{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T03:57:51Z","timestamp":1780459071213,"version":"3.54.1"},"reference-count":46,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100010253","name":"Secretar\u00eda de Ciencia y T\u00e9cnica, Universidad de Buenos Aires","doi-asserted-by":"publisher","award":["20020170100017"],"award-info":[{"award-number":["20020170100017"]}],"id":[{"id":"10.13039\/501100010253","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006668","name":"Fondo para la Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["PICT\\u20132020\\u201302532"],"award-info":[{"award-number":["PICT\\u20132020\\u201302532"]}],"id":[{"id":"10.13039\/501100006668","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006668","name":"Fondo para la Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["PICT 2018\\u20133831"],"award-info":[{"award-number":["PICT 2018\\u20133831"]}],"id":[{"id":"10.13039\/501100006668","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005363","name":"Universidad de Buenos Aires","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005363","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007351","name":"University of Buenos Aires Secretariat of Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007351","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"publisher","award":["PIP 2021 \\u2013 11220200102369CO"],"award-info":[{"award-number":["PIP 2021 \\u2013 11220200102369CO"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021778","name":"Agencia Nacional De Promocion Cientifica Y Tecnologica","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021778","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Toxicology in Vitro"],"published-print":{"date-parts":[[2025,12]]},"DOI":"10.1016\/j.tiv.2025.106123","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T15:41:39Z","timestamp":1753803699000},"page":"106123","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":2,"special_numbering":"C","title":["Employing histopathology to enhance the BCOP test: The emerging role of stromal thickness as a quantitative endpoint"],"prefix":"10.1016","volume":"109","author":[{"given":"Mart\u00edn Nicol\u00e1s","family":"Rivero","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariela","family":"Lenze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina Daniela","family":"Benedetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mora Ren\u00e9e","family":"Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Wikinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Laura","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.tiv.2025.106123_bb0005","article-title":"Corneal histomorphometric analysis: the depth of damage induced in the bovine cornea correlates with the severity of the ocular toxicity","volume":"61","author":"Andrade","year":"2019","journal-title":"Toxicol. In Vitro\u00a0Int. J. Publ. Assoc. BIBRA"},{"key":"10.1016\/j.tiv.2025.106123_bb0010","doi-asserted-by":"crossref","DOI":"10.1016\/j.tiv.2020.104851","article-title":"Innovative strategy based on mechanisms to substitute animal testing for ocular toxicity assessment of agrochemical formulations market in Brazil","volume":"66","author":"Andrade","year":"2020","journal-title":"Toxicol. in Vitro"},{"key":"10.1016\/j.tiv.2025.106123_bb0015","author":"Barroso","year":"2016"},{"issue":"1","key":"10.1016\/j.tiv.2025.106123_bb0020","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/0014-4835(91)90123-V","article-title":"Characterization of the major matrix degrading metalloproteinase of human corneal stroma. Evidence for an enzyme\/inhibitor complex","volume":"52","author":"Brown","year":"1991","journal-title":"Exp. Eye Res."},{"key":"10.1016\/j.tiv.2025.106123_bb0025","article-title":"Human-relevant approaches to assess eye corrosion\/irritation potential of agrochemical formulations","volume":"1\u201323","author":"Clippinger","year":"2021","journal-title":"Cutan. Ocul. Toxicol."},{"key":"10.1016\/j.tiv.2025.106123_bb0030","series-title":"DB-ALM Protocol n \u00b0 127: Bovine Corneal Opacity and Permeability (BCOP) (Issue 437)","author":"ECVAM","year":"2009"},{"issue":"7","key":"10.1016\/j.tiv.2025.106123_bb0035","first-page":"609","article-title":"Chemical injury to the eye from trichloroacetic acid","volume":"28","author":"Fung","year":"2002","journal-title":"Dermatol. Surg."