The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 22 , Issue 2
Showing 1-9 articles out of 9 articles from the selected issue
  • T.J. ISWARAN, M. IMAI, G.R. BETTON, R.A. SIDDALL
    1997 Volume 22 Issue 2 Pages 75-88
    Published: May 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The toxicological profile of bicalutamide in animals following acute and chronic dosing is closely associated with the drug's non-steroidal anti-androgenic pharmacological activity. Bicalutamide produces typical effects of an anti-androgen, including atrophy of the prostate, testis and seminal vesicles and Leydig cell hyperplasia resulting from inhibition of pituitary feedback by testosterone. Subsequent benign Leydig cell tumors were seen in rats, but Leydig cell hyperplasia has not been observed in patients. Bicalutamide causes liver enlargement and is a mixed function oxidase inducer in rodents and dogs, but not man. These effects lead to thyroid hypertrophy and adenoma in the rat and hepatocellular carcinoma in the male mouse. In vitro and in vivo genotoxicity studies have all given negative results. Bicalutamide also caused a reversible shortening of the electrocardiographic P-R interval in the dog without any associated pathology. This change was not detected in ECG monitoring during clinical trials. In conclusion, bicalutamide produced a range of pharmacological effects, as well as liver enlargement with enzyme induction and dog ECG changes in preclinical toxicity studies in rodents and dogs. Only the pharmacological changes were found to be relevant to human usage.
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  • Akiyoshi YOSHIDA, Takanori HARADA, Keizo MAITA
    1997 Volume 22 Issue 2 Pages 89-97
    Published: May 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The potential of ocular toxicity of fenitrothion (O, O-dimethyl O-4-nitro-m-tolyl phosphorothioate) was assessed in Sprague-Dawley (Crj:CD) rats of both sexes receiving a diet containing the test compound at concentrations of 0, 2.5, 5, 10, or 30 ppm for 13 weeks. The animals were observed daily for clinical signs and their body weights and food consumption were measured weekly during the study. At termination of treatment, surviving animals were subjected to ophthalmoscopy, electroretinography, and biochemical analyses of plasma, erythrocyte, and brain cholinesterase (ChE). Histopathological examinations of ocular tissues were performed on all animals by light microscopy and on two animals/sex/dose by electron microscopy. There were no treatment-related changes in clinical signs, body weights, and food consumption. A significant inhibition of ChE activity was observed in males (plasma and erythrocyte ChE) and females (plasma, erythrocyte, and brain ChE) at 30 ppm and in females (plasma ChE) at 1O ppm. Ophthalmological and histopathological examinations revealed neither functional nor morphological alterations in the visual system at any dose level. Under the conditions of the present study, there was no evidence of ocular toxicity of fenitrothion for male and female rats at dose levels up to 30 ppm (1.70 mg/kg/day for males and 1.96 mg/kg/day for females) where distinct inhibition of ChE activity was observed.
