Extent of initial corneal injury as the mechanistic basis for ocular irritation: key findings and recommendations for the development of alternative assays.

摘要

Currently, there are no recognized alternative tests to eliminate the use of animals in ocular irritation testing. A major reason no replacement alternatives have been developed is that the current in vivo data set provides no perspective regarding the critical cellular and molecular changes involved in initial ocular injury, subsequent responses, and repair processes in standard in vivo tests. Without this perspective, mechanistically based replacement tests cannot be developed and validated. We have proposed that the level of ocular irritation is related to the extent of initial injury, and that regardless of the processes leading to tissue damage, the extent of initial injury is the principal factor determining the outcome of ocular irritation. This article summarizes the results from our studies of various surfactants and nonsurfactants of differing irritancy that support our hypothesis. Our findings indicate that a mechanistically based alternative to in vivo ocular irritation tests would be the microscopic or biochemical measurement of initial injury using either ex vivo or in vitro corneal equivalent systems composed of corneal epithelial, stromal keratocyte, and corneal endothelial cell layers. This work also provides a well-characterized panel of materials of varying types and irritation for use in developing and validating alternative tests.