MECHANISMS OF ORGANIC SOLVENT OTOTOXICITY

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DESCRIPTION: (Adapted from the Investigator's Abstract) Organic solvents can produce permanent hearing impairment in people and in laboratory animals. The widespread use of these organic solvents and the specific nature of the hearing loss that has been reported pose a significant public health risk. Laboratory investigations appear to identify two distinct patterns of cochlear dysfunction and injury following solvent exposure. One pattern, produced by toluene, involves impairment of outer hair cells that normally encode middle frequency tones and which are located in the middle turns. The ototoxicity appears to stem from a preferential perturbation in motility of these cells and thereby of sensitivity to sound. Preferential dysmorphia in these cells and impaired regulation of free intracellular calcium level occurs rapidly and at the low concentrations of toluene predicted to occur in the brain of humans exposed at permissible levels. Because the outer hair cell alone shows rapid electromotility, a process that is sensitive to intracellular free calcium ion concentrations, it may be particularly vulnerable to ototoxic agents that disrupt intracellular calcium regulation. Trichloroethylene, by contrast, preferentially impairs inner hair cell-spiral ganglion cell function. It will be determined whether this reflects excitotoxic injury at this synapse. This proposal will characterize the development of cochlear impairment by toluene and trichloroethylene using repeated within subject assessment of distortion product otacoustic emission and the compound action potential to determine targets of injury and the lowest exposure concentrations and durations that are ototoxic. Comprehensive acute cochlear assessment of auditory nerve saturation, cochlear microphonic and endocochlear potential measures will specify the target cells. Non-ototoxic solvents will be used as controls to identify selective mechanisms of ototoxicity. Toluene preferentially disrupts slow motility in outer hair cells that encode middle frequency hearing and elevates intracellular calcium by disrupting intracellular storage and/or release mechanisms. In vitro experiments will identify the specific calcium sequestration mechanism that is impaired by this ototoxic solvent and determine the relationship between changes in outer hair cell morphometry and outer hair cell and spiral ganglion cell calcium homeostasis.