes in Leydig cells in any of the treatment groups. This is the first detailed study concerning the dose-dependent testicular toxicity of PO..
57. Akiyo Tanaka, Akira Hisanaga, Miyuki Hirata, Minoru Omura, Naohide Inoue, Noburu Ishinishi, Pulmonary toxicity of indium arsenide and arsenic selenide following repeated intratracheal instillations to the lungs of hamsters, Applied Organometallic Chemistry, 10.1002/aoc.590080318, 8, 3, 265-271, 1994, Chronic toxicity of indium arsenide (InAs) and arsenic selenide (As2Se3) was studied in male Syrian golden hamsters which received InAs or As2Se3 particles, each containing a total dose of 7.5 mg of arsenic, by intratracheal instillations once a week for 15 weeks. As a control, hamsters were treated with the vehicle, phosphate buffer solution. During their total lifespan, the cumulative body weight gain of the hamsters in the InAs group was suppressed significantly compared with that in the control group, but not in the As2Se3 group when compared with that in the control group. However, the survival rate for the InAs group was significantly higher compared with the control group, but not for the As2Se3 group when compared with the control group. During the animals' total lifespan, one lung adenoma was seen in the 27 hamsters in the InAs group and one lung adenoma in the 23 hamsters in the control group. No tumors of the lung were observed in the As2Se3 group. Malignant tumors outside the lung appeared in four hamsters in the InAs group and in two in the As2Se3 group. No non‐lung malignant tumours were seen in the control group. Total tumor incidence rates were 25.9% (7/27) in the InAs group, 10.3% (3/29) in the As2Se3 group and 8.7% (2/23) in the control group. There were therefore no significant differences in tumor incidence between the InAs or the As2Se3 group, and the control group. Regarding histopathological findings in the lung, incidence rates of proteinosis‐like lesions, pneumonia, metaplastic ossification and emphysema were seen only in the InAs group, and alveolar or bronchiolar cell hyperplasia observed in both the InAs and the As2Se3 groups were at significantly higher rates than those in the control group. From these results, it was concluded that InAs and As2Se3 particles could induce pulmonary toxicity when instilled intratracheally into hamsters. A great deal of attention should be paid to the toxicity of both InAs and As2Se3, even though in this study the adverse health effects of As2Se3 appeared to be less than those of InAs..
58. M. Omura, Y. Itonaga, H. Komatsu, Z. Mangen, Miyuki Hirata, Akiyo Tanaka, N. Inoue, The acute toxicity of allyl chloride by subcutaneous injection in mice., Fukuoka Acta Medica, 84, 10, 427-432, 1993.10, Male ICR mice were administered allyl chloride at dose of 496 mg/kg, 600 mg/kg, 720 mg/kg, 864 mg/kg or 1037 mg/kg by a single subcutaneous injection. Sixteen of 25 mice died by the 7th day after the injection and LD50 was calculated 621 mg/kg body weight (95% C.I.: 522-739 mg/kg). A marked congestion with severe hemorrhage and edema were observed in the lung. Liver and kidney damages were also found, and these were characterized by the dilated sinusoids, degenerative change of hepatic cells, and focal necrosis in the liver; and necrosis of epithelium in convoluted tubules of the kidneys. Nine mice have survived by the 7th day after the injection and all of them showed a various degree of damages in the testes. The testicular lesions could be classified into two types. One type of the lesion was characterized by degeneration and exfoliation of germ cells, appearance of polynuclear giant cells in the seminiferous tubules, and mild proliferation of Leydig cells in the interstitium. In another type of the lesion, all type of cells in tubules, including Sertoli cells, and Leydig cells became necrotic. This is the first study reporting the testicular toxicity of allyl chloride..
