TOXICOLOGY OF NASAL GAS DEPOSITION IN FIVE SPECIES

五种物种鼻气沉积的毒理学

基本信息

批准号：
3251240
负责人：
JOHN B MORRIS
金额：
$ 12.42万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-03-01 至 1997-03-31
项目状态：
已结题

项目摘要

Regional deposition patterns determine the dose delivered to respiratory tract target cells during inhalation exposure and, therefore, are critical in determining the ultimate toxic response. The proposed research focusses on upper respiratory tract (URT) deposition of reactive gases. Specifically, the research is aimed at providing detailed information on species differences in URT deposition of acetaldehyde, acrolein and nitrogen dioxide (NO2); at providing quantitative data on deposition of these gases at both high inspired concentrations, such as those used in inhalation toxicity testing, and also lower, more environmentally relevant concentrations; and at examining deposition in animals exposed to mixtures of these gases to determine if simultaneous exposure conditions such as those occurring in the environment, alter deposition patterns of these three reactive gases. In addition, these experiments will examine deposition under both unidirectional and cyclic flow conditions to determine if data obtained by commonly used unidirectional flow methodologies are reasonably predictive of events occurring under more physiologic, cyclic flow conditions. To meet these aims, deposition of acetaldehyde, acrolein and/or NO2 will be measured under constant velocity unidirectional and cyclic flow conditions in the surgically isolated URT of the anesthetized Sprague-Dawley rat, B6C3F1 mouse, Syrian hamster and Hartley guinea pig, four species commonly employed in inhalation toxicity testing. Measurements will be made in animals exposed to each gas individually and also in animals exposed to combinations of these gases. Inhalation dosimetric relationships are necessary for accurate hazard assessment, particularly for comparison of toxicity data among animal species, extrapolation of high dose (concentration) studies to low dose scenarios, and use of toxicity data derived from exposures to individual agents to predict toxicity in more complicated multi-toxicant exposure settings. By providing detailed dosimetric information on each of these areas of hazard assessment, the proposed research will, in the long-term, dramatically enhance our ability to understand and extrapolate toxicity data for reactive gases such as those used in this research. In addition, the proposed research is aimed at examination of a widely used but unvalidated mathematic mass-transfer model for URT reactive gas deposition. These modeling efforts will not only provide insights into critical factors controlling deposition mechanisms, but also may lead to the development of predictive models of URT deposition. Thus, the proposed research, by enhancing our ability to understand, extrapolate and predict URT dosimetric relationships for reactive gases, will significantly advance our knowledge in this important area of inhalation toxicology.

区域沉积模式确定输送到呼吸的剂量吸入暴露期间的靶细胞，因此是关键的在确定最终有毒反应时。拟议的研究重点反应性气体的上呼吸道（URT）沉积。具体而言，该研究旨在提供有关的详细信息乙醛，丙烯醛和二氧化氮（NO2）；提供有关沉积的定量数据这些气体在两个高启发浓度下，例如吸入毒性测试，也较低，更环保浓度；并检查暴露于混合物的动物中的沉积这些气体中以确定同时暴露条件（例如发生在环境中的那些，改变了这些模式三种反应性气体。此外，这些实验将检查在单向和环状条件下的沉积确定是否通过常用的单向流量获得数据方法论可以合理地预测更多事件生理，环状条件。为了满足这些目标，将在恒定速度下测量乙醛，丙烯醛和/或NO2 在手术隔离的URT中的单向和环状流量条件麻醉的Sprague-Dawley Rat，B6C3F1老鼠，叙利亚仓鼠和哈特利几内亚猪，四种通常用于吸入毒性的物种测试。将在暴露于每种气体的动物中进行测量单独，也是暴露于这些气体组合的动物中。吸入剂量法对于准确危害是必要的评估，特别是为了比较动物的毒性数据物种，高剂量（浓度）研究的外推到低剂量场景和使用从暴露到个人的毒性数据预测更复杂的多毒剂暴露的毒性的药物设置。通过提供有关每个的详细剂量法信息从长远来看，拟议的研究将是危险评估领域急剧增强了我们理解和推断毒性的能力反应性气体（例如本研究中使用的）数据。此外，拟议的研究旨在检查广泛使用但未经验证的数学质量转移模型，用于URT反应性气体沉积。这些建模工作不仅将提供对关键因素的见解控制沉积机制，但也可能导致 URT沉积的预测模型。因此，拟议的研究，通过增强我们理解，推断和预测URT剂量计的能力反应性气体的关系将大大提高我们的知识在这一重要的吸入毒理学领域。