{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:39:19Z","timestamp":1787510359450,"version":"build-2736575974"},"reference-count":18,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T00:00:00Z","timestamp":1734307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cDevelopment of Innovative Methodology for Safety Assessment of Industrial Nanomaterials\u201d from the Ministry of Economy, Trade, and Industry (METI) of Japan"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>The purpose of the present study is to contribute to the establishment of a standard method for evaluating the adverse effects of nanomaterials by intratracheal administration. Low and high doses of multi-walled carbon nanotubes (MWCNTs) were administered to rats in a single administration or the same final dose as the single administration but divided over four administrations. Bronchoalveolar lavage examination on day 14 showed an inflammatory reaction and cytotoxicity in the lung, generally greater at the higher dose, and tending to be greater in the rats with four administrations at both the low and high doses. Histopathologic findings showed increased alveolar macrophages and MWCNT deposition (fibers phagocytosed by alveolar macrophages and fibers that were not phagocytosed) in the alveolar space, granulomatous changes, and MWCNT deposition in bronchus-associated lymphoid tissue (BALT) and lung-related lymph nodes on days 14, 28, and 91. In addition, alveolar type II epithelial hyperplasia was observed on day 91, and fibrosis of the alveolar wall was observed on days 28 and 91. Fewer alveolar macrophages with phagocytosed MWCNTs were present at day 91 compared to day 28. MWCNT deposition tended to be higher in the BALT after a single administration, whereas deposition was higher in the lung-related lymph nodes after four administrations. MWCNTs were considered to be transported from the lungs or BALT to the lymph nodes over time. There were no significant differences in MWCNT deposition in the lung after the single administration compared with four administrations at either the low or high doses, and the histopathological findings were similar after single and four administrations, at both the low and high doses. Based on the above findings, a toxicity evaluation of the nanomaterials can be sufficiently performed by intratracheal administration, even with a single intratracheal administration.<\/jats:p>","DOI":"10.3390\/nano14242019","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T06:48:39Z","timestamp":1734331719000},"page":"2019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Comparison of Single and Multiple Intratracheal Administrations for Pulmonary Toxic Responses of Multi-Walled Carbon Nanotubes in Rats"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2825-4582","authenticated-orcid":false,"given":"Hideki","family":"Senoh","sequence":"first","affiliation":[{"name":"National Institute of Occupational Safety and Health, Japan Organization of Occupational Health and Safety, Fujisawa 251-8555, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Suzuki","sequence":"additional","affiliation":[{"name":"National Institute of Occupational Safety and Health, Japan Organization of Occupational Health and Safety, Fujisawa 251-8555, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirokazu","family":"Kano","sequence":"additional","affiliation":[{"name":"National Institute of Occupational Safety and Health, Japan Organization of Occupational Health and Safety, Kawasaki 214-8585, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Kasai","sequence":"additional","affiliation":[{"name":"National Institute of Occupational Safety and Health, Japan Organization of Occupational Health and Safety, Kawasaki 214-8585, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoji","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Former Japan Bioassay Research Center, Hadano 257-0015, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"413","DOI":"10.3109\/17435390.2014.933903","article-title":"Thirteen-week study of toxicity of fiber-like multi-walled carbon nanotubes with whole-body inhalation exposure in rats","volume":"9","author":"Kasai","year":"2015","journal-title":"Nanotoxicol"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1743-8977-10-38","article-title":"Extrapulmonary transport of MWCNT following inhalation exposure","volume":"10","author":"Mercer","year":"2013","journal-title":"Part. Fibre Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.taap.2019.05.001","article-title":"Pulmonary toxicity of two different multi-walled carbon nanotubes in rat: Comparison between intratracheal instillation and inhalation exposure","volume":"375","author":"Knudsen","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1539\/joh.16-0184-OA","article-title":"Comparison of single or multiple intratracheal administration for pulmonary toxic responses of nickel oxide nanoparticles in rats","volume":"59","author":"Senoh","year":"2017","journal-title":"J. Occup. Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1293\/tox.2014-0022","article-title":"Intratracheal instillation methods and the distribution of administered material in the lung of the rat","volume":"27","author":"Kubota","year":"2014","journal-title":"J. Toxicol. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"607","DOI":"10.3109\/17435390.2015.1104740","article-title":"Comparison of pulmonary inflammatory responses following intratracheal instillation and inhalation of nanoparticles","volume":"10","author":"Morimoto","year":"2016","journal-title":"Nanotoxicol"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1006\/faat.1997.2390","article-title":"Intratracheal inhalation vs intratracheal instillation: Differences in particle effects","volume":"40","author":"Osier","year":"1997","journal-title":"Fundam. Appl. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Tsuda, H., and Alexander, D.B. (2019). Development of Intratracheal Intrapulmonary Spraying (TIPS) administration as a feasible assay method for testing the toxicity and carcinogenic potential of multiwall carbon nanotubes. Vivo Inhalation Toxicity Screening Methods for Manufactured Nanomaterials, Springer.","DOI":"10.1007\/978-981-13-8433-2_8"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"i43","DOI":"10.1093\/annweh\/wxac087.105","article-title":"14 Carcinogenicity Risk Assessment of Various Carbon Nanotubes by Intra-Tracheal Intra-Pulmonary Spray (TIPS) Dosing Followed by 2-Year Observation","volume":"67","author":"Tsuda","year":"2023","journal-title":"Ann. Work Expo. Health"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1743-8977-8-21","article-title":"Pulmonary fibrotic response to aspiration of multi-walled carbon nanotubes","volume":"8","author":"Mercer","year":"2011","journal-title":"Part. Fibre Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s12989-020-00382-y","article-title":"Comparative carcinogenicity study of a thick, straight-type and a thin, tangled-type multi-walled carbon nanotube administered by intra-tracheal instillation in the rat","volume":"17","author":"Saleh","year":"2020","journal-title":"Part. Fibre Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1111\/cas.12954","article-title":"Multiwalled carbon nanotubes intratracheally instilled into the rat lung induce development of pleural malignant mesothelioma and lung tumors","volume":"107","author":"Suzui","year":"2016","journal-title":"Cancer Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kobayashi, T., Oshima, Y., Tsubokura, Y., Kayashima, T., Nakai, M., and Imatanaka, N. (2019). Standardization of intratracheal instillation study of manufactured nanomaterials. Vivo Inhalation Toxicity Screening Methods for Manufactured Nanomaterials, Springer.","DOI":"10.1007\/978-981-13-8433-2_6"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1111\/cas.14121","article-title":"MWCNT-7 administered to the lung by intratracheal instillation induces development of pleural mesothelioma in F344 rats","volume":"110","author":"Numano","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.tox.2010.07.021","article-title":"Biological response and morphological assessment of individually dispersed multi-wall carbon nanotubes in the lung after intratracheal instillation in rats","volume":"276","author":"Kobayashi","year":"2010","journal-title":"Toxicology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s12989-022-00478-7","article-title":"Two-year intermittent exposure of a multiwalled carbon nanotube by intratracheal instillation induces lung tumors and pleural mesotheliomas in F344 rats","volume":"19","author":"Hojo","year":"2022","journal-title":"Part. Fibre Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kasai, T., and Fukushima, S. (2023). Exposure of Rats to Multi-Walled Carbon Nanotubes: Correlation of Inhalation Exposure to Lung Burden, Bronchoalveolar Lavage Fluid Findings, and Lung Morphology. Nanomaterials, 13.","DOI":"10.3390\/nano13182598"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1111\/j.1749-6632.1972.tb40177.x","article-title":"Lymphatic drainage of the lung in dust clearance","volume":"200","author":"Morrow","year":"1972","journal-title":"Ann. N. Y. Acad. Sci."}],"container-title":["Nanomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4991\/14\/24\/2019\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:53:04Z","timestamp":1760115184000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4991\/14\/24\/2019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,16]]},"references-count":18,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["nano14242019"],"URL":"https:\/\/doi.org\/10.3390\/nano14242019","relation":{},"ISSN":["2079-4991"],"issn-type":[{"value":"2079-4991","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,16]]}}}