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  • Feng Yuan PIAO, Xue Kui XIE, Masayoshi KITABATAKE, Toru YAMAUCHI
    1997 Volume 22 Issue 2 Pages 99-109
    Published: May 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    To estimate the delayed neurotoxic effect of OPs on the next generation, we tried two examinations; one was on the distribution of leptophos in tissues and eggs of hens which are highly susceptible to the delayed neurotoxic effect of OPs but have no placenta, and the other was on the concentration of OPs in tissues of both pregnant and embryonic rats which are not susceptible to the delayed neurotoxic effect but have placenta, after leptophos was administered to the mother in both experiments. First, organophosphorus compound-induced delayed neurotoxicity (OPIDN) was checked in 4 hens and the concentration of leptophos was determined in the other 16 hens after 20 adult laying hens were given 30 mg/kg leptophos (iv), a neurotoxic organophosphate. Three out of 4 hens treated with leptophos showed OPIDN. The concentration of leptophos decreased sharply in the blood, liver, brain and spinal cord from 24 to 48 hr after leptophos administration, but clearance of leptophos was relatively slow in the ovary. Leptophos in laid egg yolk was detected every day for 10 days, and the highest concentration of leptophos in egg yolk was observed on the 6th day after administration to hens. Secondly, in order to investigate the transfer of leptophos to the embryo through the placenta, we divided the thirty-two pregnant rats into 2 groups. The first group received 10 mg/kg leptophos intraperitoneally on the 17th day of pregnancy and the second received 20 mg/kg leptophos on the same day. The time-course of leptophos concentration in the tissues of pregnant and embryonic rats was checked, and the correlation between findings in the pregnant rats and the embryos was determined. The time-course of leptophos concentration in the blood, liver, brain and placenta of the rats was similar to that in hens. Leptophos concentration in the liver and brain of the embryos was equal to approximately 60 % of leptophos concentration in each tissue of the pregnant rats, and the concentration of leptophos in the liver and brain of embryonic rats correlated with that in the blood and placenta of pregnant rats (p&lt0.01). In both groups treated with 10 and 20 mg/kg leptophos, the concentrations of leptophos in the liver and brain of embryos were lower than that of pregnant rats in the early period after dosing, but the concentrations in embryos were inversely higher than those in pregnant rats in the latter period (48 hr). Compared with the biological half-lives of leptophos in the liver and brain of pregnant rats, these parameters in embryonic rats were 1.58 and 1.87 times, respectively. These results indicate that some of the fat-soluble organophosphorus compounds readily pass through the blood-placenta barrier into the embryos and accumulate there. Therefore, the neurobehavioral development of F1 rats exposed to some organophosphorus compounds through the placenta of pregnant rats should be further examined.
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  • Susumu ITOH, Takafumi MATSUYAMA, Tetsuya KAMATAKI
    1997 Volume 22 Issue 2 Pages 111-115
    Published: May 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Suncus murinus (suncus) is an animal species highly sensitive to ethanol (Lin, S.-C., Saito, H., Yohro, T. and Shiga, J., J. Toxicol. Env. Health, 18: 575-587, 1986). To elucidate the mechanism involved in sensitivity to alcohol, we investigated the properties of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the suncus in comparison with the rat. The activities of ALDH in microsomes and mitochondria of suncus livers were lower than those in rat livers, although the activity of cytosolic ADH was not different between the suncus and the rat. We propose that the high sensitivity of the suncus to alcohol can be accounted for, at least in part, by the low activity of ALDH in suncus liver.
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  • Atsuko ISHIKAWA, Takeji OHATA, Kazunori IMAMURA, Makoto IWASAKI, Toshi ...
    1997 Volume 22 Issue 2 Pages 117-133
    Published: May 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Single and repeated intravenous toxicity studies of Pamiteplase (genetical recombination) YM866, a novel recombinant human tissue-type plasminogen activator, were conducted. No animal died from toxic effects of YM866 after single administration to F344 rats, squirrel monkeys and cynomolgus monkeys. Male and female F344 rats were given YM866 intravenously for 4 weeks at doses of 0 (vehicle), 0.1, 0.3 and 1 mg/kg/day. An increase in platelet count, slight decreases in hemoglobin and hematocrit, increases in plasma phospholipids, total cholesterol and total protein, and liver weight were observed at 1.0 mg/kg. Histopathology revealed no changes in any organ except for hemorrhage at the injection sites. These changes recovered after 4 weeks of withdrawal. Male and female squirrel monkeys were given YM866 intravenously for 4 weeks at doses of 0 (saline), 0 (vehicle), 0.1, 0.3 and 1 mg/kg/day. Prolongation of coagulation time at the injection site was observed at 0.3 mg/kg or more. Subcutaneous hemorrhage and a transient decrease in locomotor activity were observed at 1 mg/kg. Prolongation of coagulation time at the injection site was considered to be related to the pharmacological action of YM866. The results show that the approximate single lethal dose of YM866 is more than 60 mg/kg in rats, and more than 10 mg/kg in squirrel monkeys and cynomolgus monkeys. The no-toxic-effect level of YM866 after repeated administration for 4 weeks in rats and squirrel monkeys is considered to be 0.3 mg/kg.
