Hearing loss is the most common occupational injury in the United States. More than 30 million workers are exposed to potentially hazardous noise and 9 million workers have exposure to ototoxic chemicals. The focus of this grant is identifying the mechanisms and conditions under which chemical asphyxiates potentiate noise induced hearing loss (NIHL). Chemical asphyxiates serve as useful model compounds because hydrogen cyanide and carbon monoxide potentiate NIHL in rats at exposure levels relevant to the workplace. Fire fighters, operators of heavy equipment, tunnel and toll workers, and truck drivers are exposed to noise and chemical asphyxiants simultaneously. A two-stage hypothesis will be tested whereby noise and asphyxiant """"""""initiate"""""""" reactive oxygen species (ROS) generation and asphyxiants """"""""promote"""""""" this stress by impairing intrinsic ROS buffering mechanisms. Cochlear function will be compared among treatment groups using electrophysiological and acoustic methods. Corresponding histopathological injury will be detected by staining for succinate dehydrogenase activity. Potentiation of NIHL by asphyxiant exposure will be assessed following pharmacological treatments that enhance and depress intrinsic ROS buffering systems. If ROS promotion is critical to potentiation of NIHL, then treatments that enhance ROS scavenging will reduce susceptibility. Also, treatments that decrease ROS scavenging will increase susceptibility. Biochemical studies will confirm the effectiveness of drug treatment on intrinsic ROS buffering. Direct measurement of ROS will be performed in the cochlea using electron paramagnetic spin resonance spectrometry (EPR). Finally, immunohistochemical methods will be used to define the consequences of mixed exposures on selected stress pathways in the cochlea.
