Akiyo Tanaka

Interstitial Pneumonia Developed in a Worker Dealing with Particles Containing Indium-tin Oxide

The use of indium compounds in the electronics and semiconductor industry has risen sharply from the 1990s, and indium demand increased to a record 335 tons in 2000 in Japan, which was about 5 times that in 1990 . Indium-tin oxide (ITO) is a sintered alloy containing a large portion of indium oxide and a small portion of tin oxide, and is used in the making of thin-film transistor liquid crystal displays (LCDs) for television screens, portable computer screens, cell phone displays and video monitors. Japan was the world’s largest consumer of indium, with three-fourths of it going for ITO coatings in 2000. More than one-half of the world’s indium consumption is for ITO coatings . Due to the increasingly frequent industrial use of ITO, the potential occupational exposure to this material has attracted much attention. Although there are no available data about the potential of ITO to induce lung damage in humans, pulmonary and testicular toxicity was reported recently when ITO was given to hamsters in intermittent intratracheal instillations . This is the first case history to our knowledge describing a man with interstitial pneumonia consistent with the inhalation of ITO particles.

Exposure to hardly soluble indium compounds in ITO production and recycling plants is a new risk for interstitial lung damage

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.

Causal Relationship between Indium Compound Inhalation and Effects on the Lungs

Causal Relationship between Indium Compound Inhalation and Effects on the Lungs: Makiko Nakano, et al. Department of Preventive Medicine and Public Health, School of Medicine, Keio University

Effects of glutathione depletion on the acute nephrotoxic potential of arsenite and on arsenic metabolism in hamsters

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.

Testicular toxicity evaluation of arsenic-containing binary compound semiconductors, gallium arsenide and indium arsenide, in hamsters

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.

Chronic Pulmonary Toxicity Study of Indium-Tin Oxide and Indium Oxide Following Intratracheal Instillations into the Lungs of Hamsters

Chronic Pulmonary Toxicity Study of Indium‐Tin Oxide and Indium Oxide Following Intratracheal Instillations into the Lungs of Hamsters: Akiyo Tanaka, et al. Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University

Long Term Pulmonary Toxicity of Indium Arsenide and Indium Phosphide Instilled Intratracheally in Hamsters

Long Term Pulmonary Toxicity of Indium Arsenide and Indium Phosphide Instilled Intratracheally in Hamsters: Koji Yamazaki, et al. Department of Hygiene, Graduate School of Medical Sciences, Kyushu University—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.

Changes in the testicular damage caused by indium arsenide and indium phosphide in hamsters during two years after intratracheal instillations

Changes in the Testicular Damage Caused by Indium Arsenide and Indium Phosphide in Hamsters during Two Years after Intratracheal Instillations: Minoru Omura, et al. Department of Hygiene, Graduate School of Medical Sciences, Kyushu University—Change 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.

Biological monitoring of indium by means of graphite furnace atomic absorption spectrophotometry in workers exposed to particles of indium compounds.

Since the rapid expansion of III-V semiconductor and liquid crystal display production, the consumption of indium (In) has been increasing. From the mid-1990s, animal experiments have shown that the inhalation or intratracheal instillation of In compounds causes severe lung inflammation and mild adverse reproductive effects. Although the health effects of In on workers’ respiratory and reproductive systems have been unclear to date, assessing the exposure-effect relationships in Inexposed workers is a serious concern, but no information is available on the exposure-effect relationships in workers. This study attempted to estimate the In concentration in biological specimens of In-exposed workers, and to clarify the relationships among them.

Variation of trace metals in ancient and contemporary Japanese bones

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.