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 在放射性或核(RN)事件的大规模人口照射后，放射性核素生物动力学模型 可用于确定不同种类的内在化放射性核素随时间变化的活度浓度。 在分诊期间进行剂量评估所需的身体组织和器官。RN活动可能包括 放射性弥散装置、简易核装置或核反应堆释放的放射性核素 意外事件。来自国际放射防护委员会(ICRP)的生物动力学模型是 目前被实施为主要开发的确定性(即，单一“参考”)基于舱室的模型 用于职业辐射防护目的。我们假设新的生物动力学模型具有真实的RN 代表暴露人群的源项参数和代谢变异性可以可靠地用于 预测放射性核素在不同生物组织水平上的生物分布和响应。总目标 项目2的目的是将放射性核素摄取和全身生物动力学的生理学模型与 关键模型参数的随机概率分布。构建现实主义的核心挑战 代表暴露的非参考种群的生物动力学模型缺乏基本的考虑 生理过程，从从RN事件定义现实的源术语到翻译到机械论 定义吸入动力学、血液摄取和排泄的参数。拟议中的扩展 生物动力学模型将首次允许体内测试和预测新型脱孔剂的疗效 在典型人群中急性摄取RN后，人类中的药物。创新的主要要素 项目2包括：(1)开发针对实际RN来源的生物动力学模型；(2)进行 ICRP133人体呼吸道模型对真实RN源项和生物动力学的随机分析 (3)制定暴露人群的吸入剂量系数(年龄/性别/形态测量-- 具体来说)来自真实曝光源项；(4)计算流体和粒子动力学的构建 使用真实源项和测量的基于(Cfpd)的颗粒物摄入量的生理学口肺模型 肺内颗粒物分布数据；(5)基于生理学的机器学习 确定依时摄取、滞留、排泄和重建的药代动力学模型 放射性核素用于评估去孔洞对抗剂的效果；以及(6)开发一种新的放射性核素。 与随机生物动力学相关的体内放射分流体检系统用于进食重建和 监测去孔洞治疗。拟议的工作将支持项目1软件提供非 参考吸入剂量系数，以及用于分类的探测器效率全身反应函数。 将利用项目1和3的数据创建基于网格的吸入动力学CFPD模型。项目4 动物数据将被用来提出从动物到人类的去孔道效果的比例模型 代理人，包括年龄和性别变量在可能的情况下。