Toluene and styrene are two of the most commonly used solvents and both have been shown to damage the inner ear and cause a moderate, mid-frequency hearing loss. This proposal has four broad questions: (1) How do cells in the cochlea die with solvent intoxication? (2) Since solvents are neurotoxic as well as ototoxic, is there a central auditory change associated with solvent exposure? (3) Do solvents interact with the effects of noise? (4) Are the effects of solvent (styrene and toluene) exposure prevented with antioxidant therapy? Our approach to study the ototoxic potential of these chemicals is to use the Long-Evan rat as an experimental model, measure its hearing before and after solvent and noise exposure, examine the changes in the series of evoked potentials from cochlea to cortex for evidence of neurotoxic changes, examine the sensory cells for evidence of cell death (necrosis or apoptosis) and oxidative stress. The first set of experiments explore the dose/response of each of the two chemicals. Subjects will be sacrificed at either 12 or 24 hours after the exposure for evaluation of oxidative stress and mechanism of loss or 30 days to assess permanent hearing loss and pathology. The second experiment involves an assessment of peripheral and CMS changes with solvent exposure. The third set of experiments explores the interaction of noise and the chemicals. The subjects will be given a mild dose of the chemical (as determined in Experiment I) and then will be exposed for 12 hours to a 8 kHz octave band of noise at a level that will cause a 10 to 30 dB PTS. The fourth experiment evaluates the effectiveness of N-actylcysteine (L-NAC), trolox and carnitine (ALCAR), as protective drugs for chemical and noise induced hearing loss. These studies will add to our knowledge by confirming the ototoxicity of styrene and toluene; it will clarify how the two solvents interact with noise; it will also clarify if oxidative stress is a factor in solvent ototoxicity and finally, the study will explore the exciting possibility that the ototoxic effects of solvents can be prevented with antioxidants. ? ?
