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，会导致特定部位的组织损伤和重塑 肺的上皮表面。该项目基于以下相互关联的假设： O3 引起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; O3及其反应产物的分布可以通过数学输运来预测 包含有关气道解剖结构和上皮内层 O3 底物反应信息的模型 流体（ELF）。这项工作的总体目标是建立暴露-剂量-反应关系 1个月至12个月大的雄性恒河猴和1周至成年斯普拉格猴的呼吸系统 道利鼠。就人类发育而言，6个月大的恒河猴相当于1或2岁 老孩子。因此，这项研究的结果将有助于更好地了解 O3 对人体的影响。 人类儿童，并将提高我们将发育中的动物肺部的数据推断到人类的能力 ungs。这项研究的第二个目标是比较鼻腔中的剂量反应过程 发生在气管-支气管树中的那些。这将使我们能够判断鼻子是否可以 用作下呼吸道健康影响的哨兵。 该项目有以下具体目标： 1) 开发计算机重建猴和大鼠肺中轴向气道路径的几何形状。 2) 制定 ELF 中 O3 传输模型，其中包含 O3 扩散、底物流出和产生 通过 O3 和底物之间的反应产生有毒物质。 3）继续开发轴对称单路径模型来预测纵向剂量分布 O3 和有毒产物沿着发育中的大鼠和灵长类动物肺部的轴向气道路径。 4) 继续开发用于模拟三维的计算流体动力学模型 选定部位（例如鼻腔和气道分叉处）的剂量分布。 5) 通过关联预测剂量，建立大鼠和猴子的剂量反应关系 分布随组织化学终点的空间发生而变化。 6) 评估暴露-剂量-反应范式在外推 O3 敏感性方面的效用 动物产后发育不同阶段的物种、气道部位和暴露模式。 本项目中进行的 O3 分布模拟是总体计划目标的核心 了解年龄、部位、细胞和产后对 O3 暴露模式的敏感性。该项目将有 与该计划-项目的其他组成部分的强有力的互动。组织化学 O3 和生化 项目 1-3 中生成的数据对于估计模型模拟的输入参数至关重要，例如 验证模型并建立剂量反应关系。生物统计学和呼吸系统 Structure Core 将提供对于剂量测定模拟至关重要的几何气道重建。 核心 C 还将协助剂量反应关系的统计分析和评估 模型精度。