Fundamental Toxicological Sciences
Online ISSN : 2189-115X
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Toxicomics Report
Letter
  • Takashi Yamada, Yushiro Tanaka, Ryuichi Hasegawa, Toshime Igarashi, Ak ...
    5 巻 (2018) 2 号 p. 75-82
    公開日: 2018/04/18
    ジャーナル フリー

    Prolongation of prothrombin time (PT) induced by industrial chemicals was characterized using a database of repeated dose toxicity studies, HESS DB. Of the 685 chemicals in the DB, 20 chemicals markedly prolonged the PT by more than 150% of that of vehicle control. Prolonged PTs were detected in males for 20 chemicals but no significant prolongation of PT was observed in females for 19/20 chemicals, indicating that males are apparently more susceptible to PT prolongation than females. The effective dose of the chemicals for males were relatively high, in the range of 100 to 1,000 mg·kg-1·day-1, compared to the dose range of 60 to 100 μg·kg-1·day-1 for warfarin, a typical anticoagulant. Since not all chemicals had severe hepatotoxic effects at these doses, the low protein synthesis capacity of the liver may not contribute to prolonged PT. The mechanism of PT prolongation by the chemicals was considered different from that of warfarin, which is a specific inhibitor of vitamin K epoxide reductase, because of large differences in their effective dose and lack of structural similarity between them. Herein, the possible mechanisms of PT prolongation by industrial chemicals in males are explored, with a focus on the action of estradiol and vitamin K.

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Letter
  • Masaaki Kurata, Gakushi Kito, Kazuyo Sadamoto, Shingo Nemoto
    5 巻 (2018) 2 号 p. 83-85
    公開日: 2018/04/25
    ジャーナル フリー

    The systemic dose levels of eye-drop drugs are relatively low in comparison with that of systemic routes such as oral administration. We undertook overall risk assessment of eye-drop drugs for developmental and reproductive toxicity (DART) by comparing the estimated systemic dose level of eyedrop drugs with the known threshold of toxicological concern (TTC) for DART. The systemic dose level of eye-drop drugs in human were estimated to be 0.0005 to 0.05 mg/kg/day on the assumption of 0.01% to 1% of eye drop formulation, 0.04 mL/eye/time of instillation volume, and 60 kg body weight. The TTCs for DART ranged from 0.003 mg/day (0.00005 mg/kg/day; for anticacer drugs) to 7.860 mg/day (0.131 mg/kg/day). Therefore, the range of estimated systemic dose level of eye-drop drugs was almost overlapped with known TTC values for DART, excepting for that applied to the anticacer drugs. These knowledge simply indicates the safety of eye-drop drugs for DART from a view pont of absolute dosage levels, implying allowance of case by case basis planning non-clinical DART study.

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