},{"issue":"July","key":"10.1016\/j.tiv.2025.106123_bb0040","first-page":"19","article-title":"Toxicology in vitro suggestion of the updated IVIS cut-o ff values for identifying non-ocular irritants in the bovine corneal opacity and permeability (BCOP) assay","volume":"45","author":"Furukawa","year":"2017"},{"issue":"3","key":"10.1016\/j.tiv.2025.106123_bb0045","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/0272-0590(92)90142-5","article-title":"Bovine corneal opacity and permeability test: an in vitro assay of ocular irritancy","volume":"18","author":"Gautheron","year":"1992","journal-title":"Fundamental Appl. Toxicol."},{"issue":"3","key":"10.1016\/j.tiv.2025.106123_bb0050","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/0887-2333(94)90159-7","article-title":"Interlaboratory assessment of the bovine corneal opacity and permeability (BCOP) assay","volume":"8","author":"Gautheron","year":"1994","journal-title":"Toxicol. in Vitro"},{"key":"10.1016\/j.tiv.2025.106123_bb0055","doi-asserted-by":"crossref","unstructured":"Girard, M. T., Matsubara, M., Kublin, C., Tessier, M. J., Cintron, C., & Fini, M. E. (1993). Stromal fibroblasts synthesize collagenase and stromelysin during long-term tissue remodeling. J. Cell Sci., 104 (Pt 4, 1001\u20131011.","DOI":"10.1242\/jcs.104.4.1001"},{"issue":"6","key":"10.1016\/j.tiv.2025.106123_bb0060","article-title":"Ocular dominance and its association with central corneal thickness: an observational study in Central India","volume":"15","author":"Gundreddy","year":"2023","journal-title":"Cureus"},{"key":"10.1016\/j.tiv.2025.106123_bb0065","author":"ICCVAM"},{"key":"10.1016\/j.tiv.2025.106123_bb0070","series-title":"ICCVAM Test Method Evaluation Report: Current Validation Status of In Vitro Test Methods Proposed for Identifying Eye Injury Hazard Potential of Chemicals and Product - NIH Publication No. 10\u20137553","volume":"10","author":"ICCVAM - Interagency Coordinating Committee on the Validation of Alternative Methods","year":"2010"},{"issue":"1","key":"10.1016\/j.tiv.2025.106123_bb0075","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s43188-021-00099-w","article-title":"Grading criteria of histopathological evaluation in BCOP assay by various staining methods","volume":"38","author":"Jeong","year":"2022","journal-title":"Toxicol. Res."},{"issue":"4","key":"10.1016\/j.tiv.2025.106123_bb0080","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1177\/019262339602400404","article-title":"Application of in vivo confocal microscopy to the understanding of surfactant-induced ocular irritation","volume":"24","author":"Jester","year":"1996","journal-title":"Toxicol. Pathol."},{"issue":"6","key":"10.1016\/j.tiv.2025.106123_bb0085","first-page":"922","article-title":"Area and depth of surfactant-induced corneal injury correlates with cell death","volume":"39","author":"Jester","year":"1998","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"issue":"2","key":"10.1016\/j.tiv.2025.106123_bb0090","first-page":"115","article-title":"Extent of initial corneal injury as a basis for alternative eye irritation tests","volume":"15","author":"Jester","year":"2001","journal-title":"Toxicol. In Vitro\u00a0Int. J. Publ. Assoc. BIBRA"},{"issue":"2","key":"10.1016\/j.tiv.2025.106123_bb0095","first-page":"597","article-title":"Measuring depth of injury (DOI) in an isolated rabbit eye irritation test (IRE) using biomarkers of cell death and viability","volume":"24","author":"Jester","year":"2010","journal-title":"Toxicol. In Vitro\u00a0Int. J. Publ. Assoc. BIBRA"},{"key":"10.1016\/j.tiv.2025.106123_bb0100","first-page":"922","article-title":"Area and depth of surfactant-induced corneal injury correlates with cell death","author":"Jester","year":"2017","journal-title":"Cm"},{"issue":"2","key":"10.1016\/j.tiv.2025.106123_bb0105","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.exer.2009.03.001","article-title":"Corneal myofibroblast viability\u00a0: opposing effects of IL-1 and TGF b 1","volume":"89","author":"Kaur","year":"2009","journal-title":"Exp. Eye Res."