Hearing Loss by the Synergistic Effect of Chronic Inhalation of Exposure of Manganese Fumes with Occupational Noise Exposure

Abstract Workers in industries such as mining, welding, smelting, and ceramic industry were chronically exposed to Manganese (Mn) fumes. The percent risk of Mn toxicity by inhalation is high. This occupational exposure by inhalation leads to Mn accumulation in the extrapyramidal system of the brain and manifests neurological symptoms similar to Parkinsonism referred to as Manganism. Welders exposed to Mn fumes were evidenced by hearing loss clinically. However, workers in these occupational settings were further exposed to occupational noise as well and at the highest risk for occupational noise-induced hearing loss. Given the high socio-economic impact of occupational noise exposure and Mn toxicity, it is vital to determine if Mn fume inhalation is ototoxic and Mn fume inhalation potentiates occupational noise-induced hearing loss or occupational noise exposure potentiates Mn fume-induced ototoxicity. Toxicokinetics and toxicodynamics of Mn toxicity are determined oxidative nature of exposure in addition to dose, route, and duration. Recent evidence indicates that the determination of the Mn species and Mn complexes with low molecular mass compounds (Mn-LMMs) in serum could be a potential marker for biomonitoring of occupational Mn exposures. An earlier study indicated that Mn exposure results in Mn accumulation in the cochlea and brain regions. Given the clinical evidence of hearing loss and in vitro ototoxicity, we hypothesized that chronic Mn fume inhalation might be ototoxic and potentiate occupational noise-induced hearing loss. Thus, in the proposed study, the central objective is to determine if chronic inhalation of Mn fumes induces hearing loss and if it has a synergistic effect with concurrent occupational noise exposure. This objective will be tested using three specific aims in the animal model of a chinchilla exposed to Mn aerosols and occupational noise exposure. Chinchilla is used as a model as its audiogram and the size of the tympanic membrane are similar to humans. Aim1 characterizes the Manganese fumes-induced hearing loss and its potentiating effect by occupational noise exposure in chinchillas using various metrics of functional auditory assays indicating the integrity of the auditory system. Aim2 investigates Mn metallomics by determining the spatial distribution and localization of Mn-species and Mn-LMMs in the central auditory pathway (cochlear nucleus, inferior colliculus, and auditory cortex) along with its quantification in serum and cochlea following chronic Mn fume inhalation. Aim 3 characterizes the chronic Mn fume inhalation-induced cochlear histopathology using cytocochleogram and synaptic cochleogram. The proposed study addresses the NORA sector of mining. In addition to establishing Mn-induced ototoxicity and its potentiating effect, the study outcome provides insights on Mn pathomechanism causing Manganism and as Research to Practice the study helps to determine exposure standards for different oxidation states and improves risk assessment in these workers.