Naohide Inoue

Toxic polyneuropathy due to glue sniffing

Four cases of toxic polyneuropathy due to glue-sniffing were reported. Neurological examination revealed motor predominant mixed type polyneuropathy. The cause of polyneuropathies in these cases was considered to be due to the inhalation of the vaporized elements of the adhesive agent, which contain mainly n-hexane and toluene. N-hexane is considered to be chiefly responsible for the polyneuropathy, though toluene also could have some influence on the illness.

Two-generation reproductive toxicity study of tributyltin chloride in female rats

A two-generation reproductive toxicity study of the effects of tributyltin chloride (TBTCl) was conducted in female rats using dietary concentrations of 5, 25, and 125 ppm TBTCl. Reproductive outcomes of dams (number and body weight of pups and the percentage of live pups) and the growth of female pups (the day of eye opening and body weight gain) were significantly decreased in the 125 ppm TBTCl group. A delay in vaginal opening and impaired estrous cyclicity were also observed in the 125 ppm TBTCl group. However, an increase in anogenital distance was found in all TBTCl groups on postnatal d 1. A dose-effect relationship was observed in TBTCl-induced changes in anogenital distance. These results indicate that the whole-life exposure to TBTCl affects the sexual development and reproductive function of female rats. In addition, the TBTCl-induced increase in anogenital distance seems to suggest it may exert a masculinizing effect on female neonates. However, the concentrations of TBTCl used in this study are not environmentally relevant.

Histopathological evidence that spermatogonia are the target cells of 2-bromopropane.

To confirm the target cell of 2-bromopropane within the testis, 1355 mg/kg of 2-bromopropane was subcutaneously injected to rats for 1-5 days and the numbers of spermatogonia and spermatocytes were examined 6 h after each last injection. The number of stage I spermatogonia decreased after the first 2-bromopropane injection and the number of spermatogonia at the other stages also decreased following repetitive injection. The number of these spermatogonia decreased further by the repetition of 2-bromopropane injection. In addition, the delay in mitotic division of type B spermatogonia was frequently observed after the fifth 2-bromopropane injection. The number of stage I pachytene spermatocytes also decreased slightly after the first 2-bromopropane injection, although it did not decrease further following repetitive injection. Therefore, we concluded that spermatogonia are the target cells of 2-bromopropane in rats.

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.

Dose dependent effects of inhaled ethylene oxide on spermatogenesis in rats.

Male Wistar rats were exposed to ethylene oxide (EO) at concentrations of 50, 100, or 250 ppm for six hours a day, on five days a week for 13 weeks. Dose effect relations of inhaled EO on spermatogenesis were evaluated from testicular and epididymal weights, histopathological changes and lactate dehydrogenase X (LDH X) activity in the testis, and sperm counts and sperm head abnormalities in the epididymis. At 250 ppm, a decrease in epididymal weights, slight degenerations in the seminiferous tubules, decreased sperm counts, and increased numbers of abnormal sperm heads in the tail of the epididymis were found; these were not seen at lower doses. When the abnormal sperm heads were classified into immature types and teratic types, the number of immature heads increased only at 250 ppm. On the other hand, the teratic type had increased at doses of 50 and 100 ppm EO when compared with the control group. Hence, subchronic inhalation of EO at low concentrations affects spermatogenesis in rats.

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.

Ethylene oxide induces central-peripheral distal axonal degeneration of the lumbar primary neurones in rats.

Wistar rats subjected to a single exposure lasting six hours to ethylene oxide (EO) at a concentration of 500 parts per million three times a week for 13 weeks developed ataxia in the hindlegs. Myelinated fibres in hindleg nerves and in the fasciculus gracilis showed axonal degeneration sparing the nerve cell body of the lumbar dorsal root ganglion and myelinated fibres of lumbar dorsal and ventral roots. These pathological findings are compatible with central-peripheral distal axonal degeneration. This is the first animal model of EO neuropathy to be histopathologically verified.

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.

Testicular toxicity and alterations of glutathione metabolism resulting from chronic inhalation of ethylene oxide in rats

Wistar male rats were exposed to ethylene oxide (EtO) at a concentration of 500 ppm, 6 hr a day, 3 days a week, for 2, 4, 6, or 13 weeks. Testicular toxicity and changes in glutathione metabolism in the testis were investigated. The relative weights of the testes and the epididymes of the EtO-exposed group decreased in a time-dependent manner. Light microscopic examination revealed degeneration and exfoliation of germ cells. Although the severity of damage became apparent over the course of exposure, some seminiferous tubules showed germ cell recovery at 13 weeks compared with 6 weeks. There was no alteration in plasma testosterone concentration. Glutathione reductase (GR) activity decreased during the entire examination period, and recovery from the decrease was not achieved by addition of flavin adenine dinucleotide (FAD). On the other hand, glutathione peroxidase (GPx) activity decreased at 2 weeks, and then increased at 6 and 13 weeks. In spite of alterations in the glutathione redox cycle, the level of reduced glutathione (GSH) in the testes was not affected. Glutathione S-transferase activity, measured with 1-chloro-2,4-dinitrobenzene (CDNB) as substrate, increased at 6 and 13 weeks and, measured with 1,2-epoxy-3-(p-nitrophenoxy)propane, increased at 4, 6, and 13 weeks. These data indicate that chronic inhalation of EtO induces testicular atrophy. Alterations in the glutathione redox cycle and glutathione S-transferase activity might play important roles in the toxicity and the detoxifying mechanism of the testis.