{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T11:05:05Z","timestamp":1784286305581,"version":"3.55.0"},"reference-count":46,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Carbon monoxide (CO) occupies an unusual position at the boundary between environmental toxicology and therapeutic pharmacology. The same molecule is regulated as an involuntary toxic exposure in public\u2010health and occupational settings, yet it is also being explored as a controlled therapeutic agent in acute inflammation, organ preservation, wound repair and selected local\u2010delivery indications. This critical narrative review was written to clarify three issues that have repeatedly distorted interpretation of the field: the quantitative endogenous baseline of CO (a haem\u2010derived pool that can approach roughly 150\u2009\u03bcmol\/L in blood, far above a trace contaminant), the analytical validity of CO donor systems and the need to keep environmental exposure limits separate from drug\u2010development risk assessment. Structured scoping searches of PubMed, Web of Science and the Cochrane Library were used to identify mechanistic, toxicological, donor chemistry, exposure metric and regulatory literature through November 2025. We place particular weight on post\u20102018 evidence showing that widely used ruthenium carbonyls, especially CORM\u20102 and CORM\u20103, do not behave as reliable CO donors under many physiological conditions and that several historical biological effects may reflect ruthenium reactivity rather than CO signalling. We argue that CO studies should be read through a donor\u2010validation filter that favours gaseous CO, physiologically characterised organic donors, gas\u2010entrapping materials and measured exposure metrics such as carboxyhaemoglobin (COHb). To make this operational, we propose a three\u2010tier evidence scheme for grading CO biology and a minimum reporting set for CO intervention studies. The most defensible translational opportunities are short, monitored and reversible interventions in acute or localised settings; chronic systemic inhalation for diffuse disease remains less plausible because systemic COHb elevation cannot be confined to the diseased tissue. For applied toxicology, a coherent framework for CO therefore requires validated exposure metrics, explicit donor chemistry and strict separation of therapeutic benefit\u2013risk assessment from population\u2010protective environmental limits.<\/jats:p>","DOI":"10.1002\/jat.70356","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T10:23:15Z","timestamp":1784283795000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Carbon Monoxide at the Toxicology\u2013Therapeutics Interface: Donor Validation, the Endogenous Baseline and Regulatory Separation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2888-5699","authenticated-orcid":false,"given":"Syako S.","family":"Hasan","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Science and Health Koya University  Koya Kurdistan Region Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0158-2834","authenticated-orcid":false,"given":"Rebaz M.","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science and Health Koya University  Koya Kurdistan Region Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2071-7167","authenticated-orcid":false,"given":"Dlzar D.","family":"Ghafoor","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science, College of Science Komar University of Science and Technology  Sulaimani Kurdistan Region Iraq"},{"name":"Department of Chemistry, College of Science University of Sulaimani  Sulaimani Kurdistan Region Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3759-3132","authenticated-orcid":false,"given":"Akam Jasim","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science Soran University  Soran Kurdistan Region Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1307-4271","authenticated-orcid":false,"given":"Harmand A.","family":"Hama","sequence":"additional","affiliation":[{"name":"Biology Education Department Tishk International University  Erbil Kurdistan Region Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nyan","family":"Masud","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science and Health Koya University  Koya Kurdistan Region Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayan A.","family":"Hussain","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science and Health Koya University  Koya Kurdistan Region Iraq"},{"name":"Department of Pharmacy, College of Pharmacy Knowledge University  Erbil Kurdistan Region Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3248-4586","authenticated-orcid":false,"given":"Abdulrahman","family":"Ismael","sequence":"additional","affiliation":[{"name":"Department of Community Health Nursing Cihan University\u2010Erbil  Erbil Kurdistan Region Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4799-1185","authenticated-orcid":false,"given":"Rebaz","family":"Qader","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science and Health Koya University  Koya Kurdistan Region Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"e_1_2_17_2_1","volume-title":"Toxicological Profile for Carbon Monoxide","author":"ATSDR","year":"2012"},{"key":"e_1_2_17_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41073\u2010019\u20100064\u20108"},{"key":"e_1_2_17_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00823"},{"key":"e_1_2_17_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2023.115642"},{"issue":"651","key":"e_1_2_17_6_1","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.abl4135","article-title":"Delivery of Therapeutic Carbon Monoxide by Gas\u2010Entrapping Materials","volume":"14","author":"Byrne J. 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