The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 23 , Issue SupplementIV
Showing 1-8 articles out of 8 articles from the selected issue
  • Toshiro YAMAGUCHI, Yoshitsugu NAKAJIMA, Hiroyuki MIYAMOTO, Minoru MIZO ...
    1998 Volume 23 Issue SupplementIV Pages 577-585
    Published: October 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Disodium mercaptoundecahydro-closo-dodecaborate (BSH) is an important compound for boron neutron capture therapy. The pharmacokinetics of boron by BSH were studied in normal rats after rapid intravenous injection at three doses (30, 100, 300 mg/kg) or continuous infusion (100 mg/kg/30 min). The boron concentration in biological samples was measured by inductively coupled plasma atomic emission spectroscopy. The blood half-lives of boron in the elimination phase (t1/2β) after rapid injection of BSH at doses of 30, 100 and 300 mg/kg were 1.7, 17 and 19 hr, respectively. AUC (32, 219 and 4030 μg·hr/ml) increased with the dose, but there was no proportionality among the values. Total clearance decreased drastically from 233 ml/hr/kg (100 mg/kg) to 38 ml/hr/kg (300 mg/kg). As boron was excreted mainly into urine, these results suggest that renal function failure might occur with dosing of 300 mg/kg. In the case of continuous infusion of 100 mg/kg of BSH for 30 min, the pharmacokinetic parameters were similar to those of rapid injection of 100 mg/kg. The highest boron concentration was observed in the kidney and the lowest in the brain. After multiple dosing of BSH at 100 mg/kg/day×14 days, the boron concentrations in blood, liver, lung and kidney at 24 hr after the last dosing were higher than those after single dosing and were similar to those of simulated values calculated from the single dosing parameters. These results clearly indicated that boron does not accumulate unexpectedly in any tissue with multiple dosing of 100 mg/kg of BSH for two weeks.
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  • Fumio ITOH, Kazuya YABUUCHI, Kouji OHNO, Isao IKEUCHI, Yoshihiro MURAO ...
    1998 Volume 23 Issue SupplementIV Pages 587-611
    Published: October 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Disodium mercaptoundecahydro-closo-dodecaborate (BSH) is a boron compound used in Boron Neutron Capture Therapy for malignant brain tumors. Intravenous single and 2-week repeated dose toxicity studies of BSH were performed in Sprague-Dawley rats. In the single-dose study, BSH was administered at doses of 100, 300 or 600 mg/kg. Death occurred within 10 min (acute type) or from 5 hr to 2 days (delayed type) after dosing in the 600 mg/kg group. No differences in mortality by sex and dosing speed were observed. Major causes of death were considered to be circulatory disorder in acute death and renal injury in delayed death. The renal injury was observed in the 300 and 600 mg/kg groups. In the 2-week repeated dose study, BSH was administered at doses of 30, 100 or 300 mg/kg/day for 14 days. Body weight gain was suppressed in the 100 and 300 mg/kg groups. One male in the 300 mg/kg group died due to renal and pulmonary lesions at day 8. Slight anemia was observed in the 300 mg/kg group. Pathologically, the kidney showed tubular regeneration with increase of weight in the 300 mg/kg. From these results, the NOAEL of BSH is 30 mg/kg/day.
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  • Yukio MIYAKE, Youzi NISHIMOTO
    1998 Volume 23 Issue SupplementIV Pages 613-618
    Published: October 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Disodium mercaptoundecahydro-closo-dodecaborate (BSH) was studied for mutgenic potential by reverse mutation test with bacteria. The test was carried out using five different tester strains, S.typhimurium TA100, TA1535, TA98 and TA1537, and E.coli WP2uvrA by the preincubation method. BSH was tested at concentrations ranging from 156 to 5000 μg per plate. The test substance did not induce revertants dose-dependently in any strains with or without a metabolic activation system. Therefore, it was concluded that BSH was not mutagenic in the present reverse mutation test.
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  • Toshihiko YANAGISAWA, Shunichi MAEMURA, Hiromi SASAKI, Toru ENDO, Mino ...
    1998 Volume 23 Issue SupplementIV Pages 619-642
    Published: October 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Triethylenetetramine dihydrochloride (trientine-2HCl, TJA-250), a copper chelating agent used to treat Wilson's disease, was administered orally to male and female F-344 rats for 4 or 8 weeks at dosages of 0, 100, 350 or 1200 mg/kg/day or for 26 weeks at dosages of 50, 175 or 600 mg/kg/day. 4 or 8-week study. Two males receiving 1200 mg/kg/day died during week 8 of treatment. In males receiving 1200 mg/kg/day during weeks 5 to 8 of treatment, body weight gain and food consumption were decreased and hunched posture and thin build were observed. During week 4 or 8 of treatment urinalysis revealed, for males receiving 100 mg/kg/day or animals receiving 350 mg/kg/day or more, increased electrolyte outputs possibly due to the hydrochloride nature of trientine-2HCl, with low plasma alkaline phosphatase activities evident in animals receiving 350 or 1200 mg/kg/day. After 4 and 8 weeks, and during 8 weeks of treatment, high lung weights and bronchiolar epithelium hypertrophy and broncho-alveolar pneumonia were recorded for animals receiving 1200 mg/kg/day, and submucosal acute inflammation within the glandular region of the stomach was recorded for males receiving 350 or 1200 mg/kg/day and in all treated female groups. 26-week study. One male receiving 175 mg/kg/day and three males receiving 600 mg/kg/day died, showing lung changes. The body weight gain of animals receiving 600 mg/kg/day was slightly decreased. Blood chemistry and urinalysis examinations showed changes similar to those indicated in the 4- or 8-week study. The low plasma copper concentrations seen in males receiving 600 mg/kg/day, the slightly low liver copper concentrations found in animals receiving 600 or 175 mg/kg/day and the high urinary copper concentrations found in all treated groups, are attributed to the pharmacological action of trientine-2HCl. Histopathology revealed a dosage-related incidence and severity of focal chronic interstitial pneumonitis accompanied by fibrosis of the alveolar walls in females receiving 175 mg/kg/day or more and all treated male groups, but no significant pathological changes in the stomach. Apart from the histological changes found in the lung, all the above changes were reversible. In conclusion, the NOAEL of trientine-2HCl in this 26-week study was considered to be 50 mg/kg/day for females and less than 50 mg/kg/day for males.
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  • Yuichi SUGIYAMA, Kiyomi ITO
    1998 Volume 23 Issue SupplementIV Pages 647-652
    Published: October 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
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  • Hwan Mook Kim, Dong Ho Hong, Chang Woo Lee, Young Hee Kim, Moon Soon K ...
    1998 Volume 23 Issue SupplementIV Pages 653-656
    Published: October 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
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  • Yo-Chan Jeong, Dong-Hyun Kim, Bok Ryang Kim, Misun Park
    1998 Volume 23 Issue SupplementIV Pages 660-661
    Published: October 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
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  • Ky. Kim, HS. Kim, HS. Kim, Jy. Jeong, KS. Kil, BS. Yu
    1998 Volume 23 Issue SupplementIV Pages 662-663
    Published: October 28, 1998
    Released: February 21, 2008
    JOURNALS FREE ACCESS
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