TOXICOLOGY OF NASAL GAS DEPOSITION IN FIVE SPECIES

最近发现，鼻黏膜中含有丰富的 然而，异源生物代谢酶，其数量 在活体环境中的重要性尚不清楚。主要目标是 建议的研究的目的是提供关于 吸入的蒸汽在鼻腔内代谢的程度 体内的组织。为此，沉积了九种水蒸气 会在手术隔离的上呼吸道进行测量 麻醉的费舍尔344只大鼠和金色叙利亚仓鼠。这个 选定的蒸气是酒精脱氢酶的底物， 羧酸酯酶或混合功能氧化酶，已知的 在鼻黏膜中含量较高。其影响范围 新陈代谢将通过数学模型来估计 沉积数据和通过测量在幼稚和 新陈代谢抑制因子--预处理的动物。 鼻黏膜的新陈代谢有可能是至关重要的。 在呼吸系统和全身性疾病中 吸入蒸汽的毒性。进入结果部位的新陈代谢 在高局部浓度的代谢物中(S)，并限制 可吸收到的母体化合物的量 一般环流。鼻部新陈代谢也促进了 吸入现场的蒸气，从而使肺免于受到 有毒的影响。目前在上提供的有限信息 沉积的蒸气的处置表明50%或更多 沉积的负荷物可在鼻部组织中进行原位代谢。 因为它可能会对整体毒性产生深远的影响， 对人体各部位代谢程度的定量认识 要想全面了解 任何物质。通过量化和提供对 这一过程中涉及的重要因素，拟议的研究 将极大地推动我们从根本上 吸入毒理学和长期的重要原则 将增强我们预测和解读区域气候变化的能力 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.