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Changes in the Testicular Damage Caused by and in Hamsters during Two Years after Intratracheal Instillations

Minoru OMURA1,Koji YAMAZAKI1,2,Akiyo TANAKA1,Miyuki HIRATA1, Yuji MAKITA1and Naohide INOUE1

1 Department of Hygiene, 2Department of GraduateGeneral SchoolSurgery of Medical Sciences, Kyushu University , Graduate School of Medical Sciences, Kyushu University

Abstract: Changes in the Testicular Damage materials is apparent in human subjects. Caused by Indium Arsenide and Indium Phosphide (J Occup Health 2000; 42: 196-204) in Hamsters during Two Years after Intratracheal Instillations: Minoru OMURA,et al. Department of Key words: Indium arsenide, Indium phosphide, Hygiene, Graduate School of Medical Sciences, Indium, Intratracheal instillation,Testicular toxicity,Long Kyushu University-Change in the testicular damage term observation, Sertoli cell, Spermatogonia caused by indium arsenide (InAs) and indium phosphide (InP) was examined during two yr after III-V compound semiconductor materials, such as repetitive intratracheal instillations in hamsters. In this (GaAs), are now extensively used for study, 4.0 mg/kg body weight/day of InAs or 3.0 mg/kg manufacturing light-emitting diodes, semiconductor body weight/day of InP was instilled intratracheally and microcircuits''. This means that the health risk twice weekly for eight wk. A single instillation dose of due to these materials needs to be properly assessed. indium was 2.4 mg/kg body weight in both groups. Testicular damage was evaluated 0, 8, 16, 40, 64 and Indium is an element in the IIIa column of the periodic 88 wk after the last instillation. Both InAs and InP were table and is incorporated into III-V compound proved to be definite testicular toxicants. Both materials semiconductor materials, such as indium arsenide (InAs) decreased reproductive organ weight and caudal sperm and indium phosphide (InP). Only a few data are count, and caused severe histopathologic changes in available to assess the health risk of indium-containing the testes. InAs-induced testicular damage was always compound semiconductor materials'-", especially to more serious than InP-induced testicular damage. The assess the risk to the reproductive system' ". We serum indium concentration in the InAs group was previously examined the testicular toxicity of GaAs and always higher than that in the InP group, and indium InAs immediately after eight-week repetitive intratracheal was probably a toxic element in both materials. In the instillation (7.7 mg/kg body weight/day, twice a week) histopathologic examination, vacuolization of in rats' and hamsters". GaAs showed a definite testicular seminiferous epithelium was frequently observed as an early histopathologic change and spermatogonia toxicity in both species. InAs showed only a weak remained in general even in the seminiferous tubules testicular toxicity in rats and did not show any sign of with severe histopathologic changes in both groups. It testicular toxicity in hamsters. But our study on hamsters is therefore estimated that Sertoli cells, not stem cell was inadequate to evaluate the testicular toxicity of InAs. spermatogonia, were the target cells of these indium In the study, eight-wk intratracheal instillation could not containing compound semiconductor materials. The be completed because of emaciation of the animals". We threat of InAs and InP to male reproduction was proved also thought that our study on rats might have in this study. We concluded that male reproductive underestimated the testicular toxicity of InAs because disorders should not be overlooked when severe high concentrations of indium and were still exposure to indium-containing compound detected in the serum of hamsters a long time after the Received March 22, 2000; Accepted April 24, 2000 intratracheal instillations of InAs''. Chemical-induced Correspondence to: M. Omura, Department of Hygiene, Graduate adverse effects on the male reproductive system are School of Medical Sciences, Kyushu University, Fukuoka 812-8582, drawing attention in the field of industrial hygiene in Japans Japan because of 2-bromopropane-induced reproductive hazards in a Korean electronic company'-"' and group and 3.0 mg/kg body weight in the InP group. The widespread anxiety about endocrine-disrupting chemicals. single instillation dose of indium was 2.4 mg/kg body We therefore