Nanotoxicology: Assessing the Health Hazards of Engineered Nanomaterials Nigel Walker, PhD DABT National Toxicology Program National Institute of Environmental Health Sciences, NIH Research Triangle Park, North Carolina, USA Nanomedicine and Molecular Imaging Summit Society of Nuclear Medicine Midwinter Meeting - Albuquerque, NM
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Nanotoxicology: Assessing the Health Hazards of Engineered Nanomaterials
Nanotoxicology: Assessing the Health Hazards of Engineered Nanomaterials. Nigel Walker, PhD DABT National Toxicology Program National Institute of Environmental Health Sciences, NIH Research Triangle Park, North Carolina, USA Nanomedicine and Molecular Imaging Summit - PowerPoint PPT Presentation
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Nanotoxicology: Assessing the Health Hazards of Engineered Nanomaterials
Nigel Walker, PhD DABT
National Toxicology Program
National Institute of Environmental Health Sciences, NIH
Research Triangle Park, North Carolina, USA
Nanomedicine and Molecular Imaging Summit
Society of Nuclear Medicine Midwinter Meeting - Albuquerque, NM
January 31-February 1, 2010
Outline
• Early fears over nanotechnology and nanomaterials
– Division of Extramural Research and Training (DERT)
• Grants
• Training
• Research at NIEHS
– Division of Intramural Research (DIR)
– National Toxicology Program (NTP)
• Contract based research and testing
– DIR Investigator Initiated
• Application of nanotechnology in EHS
Early fears
• Self replicating nanobots
– “Grey goo” scenario
• Past examples of “technology gone wrong”
– Genetically Modified Organisms (GMO)
– Ethyl lead
– Asbestos
• “Fear of the unknown”
“Early” studies on showing toxicity of nanotubes
• Carbon nanotubes
• Lung granulomas after intratracheal instillation in rats and mice
– Warheit et al 2003
– Lam et al 2003
– Reaction to foreign particulate
• Supported by later studies
– Mueller et al 2005
• MWCNT
– Shvedova et al 2006
How do you assess safety?
Safety = lack of risk Risk = hazard x exposure
• Exposure assessment
• Hazard identification
• Hazard characterisation
• Dose-response
All nanomaterials are not the same
1nm 10nm 100nm 1um100 pm 10um
C60
Quantum dots
Gold Nanoshells
Nanotubes
Human cell
Grain of salt
H20
H2
100um
Thickness of a cell membrane
Organic molecules
Proteins
Dust Particles
Dendrimers
Viruses
Nanosilver
polymers
Metal oxides
Bacteria
“Nano-sized” is already part of our knowledge base
Atomic Physical
Diversity of size and shape of “nanomaterials”
Diversity of nanomaterials
Multiwalled Carbon Nanotubes
Fullerene C60 aggregates
Anatase Ti02
Rutile Ti02
Why would nanomaterials be different?
General concerns over nanoscale vs microscale materials
• Routes of exposure may differ
– Different portal of entry and target cell populations
• Different kinetics and distribution to tissues
– Due to size or surface coating/chemistry
• Higher exposure per unit mass
– Biological effects may correlate more closely a surface area dose metric
• Unique properties = unique modes of action ?
Routes of exposure and kinetics may differ
Contexts for use and exposure to nanoscale materials
• Materials may be “nano” in only certain contexts for exposure or applications
• The “nano”context may change through the materials life-cycle
– Bulk production
– Incorporation into products
– Use
– Disposal
– Environmental cycling
• Nanomaterials as “particles” in dispersed applications are likely to be of high initial concern than in “closed” or embedded applications
Hansen et al 2007
Increased uptake of nanoscale vs microscale particles
• Jani et al 1990.
