Mechanistic studies of the inhaled neurotoxicants, manganese and hydrogen sulfide

The purpose of this research was to develop a better understanding of the toxicity of low-level long-term exposure to the inhaled neurotoxicants, manganese (Mn) and hydrogen sulfide (H₂S). My first research project investigated the neurotoxicity of Mn and the role of Mn-mediated oxidative damage in the neonatal CD rat. Oral exposure to high levels of MnCl₂ in developing rats resulted in increased brain regional (striatum, cerebellum, and rest of brain) and mitochondrial Mn levels, increased motor activity, and decreased terminal body weights. The second Mn project addressed the role of olfactory transport in the delivery of inhaled 54MnCl ₂ from the nose to the brain in the male CD rat. A novel unilateral nasal occlusion model was used to demonstrate for the first time that inhaled 54Mn undergoes transport to the olfactory pathway of the brain within 24–48 hrs following inhalation exposure and that this route contributes up to approximately 90% of the 54Mn delivered to the olfactory pathway.; Hydrogen sulfide is encountered as a byproduct of bacterial decomposition as well as many industrial processes. My third research project investigated the nasal toxicity of H₂S following subchronic (70-day) low-level inhalation exposure to 0, 10, 30, or 80 ppm H₂S in male CD rats. For the first time, nasal lesions associated with low-level subchronic H ₂S exposure were demonstrated in an experimental animal. My fourth research project investigated the pathogenesis of H₂S-induced olfactory toxicity following acute (1-day or 5-day) inhalation exposures to 0, 30, 80, 200, or 400 ppm H₂S. Acute exposure to ≥80 ppm H₂S caused full-thickness necrosis of the olfactory mucosa. Analysis of the distribution pattern of olfactory lesions observed in both the acute and subchronic studies implicated roles for both tissue susceptibility and regional dosimetry in H₂S-induced olfactory toxicity in the rat. The results of these toxicologic investigations in the CD rat improve our understanding of the mechanism of toxicity of Mn and H₂S in the rat. However, consideration must be given to interspecies differences in anatomy, physiology, and other factors when interpreting the relevance of these findings to a human health risk assessment. (Abstract shortened by UMI.)...