TOXICOLOGY OF NASAL GAS DEPOSITION IN FIVE SPECIES

最近发现鼻粘膜富含 异生物质代谢酶，然而，其定量 在体内环境中的重要性尚不清楚。 主要目的 研究的目的是提供定量信息， 吸入蒸汽在鼻内代谢的程度 体内组织。 为此，九气的沉积 将在手术隔离的上呼吸道中测量 麻醉的Fischer 344大鼠和金黄色的叙利亚仓鼠。 的 选择的蒸气是醇脱氢酶的底物， 羧酸酯酶或混合功能氧化酶，已知 存在于鼻粘膜中的高水平。 的程度 代谢将通过数学建模来估计 沉积数据，并通过测量沉积在幼稚和 代谢前体预处理的动物。 鼻粘膜中的代谢有可能是至关重要的 在呼吸系统和全身 吸入蒸汽的毒性。 入组部位代谢结果 局部代谢物浓度高， 可用于吸收的母体化合物量 总循环 鼻内代谢也会促进 吸入的蒸汽在网站上，因此，从他们的肺 毒性作用。 目前关于 沉积蒸汽的处置表明， 沉积的负荷可在鼻组织中原位代谢。 因为它可能会对整体毒性产生深远的影响， 对代谢程度的定量知识， 进入对于全面了解毒性至关重要， 任何物质。 通过量化和提供对 在这一过程中涉及的重要因素，建议研究 将极大地推进我们对 吸入毒理学的重要原则， 将提高我们预测和解释区域性气候变化的能力， 吸入蒸气的呼吸道和全身毒性。

It has recently been discovered that the nasal mucosa is rich in xenobiotic metabolizing enzymes, however, their quantitative importance in the in vivo setting is not known. The primary aim of the proposed research is to provide quantitative information on the extent to which inhaled vapors are metabolized in nasal tissues in vivo. Towards this end the deposition of nine vapors will be measured in the surgically isolated upper respiratory tract of anesthetized Fischer 344 rats and golden Syrian hamsters. The selected vapors are substrates for either alcohol dehydrogenase, carboxylesterase or mixed function oxidases, enzymes known to be present in the nasal mucosa in high levels. The extent of metabolism will be estimated by mathematic modeling of the deposition data and by measurement of deposition in naive and metabolic inhibitor-pretreated animals. Metabolism in the nasal mucosa has the potential to be of critical and fundamental importance in the respiratory and systemic toxicity of inhaled vapors. Metabolism at the site of entry results in high local concentrations of metabolite(s) and limits the amount of parent compound available for absorption into the general circulation. Nasal metabolism also enhances deposition of inhaled vapors in the site and, thus, spares the lungs from their toxic effects. The limited information currently available on the disposition of deposited vapors suggests 50% or more of the deposited burden may be metabolized in situ in nasal tissues. Because it may exert a profound effect on overall toxicity, quantitative knowledge on the extent of metabolism at the site of entry is essential for a complete understanding of the toxicity of any substance. By quantitating and providing insights into the important factors involved in this processs, the proposed research will significantly advance our knowledge of fundamentally important principles of inhalation toxicology and in the long-term will enhance our ability to predict and interpret the regional respiratory and systemic toxicity of inhaled vapors.