• Uptake of polystyrene microspheres
– 50, 100, 300, 500, 1000 and 3000 nm
– Oral administration to female SD rats
• Size dependent increase in uptake
• As particle size changes so does the bioavailability
Size determines sites of deposition within the lung
Mass-based “dose” may be inadequate
Effects may be related to surface area based “dose”
• 1um cube
– e.g. respirable particle
– Surface area of = 6um2
• 100nm cube
– 1000 cubes is equivalent volume
– Surface area = 60 um2
• 10x more surface area for the same mass
Surface area metrics: A key consideration
• Particle number-based and surface area-based metrics increase with decreasing particle size
• Mass-based potency may differ, but surface area-based potency may not
• Requires studying particles of similar composition but varying particle size, coatings, shape or other physicochemical parameter
Mass-based Surface area-based
The importance of characterization
Nanomaterial characterization requires new skills sets
• Chemical:
– Unequivocal Identity
• Spectroscopic techniques
– Physical Constants
– Purity Determination
• Chromatographic Analyses – (Organics)
• Inductively Coupled Plasma/AES or MS, XRD - (Inorganics)
– Water Determination
– Elemental Analysis
– Constituents identified when at < 1 %, (primary and byproducts)
– Byproducts when between 0.1 and 1 %,
• Nanomaterial:
– Size, shape and size distribution
• Electron microscopy
• Atomic force microscopy
• Dynamic light scattering
– XRD-Crystalline state
– Surface area
• BET analysis
– Charge
• Zeta potential
– Surface chemistry
• Stoichiometry of targeting molecules on surface
“Indeed, in the absence of a careful and complete description of the nanoparticle-type being evaluated (as well as the experimental conditions being employed), the results of nanotoxicity experiments will have limited value or significance.”
David Warheit, Toxicological Sciences , 2008
New properties lead to new mode of action
Protein fibrillation in vitro induced by nanoparticles
• Linse et al 2007, PNAS 104,8691
• Induction of b2-microglubulin protein fibril formation in vitro
– Surface assisted nucleation
• Observed with multiple NPs
– 70, 200 nm NIPAM/BAM NPs
– 16nm Cerium oxide NPs
– 16nm quantum dots
– 6nm dia MWCNTs
• Fibril formation is implicated in development of human disease
– Alzheimer's
– Creutzfeldt-Jakob disease
– Dialysis related amyloidosis
Strategies and pitfalls
Biological levels and hazard evaluation strategies
We have experimental strategies to detect hazards
• In vivo toxicity testing models can detect manifestations of novel mechanisms of action if there are any.
– Based on apical endpoints
• Several workshops/reports with common issues/recommendations
– NTP workshop on Experimental strategies
• University of Florida-Nov 2004
• http://ntp.niehs.nih.gov/go/100
– ILSI-RSI report
• Oberdorster et al 2005, Particle Fibre Toxicol 2:8
• Use of both in vivo and in vitro approaches
• Need comprehensive physical/chemical characterizations
Carbon-based NSMs
• Fullerenes
– eg C60 “Buckyballs”
• Nanotubes”
– Single walled (SWNT)
– Multi walled (MWNT)
• Nanofibres/nanofibrils
Source: J Nucl Med 48: 1039
Technegas
• Diagnostic radio-aerosol used in lung ventilation scintigraphy
• Technegas is comprised of nanoparticles
• Mesoscopic fullerenes
– Hexagonal platelets of metallic technetium, each closely encapsulated with a thin layer of graphitic carbon.
• Size: 30-60nm X 5nm
• Selden et al J Nucl Med 1997; 38:1327-1333
Pulmonary toxicity evaluation of Fullerene-C60
• NTP inhalation study conducted under GLP
– 90 days-nose only exposure, 3hrs/day, 5d/wk
– B6C3F1 mice and Wistar-Han rats,
– 50nm (0.5 and 2 mg/m3)
– 1um (2, 15 and 30 mg/m3 )
• Preliminary findings
– Shorter clearance in mouse vs rat
• Not different by size
– No biologically significant toxic responses
– Expected response to particles
– Comparable surface area-based doses between 50nm and 1um study