Abstract
Purpose :
Isocyanates are highly reactive, volatile chemical feedstocks used in numerous industries with a $13 billion global demand. While cornea exposure to methyl isocyanate vapor is known to be chemotoxic, the corneal toxicities presented by other industrial isocyanates remain unknown. Here, we have characterized the toxic effects of four isocyanates on the cornea.
Methods :
Purchased rabbit eyes were exposed to increasing vapor doses of four reactive isocyanates (cyclohexyl isocyanate, phenyl isocyanate, ethyl isocyanate, methyl isocyanate) and nor-nitrogen mustard (genotoxic control) using our vapor cap exposure model. The dose-dependent effects of each agent were studied 24 h after exposure using clinical and histochemical assays, including ocular coherence tomography, live/dead staining, imaging of apoptosis, genetic damage, and ROS assays. The toxic effects of cyclohexyl isocyanate vapor were also assessed in fresh human cadaver eyes. Finally, to develop a standardized injury model for therapeutic testing, rabbit corneal injury progression is being characterized in vivo using clinical evaluations and post-mortem histology over eight weeks after exposure to different isocyanates.
Results :
Each isocyanate produced dose-dependent corneal lesions within 24 h, including corneal edema, partial-to-full thickness cytotoxicity and molecular markers of genotoxic lesions. The relative toxicities varied depending on the physicochemical differences among the isocyanates. Interestingly, we repeatedly observed bands of cytotoxicity in the stroma after exposure to cyclohexyl isocyanate, suggesting the presence of layers of stromal cells marked by alternating sensitivity to cyclohexyl isocyanate. Finally, in vivo studies corroborate ex vivo evaluation of relative toxicities and reveal acute and chronic corneal effects from isocyanate exposure.
Conclusions :
All isocyanates pose significant vapor threats to the cornea. Due to their high rate of evaporation, toxicity, and ready absorption into the eye, accidental or purposeful release of isocyanates represents a potential mass-casualty scenario. In addition to emphasizing the high risks of exposure to industrial chemicals, our data suggest ex vivo studies are a relevant platform to estimate acute corneal toxicities caused by reactive chemical vapors.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.