{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:37:28Z","timestamp":1790095048848,"version":"4.0.1"},"reference-count":18,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"vor","delay-in-days":41,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,7]]},"abstract":"Abstract<\/jats:title>\n \n Objectives<\/jats:title>\n Our aim was to report integrative evidence for the health risk assessment of ortho-toluidine (OT) in bladder cancer in a mini-review of the recent studies of humans, experimental animals, and OT skin permeability.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n Bladder cancer cases were identified in workers in Japan who were occupationally exposed in 2014-2017 to aromatic amines, primarily to the human carcinogen OT.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n A key epidemiological study of 98 aromatic amine\u2013exposed workers in Japan showed a clear OT exposure\u2013response relationship with a standardized incidence ratio. A rat model experimental study also indicated that OT and acetoaceto-o-toluidine are potent bladder carcinogens. Multiple mechanisms of OT-related bladder cancer have been proposed: metabolic activation to reactive metabolites that bind DNA and proteins, mutagenicity, oxidative DNA damage, chromosomal damage, and cytotoxicity by OT. Recent comprehensive analyses of DNA adducts in rats identified a number of common oxidative DNA adducts, including 8-OHdG, in the rat urothelium and indicated that oxidative stress may play a crucial role in the development of urinary cancer caused by OT. The skin permeability of 6 aromatic amines (o-toluidine, aniline, p-toluidine, o-anisidine, 2,4-dimethylaniline, and o-chloroaniline) was examined with the use of a 3-dimensional (3D) reconstructed human skin model; ~70%-80% of the 6 aromatic amines had permeated through the 3D skin within 8\u00a0hours. Genotoxic potency testing in a human urothelial cell line using \u03b3-H2AX, a marker of DNA damage, suggested that OT exhibited strong \u03b3-H2AX generation.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Prolonged dermal exposure to OT along with other genotoxic aromatic amines over many years may contribute to the development of bladder cancer.<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/joccuh\/uiaf005","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T06:48:46Z","timestamp":1739256526000},"source":"Crossref","is-referenced-by-count":4,"title":["Epidemiological and toxicological risk assessments of ortho<\/i>-toluidine for bladder cancer"],"prefix":"10.1093","volume":"67","author":[{"given":"Makiko","family":"Nakano","sequence":"first","affiliation":[{"name":"Division of Epidemiological Research for Chemical Disorders, Research Center for Chemical Information and Management, National Institute of Occupational Safety and Health , Kawasaki ,","place":["Japan"]},{"name":"Department of Preventive Medicine and Public Health, Keio University School of Medicine , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Gi","sequence":"additional","affiliation":[{"name":"Department of Environmental Risk Assessment, Osaka Metropolitan University Graduate School of Medicine , Osaka ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsushi","family":"Toyooka","sequence":"additional","affiliation":[{"name":"Toxicological Test Methodology Development Group, National Institute of Occupational Safety and Health , Fujisawa ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shugo","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Osaka Metropolitan University Graduate School of Medicine , Osaka ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Wanibuchi","sequence":"additional","affiliation":[{"name":"Department of Environmental Risk Assessment, Osaka Metropolitan University Graduate School of Medicine , Osaka ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8268-8026","authenticated-orcid":false,"given":"Toru","family":"Takebayashi","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine and Public Health, Keio University School of Medicine , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,2,11]]},"reference":[{"key":"2025050420113495600_ref1","article-title":"Chemical agents and related occupations","author":"IARC"},{"issue":"4 Spec","key":"2025050420113495600_ref2","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1539\/joh.16-0155-OP","article-title":"Occupational exposure limits of lead, dimethylamine, n-butyl-2,3-epoxypropyl ether, and 2-ethyl-1-hexanol and carcinogenicity and occupational sensitizer classification","volume":"58","author":"Committee for Recommendation of Occupational Exposure Limits, Japan Society for Occupational Health","year":"2016","journal-title":"J Occup Health"},{"key":"2025050420113495600_ref3","article-title":"Report on the disaster investigation: A-2015-07. 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