decided to re-examined the testicular weight in both groups. Hamsters in the control group toxicity of InAs in hamsters. Testicular toxicities of InP were given phosphate buffer solution only. Hamsters were also examined and were compared with those of were thus treated twice weekly for eight weeks. No InAs in order to clarify the contribution of indium to the animals died during the administration period. testicular toxicity of indium-containing compound semiconductor materials. Examination of the effects on the male reproductive system Materials and Methods Eight hamsters died of emaciation (five in the InAs Test materials group and three in the InP group), seven were cannibalized InAs and InP were provided by Mitsuwa Chemicals (four in the control group and three in the InAs group), (Osaka, Japan) and had a purity of more than 99.99%. and four were killed accidentally before examination in These materials were finely pulverized in an agate mortar. the control group during the observation period. These The mean count diameter for InAs and InP was 1.58 ,um animals were excluded from all evaluations. Four to eight [6g (geometric standard deviation): 2.15] and 1.06 ym hamsters in each group were weighed and killed with an [6g: 1.80], respectively. Both powders were analyzed in overdose of ether 0, 8, 16, 40, 64 and 88 wk after the last an energy dispersive X-ray fluorescence element analyzer instillation. The testes and epididymes were removed (MESA-500, Horiba, Ltd., Kyoto, Japan). InAs powder and weighed. The right cauda epididymidis was contained 0.01% (wt%) of zirconium and 0.01% of homogenized in saline containing 0.05% (v/v) Triton X yttrium, and InP powder contained 0.01 % of zirconium 100 in a blender and homogenization-resistant sperm were and a trace amount of yttrium. Test materials were counted in a hemocytometer. The right testis was fixed suspended in particle form in pathogen-free phosphate in Bouin's solution, embedded in paraffin wax, thinly buffer solution (0.025 M, pH 6.86) just before instillation. sectioned and stained with periodic acid Schiff reagent The concentrations of InAs and InP in the suspension (PAS) and hematoxylin. Histopathologic changes in the were 2.0 mg/ml and 1.5 mg/ml, respectively. testis were examined under an optical microscope. All cross-sections of seminiferous tubules in one transverse Animal section of the testis (about 200-400 cross-sections of the Male Syrian golden hamsters were purchased at six tubule) were examined and the seminiferous tubules with weeks of age from Japan SLC, Inc., (Shizuoka, Japan). histopathologic changes were counted. Degeneration of The animals were housed four per stainless cage and were one or two germ cells was not regarded as a maintained in a specific pathogen-free laboratory room histopathologic change. of the Laboratory of Animal Experiments, Faculty of The results of this study concerning the pulmonary Medicine. Kyushu University. The light cycle was 12 h: toxicity and serum concentrations of indium and arsenic 12 h (light/dark), the temperature was 22-25°C, and the have already been reported by Yamazaki et al.". air humidity was 50-60%. The animals were provided with CE-2 feed (Clea Japan Inc., Tokyo, Japan) and tap Statistical analysis water ad libitum. This experiment was reviewed by the Data were analyzed for the mean and standard deviation Committee of Ethics on Animal Experiments in the and F test was performed to evaluate equality of variance. Faculty of Medicine, Kyushu University and was carried If a significant difference was found in a variance, t test out under the Guidelines for Animal Experiment of the with Welch's correction was used for the statistical Faculty of Medicine, Kyushu University and the Law analysis, and otherwise a t test without a correction was (No. 105) and Notification (No. 6) of the Government of used. The differences were interpreted as significant at Japan. p<0.05. There were only two hamsters adequate for evaluation in the control group 8 wk after the last Treatment instillation, (four were killed accidentally before After a two-week acclimation period, 144 hamsters, examination and two had marked unilateral atrophy of eight weeks of age, were randomized into three groups the testis and the epididymis). Therefore, statistical by weight: a control group, an InAs group and an InP analysis was not performed at this point. group. The mean body weights of hamsters