Project 4 - Dosimetry Modeling and Interspecies Extrapolation

项目 4 - 剂量测定建模和种间外推

• 批准号: 7089271
• 负责人: James S Ultman
• 金额: $ 13.43万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7089271
• 关键词: age difference; chemical kinetics; computer simulation; dosage; environmental exposure; environmental toxicology; mathematical model; microfluidics; model design /development; morphometry; nitric oxide; oxidizing agents; ozone; respiratory epithelium; trachea

Ozone (O3) is an outdoor air pollutant that causes site-specific damage and remodeling of tissue along the epithelial surface of the lungs. This project is based on the following interrelated hypotheses: the focal nature of O3-induced tissue responses is directly related to the spatial distribution of O3and its reaction products; and the distribution of O3 and its reaction products can be predicted from mathematical transport models that incorporate information about airway anatomy and O3-substrate reactions in the epithelial lining Fluid (ELF). The overarching objective of this work is to develop exposure-dose-response relationships in the respiratory system of 1 month to 12 month old male rhesus monkeys and 1 week to adult Sprague- Dawley rats. In terms of human development, a 6 month old rhesus monkey corresponds to a 1 or 2 year old child. Therefore, the results of this study will lead to a better understanding of the effect that O3 has on human children, and will improve our ability to extrapolate data from developing animal lungs to human ungs. A second objective of this research is to compare the dose-response processes in the nasal cavities to those occurring in the tracheo-bronchial tree. This will allow us to judge whether or not the nose can be used as a sentinel of health effects in the lower respiratory tract. The following specific aims are associated with this project: 1) Develop computer reconstructions of the geometries along axial airway paths in monkey and rat lungs. 2) Formulate models of O3 transport in ELF that incorporate O3 diffusion, substrate efflux and the production of toxic substances by reactions between O3 and substrates. 3) Continue development of axisymmetric single-path models that predict longitudinal dose distributions of O3 and toxic products along axial airway paths in the developing rat and primate lungs. 4) Continue the development of computational fluid dynamics models for simulating the threedimensional dose distributions at selected sites such as the nasal cavities and airway bifurcations. 5) Establish dose-response relationships for rats and for monkeys by correlating the predicted dose distributions with the spatial occurrence of histochemical endpoints. 6) Evaluate the utility of the exposure-dose-response paradigm in extrapolating O3 susceptibility across species, airway sites and exposure patterns in animals at various stages of post-natal development. The simulations of O3 distribution carried out in this project are central to the overall Program Objective to understand the age, site, cell, and post-natal susceptibilities to O3 exposure pattern. This project will have strong interactions with the other components of this Program-Project. Histochemical O3 and biochemical data generated in Projects 1-3 will be crucial for estimating input parameters to the model simulations, for validating models, and for developing dose-response relationships. The Biostatistics and Respiratory Structure Core will provide geometric airway .reconstructions that are essential to the dosimetry simulations. Core C will also assist in the statistical analyses of dose-response relationships and in the evaluation of model precision.

臭氧（O3）是一种室外空气污染物，可造成特定地点的损害和沿着组织的重塑 肺的上皮表面。该项目基于以下相互关联的假设：焦点 O3诱导的组织反应的性质与O3的空间分布及其反应直接相关 产品;并且可以通过数学传输来预测O3及其反应产物的分布 在上皮衬里中包含有关气道解剖结构和O3底物反应的信息的模型 液体（精灵）。这项工作的总体目的是建立在 1个月至12个月大的雄性恒河猴的呼吸系统和成人Sprague的1周 道利老鼠。在人类发展方面，一个6个月大的恒河猴对应于1或2年 老孩子。因此，这项研究的结果将更好地理解O3对 人类儿童，并将提高我们从发展动物肺到人的数据推断数据的能力 ungs。这项研究的第二个目标是比较鼻腔中的剂量反应过程 对于在气管支气管树中发生的人。这将使我们能够判断鼻子是否可以 在下呼吸道中用作健康效应的前哨。 以下特定目标与该项目有关： 1）沿着猴子和大鼠肺的轴向气道路径的几何形状进行计算机重建。 2）在ELF中制定O3转运的模型，该模型融合了O3扩散，底物外排和生产 O3和底物之间的反应是有毒物质的。 3）继续开发轴对称单路径模型，以预测 O3和有毒产品沿着发育中的大鼠和灵长类肺的轴向气道路径。 4）继续开发计算流体动力学模型，以模拟三维 鼻腔和气道分叉等选定部位的剂量分布。 5）通过将预测剂量相关联，建立大鼠和猴子的剂量反应关系 与组织化学终点的空间发生分布。 6）评估曝光剂量响应范式在推断O3易感性方面的效用 在产后发育的各个阶段，动物的物种，气道部位和暴露方式。 该项目中对O3分配的模拟是整体计划目标的核心 了解O3暴露模式的年龄，现场，细胞和产后敏感性。这个项目将有 与该程序项目的其他组件进行强烈的相互作用。组织化学O3和生化 项目1-3中生成的数据对于估算模型模拟的输入参数至关重要 验证模型，以及开发剂量反应关系。生物统计学和呼吸系统 结构核心将提供几何气道。对剂量模拟必不可少的构造。 核心C还将协助剂量反应关系的统计分析以及评估 模型精度。