Abstract
Purpose :
Many volatile organic compounds (VOC) are economically important chemicals that are stored and transported in large quantities. Certain VOCs can penetrate the cornea and cause cytotoxic lesions that impair vision, potentially causing mass casualty incidents after accidental release. However, whether a given VOC presents a genuine ocular risk remains unknown. Here we used fundamental and clinical studies to characterize the dose-dependent effects of 15 chemically diverse, high-priority VOCs on the cornea ex vivo and in vivo.
Methods :
Fresh rabbit and cadaver eyes were exposed to increasing doses of VOCs using a well-described vapor cap exposure model. At 24 h after exposure, corneas were characterized for acute lesions using ocular coherence tomography, live/dead staining, and immunohistochemistry for toxic injury markers. For select VOCs, acute and long-term corneal effects were studied in vivo using clinical assays followed by post-mortem histology and molecular assays.
Results :
VOCs produced dose-dependent corneal lesions, including edema, cytotoxicity, genotoxicity and reactive oxygen species. The manifestation of genotoxic lesions was predictable via the Pearson hard-soft acid-base theory, providing insight into toxic mechanisms. Many VOCs exhibited a steep dose response over a three-fold dose range. While most VOCs produced full-thickness corneal lesions after a 2-3 min exposure, some caused full-thickness corneal lesions after 0.5 min. In vivo studies were consistent with ex vivo data and demonstrated the delayed emergence of vision impairing keratopathies at high doses. Intriguingly, one VOC produced alternating layers of toxicity in the stroma, the mechanisms of which are under investigation.
Conclusions :
Most VOCs tested caused dose-dependent corneal lesions at relatively low doses. We are using these data to develop risk profiles based on physicochemical properties, dose, tissue-specific cytotoxicities and pathophysiological responses. In addition to identifying toxic mechanisms and expanding our understanding of chemotoxic injury in the cornea, we are testing potential candidate medical countermeasures. It is anticipated these studies will inform risk assessments and exposure management plans for highly toxic VOCs and related chemicals.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.