in the control Results group, InAs group and InP group were 109.5 g, 111.5 g, and 111.6 g, respectively. Hamsters in each group were Body weight, reproductive organs weights, and sperm intratracheally instilled with a 2.0 ml suspension/kg body count in the cauda epididymidis weight under ether anesthesia. A single instillation dose Body weight in the InAs group had already decreased of test material was 4.0 mg/kg body weight in the InAs significantly immediately (0 wk) after the last instillation and was always approximately 70% of the control value the InP group were compatible with those in the control thereafter (Fig. 1). Body weight in the InP group was group from 0 wk to 8 wk after the last instillation. compatible with that in the control group immediately Reproductive organ weights in this group decreased after the last instillation. Body weight in this group significantly from 16 wk to 64 wk after the last instillation decreased significantly from 16 wk to 64 wk after the and were 60-70% of the control values in this period. In last instillation and was 80-90% of the control value in the InP group, reproductive organ weights became this period. In the InP groups, body weight became compatible with the control values again 88 wk after the compatible with the control value again 88 wk after the last instillation (Figs. 2, 3). last instillation (Fig. 1). The sperm count in the cauda epididymidis in the InAs Weights of the two reproductive organs in the InAs group had already decreased significantly immediately group had already decreased significantly immediately after the last instillation. The caudal sperm count in this after the last instillation. Reproductive organ weights in group decreased further afterwards and was 10-30% of this group decreased further afterwards and were 30-50% the control value from 16 wk to 88 wk after the last of the control values from 16 wk to 88 wk after the last instillation (Fig. 4). Unlike body weight and reproductive instillation (Figs. 2, 3). Reproductive organ weights in organ weights, the caudal sperm count in the InP group

Fig. 1. Body weight change in two yr after the repetitive Fig. 2. Testes weight change in two yr after the repetitive intratracheal instillations of indium arsenide (4.0 m(y/ intratracheal instillations of indium arsenide (4.0 mg/ kg body weight/d, •) and indium phosphide (3.0 mg/ kg body weight/d, •) and indium phosphide (3.0 mg/ kg body weight/d. ) twice weekly for eight wk ((A) kg body weight/d, ) twice weekly for eight wk ((A) absolute value (F]; control group), (B) 9c mean control absolute value (0; control group), (B) % mean control value). Error bars indicate standard deviation. The value). Error bars indicate standard deviation. The number under a mean bar is the number of animals number under a mean bar is the number of animals. Statistical significance is analyzed with the t-test; Statistical significance is analyzed with the t-test; *p<0 .05, *"p<0.01. Statistical analysis is not *p<0 .05, -"`*p<0.01. Statistical analysis is not performed 8 wk after the last instillation because of the performed 8 wk after the last instillation because of the small number of animals in the control group. small number of animals in the control group. Fig. 3. Epididymes weight change in two yr after the Fig. 4. Change in sperm count in cauda epididymidis in two repetitive intratracheal instillations of indium yr after the repetitive intratracheal instillations of arsenide (4.0 mg/kg body weight/d. •) and indium indium arsenide (4.0 mg/kg body weight/d, •) and phosphide (3 0 mg/kg body weight/d, ) twice indium phosphide (3.0 mg/kg body weight/d, ) weekly for eight wk ((A) absolute value (L]; control twice weekly for eight wk ((A) absolute value (0; group), (B) % mean control value). Error bars control group), (B) % mean control value). Error indicate standard deviation. The number under a bars indicate standard deviation. The number under mean bar is the number of animals. Statistical a mean bar is the number of animals. Statistical significance is analyzed with the t-test; Yp<0.05, significance is analyzed with the t-test; 4p<0.05, ~p<0 .01 Statistical analysis is not performed 8 wk **p<0 .01. Statistical analysis is not performed 8 wk after the last instillation because of the small number after the last instillation because of the small number of animals in the control group. of animals in the control group.