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  • Tetsuo AIDA, Nobuhiro ISHIKAWA, Kenkichi SHINKAI
    1997 Volume 22 Issue 2 Pages 135-140
    Published: May 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The present experiments were undertaken to clarify the differences in humoral and cellular immune responses to a low-molecular compound, sodium 2, 4, 6-trini-trobenzenesul fonate dihydrate (TNBS) in guinea-pig strains. Guinea pigs of three different strains, Hartley, Strain 2 and Strain 13, were immunized subcutaneously with TNBS (3mg/body) 2 or 3 times a week, 9 times in total. Humoral immune responses to TNBS were assessed by passive cutaneous anaphylaxis (PCA) and Arthus reaction, and cellular immune response was assessed by delayed-type hypersensitivity (DTH). Hartley guinea pigs showed high humoral immune responses to TNBS, whereas Strain 2 and 13 guinea pigs showed low responses. Strain 2 guinea pigs displayed high cellular immune response to TNBS, and Strain 13 displayed low cellular immune responses. These results suggest that the pattern of humoral immune response to TNBS does not correlate with that of the cellular immune responses to TNBS for Strain 2 and Hartley guinea pigs.
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  • Toshi WATANABE, Yoshihiro KISHIKAWA, Wataru SHIRAI
    1997 Volume 22 Issue 2 Pages 141-152
    Published: May 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Alkaline ionized water (AKW) produced by the electrolysis of tap water (TPW) was given to pregnant rats throughout gestation. AKW was subsequently given to infants as a test group until 15 weeks old to determine changes in body and organ weights, erythrocyte hexokinase (HK) activity and histological preparations of myocardiac muscle. The results were compared with those for rats given TPW. Body weight of male and female rats given AKW at 3 to 11 weeks of age after birth significantly increased beyond control group values. Organ weights of offspring at 15weeks-old showed no statistical difference for either group. HK activity, the rate-determining enzyme in erythrocyte glycolysis, significantly increased in males given AKW at 15 weeks-old. This suggests that AKW intake causes elevation of metabolic activity. Hyperkalemia was observed in males and females given AKW at 15 weeks-old. Especially in males, pathological changes of necrosis in myocardiac muscle were observed.
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  • Yasumasa KUBOYAMA, Kazuo SUZUKI, Takuji HARA
    1997 Volume 22 Issue 2 Pages 153-160
    Published: May 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    We investigated the lesions of nasal cavity mucous membrane caused by administration of 0.01, 0.05 and 0.10 w/v% Benzalkonium chloride (BZC) solutions in the nasal cavity of rats. No BZC-induced symptoms or nasal lesions were seen in the 0.01 w/v% BZC-treated group. On the other hand, BZC-induced symptoms such as nasal sound and rubbing the nose with forelegs were observed in the 0.05 and 0.10 w/v% BZC-treated groups. Additionally, BZC-induced lesions, including epithelial desquamation, inflammation and edema, occurred in the anterior nasal cavity in the 0.05 and 0.10w/v% BZC-treated groups, but these lesions were confined to the dorsal meatus and the adjacent nasal septum. These results indicate that 0.01 w/v% BZC solution has no effect on the nasal cavity mucous membrane. However, 0.05 and 0.10 w/v% BZC solutions induce lesions in the nasal cavity mucous membrane due to their irritating effect.
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  • [in Japanese]
    1997 Volume 22 Issue 2 Pages App63-App65
    Published: May 25, 1997
    Released: February 21, 2008
    JOURNALS FREE ACCESS
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