Beyond Acute Cytotoxicity: A Repair-Exhaustion Framework for Chronic Sublethal Benzalkonium Chloride Toxicity in...

Benzalkonium chloride (BAK), a common preservative in multi-dose ophthalmic products, is often studied under acute high-dose exposure, which highlights overt damage to corneal epithelial cells. These studies tend to exaggerate the maximum cytotoxic effects and do not accurately reflect the gradual, cumulative damage seen during long-term use. By reviewing clinical, animal, and cellular data, we argue that repeated low-dose BAK exposure leads to barrier dysfunction, energy depletion, priming of inflammation, and impaired regeneration before significant cell death occurs. We suggest a repair-exhaustion model: minor injuries from repeated exposure are initially managed by membrane resealing and epithelial renewal, but over time, repair capacity becomes exhausted. This has two main implications: (i) long-term toxicity should be evaluated using functional measures such as barrier integrity, mitochondrial health, inflammation, and repair ability, and not cell viability alone; (ii) there may be a window during which reducing preservative levels or adding barrier-supporting and mitochondrial-protective agents can minimize cumulative damage. Instead of simply using or avoiding the preservative, this approach encourages formulation and clinical strategies that maintain antimicrobial effects while strengthening tissue resilience.