Integrating Structive Activity, Biokinetics and Response for ENP Risk Assessment

整合结构活动、生物动力学和反应进行 ENP 风险评估

• 批准号: 8150410
• 负责人: Joel G Pounds
• 金额: $ 119.91万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-28 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150410
• 关键词: Integrating; Structive; Activity; Biokinetics; Response

DESCRIPTION (provided by applicant): The PNNL U19 program builds on existing expertise in systems approaches to nanotoxicology to develop a quantitative understanding of how engineered nanomaterial (ENP) properties interact with biological systems and ultimately drive tissue disposition, physiological responses, and risk of initiating or promoting disease. One of the major innovations of our research program is the development of complimentary in vitro and in vitro dosimetry models, which together overcome a key obstacle to the use of in vitro systems for hazard ranking by providing a means of extrapolating doses across systems. We have chosen to focus on macrophage inflammation and pathogen clearance because, in contrast to high dose cytotoxicity, we expect that disruption of these key, linked physiological functions of macrophages can increase risk of pulmonary infection at low, environmentally relevant exposures, as has been shown for air pollution. The organization of our research program around integration of results at multiple levels of biological organization and systems through measurement and simulation of biologically relevant measures of nanoparticle target cell or tissue dose in each system, is an innovation rising from our interdisciplinary team's prior integrative research in nanotoxicology. To meet our objectives, we propose 3 projects with the following broad objectives: Project 1: Provide a mechanistic-level understanding of how physical chemical and structural features of ENP dictate macrophage uptake, internal trafficking, inflammasome signaling and impairment of phagocytic bacterial clearance for use in QSAR-based hazard rankings and risk assessment Project 2: Characterize and model the pulmonary and systemic pharmacokinetics of a selected series of poorly soluble ENP and identify ENP properties and genetic/phenotypic factors that modulate response to pulmonary inflammation and susceptibility to pneumonia for use in pharmacokinetic modeling and risk assessment. Project 3: Develop a complete suite of in vitro and in vivo nanomaterial dosimetry models and apply them to establish QSAR based hazard rankings human exposure limits based on the effects of ENP on the inflammasome and impairment of phagocytic bacterial clearance This multidisciplinary program's assessment of biokinetics, inflammatory response and pathogen clearance in vitro and in vivo, enables comparison of dose-response across these systems, and eventually, to human epidemiology for scientifically based risk assessment of ENP.

描述（由申请人提供）：PNNL U19计划建立在纳米毒理学系统方法的现有专业知识基础上，以定量了解工程纳米材料（ENP）特性如何与生物系统相互作用，并最终驱动组织处置，生理反应以及引发或促进疾病的风险。我们的研究计划的主要创新之一是免费的体外和体外剂量测定模型的开发，它们通过提供跨系统外推剂量的方法，共同克服了使用体外系统进行危害排名的关键障碍。我们选择专注于巨噬细胞炎症和病原体清除，因为与高剂量细胞毒性相比，我们预计巨噬细胞这些关键的相关生理功能的破坏可以在低环境相关暴露下增加肺部感染的风险，如空气污染所示。我们的研究计划的组织围绕在生物组织和系统的多个层次的结果的整合，通过测量和模拟每个系统中的纳米颗粒靶细胞或组织剂量的生物相关措施，是从我们的跨学科团队的创新上升在纳米毒理学的先前综合研究。为了实现我们的目标，我们提出了3个项目，具有以下广泛的目标：项目1：提供ENP的物理化学和结构特征如何决定巨噬细胞摄取，内部运输，炎性体信号传导和吞噬细菌清除障碍的机制水平的理解，用于基于QSAR的危害排名和风险评估项目2：表征和模拟选定系列的难溶性ENP的肺部和全身药代动力学，并确定ENP特性和调节肺部炎症反应和肺炎易感性的遗传/表型因素，用于药代动力学建模和风险评估。项目三：开发一套完整的体外和体内纳米材料剂量测定模型，并将其应用于建立基于QSAR的危害等级人体暴露限值，该限值基于ENP对炎性小体的影响和吞噬细菌清除的损害。该多学科计划评估体外和体内的生物代谢、炎症反应和病原体清除，能够比较这些系统的剂量反应，最终，人类流行病学的科学基础上的风险评估ENP。