Carbon Monoxide at the Toxicology–Therapeutics Interface: Donor Validation, the Endogenous Baseline and Regulatory Separation

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-health and occupational settings, yet it is also being explored as a controlled therapeutic agent in acute inflammation, organ preservation, wound repair and selected local-delivery 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-derived pool that can approach roughly 150 μmol/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-development 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-2018 evidence showing that widely used ruthenium carbonyls, especially CORM-2 and CORM-3, 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-validation filter that favours gaseous CO, physiologically characterised organic donors, gas-entrapping materials and measured exposure metrics such as carboxyhaemoglobin (COHb). To make this operational, we propose a three-tier 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-risk assessment from population-protective environmental limits.