2024/12/24 更新

写真a

オノ アツシ
小野 敦
ONO Atsushi
所属
医歯薬学域 教授
職名
教授
外部リンク

学位

  • 薬学博士 ( 2000年7月   昭和大学 )

研究キーワード

  • 構造活性相関

  • トランスクリプトーム

  • Toxicogenimics

  • 情報毒性学

  • 皮膚感作性

  • 内分泌かく乱物質

研究分野

  • ライフサイエンス / 薬系衛生、生物化学  / 毒性学

学歴

  • 北海道大学    

    1990年 - 1992年

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    国名: 日本国

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  • 北海道大学   Faculty of Pharmaceutical Sciences  

    1987年 - 1990年

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経歴

  • 岡山大学   教授

    2016年8月 - 現在

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    国名:日本国

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  • 厚生労働省 国立医薬品食品衛生研究所

    1993年 - 2016年

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所属学協会

  • 日本中毒学会

    2022年1月 - 現在

  • 日本毒性学会

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  • 日本薬物動態学会

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  • 日本薬学会

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  • 日本動物実験代替法学会

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委員歴

  • 厚生労働省   薬事・食品衛生審議会専門委員  

    2021年1月 - 現在   

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    団体区分:政府

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  • 内閣府   食品安全委員会専門委員  

    2020年4月 - 現在   

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    団体区分:政府

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  • OECD   Advisory Group on Endocrine Disrupters Testing and Assessment  

    2020年3月 - 現在   

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    団体区分:政府

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  • 厚生労働省   労働安全衛生法GLP専門家  

    2020年2月 - 現在   

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    団体区分:政府

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  • OECD   Residue Definition Working Group  

    2019年4月 - 現在   

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    団体区分:政府

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論文

  • Borderline Range Determined Using Data From Validation Study of Alternative Methods for Skin Sensitization: ADRA, IL-8 Luc Assay, and EpiSensA. 国際誌

    Toshihiko Kasahara, Yusuke Yamamoto, Natsumi Nakashima, Mika Imamura, Hideyuki Mizumachi, Sho Suzuki, Setsuya Aiba, Yutaka Kimura, Takao Ashikaga, Hajime Kojima, Atsushi Ono, Kazuhiko Matsumoto

    Journal of applied toxicology : JAT   2024年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Most predictive models that use alternatives to animal experiments divide judgements into two classes with a cutoff value for each model. However, if the results of alternative methods are close to the cutoff values, the true result may be ambiguous because of variability in the data. Therefore, the OECD GL497 uses a judgement method that establishes a borderline range (BR) around a cutoff value using a statistical method. However, because there is no detailed description of how the BR is calculated, we clarified two specific points. The scale-constant correction method was used to calculate the median absolute deviation (MAD) around the median. In addition, the bottom-raised transformation method was used when the data were "0" because calculation of the BR requires that all data are logarithmic. Indeed, the BRs for the amino acid derivative reactivity assay (ADRA), interleukin-8 reporter gene assay (IL-8 Luc), and epidermal sensitization assay (EpiSensA) were calculated using data from each validation study. The results showed that the BR for ADRA and IL-8 Luc ranged from 4.1 to 5.9 and 1.25 to 1.57, respectively. Furthermore, the BRs of four genes (ATF3, GCLM, DNAJB4, and IL-8) evaluated using EpiSensA ranged from 10.71 to 21.02, 1.64 to 2.45, 1.61 to 2.52, and 3.11 to 5.16, respectively. The difference (deviation) between the lower and upper BR limits and cutoff value for each alternative method were comparable to those of the alternative methods listed in the guidelines (DPRA, KerarinoSens, and h-CLAT) and thus were considered as adequate.