had already decreased significantly immediately after the histopathologic changes in the InP group were compatible last instillation. The caudal sperm count in this group with the control value until 8 wk after the last instillation decreased further thereafter and was 40-50% of the and, first increased significantly 16 wk after the last control value from 16 wk to 64 wk after the last instillation (Fig. 5). Both in the InAs and InP groups, instillation. In the InP group, like body weight and vacuolization of seminiferous epithelium was frequently reproductive organ weights, the caudal sperm count observed as an early histopathologic change (Figs. 6b, recovered to the control level 88 wk after the last 6c). During the observation period, severe instillation (Fig. 4). histopathologic changes were always observed in the InAs group. In this group, 70-90% of seminiferous tubules Histopathologic changes in the testis had histopathologic changes from 16 wk to 88 wk after In the InAs group, the frequency of seminiferous the last instillation (Fig. 5). These histopathologic tubules with histopathologic changes had already changes included degeneration and loss of germ cells, increased immediately after the last instillation (Fig. 5). exfoliation and disarrangement of seminiferous The frequency of seminiferous tubules with epithelium, and atrophy of seminiferous tubules, but inadequate to evaluate the testicular toxicity of InAs because planned repetitive intratracheal instillations could not be completed because of emaciation of the animals. We therefore re-examined the testicular toxicity of InAs in hamsters in this study. We used approximately half the daily dose of InAs in this study to prevent animal emaciation. No animals died during the administration period and more than 80% survived until the planned day of euthanasia in the InAs and InP groups, so that the testicular toxicities of InAs and InP were thought to be adequately evaluated in this study. The Table 1 summarizes the results of this study. Both InAs and InP were proved to be definite testicular toxicants. Testicular toxicity of InAs was first proved in Fig. 5. Change in the frequency of seminiferous tubules hamsters and the toxicity was far more greater than that with histopathologic lesions in two yr after the seen in rats in our previous study''. In our two previous repetitive intratracheal instillations of indium studies, testicular toxicity of InAs was once evaluated arsenide (4.0 mg/k(y body weight/d, •) and immediately after the last of the repetitive instillation' ". indium phosphide (3.0 mg/kg body weight/d, ) twice weekly for eight wk (E]; control group). In this study, the testicular toxicity of InAs was repeatedly Error bars indicate standard deviation. The evaluated until 88 wk after the last of the repetitive number under a mean bar is the number of instillations and, as shown in Figs. 2-5, InAs-induced animals. Statistical significance is analyzed with testicular damage became more severe until 16 wk after the t-test; ''`p<0.05, **p<0.01. Statistical analysis the last instillation. Testicular damage was still in is not performed 8 wk after the last instillation because of the small number of animals in the progress immediately after the last instillation of InAs in control group. this study, and therefore the testicular toxicity of InAs had been underestimated in our two previous studies. We proved the testicular toxicity of InP for the first time in this study. As shown in Figs. 2-5, InP-induced testicular spermatogonia remained in general even in the damage was always less than InAs-induced damage. seminiferous tubules with severe histopathologic changes There are two possible ways to explain this difference. (Fig. 6d). Severe histopathologic changes were also One is the existence of internal exposure to arsenic in the observed in the InP group from 16 wk to 64 wk after the InAs group and the absence of this exposure in the InP last instillation, although the frequency was always less group. In this study, 0.4 pM arsenic was constantly than that in the InAs group (30-50%, Fig. 5). detected in the serum of InAs-treated hamsters and the Spermatogonia remained in general in the seminiferous serum concentration of arsenic in the InP group (0.05 tubules in the InP group, also (Fig. 6e). In the control pM) was similar to the control value (0.04,uM) during group, the frequency of seminiferous tubules with the observation period (Fig. 7)6'. In our previous study", histopathologic changes gradually increased with age and the mean serum concentration of arsenic in As,O3-treated 13.6 ± 8.9% of seminiferous tubules had histopathologic hamsters was 1.31 pM immediately after the last changes 88 wk after the last instillation (104 wk of age, instillation. This concentration