},{"issue":"3","key":"10.1016\/j.tiv.2025.106123_bb0110","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1177\/026119291504300307","article-title":"The EpiOcular\u2122 eye irritation test is the method of choice for the in vitro eye irritation testing of agrochemical formulations: correlation analysis of epiocular eye irritation test and BCOP test data according to the un GHS, US EPA and Brazil ANVISA cla","volume":"43","author":"Kolle","year":"2015","journal-title":"ATLA Alternatives Laboratory Animals"},{"key":"10.1016\/j.tiv.2025.106123_bb0115","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.yrtph.2017.01.013","article-title":"Lacking applicability of in vitro eye irritation methods to identify seriously eye irritating agrochemical formulations: results of bovine cornea opacity and permeability assay, isolated chicken eye test and the EpiOcular\u2122 ET-50 method to classify accordi","volume":"85","author":"Kolle","year":"2017","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"10.1016\/j.tiv.2025.106123_bb0120","article-title":"An in vitro depth of injury prediction model for a histopathologic classification of EPA and GHS eye irritants","volume":"61","author":"Lebrun","year":"2019","journal-title":"Toxicol. In Vitro\u00a0Int. J. Publ. Assoc. BIBRA"},{"key":"10.1016\/j.tiv.2025.106123_bb0125","doi-asserted-by":"crossref","DOI":"10.1016\/j.toxlet.2024.03.003","article-title":"Advancing ocular safety research: A comprehensive examination of benzocaine acute exposure without animal testing","author":"Lenze","year":"2024","journal-title":"Toxicol. Lett."},{"issue":"310","key":"10.1016\/j.tiv.2025.106123_bb0130","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.preteyeres.2015.07.002","article-title":"Progress in corneal wound healing","volume":"49","author":"Ljubimov","year":"2015","journal-title":"Prog. Retin. Eye Res."},{"issue":"4","key":"10.1016\/j.tiv.2025.106123_bb0135","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1177\/019262339602400403","article-title":"Light microscopic comparison of surfactant-induced eye irritation in rabbits and rats at three hours and recovery\/day 35","volume":"24","author":"Maurer","year":"1996","journal-title":"Toxicol. Pathol."},{"issue":"3","key":"10.1016\/j.tiv.2025.106123_bb0140","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1080\/019262301316905264","article-title":"Pathology of ocular irritation with bleaching agents in the rabbit low-volume eye test","volume":"29","author":"Maurer","year":"2001","journal-title":"Toxicol. Pathol."},{"key":"10.1016\/j.tiv.2025.106123_bb0145","series-title":"Extent of Initial Corneal Injury as the Mechanistic Basis for Ocular Irritation\u00a0: Key Findings and Recommendations for the Development of Alternative Assays.","first-page":"106","volume":"117","author":"Maurer","year":"2002"},{"issue":"2\u20133","key":"10.1016\/j.tiv.2025.106123_bb0150","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0378-4274(85)90052-9","article-title":"Opacity of bovine cornea in vitro induced by surfactants and industrial chemicals compared with ocular irritancy in vivo","volume":"24","author":"Muir","year":"1985","journal-title":"Toxicol. Lett."},{"issue":"1\u20132","key":"10.1016\/j.tiv.2025.106123_bb0155","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/0378-4274(87)90110-X","article-title":"Surfactant-induced opacity of bovine isolated cornea: an epithelial phenomenon?","volume":"38","author":"Muir","year":"1987","journal-title":"Toxicol. Lett."},{"key":"10.1016\/j.tiv.2025.106123_bb0160","article-title":"Guidance document on the collection of eye tissues for histological evaluation and collection of data series on testing and assessment number 160","author":"OECD","year":"2018","journal-title":"OECD"},{"key":"10.1016\/j.tiv.2025.106123_bb0165","article-title":"Test guideline no. 437 bovine corneal opacity and permeability test method for identifying ocular corrosives and severe irritants","author":"OECD","year":"2020","journal-title":"OECD"},{"key":"10.1016\/j.tiv.2025.106123_bb0170","series-title":"Test no. 437: bovine corneal opacity and permeability test method for identifying (i) chemicals inducing serious eye damage and (ii) chemicals not requiring classification for eye irritation or serious eye damage","author":"OECD","year":"2020"},{"key":"10.1016\/j.tiv.2025.106123_bb0175","series-title":"Test no. 492B: reconstructed human cornea-like epithelium (RHCE) test method for eye Hazard identification","author":"OECD","year":"2022"},{"key":"10.1016\/j.tiv.2025.106123_bb0180","first-page":"1687","article-title":"Central corneal thickness in patients with atopic keratoconjunctivitis","volume":"20","author":"Ondas","year":"2014","journal-title":"Med. Sci. Monitor\u00a0Int. Med. J. Exp. Clin. Res."