Because olfactory receptor neurons directly contact both the external environment at the nasal lumen and the central nervous system (CNS), nonsystemic access of toxicants to the CNS via transport through these neurons has been proposed as causal in such memory-related disease's as Alzheimer's. Data indicate that such transport of materials is possible in laboratory animals receiving intranasal instillation of various materials, but to date, the importance of this phenomenon to the human population with respect to environmental exposure to toxic inhalants is unstudied. The objective of this proposal is to determine the specific disposition of inhaled toxicants in the olfactory system including both the olfactory epithelium and its CNS projections. The specific goal of the project is to assess the importance of the phenomenon of olfactory transport of inhalants as a risk factor to human health by using an environmentally relevant exposure route (inhalation) and plausible concentrations of materials (threshold limit value exposures). We will begin to determine what inhalants are subject to transport by varying the physico-chemical characteristics of metals and thereby determining the importance of solubility on distribution of materials by nonsystemic means. By inhibiting specific metabolic pathways, we can assess the role of metabolism in the nasal mucosa and the olfactory bulbs on the disposition of solvents varying in metabolic pathways and the interaction of metabolism with solubility. Many toxicants and infectious agents are known to injure the olfactory epithelium. To determine whether such lesions are protective or pathological with respect to olfactory transport of inhalants, we will use a toxicant known to specifically injure the olfactory epithelium (methyl bromide), and examine alterations in disposition occurring through stages of epithelial regeneration. We will analyze the disposition of the inhaled toxicants in the olfactory epithelium and brain regions both receiving afferent projections from the epithelium or sending efferent projections to the epithelium. To control for systemic delivery of material, we will also examine brain regions not known to have direct anatomical connections to the olfactory region. The results of these studies will provide a broad outline of the factors influencing transport of inhalants through the olfactory mucosa into the CNS from which definitive studies can be planned.
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