    DOI: 10.1002/jat.4712

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  • Assessment of commercial polymers with and without reactive groups using amino acid derivative reactivity assay based on both molar concentration approach and gravimetric approach. 国際誌

    Masaharu Fujita, Natsumi Nakashima, Sayaka Wanibuchi, Yusuke Yamamoto, Hajime Kojima, Atsushi Ono, Toshihiko Kasahara

    Journal of applied toxicology : JAT   43 ( 3 )   446 - 457   2023年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The amino acid derivative reactivity assay (ADRA), an alternative method for testing skin sensitization, has been established based on the molar concentration approach. However, the additional development of gravimetric concentration and fluorescence detection methods has expanded its range of application to mixtures, which cannot be evaluated using the conventional testing method, the direct peptide reactivity assay (DPRA). Although polymers are generally treated as mixtures, there have been no reports of actual polymer evaluations using alternative methods owing to their insolubility. Therefore, in this study, we evaluated skin sensitization potential of polymers, which is difficult to predict, using ADRA. As polymers have molecular weights ranging from several thousand to more than several tens of thousand Daltons, they are unlikely to cause skin sensitization due to their extremely low penetration into the skin, according to the 500-Da rule. However, if highly reactive functional groups remain at the ends or side chains of polymers, relatively low-molecular-weight polymer components may penetrate the skin to cause sensitization. Polymers can be roughly classified into three major types based on the features of their constituent monomers; we investigated the sensitization capacity of each type of polymer. Polymers with alert sensitization structures at their ends were classified as skin sensitizers, whereas those with no residual reactive groups were classified as nonsensitizers. Although polymers with a glycidyl group need to be evaluated carefully, we concluded that ADRA (0.5 mg/ml) is generally sufficient for polymer hazard assessment.

    DOI: 10.1002/jat.4395

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  • Structural characterization of 1,3-bis-tert-butyl monocyclic benzene derivatives with agonistic activity towards retinoid X receptor alpha. 国際誌

    Susumu Kodama, Shuzo Matsumoto, Yuta Takamura, Michiko Fujihara, Masaki Watanabe, Atsushi Ono, Hiroki Kakuta

    Toxicology letters   373   76 - 83   2023年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Retinoid X receptor alpha (RXRα) plays pivotal roles in multiple biological processes, but limited information is available on the structural features of chemicals that show low affinity for RXRα, but nevertheless cause significant activation, though these may represent a human health hazard. We recently discovered that several industrial chemicals having 1,3-bis-tert-butylbenzene as a common chemical structure exhibit agonistic activity towards rat RXRα. In this study, we explored the structure-activity relationship of 1,3-bis-tert-butyl monocyclic benzene derivatives for RXRα activation by means of in vitro and in silico analyses. The results indicate that a bulky substituent at the 5-position is favorable for agonistic activity towards human RXRα. Since 1,3-bis-tert-butyl monocyclic benzene derivatives with bulky hydrophobic moieties differ structurally from known RXRα ligands such as 9-cis-retinoic acid and bexarotene, our findings may be helpful for the development of structural alerts in the safety evaluation of industrial chemicals for RXRα-based toxicity to living organisms.

    DOI: 10.1016/j.toxlet.2022.11.003

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  • Applicability of amino acid derivative reactivity assay (4 mM) for the prediction of skin sensitization by combining multiple alternative methods to evaluate key events 国際誌

    Mika Imamura, Yusuke Yamamoto, Masaharu Fujita, Sayaka Wanibuchi, Natsumi Nakashima, Hajime Kojima, Atsushi Ono, Toshihiko Kasahara

    Journal of Applied Toxicology   42 ( 7 )   1159 - 1167   2022年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    The amino acid derivative reactivity assay (ADRA) is an alternative method for evaluating key event 1 (KE-1) in the skin sensitization mechanism included in OECD TG442C (OECD, 2021). Recently, we found that ADRA with a 4-mM test chemical solution had a higher accuracy than the original ADRA (1 mM). However, ADRA (4 mM) has yet to be evaluated using integrated approaches to testing and assessment (IATA), a combination of alternative methods for evaluating KE. In this study, the sensitization potency of three defined approaches (DAs) using ADRA (4 mM) as KE-1 was predicted and compared with those of two additional ADRAs or direct peptide reactivity assay (DPRA): (i) "2 out of 3" approach, (ii) "3 out of 3" approach, and (iii) integrated testing strategy (ITS). In the hazard identification of chemical sensitizers, the accuracy of human data and local lymph node assay (LLNA) remained almost unchanged among the three approaches evaluated. Potency classifications for sensitization were predicted with the LLNA and human data sets using ITS. The potency classifications for the sensitization potency prediction accuracy of LLNA data using any alternative method were almost unchanged, at approximately 70%, and those with ITS were not significantly different. When ITS was performed using DPRA, the prediction accuracy was approximately 73% for human data, which was similar to that of the LLNA data; however, the accuracy tended to increase for all ADRA methods. In particular, when ITS was performed using ADRA (4 mM), the prediction accuracy was approximately 78%, which proved to be a practical level.

