Accurate prediction of environmental agents likely to produce specific injury to the auditory system requires an understanding of general mechanisms of ototoxicity, normal physiological adaptation of the cochlea to stress and basic metabolic requirements of the inner ear. We have been studying the ototoxicity of tin compounds and have demonstrated a very long lasting, but partially reversible patterns of hearing loss which is unusual for chemical ototoxics. We propose to determine the mechanism by which TMT produces high frequency hearing loss with particular attention paid to its possible disrupting effects on energy metabolism. We have also been studying the vulnerability of the inner ear to hypoxic exposure produced by carbon monoxide (CO) under conditions of noise exposure and in quiet. We have noted a large increase in cochlear bloodflow which results from CO exposure and may serve to maintain normal cochlear oxygen tension. However, at high carboxyhemoglobin levels we have noted a transient and specific high frequency hearing loss. CO hypoxia present concurrently during noise exposure produces a more profound and longer lasting hearing loss than does noise alone. Further, co-exposure to noise and CO shifts the region of greatest auditory loss toward higher frequencies than noise alone. We will continue to address the reason that noise and hypoxia presented simultaneously produce synergistic effects. Our study of oxidative metabolism as a general mechanism of auditory dysfunction will employ measures of hearing based on reflex modification audiometry, and electrophysiological measures of cochlear function, along with measurement of oxygen delivery and cochlear blood flow. Direct measurement of oxidative phosphorylation, tin accumulation and binding in the cochlea and subsequent histopathological studies using both surface preparation of the organ of Corti and plastic embedded thick sections for light microscopy will provide biochemical and histopathological data essential to determining mechanisms of ototoxicity.