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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19ES019544-03
Application #
8274452
Study Section
Special Emphasis Panel (ZES1-SET-V (03))
Program Officer
Nadadur, Srikanth
Project Start
2010-09-28
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$1,184,658
Indirect Cost
$514,646
Name
Battelle Pacific Northwest Laboratories
Department
Type
DUNS #
032987476
City
Richland
State
WA
Country
United States
Zip Code
99352
Larson, Jeremy K; Carvan 3rd, Michael J; Teeguarden, Justin G et al. (2014) Low-dose gold nanoparticles exert subtle endocrine-modulating effects on the ovarian steroidogenic pathway ex vivo independent of oxidative stress. Nanotoxicology 8:856-66
Sharma, Gaurav; Kodali, Vamsi; Gaffrey, Matthew et al. (2014) Iron oxide nanoparticle agglomeration influences dose rates and modulates oxidative stress-mediated dose-response profiles in vitro. Nanotoxicology 8:663-75
Cohen, Joel M; Teeguarden, Justin G; Demokritou, Philip (2014) An integrated approach for the in vitro dosimetry of engineered nanomaterials. Part Fibre Toxicol 11:20
Minard, Kevin R; Littke, Matthew H; Wang, Wei et al. (2013) Magnetic particle detection (MPD) for in-vitro dosimetry. Biosens Bioelectron 43:88-93
Kodali, Vamsi; Littke, Matthew H; Tilton, Susan C et al. (2013) Dysregulation of macrophage activation profiles by engineered nanoparticles. ACS Nano 7:6997-7010
Techane, Sirnegeda; Baer, Donald R; Castner, David G (2011) Simulation and modeling of self-assembled monolayers of carboxylic acid thiols on flat and nanoparticle gold surfaces. Anal Chem 83:6704-12
Zhang, Haizhen; Burnum, Kristin E; Luna, Maria L et al. (2011) Quantitative proteomics analysis of adsorbed plasma proteins classifies nanoparticles with different surface properties and size. Proteomics 11:4569-77