59. N. Inoue, M. Omura, Miyuki Hirata, Methyl alcohol poisoning, Fukuoka Acta Medica, 84, 2, 37-42, 1993.02.
60. Miyuki Hirata, Akiyo Tanaka, Akira Hisanaga, Noburu Ishinishi, Effects of glutathione depletion on the acute nephrotoxic potential of arsenite and on arsenic metabolism in hamsters, Toxicology and Applied Pharmacology, 10.1016/0041-008X(90)90342-R, 106, 3, 469-481, 1990.01, Our previous study showed that pretreatment with buthionine sulfoximine (BSO), which inhibits glutathione synthesis, results in acute renal failure with oliguria in hamsters ingesting sodium arsenite (5 mg As/kg). For a deeper understanding of the relationship between arsenic metabolism and the subsequent development of nephrotoxicity, we studied excretion, tissue retention, biotransformation, pharmacokinetics, and histopathological events in the kidneys of hamsters both with and without BSO pretreatment. The total amount of arsenic excreted in the urine and feces within 72 hr of arsenite administration was more than fivefold lower in BSO-pretreated animals than in the controls without pretreatment (9.2 versus 53.4% of the arsenic dose). The persistence of high amounts of total arsenic was apparent in the blood, liver, and kidneys of BSO-pretreated hamsters, even though the content of inorganic arsenic steadily decreased with time. The disappearance of inorganic arsenic from the blood showed a biphasic elimination pattern characterized first by a rapid component with a half-life of 4.5 hr and second by a slower component with a half-life of 58.0 hr in the BSO-pretreated hamsters, while these half-lives were 0.6 and 11.0 hr, respectively, in the controls. BSO pretreatment not only impaired the excretion of inorganic arsenic, but also impaired its methylation. Combined BSO/arsenite treatment resulted in renal tubular necrosis which was prominent at 1 hr after arsenite administration. By 1 hr, the renal content of inorganic arsenic in the BSO-pretreated animals was 1.7 times higher than that in the controls. This study demonstrates that glutathione depletion elicits the nephrotoxic manifestations of arsenic poisoning..
61. Akiyo Tanaka, Akira Hisanaga, Miyuki Hirata, Noburu Ishinishi, Comparative study on the tumorigenicity in mice of gallium arsenide, gallium phosphide and gallium oxide following subcutaneous and intraperitoneal injections, Applied Organometallic Chemistry, 10.1002/aoc.590040309, 4, 3, 231-237, 1990, Chronic toxicity, including tumorigenicity, of gallium arsenide (GaAs), gallium phosphide (GaP) and gallium oxide (Ga2O3) was studied in male ICR mice which received either a subcutaneous or an intraperitoneal injection of each material once only. The doses received either subcutaneously or intraperitoneally were 48 mg Kg−1 as Ga or 480 mg Kg−1 as Ga of each material suspended in 0.2 cm3 of olive oil. The control groups received the vehicle only, either subcutaneously or intraperitoneally. In the study using subcutaneous injections, no tumors were observed in the subcutis at the site of injection, and there was no significant difference concerning the survival periods of each group compared with the control group at the termination of the observation period. In the study using intraperitoneal injections, the total tumor incidence in all the experimental groups, except for the GaAs (480 mg Ga Kg−1) groups, was significantly different compared with the control group. However, all these tumors appeared to be spontaneous, rather than induced by the materials themselves. Moreover, in the GaAs (480 mg Ga Kg−1) and Ga2O3 (48 mg Ga Kg−1) groups, the number of survival days was significantly lower compared with the control group. From this study, it seems that neither GaAs, GaP nor Ga2O3 were tumorigenic to mice when injected subcutaneously. Although it remains unclear whether the increased production of total tumors in each group following intraperitoneal injections was directly due to the tumorigenic action of GaAs, GaP or Ga2O3 or not, it appears that these substances produce a potential systemic toxicity in mice following intraperitoneal injections..
62. Akira Hisanaga, Miyuki Hirata, Akiyo Tanaka, Noburu Ishinishi, Yukuo Eguchi, Variation of trace metals in ancient and contemporary Japanese bones, Biological Trace Element Research, 10.1007/BF02916610, 22, 3, 221-231, 1989.12, Excavated and contemporary bones (rib cortexes) of a mature age (40-60 yr) were analyzed by atomic absorption spectrometry for the concentration of seven elements, including Ca, Cd, Cu, Fe, Mn, Ni, and Pb, with a view to historically evaluating the chemical composition of the bones. Fifty-two well-preserved specimens, obtained from western Japan, were classified into six groups according to Japanese prehistoric and historic eras (Jomon, Yayoi, Kofun, Muromachi, Edo, and Contemporary). Average concentrations of Ca were 0.20-0.33 g/g in the excavated bones and 0.17 g/g in the contemporary bones. Among the trace metals, such as Cu, Fe, Mn, and Pb, which showed remarkably elevated concentrations in the Edo era bones, Cu, Fe, and Mn were found to be strongly associated with soil contamination. Lead levels only slightly increased between the Jomon and Kofun eras, but became abruptly elevated following the Edo era. In contrast, the concentrations of Cd increased abruptly in the Yayoi era to a level with an order of magnitude higher than the Edo era, and they have recently decreased to rather low contemporary levels. This tendency becomes clearer when comparing the molar ratio of trace metals to Ca. The cause of elevated Cd concentrations in early excavated bones is discussed in relation to the mineralization of bones and the surrounding environment..
