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.
Conventional safety assessment, involving on chronic rodent bioassays, is widely recognized to be too time and resource consuming for successful application to the vast number of engineered nanoparticles in commerce or development. The PNNL's integrated in vitro/ in vivo experimental discovery platforms and dosimetry tools, we will deliver the first complete experimental and computational framework for hazard and risk assessment of ENP for a clinically relevant endpoint that can be readily adapted to additional ENP.
|Thomas, Dennis G; Smith, Jordan N; Thrall, Brian D et al. (2018) ISD3: a particokinetic model for predicting the combined effects of particle sedimentation, diffusion and dissolution on cellular dosimetry for in vitro systems. Part Fibre Toxicol 15:6|
|Duan, Jicheng; Kodali, Vamsi K; Gaffrey, Matthew J et al. (2016) Quantitative Profiling of Protein S-Glutathionylation Reveals Redox-Dependent Regulation of Macrophage Function during Nanoparticle-Induced Oxidative Stress. ACS Nano 10:524-38|
|Baer, Donald R; Munusamy, Prabhakaran; Thrall, Brian D (2016) Provenance information as a tool for addressing engineered nanoparticle reproducibility challenges. Biointerphases 11:04B401|
|Wang, Yung-Chen; Engelhard, Mark H; Baer, Donald R et al. (2016) Quantifying the Impact of Nanoparticle Coatings and Nonuniformities on XPS Analysis: Gold/Silver Core-Shell Nanoparticles. Anal Chem 88:3917-25|
|Holland, Nathan A; Thompson, Leslie C; Vidanapathirana, Achini K et al. (2016) Impact of pulmonary exposure to gold core silver nanoparticles of different size and capping agents on cardiovascular injury. Part Fibre Toxicol 13:48|
|Cartwright, Megan M; Schmuck, Stefanie C; Corredor, Charlie et al. (2016) The pulmonary inflammatory response to multiwalled carbon nanotubes is influenced by gender and glutathione synthesis. Redox Biol 9:264-275|
|Baer, Donald R; Wang, Yung-Cheng; Castner, David G (2016) Use of XPS to Quantify Thickness of Coatings on Nanoparticles. Micros Today 24:40-45|
|Scoville, David K; White, Collin C; Botta, Dianne et al. (2015) Susceptibility to quantum dot induced lung inflammation differs widely among the Collaborative Cross founder mouse strains. Toxicol Appl Pharmacol 289:240-50|
|Szymanski, Craig J; Munusamy, Prabhakaran; Mihai, Cosmin et al. (2015) Shifts in oxidation states of cerium oxide nanoparticles detected inside intact hydrated cells and organelles. Biomaterials 62:147-54|
|Holland, N A; Becak, D P; Shannahan, Jonathan H et al. (2015) Cardiac Ischemia Reperfusion Injury Following Instillation of 20 nm Citrate-capped Nanosilver. J Nanomed Nanotechnol 6:|
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