    DOI: 10.1002/jat.4283

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jat.4283

  • Within‐ and between‐laboratory reproducibility and predictive capacity of amino acid derivative reactivity assay (ADRA) using a 0.5 mg/mL test chemical solution: Results of the study for reproducibility confirmation implemented in five participating laboratories 査読 国際誌

    Yusuke Yamamoto, Masaharu Fujita, Shinichi Watanabe, Hiroaki Yamaga, Koji Wakabayashi, Yu Tahara, Nobuyuki Horie, Keiichi Fujimoto, Kazuya Takeuchi, Kohei Kamiya, Tsuyoshi Kawakami, Kohichi Kojima, Takashi Sozu, Hajime Kojima, Toshihiko Kasahara, Atsushi Ono

    Journal of Applied Toxicology   42 ( 6 )   1078 - 1090   2022年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    The amino acid derivative reactivity assay (ADRA) is an in chemico alternative assay for skin sensitization listed in OECD test guideline 442C. ADRA evaluates the reactivity of sensitizers to proteins, which is key event 1 in the skin sensitization adverse outcome pathway. Although the current key event 1 evaluation method is a simple assay that evaluates nucleophile and test chemical reactivity, mixtures of unknown molecular weights cannot be evaluated because a constant molar ratio between the nucleophile and test chemical is necessary. In addition, because the nucleophile is quantified by HPLC, the frequency of co-eluting the test chemical and nucleophile increases when measuring multi-component mixtures. To solve these issues, test conditions have been developed using a 0.5 mg/mL test chemical solution and fluorescence-based detection. Since the practicality of these methods has not been substantiated, a validation test to confirm reproducibility was conducted in this study. The 10 proficiency substances listed in the ADRA guidelines were tested three times at five different laboratories. The results of both within- and between-laboratory reproducibility were 100%, and the results of ultraviolet- and fluorescence-based measurements were also consistent. In addition to the proficiency substances, a new positive control, squaric acid diethyl ester, was tested three times at the five laboratories. The results showed high reproducibility with N-(2-(1-naphthyl)acetyl)-l-cysteine depletion of 37%-52% and α-N-(2-(1-naphthyl)acetyl)-l-lysine depletion of 99%-100%. Thus, high reproducibility was confirmed in both evaluations of the 0.5 mg/mL test chemical and the fluorescence-based measurements, validating the practicability of these methods.

    DOI: 10.1002/jat.4279

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jat.4279

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書籍等出版物

MISC

  • Initial hazard assessment of benzyl salicylate: In vitro genotoxicity test and combined repeated-dose and reproductive/developmental toxicity screening test in rats

    Igarashi, T., Takashima, H., Takabe, M., Suzuki, H., Ushida, K., Kawamura, T., Matsumoto, M., Iso, T., Tanabe, S., Inoue, K., Ono, A., Yamada, T., Hirose, A.