63. Miyuki Hirata, Takami Mohri, Akira Hisanaga, Noburu Ishinishi, Conversion of arsenite and arsenate to methylarsenic and dimethylarsenic compounds by homogenates prepared from livers and kidneys of rats and mice, Applied Organometallic Chemistry, 10.1002/aoc.590030406, 3, 4, 335-341, 1989, Pooled livers and pooled kidneys from rats or mice were homogenized and spiked with arsenite or arsenate in the concentration range 1.3–20 μmol dm−3. Methylarsenic and dimethylarsenic compounds were determined by the hydride generation technique in the homogenates after a 90 min incubation at 37°C. The rat homogenates methylated arsenite and arsenate more efficiently than the mouse homogenates. Monomethylated arsenic was present in larger amounts than dimethylated arsenic in the rat homogenates. In the absence of reduced glutathione (GSH), no methylation occurred. Addition of GSH promoted monomethylation and dimethylation, whereas dithiothreitol and mercaptoethanol (10 mmol dm−3) fostered only monomethylation. The amounts of monomethylated arsenic in the rat liver homogenates increased with increasing arsenite concentration (1.3–20 μmol dm−3) however, the percentage of arsenic that had been methylated decreased. A similar trend, but with much less monomethylarsenic formed, was observed for arsenate‐spiked homogenates. Rat kidney homogenates methylated arsenite and arsenate to a much smaller extent than rat liver homogenates. The Km values for the monomethylation in rat liver homogenates were found to be 5.3 μmol dm−3 for arsenite and 59 μmol dm−3 for arsenate..
64. Noburu Ishinishi, Akiyo Tanaka, Akira Hisanaga, Takeo Inamasu, Miyuki Hirata, Comparative study on the carcinogenicity of N-nitrosodiethylamine, N-nitrosodhnethylamine, N-nitrosomorpholine, N-nitrosopyrrolidine and N-nitrosodi-N-propylamine to the lung of syrian golden hamsters following intermittent instillations to the trachea, Carcinogenesis, 10.1093/carcin/9.6.947, 9, 6, 947-950, 1988.06, N-Nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), N-mtrosomorpholine (NMOR), N-nitrosopyrroli dine (NPYR) and N-nitrosodi-N-propylainine (NDPA) were instilled into the lungs of male Syrian golden hamsters by intratracheal instillatlons once a week for 15 weeks. The total doses given were 1.5 mg of each drug. As a control, hamsters were treated with the vehicle, phosphate buffer solution. During the total lifespan, tumor incidence rates in the respiratory organs were 100% in the NDEA group, 6% in the NDMA group, 43% in the NMOR group, 0% in the NPYR group, 72% in the NDPA group and 4% in the control group. The incidence rates in the liver were 19% in the NDMA group and 4% in the NPYR group. No liver tumors developed in the other groups. The carcinogenic potencies of these N-nitroso compounds to the respiratory organs was provisionally estimated to be in the following order: NDEA > NDPA> NMOR > NDMA ≒NPYR, at the 1.5 mg dosage level. However, the difference in the rates of tumor incidence between the NDMA or NPYR group and the control group was not significant..
65. Akira Hisanaga, Yukuo Eguchi, Miyuki Hirata, Noburu Ishinishi, Lead levels in ancient and contemporary Japanese bones, Biological Trace Element Research, 10.1007/BF02795336, 16, 1, 77-85, 1988.06, During the past few centuries, lead production, consumption and emissions, to our total environment have increased remarkably. We have determined the concentrations of lead in 41 well-preserved ancient and 11 contemporary rib bones of a mature age (40-60 y), with a view to historically evaluating lead exposure in humans. The oldest Japanese bones (1000-300 b.c.) were found to contain a mean of 0.58 μg Pb/g dry wt and a mean molar ratio of lead to calcium of 0.6×10-6, compared with 4.7-5.2×10-6 in the bones of the Edo era (1600-1867 a.d.) and contemporary residents in Japan. The mean molar ratios of female bones were always higher than those of male bones for each era. From this fact we may assume that facial cosmetics were one of the main routes of lead exposure among the ancient Japanese, especially those who lived during the Edo era..
66. Akiyo Tanaka, A. Hisanaga, T. Inamasu, Miyuki Hirata, N. Ishinishi, A comparison of the carcinogenicity of N-nitrosodiethylamine and N-nitrosodimethylamine after intratracheal instillation into Syrian golden hamsters, Food and Chemical Toxicology, 10.1016/0278-6915(88)90025-7, 26, 10, 847-850, 1988.01, N-Nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) were instilled intratracheally into male Syrian golden hamsters once a week for 15 wk. The total dosages were 1.5 mg and 7.5 mg of NDEA and 0.75 mg and 1.5 mg of NDMA. A control group simultaneously received phosphate buffer vehicle. Tumours related to instillation appeared principally in the respiratory tract and the liver. Over the entire lifespan of the animals tumour incidence rates in the respiratory tract were 100% in both the NDEA groups, 6% in both NDMA groups and 8% in the control group. The total incidences of liver tumours were 6% in the 0.75 mg NDMA group, 19% in the 1.5 mg NDMA group, zero in the NDEA groups, and 4% in the control group. These results indicate that, when administered by this route, NDEA is a much more potent carcinogen in the respiratory tract than is NDMA but NDMA alone seems to be carcinogenic to the liver, at a total dosage of 1.5 mg..