},{"issue":"1","key":"10.1016\/j.tiv.2025.106123_bb0185","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s10792-016-0218-3","article-title":"Ocular response analyser measurements and central corneal thickness in ocular rosacea patients","volume":"37","author":"Palamar","year":"2017","journal-title":"Int. Ophthalmol."},{"key":"10.1016\/j.tiv.2025.106123_bb0190","series-title":"Biomicroscop\u00eda de la c\u00f3rnea","article-title":"Patolog\u00eda de la c\u00f3rnea. Edema corneal","author":"Pazos Gonz\u00e1lez","year":"2004"},{"issue":"8","key":"10.1016\/j.tiv.2025.106123_bb0195","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1016\/j.tiv.2011.06.008","article-title":"Toxicology in vitro porcine corneal ocular reversibility assay (PorCORA) predicts ocular damage and recovery for global regulatory agency hazard categories","volume":"25","author":"Piehl","year":"2011","journal-title":"Toxicol. in Vitro"},{"key":"10.1016\/j.tiv.2025.106123_bb0200","series-title":"US Environmental Protection Agency Office of Pesticide Programs","article-title":"Voluntary pilot program to evaluate use of a non-animal testing approach to EPA labeling for eye irritation for certain an timicrobial products with cleaning claims","author":"Redden","year":"2009"},{"issue":"1","key":"10.1016\/j.tiv.2025.106123_bb0205","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tiv.2009.05.019","article-title":"A proposed eye irritation testing strategy to reduce and replace in vivo studies using bottom-up and top-down approaches","volume":"24","author":"Scott","year":"2010","journal-title":"Toxicol. in Vitro"},{"issue":"34","key":"10.1016\/j.tiv.2025.106123_bb0210","doi-asserted-by":"crossref","first-page":"55863","DOI":"10.18632\/oncotarget.10150","article-title":"Cytoplasmic vacuolization in cell death and survival","volume":"7","author":"Shubin","year":"2016","journal-title":"Oncotarget"},{"issue":"11","key":"10.1016\/j.tiv.2025.106123_bb0215","doi-asserted-by":"crossref","first-page":"4010","DOI":"10.1167\/iovs.03-1057","article-title":"Uncoupling keratocyte loss of corneal crystallin from markers of fibrotic repair","volume":"45","author":"Stramer","year":"2004","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"10.1016\/j.tiv.2025.106123_bb0220","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.exer.2014.09.013","article-title":"Cellular and extracellular matrix modulation of corneal stromal opacity","volume":"129","author":"Torricelli","year":"2014","journal-title":"Exp. Eye Res."},{"issue":"0","key":"10.1016\/j.tiv.2025.106123_bb0225","first-page":"1","article-title":"Defined approaches to classify agrochemical formulations into EPA hazard categories developed using EpiOcularTM reconstructed human corneal epithelium and bovine corneal opacity and permeability assays","volume":"0","author":"van der Zalm","year":"2023","journal-title":"Cutan. Ocul. Toxicol."},{"key":"10.1016\/j.tiv.2025.106123_bb0230","series-title":"Evaluation of dermal and ophthalmic irritation of cosmetic creams D-009a and d-009b in rabbits","first-page":"173","article-title":"Evaluaci\u00f3n de la irritabilidad d\u00e9rmica y oft\u00e1lmica de las cremas cosm\u00e9ticas d-009a y d- 009b en conejos","volume":"50(2)","author":"Zamora Rodr\u00edguez","year":"2019"}],"container-title":["Toxicology in Vitro"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0887233325001171?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0887233325001171?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T06:20:03Z","timestamp":1756880403000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0887233325001171"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":46,"alternative-id":["S0887233325001171"],"URL":"https:\/\/doi.org\/10.1016\/j.tiv.2025.106123","relation":{},"ISSN":["0887-2333"],"issn-type":[{"value":"0887-2333","type":"print"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Employing histopathology to enhance the BCOP test: The emerging role of stromal thickness as a quantitative endpoint","name":"articletitle","label":"Article Title"},{"value":"Toxicology in Vitro","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.tiv.2025.106123","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"106123"}}