著者

永田 次雄 永田 貴久 浜畑 美智子 佐藤 堅 村上 氏廣 榎本 真 田村 穣

出版者

日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.8, pp.51-83, 1983-01-25

被引用文献数

1 1

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ヒスタミンH_2-受容体拮抗剤ranitidineをビーグルに経口投与し, 急性毒性, 5週間亜急性毒性, 26週間慢性毒性および回復試験を行った。I. 急性毒性 1000, 1500, 2500, 3000 または 3500 mg/kgを雌雄各1頭に1回経口投与により, 投与直後より嘔吐, 振戦, 歩行失調を認めた。最高用量においては死亡例を認めなかったが3000 mg/kg群の雄1頭が死亡した。なお, 嘔吐が著しかったので3500 mg/kg以上の投与量での検討は行わなかった。II. 5週間亜急性毒性 1) 40, 80, 160 または 320 mg/kgを1日1回5週間経口投与において死亡例は認められず, 40 mg/kg群では異常は認められなかった。2) 80 mg/kg群では流涎以外に異常は認められず, 160 mg/kg以上の群においては流涎, 嘔吐および軟便などの症状を認め, 雄に軟便にともなう下部消化管の微細出血に関連して赤血球数, ヘマトクリットおよびヘモグロビンの有意な減少を認めた。3) 320 mg/kg群では体重の減少がみられたが有意差はなかった。また, 摂餌量の減少, 散発的な軽度のタール便を認めた。雄の赤血球数, 血清総蛋白の減少ならびに血小板数および網赤血球率の増加を認めた。4) 病理組織学的な検査において80 mg/kg群の雌1頭に大腸粘膜の一部に萎縮およびびらん形成を認め, 320 mg/kg群の雄1頭に大腸粘膜にびらん形成を認めたのみで他に特記すべき異常を認めなかった。5) 最大無作用量は40 mg/kgと推定され, これはヒト1日臨床用量の約7-8倍に相当する。III. 26週間慢性毒性 1) 40, 80または160 mg/kgを1日1回26週間経口投与を行い, 80および160 mg/kg群では試験終了後30日間休薬による回復試験を行った。この試験において死亡例は認められず, 40 mg/kg群では異常を認めなかった。2) 80 mg/kg以上の群では流涎, 嘔吐, 軟便など亜急性毒性試験に認められたのと同様な症状がみられた。3) 160 mg/kgでは摂餌量の減少, 体重増加抑制, 便潜血反応陽性を示し, これに関連した赤血球数の減少, さらに雄ではヘマトクリット値およびヘモグロビン値の減少を認めたが, 他に特記すべき変化は認めなかった。4) 病理組織学的所見においては, 特記すべき異常は認めなかった。5) 電子顕微鏡学的所見においては, 160および320 mg/kg投与群の輝板に軽度な変化がみられたのみで, 他に特記すべき変化はなかった。6) 慢性毒性試験にみられた上記の所見は, 休薬後は認めなかった。7)最大無作用量は40 mg/kgと推定され, これはヒト1日臨床用量の約7-8倍に相当する。(試験実施期間 昭和55年1月〜昭和56年8月)

著者

Masaaki Miyazawa Yuichi Ito Nanae Kosaka Yuko Nukada Hitoshi Sakaguchi Hiroyuki Suzuki Naohiro Nishiyama

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.33, no.1, pp.71-83, 2008 (Released:2008-02-26)

参考文献数

37

被引用文献数

19 24 18

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Dendritic cells (DCs), including Langerhans cells (LCs), play a critical role in the induction phase of allergic contact hypersensitivity. Following exposure to chemical allergens in the skin, LCs undergo a maturation process leading to the up-regulation of expression of co-stimulatory molecules, such as CD86, CD54 and CD40. Our previous study revealed that chemical allergens induce phenotype alterations (e.g., CD86, CD54 and CD40) and cytokine production (TNF-α and IL-8) in THP-1 cells that possibly reflect the maturation of dendritic cells during skin sensitization. However, the physiological signals for phenotypic alterations by chemical allergens are still not fully understood. Therefore, in this study, we investigated the effect of TNF-α and extracellular ATP on THP-1 cell activation induced by chemical allergens. Kinetic studies revealed that TNF-α and IL-8 release occurred in a time-dependent manner with release of two cytokines beginning at 3 hr post-exposure to well-known haptens, DNCB and NiSO4. While recombinant human TNF-α augmented CD54 and CD40 expression in a dose-dependent manner, rhTNF-α did not increase CD86 expression. Furthermore, neutralization of TNF-α activity strongly inhibited CD54 and CD40 expression induced by allergens. On the contrary, extracellular ATP induced the up-regulation of both CD86 and CD54 expression. In the presence of the P2 receptor antagonist suramin, the up-regulation of CD86 and CD54 expression by allergens was in part suppressed. Therefore, we postulate that not only TNF-α but also extracellular ATP may contribute to cell activation following allergen stimulation, which might reflect the mechanism by which DCs respond to allergens.

