Project 2: Enhancement of Biokinetics using Physiologically-Based Models for Internalized Radionuclides

项目 2：使用基于生理学的内化放射性核素模型增强生物动力学

• 批准号: 10327397
• 负责人: Shaheen Azim Dewji
• 金额: $ 37.45万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327397
• 关键词: Acute; Adult; Aerosols; Age; Animals; Bayesian Analysis; Bayesian Modeling; Behavior; Benchmarking; Biodistribution; Biological; Biological Assay; Blood; Chemicals; Child; Computer software; Consultations; Data; Deposition; Development; Devices; Dose; Drug Kinetics; Elements; Employment; Equipment and supply inventories; Evaluation; Event; Excision; Excretory function; Female; Gamma Rays; Goals; Human; In Vitro; Inhalation; Intake; International; Kinetics; Liquid substance; Lung; Machine Learning; Measurement; Metabolic; Methodology; Modeling; Monitor; Monte Carlo Method; Morphology; Mus; Nuclear; Nuclear Accidents; Nuclear Reactor Accidents; Occupational; Oral cavity; Organ; Particle Size; Particulate; Pathway interactions; Physiological; Physiological Processes; Population; Probability; Probability Samples; Radiation Accidents; Radiation Protection; Radioisotopes; Radiology Specialty; Reporting; Respiratory System; Sampling; Scanning; Sodium Iodide; Solubility; Source; System; Thick; Time; Tissues; Tomogram; Toxic effect; Translations; Triage; Update; Urinalysis; Work; animal data; artificial neural network; base; data modeling; design; detector; efficacy evaluation; in silico; in vivo; innovation; member; morphometry; novel; particle; pharmacokinetic model; pregnant; reconstruction; response; sex; thallium-doped sodium iodide; uptake

PROJECT 2: ABSTRACT Following mass population exposures from radiological or nuclear (RN) events, radionuclide biokinetic models can be used to determine the time-dependent activity concentrations of internalized radionuclides in various tissues and organs of the body as needed for dose assessment during triage. RN events may include radionuclide releases from a radiological dispersion device, an improvised nuclear device, or a nuclear reactor accident event. Biokinetic models from the International Commission on Radiological Protection (ICRP) are currently implemented as deterministic (i.e., single “reference”) compartment-based models developed primarily for occupational radiation protection purposes. We hypothesize that new biokinetic models with realistic RN source term parameters and metabolic variability representative of an exposed population can be used to reliably predict radionuclide biodistribution and responses at different levels of biological organization. The overall goal of Project 2 is to integrate physiologically-based models of radionuclide intake and systemic biokinetics with stochastic probability distributions of key model parameters. The core challenge in constructing realistic biokinetic models representative of an exposed non-reference population is the lack of consideration of basic physiological processes, from defining realistic source terms from RN events and translation to mechanistic parameters that define inhalation intake kinetics, uptake into blood, and excretion. The proposed expansion in biokinetic modeling will for the first time allow in-vivo assay and prediction of the efficacy of novel decorporation agents in humans following an acute RN uptake for a representative population. Primary elements of innovation in Project 2 include: (1) Development of biokinetic models specific to realistic RN sources; (2) Conducting stochastic analysis of ICRP 133 Human Respiratory Tract Model for realistic RN source term and biokinetic behavior; (3) Development of inhalation dose coefficients for exposed population (age/sex/morphometry- specific) from realistic exposure source terms; (4) Construction of computational fluid and particle dynamics (CFPD)-based physiological mouth-lung model of particle intake using realistic source terms and measurement data of particulate distribution in the lungs; (5) Employment of machine learning with physiologically-based pharmacokinetic models to determine the time-dependent uptake, retention, excretion, and reconstruction of radionuclides to evaluate the efficacy of decorporation countermeasure agents; and (6) Development of an in- vivo radiological triage body scanning system correlated with stochastic biokinetics for intake reconstruction and monitoring of decorporation therapy. The proposed work will support Project 1 software in providing non- reference inhalation dose coefficients, as well as detector efficiency whole body response functions for triage. Project 1 and 3 data will be leveraged to a create mesh-based CFPD model of inhalation kinetics. Project 4 animal data will be leveraged to propose animal-to-human scaling models of the efficacy of the decorporation agent, inclusive of age and sex variables where posible.

项目2：摘要 随着放射学或核（RN）事件的大规模群体暴露，放射性生物动力学模型 可用于确定各种内部放射线的时间依赖性活性浓度 人体的组织和器官根据需要进行剂量评估。 RN事件可能包括 从放射性分散装置，改进的核装置或核反应堆中释放了放射线 事故事件。国际放射保护委员会（ICRP）的生物动力学模型是 目前以确定性（即单个“参考”）隔室模型实施 用于职业辐射保护目的。我们假设具有现实RN的新生物动力学模型 曝光人群的来源项参数和代谢变异性可用于可靠 预测不同级别的生物组织的辐射生物分布和反应。总体目标 项目2的内容是将基于物理的放射性摄入量和全身生物动力学的模型与 关键模型参数的随机概率分布。构建现实的核心挑战 代表暴露于非参考人群的生物动力学模型缺乏对基本的考虑 物理过程，从定义现实的源术语从RN事件到翻译到机械 定义吸入摄入动力学，吸收血液和排泄物的参数。提议的扩展 生物动力学建模将首次允许在体内评估和预测新型装饰的效率 急性RN吸收人类的代理人对代表人群。创新的主要要素 在项目2中包括：（1）开发针对现实的RN来源的生物动力学模型； （2）进行 ICRP的随机分析133人类呼吸道模型，用于现实的RN源项和生物动力学 行为; （3）开发暴露人群的吸入剂量系数（年龄/性别/形态计量学 具体）来自现实的暴露源术语； （4）计算流体和粒子动力学的构建 （CFPD）使用逼真的源术语和测量 肺部特定分布的数据； （5）基于身体的机器学习 药代动力学模型，以确定时间依赖性的摄取，保留，排泄和重建 放射线以评估装饰对策剂的效率； （6）发展 体内放射分类身体扫描系统与随机生物动力学相关，用于摄入和重建和 监测装饰疗法。拟议的工作将支持项目1软件，以提供非 - 参考吸入剂量系数以及检测器的效率全身反应分类功能。 项目1和3数据将被利用为基于网格的吸入动力学的CFPD模型。项目4 动物数据将被利用以提出装饰效率的动物到人类缩放模型 特工，包括年龄和性变量的阳性。