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程序建立在纳米毒理学方法中的现有专业知识的基础上，以对工程纳米材料（ENP）特性如何与生物系统相互作用，并最终驱动组织处置，生理应对以及起始或促进疾病的风险。我们研究计划的主要创新之一是开发免费的体外和体外剂量测定模型，这些模型共同克服了将体外系统用于危害排名的关键障碍，通过提供跨系统的推断剂量的方法。我们选择着重于巨噬细胞炎症和病原体清除率，因为与高剂量的细胞毒性相反，我们希望这些关键的，连接的巨噬细胞的破坏巨噬细胞可以增加在低，环境相关的暴露率下增加肺部感染的风险，如空中污染所示。通过测量和模拟每个系统中纳米颗粒靶细胞或组织剂量的生物学相关测量方法，我们的研究计划的组织围绕生物组织和系统的结果整合，这是我们跨学科团队先前的纳米毒理学整合研究的创新。为了实现我们的目标，我们提出了3个具有以下广泛目标的项目：项目1：对ENP的物理化学化学和结构特征提供一个机械级别的了解，该理解如何决定巨噬细胞的吸收，内部贩运，炎症体信号传导，炎症的信号传导和吞噬细菌的障碍，用于贫穷的细菌清除量，以在基于QSAR的危害和模型中使用QSAR的危险和模型。可溶性ENP并识别ENP的特性以及遗传/表型因子，这些因素调节对肺部炎症的反应以及对肺炎的易感性用于药代动力学建模和风险评估。项目3：开发一套完整的体外和体内纳米材料剂量模型，并根据ENP对ENP对炎症和障碍的吞噬细菌清除的影响，将其用于基于QSAR的危险等级，以相比，该多学科响应，并确定生物基因的疾病，并确定生物基因的评估，并确定吞噬细菌的障碍，并确定生物基础的疾病，并确定了疾病的范围。这些系统之间的剂量反应，最终是人类流行病学，以基于科学的ENP风险评估。