67. Miyuki Hirata, Akira Hisanaga, Akiyo Tanaka, Noburu Ishinishi, Glutathione and methylation of inorganic arsenic in hamsters, Applied Organometallic Chemistry, 10.1002/aoc.590020407, 2, 4, 315-321, 1988, The effect of giutathione (GSH) concentrations in livers and kidneys of hamsters on the toxicity and methylation of arsenite in these animals was studied. No significant changes in hepatic and renal GSH concentrations were observed after a single arsenite administration (5 mg As kg−1, p.o.). When buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, was given (4 mmol kg−1, i.p.) two hours before administration of arsenite, hepatic and renal GSH concentrations were more severely and persistently depressed than in the case of BSO administration not followed by arsenite. Hamsters treated with BSO plus arsenite suffered from severe nephrotoxicity (acute renal failure) characterized by increases in plasma creatinine and urea nitrogen and by proximal tubular necrosis. Concurrently, transient hepatotoxicity was observed in the BSO plus arsenite group. Neither arsenite alone nor BSO alone produced liver or kidney injury. The BSO plus arsenite‐treated animals excreted in the urine only 3.5% of the arsenic dose during the 72 h period after administration of arsenite, probably because of a decrease in urine volume caused by kidney injury, whereas the arsenite‐only group excreted 27%. In addition, BSO pretreatment influenced the relative proportion of arsenic metabolites excreted in the urine during the first 24 h after administration. Urinary metabolites in the BSO plus arsenite group were predominantly inorganic arsenic. These results suggest that GSH provides protection against arsenic toxicity..
68. Shiro Ohyama, Akira Hisanaga, Takeo Inamasu, Akiyo Yamamoto, Miyuki Hirata, Noburu Ishinishi, Some secular changes in body height and proportion of Japanese medical students, American Journal of Physical Anthropology, 10.1002/ajpa.1330730204, 73, 2, 179-183, 1987.01, Anthropometric dimensions of 738 medical students at Kyushu University in Japan were analyzed to determine secular changes of height and body proportions during a 20‐year period. Since 1961, means of standing height, leg length, and ratio of leg length to standing height have increased, although the rate of increase from 1971 to 1981 has been rather slow. On the contrary, the mean sitting height × 100/standing height has declined during this same period. Compared with data on the Japanese general population, the medical students were considerably taller, but the difference has decreased..
69. Tadashi Ueda, H. Yamada, Miyuki Hirata, T. Imoto, An intramolecular cross-linkage of lysozyme. Formation of cross-links between lysine-1 and histidine-15 with bis(bromoacetamide) derivatives by a two-stage reaction procedure and properties of the resulting derivatives, Biochemistry, 24, 22, 6316-6322, 1985.
70. Hidenori Yamada, Ryota Kuroki, Miyuki Hirata, Taiji Imoto, Intramolecular Cross-Linkage of Lysozyme. Imidazole Catalysis of the Formation of the Cross-Link between Lysine-13 (ϵ-Amino) and Leucine-129 (α-Carboxyl) by Carbodiimide Reaction, Biochemistry, 10.1021/bi00288a031, 22, 19, 4551-4556, 1983.01, The salt bridge between Lys-13 (ϵ-NH3+) and Leu-129 (α-COO) in lysozyme was converted to an amide bond by 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC) reaction in the presence of imidazole (0.3–1 M) at pH 5 and room temperature, followed by dialysis at pH 10. Absence of imidazole under a similar condition did not give this intramolecularly cross-linked lysozyme derivative (CL-lysozyme) but resulted in the formation of intermolecularly cross-linked lysozyme oligomers. From the mechanistic studies on the formation of CL-lysozyme, imidazole was suggested to play the following three roles. (1) Some carboxyl groups activated by EDC in lysozyme were converted to acylimidazole groups which protected them from the reaction with amino groups in other lysozyme molecules at pH 5. These could be hydrolyzed at pH 10 to regenerate free carboxyls. (2) High concentrations of imidazole (pH 5) increased the ionic strength of the solution which weakened the salt bridge in lysozyme and facilitated the activation of the a-carboxyl group by EDC. (3) The α-carboxyl group activated by EDC was converted to an acylimidazole group which could react with the ϵ-amino group of Lys-13 in the same molecule to form an amide bond. The last step may involve some conformational change of the backbone of lysozyme and be slower than the hydrolysis reaction of the α-carboxyl group activated by EDC itself. However, acylimidazole groups are stable against hydrolysis at pH 5. This may afford enough time to allow the ϵ-amino group of Lys-13 to attack the acylimidazole group of Leu-129..