    Regulatory Toxicology and Pharmacology   100   105 - 117   2018年12月

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    出版者・発行元:Elsevier BV  

    © 2018 Elsevier Inc. Benzyl salicylate is used as a fragrance ingredient and an ultraviolet light absorber, but its toxicity is unknown. Therefore, toxicity tests and hazard classification were conducted for screening assessment under the Japanese Chemical Substances Control Law. Benzyl salicylate was found to be non-genotoxic in vitro based on the chromosomal aberration test using Chinese hamster lung cells. However, the combined repeated-dose and reproductive/developmental screening toxicity test, in which male and female rats were administered benzyl salicylate by gavage at 0, 30, 100, or 300 mg/kg/day for 42 and 41–46 days, respectively, from 14 days before mating until postnatal Day 4, showed that repeated doses had major effects on the thymus, liver, epididymis, and femur at 100 and/or 300 mg/kg/day. Furthermore, although benzyl salicylate had no effect on the estrus cycle, fertility, corpus lutea, or implantation rate, embryonic resorption, offspring mortality, and neural tube defects were observed at 300 mg/kg/day, and the offspring had lower body weights at 30 and 100 mg/kg/day, suggesting teratogenicity similar to other salicylates. Based on the developmental toxicity, this chemical was classified as hazard class 2, with a lowest observed adverse effect level (LOAEL) of 30 mg/kg/day and a D-value of 0.003 mg/kg/day.

    DOI: 10.1016/j.yrtph.2018.10.018

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  • サリチル酸ベンジルの遺伝毒性、反復投与毒性及び生殖発生毒性のスクリーニング

    五十嵐智女, 髙部道仁, 髙島宏昌, 鈴木洋, 牛田和夫, 松本真理子, 磯貴子, 川村智子, 井上薫, 小野敦, 山田隆志, 広瀬明彦

    Journal of Toxicological Sciences   43 ( Supplement )   P-110   2018年

  • Japan Flavour and Fragrance Materials Association’s (JFFMA) safety assessment of food-flavouring substances uniquely used in Japan that belong to the class of aliphatic primary alcohols, aldehydes, carboxylic acids, acetals and esters containing additiona

    Kenji Saito, Yasuko Hasegawa-Baba, Fumiko Sekiya, Shim mo Hayashi, Yoshiharu Mirokuji, Hiroyuki Okamura, Shinpei Maruyama, Atsushi Ono, Madoka Nakajima, Masakuni Degawa, Shogo Ozawa, Makoto Shibutani, Tamio Maitani

    Food Additives and Contaminants - Part A Chemistry, Analysis, Control, Exposure and Risk Assessment   34 ( 9 )   1474 - 1484   2017年

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    記述言語:英語  

    © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. We performed a safety evaluation using the procedure devised by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) of the following four flavouring substances that belong to the class of ‘aliphatic primary alcohols, aldehydes, carboxylic acids, acetals, and esters containing additional oxygenated functional groups’ and are uniquely used in Japan: butyl butyrylacetate, ethyl 2-hydroxy-4-methylpentanoate, 3-hydroxyhexanoic acid and methyl hydroxyacetate. Although no genotoxicity study data were found in the published literature, none of the four substances had chemical structural alerts predicting genotoxicity. All four substances were categorised as class I by using Cramer’s classification. The estimated daily intake of each of the four substances was determined to be 0.007–2.9 μg/person/day by using the maximised survey-derived intake method and based on the annual production data in Japan in 2001, 2005 and 2010, and was determined to be 0.250–600.0 μg/person/day by using the single-portion exposure technique and based on average-use levels in standard portion sizes of flavoured foods. Both of these estimated daily intake ranges were below the threshold of toxicological concern for class I substances, which is 1800 μg/person/day. Although no information from in vitro and in vivo toxicity studies for the four substances was available, these substances were judged to raise no safety concerns at the current levels of intake.

    DOI: 10.1080/19440049.2017.1333160

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  • Risk assessment of skin lightening cosmetics containing hydroquinone

    Mariko Matsumoto, Hiroaki Todo, Takumi Akiyama, Mutsuko Hirata-Koizumi, Kenji Sugibayashi, Yoshiaki Ikarashi, Atsushi Ono, Akihiko Hirose, Kazuhito Yokoyama