was three times higher Fig. 5). At this point, the frequency of seminiferous than that in the InAs group in this study, although no tubules with histopathologic changes was 31.2 ± 38.7% sign of testicular damage was found in As,O`-treated in the InP group, but the frequency was 14.2 ± 8.0% in hamsters in our previous study''. These results indicate this group at this point when one animal with extremely that the internal exposure to arsenic did not fully explain high frequency (99.4%) was excluded. In the InP group, the more potent testicular toxicity of InAs. The other the histopathologic findings 88 wk after the last cause is higher internal exposure to indium in the InAs instillation were apparently different from those until 64 group than in the InP Group. In this study, a single wk after the last instillation. At this point, most of instillation dose of indium was the same in both groups. seminiferous tubules were normal and a few seminiferous But, as shown in Fig. 7, the serum indium concentration tubules with severe atrophy were mingled in some places in InAs-treated hamsters was constantly more than twice in the InP group (Fig. 6g). that in InP-treated hamsters'. This is probably due to a greater influx of indium into serum in the InAs group Discussion than in the InP group'. The hypothesis that the difference In the previous study, we could not prove the testicular in the internal exposure to indium was the cause of the toxicity of InAs in hamsters". but that study was difference in the testicular toxicity of the two materials Fig. 6. Histopathologic findings in the testis in the control group (a), indium arsenide (InAs) group (b, d, f) and indium phosphide (InP) group (c, e, g) Vacuolizations of seminiterous epithelium (arrow heads) are observed as an early histopathological change (b, InAs group at 0 wk, c, InP group at 16 wk) Spermatogonia (arrow heads) remain in the seminiferous tubule with severe histopathological changes (d, InAs group at 16 wk, e, InP group at 16 wk) At 88 wk after the last instillation, almost all seminiterous tubules are severely aftected in the InAs group (f), but most of the seminiterous tubules are noimal and a tew seminiferous tubules with severe atrophy (arrow heads) are mingled in some places in the InP group (g) Bar indicates 100 ,um Table 1. Summary of the results of this study

ai Severity of the effect is classified as follows: -: The reduction was not significant or less than 20% of the control value. +: The reduction was significant or more than 20% of the control value. ++: The reduction was more than 30% of the control value. +++: The reduction was more than 50% of the control value. b) Severity of the effect is classified as follows: -: Less than 20% of the seminiferous tubules were damaged . +: More than 20% of the seminiferous tubules were damaged. ++: More than 30% of the seminiferous tubules were damaged. +++: More than 50% of the seminiferous tubules were damaged. c? One animal with an extremely high frequency of damaged tubules is excluded .

Fig. 7. Changes in the serum indium concentration (/; indium arsenide group, A; indium phosphide group) and serum arsenic concentration (L; indium arsenide group) in two yr after the repetitive intratracheal instillations of indium arsenide (4.0 mg/kg body weight/d) and indium phosphide (3.0 mg/ kg body weight/d) twice weekly for eight wk. Error bars indicate standard deviation (n=4-8). (Figure is reproduced from Yamazaki et al.7) and used with permission of the Japan Society for Occupational Health). was supported by other results in this study. In the InP this mean that testicular damage caused by InAs and InP group, testicular damage was found from 0 wk to 64 wk was irreversible? The answer is no. In the histopathologic after the last instillation and recovered 88 wk after the examination, severe tubular damage was always observed last instillation (Table I). In line with the recovery of in both groups, but seminiferous tubules containing only testicular damage, the serum indium concentration Sertoli cells were rarely observed and spermatogonia decreased by approximately half in the InP group (Fig. remained in general even in the seminiferous tubules with 7)". These results indicate that indium was primarily severe histopathologic changes in both groups. This responsible for the toxic effect of InP, and that the means that seminiferous tubules did not lose their ability difference in the internal exposure to indium was the main to regenerate germ cells and that spermatogenesis always cause of the difference in the testicular toxicities of InAs occurred in both groups during the observation period. and InP. In fact, testicular damage in the InP group recovered 88 Body weight of the hamsters decreased to a maximum wk after the last instillation, in