著者

Atsuya Takagi Akihiko Hirose Tetsuji Nishimura Nobutaka Fukumori Akio Ogata Norio Ohashi Satoshi Kitajima Jun Kanno

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.33, no.1, pp.105-116, 2008 (Released:2008-02-26)

参考文献数

22

被引用文献数

428 655

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Nanomaterials of carbon origin tend to form various shapes of particles in micrometer dimensions. Among them, multi-wall carbon nanotubes (MWCNT) form fibrous or rod-shaped particles of length around 10 to 20 micrometers with an aspect ratio of more than three. Fibrous particles of this dimension including asbestos and some man-made fibers are reported to be carcinogenic, typically inducing mesothelioma. Here we report that MWCNT induces mesothelioma along with a positive control, crocidolite (blue asbestos), when administered intraperitoneally to p53 heterozygous mice that have been reported to be sensitive to asbestos. Our results point out the possibility that carbon-made fibrous or rod-shaped micrometer particles may share the carcinogenic mechanisms postulated for asbestos. To maintain sound activity of industrialization of nanomaterials, it would be prudent to implement strategies to keep good control of exposure to fibrous or rod-shaped carbon materials both in the workplace and in the future market until the biological/ carcinogenic properties, especially of their long-term biodurability, are fully assessed.

著者

Takagi Atsuya Hirose Akihiko Nishimura Tetsuji Fukumori Nobutaka Ogata Akio Ohashi Norio Kitajima Satoshi Kanno Jun

出版者

日本毒性学会

雑誌

Journal of toxicological sciences (ISSN:03881350)

巻号頁・発行日

vol.33, no.1, pp.105-116, 2008-02-15

参考文献数

21

被引用文献数

35 655

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Nanomaterials of carbon origin tend to form various shapes of particles in micrometer dimensions. Among them, multi-wall carbon nanotubes (MWCNT) form fibrous or rod-shaped particles of length around 10 to 20 micrometers with an aspect ratio of more than three. Fibrous particles of this dimension including asbestos and some man-made fibers are reported to be carcinogenic, typically inducing mesothelioma. Here we report that MWCNT induces mesothelioma along with a positive control, crocidolite (blue asbestos), when administered intraperitoneally to p53 heterozygous mice that have been reported to be sensitive to asbestos. Our results point out the possibility that carbon-made fibrous or rod-shaped micrometer particles may share the carcinogenic mechanisms postulated for asbestos. To maintain sound activity of industrialization of nanomaterials, it would be prudent to implement strategies to keep good control of exposure to fibrous or rod-shaped carbon materials both in the workplace and in the future market until the biological/carcinogenic properties, especially of their long-term biodurability, are fully assessed.

著者

Jun SATO Yasuhito YAMAMOTO Tsuneaki NAKAMURA Shigeru ISHIDA Yutaka TAKAGI

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.30, no.4, pp.339-347, 2005 (Released:2006-01-11)

参考文献数

14

被引用文献数

3 3

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We evaluated the toxicity of tetradecanoic acid methyl ester sodium salt (C14-MES), a major component of fabric detergents, following the test guidelines of the Organization for Economic Cooperation and Development. The rat acute oral LD50 was 1,000 mg/kg in males and 500 mg/kg in females. Applying the combined repeated dose and reproductive/developmental toxicity screening test (ReproTox), we exposed groups of Crj:CD (SD) IGS rats to C14-MES in the diet at concentrations of 0, 0.3, 0.6, or 1.2%. We observed decreases in fibrinogen levels and longer prothrombin time at the 1.2% treated level in females and decreases in serum triglyceride levels in both sexes at the 0.6% and 1.2% treatment levels, but the effects were not clinically significant. The no-observed-effect-level (NOEL) for repeated dose toxicity was 0.3% (175 mg/kg body weight/day for males, 249 for females). The NOEL for reproduction/developmental toxicity was 1.2% (740 mg/kg for males, 1039 for females). C14-MES was negative in the reverse gene mutation assay and the chromosomal aberration test and did not induce skin sensitization in the guinea pig maximization test. These data confirm that C14-MES is of low hazard potential.