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

基本信息

批准号：
10589877
负责人：
Shaheen Azim Dewji
金额：
$ 37.03万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10589877
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 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

项目摘要

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：摘要大规模人口暴露于放射性或核 (RN) 事件后，放射性核素生物动力学模型可用于确定各种内化放射性核素的时间依赖性活度浓度 RN 事件期间需要进行剂量评估的身体组织和器官可能包括。放射性分散装置、简易核装置或核反应堆释放的放射性核素国际放射防护委员会 (ICRP) 的生物动力学模型是目前主要作为确定性（即单一“参考”）基于隔间的模型来实现为了职业辐射防护的目的，我们勇敢地采用了具有现实 RN 的新生物动力学模型。代表暴露群体的源项参数和代谢变异性可用于可靠地预测生物组织不同水平的放射性核素生物分布和反应的总体目标。项目 2 的目的是将基于生理学的放射性核素摄入模型和全身生物动力学与关键模型参数的随机概率分布是构建现实的核心挑战。代表暴露的非参考人群的生物动力学模型缺乏考虑基本因素生理过程，从定义来自 RN 事件的现实源术语以及翻译到机械学定义吸入动力学、血液摄取和排泄的参数。生物动力学模型将首次允许体内分析和预测新型修饰的功效代表性人群对 RN 的急性吸收后，人类中的代理。创新的主要要素。项目 2 包括：(1) 开发针对实际 RN 源的生物动力学模型；(2) 进行 ICRP 133 人类呼吸道模型的随机分析，用于现实 RN 源项和生物动力学行为；（3）制定暴露人群的吸入剂量系数（年龄/性别/形态测量- (4)计算流体与粒子动力学的构建基于 (CFPD) 的颗粒摄入生理口肺模型，使用现实源项和测量 (5)基于生理学的机器学习的应用；药代动力学模型，以确定时间依赖性的摄取、保留、排泄和重建放射性核素来评估去核对抗剂的功效；以及 (6) 开发一种in- 体内放射分类身体扫描系统与随机生物动力学相关，用于摄入重建和拟议的工作将支持项目 1 软件提供非参考吸入剂量系数，以及用于分类的检测器效率全身响应函数。项目 1 和 3 的数据将用于创建项目 4 的基于网格的 CFPD 吸入动力学模型。将利用动物数据提出装饰功效的动物到人类的缩放模型代理人，尽可能包括年龄和性别变量。