    REGULATORY TOXICOLOGY AND PHARMACOLOGY   81   128 - 135   2016年11月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Following reports on potential risks of hydroquinone (HQ), HQ for skin lightening has been banned or restricted in Europe and the US. In contrast, HQ is not listed as a prohibited or limited ingredient for cosmetic use in Japan, and many HQ cosmetics are sold without restriction. To assess the risk of systemic effects of HQ we examined the rat skin permeation rates of four HQ (0.3%, 1.0%, 2.6%, and 33%) cosmetics. The permeation coefficients ranged from 1.2 x 10(-9) to 3.1 x 10(-7) cm/s, with the highest value superior than the HQ aqueous solution (1.6 x 10(-7) cm/s). After dermal application of the HQ cosmetics to rats, HQ in plasma was detected only in the treatment by highest coefficient cosmetic. Absorbed HQ levels treated with this highest coefficient cosmetic in humans were estimated by numerical methods, and we calculated the margin of exposure (MOE) for the estimated dose (0.017 mg/kg-bw/day in proper use) to a benchmark dose for rat renal tubule adenomas. The MOE of 559 is judged to be in a range safe for the consumer. However, further consideration may be required for regulation of cosmetic ingredients. (C) 2016 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.yrtph.2016.08.005

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  • Transcriptome analyses demonstrate that peroxisome proliferator-activated receptor α (PPARα) activity of an ultraviolet absorber, 2-(2’-hydroxy-3’,5’-di-tert-butylphenyl) benzotriazole, as possible mechanism of their toxicity and the gender differences

    Mutsuko Hirata-Koizumi, Ryota Ise, Hirohito Kato, Takashi Matsuyama, Tomoko Nishimaki-Mogami, Mika Takahashi, Atsushi Ono, Makoto Ema, Akihiko Hirose

    Journal of Toxicological Sciences   41 ( 5 )   693 - 700   2016年10月

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    記述言語:英語  

    © 2016, Japanese Society of Toxicology. All rights reserved. 2-(2′-Hydroxy-3′,5′-di-tert-butylphenyl)benzotriazole (HDBB), the Benzotriazole UV-stabilizer (BUVSs) known as UV-320, is widely used in plastic materials for protection against UV-ir-radiation. Previously, we reported that oral ingestion of HDBB induce hepatotoxicity including hepatocyte hypertrophy and necrosis in rats and, males was more susceptible compared with females in young rats while no sex-related difference was observed in preweaning rats. Phenotypes observed in our previous study imply involvement of peroxisome proliferator-activated receptor (PPAR) α in HDBB hepatotoxicity, however, direct evidence that HDBB can activate PPARα has not been provided and the mechanism which underlying the gender difference of HDBB hepatotoxicity was not clearly elucidated. Here, we conduct transcriptome analysis using microarray expression profiles in the livers of rats administered HDBB. PPARα agonist activity of HDBB was elucidated by comparison with gene expression data of typical PPARα agonist, i.e. clofibrate, WY-14643, gemfibrozil, and fenofibrate, from TG GATEs database. Moreover, we analyzed for PPARα mRNA expression in the liver of developing male and female rats. PPARα mRNA expression level was higher in males than in females on postnatal days (PNDs) 28 and 35, whereas no sex-related difference was found on PNDs 7 and 22. These results suggest that HDBB exerts its hepatotoxicity through the PPARα signal pathway and the sex-related difference in PPARα expression may contribute to the sex-related difference in susceptibility to hepatotoxicity.

    DOI: 10.2131/jts.41.693

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受賞

  • ファイザー賞

    2024年7月   日本毒性学会  

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  • 学会賞

    2020年11月   日本実験動物代替法学会  

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  • 田邊賞

    2020年6月   日本毒性学会  

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共同研究・競争的資金等の研究

  • 内分泌かく乱in vitroスクリーニング

    厚生労働科学研究費補助金 

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    資金種別:競争的資金

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  • 構造活性相関

    厚生労働科学研究費補助金 

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    資金種別:競争的資金

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  • トキシコゲノミクス

    厚生労働科学研究費補助金 

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    資金種別:競争的資金

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  • -

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    資金種別:競争的資金

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担当授業科目

  • 化学物質って危ないの? (2024年度) 第3学期  - 火3~4

  • 毒性学 (2024年度) 特別  - その他

  • 毒性学 (2024年度) 特別  - その他

  • 毒性学実習 (2024年度) 特別  - その他

  • 毒性学演習 (2024年度) 特別  - その他

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