line with the decrease in of 70% of the control value in the InAs group and the serum indium concentration. Probably the internal decreased up to 80-90% of the control value in the InP exposure to indium was sufficiently high to prevent group in this study (Fig. 1). Feed restriction and body spermatogenesis for even more than one yr after the weight reduction impair the reproduction of animals' '--'6'. cessation of the instillations in both groups, and then Feed restriction which decreased body weight to 70% of testicular damage lasted. The serum indium concentration the control value caused little testicular damage in rats'''. decreased with age in the InAs group as in the InP group, Feed restriction to the same degree caused a 10-20% although testicular damage in the InAs group did not decrease in reproductive organ weights and caudal sperm recover during the observation period. The serum indium count in mice''. Feed restriction and body weight concentration in the InAs group 88 wk after the last reduction severely affect the reproduction of hamsters. instillation was higher than that in the InP group 40 wk Eskes reported that feed restriction which decreased body after the last instillation. This means that the serum weight to 70% of the control value decreased the width indium concentration in the InAs group was always high of the testis to 60-80% of the control value'". Pieper enough to prevent spermatogenesis throughout the and colleagues reported that feed restriction which observation period, and testicular damage did not recover decreased body weight to 70% of the control value halved in this group. Both in the InAs and InP groups, testis size (=the length times the width of the testis)''. vacuolization of seminiferous epithelium was frequently We must therefore consider the possibility that a decrease observed as an early histopathologic change. in food intake and a body weight reduction were Vacuolization of seminiferous epithelium is a sign of responsible for testicular damage in the two groups. In Sertoli cell damage"-"'. Considering histopathologic the InP group, body weight began to decrease 16 wk after changes in the testes, we estimate that Sertoli cells were the last instillation but caudal sperm reduction had already first damaged but that stem cell spermatogonia were rarely been apparent immediately after the last instillation. damaged in the InAs and InP groups. We reported that Testicular damage preceded body weight reduction in the gallium arsenide, other 111-V compound semiconductor InP group and then it was improbable that a decrease in material, causes spermatid retention in seminiferous food intake and a body weight reduction were responsible tubules and that gallium plays the main role in the for testicular damage in this group. Testicular damage in testicular toxicity of gallium arsenide in hamsters'-''. the InP group was primarily due to the toxic effect of Because spermatid retention in seminiferous tubules is indium. High internal exposure to indium was found in also a sign of Sertoli cell damage" "', elements in the III the InAs group, also, and, as described below, the same column of the periodic table might have toxic effects on histopathologic changes were seen in the testes in the Sertoli cells. InAs and InP groups, so that it is reasonable to estimate Indium-containing compound semiconductor materials, that testicular damage in the InAs group was primarily InAs and InP, were proved to be definite testicular due to the toxic effect of indium as in the InP group. But toxicants. It is estimated that indium was the main toxic both testicular damage and a body weight reduction had element in the two materials and that Sertoli cells were already been apparent immediately after the last damaged by them. Actual inhalation doses of InAs and instillation in the InAs group. The possibility that a InP in workplaces would be much lower than the doses decrease in food intake and a body weight reduction were used in this study and further studies are needed to assess responsible for testicular damage in the InAs group could the risk of low-dose indium-containing compound not be excluded in this study. Further study with smaller semiconductor materials on the human male reproductive instillation doses of InAs is needed to verify this function. Nevertheless, the threat of these materials to possibility. male reproductive function was proved in this study. Testicular damage lasted for even more than one yr Therefore, we thought that male reproductive disorders after the cessation of the instillations in both groups. Does should not be overlooked when severe exposure to indium-containing compound semiconductor materials is 9) Kim Y, Jung K, Hwang T, et al. 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