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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

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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

Society of Nuclear Medicine Midwinter Meeting - Albuquerque, NM

January 31-February 1, 2010


Outline
Outline Nanomaterials

  • Early fears over nanotechnology and nanomaterials

  • How do you assess safety?

  • Are all nanomaterials the same?

  • Why would nanomaterials be different?

  • Importance of characterization

  • Strategies and pitfalls

  • Examples: Carbon based nanomaterails

  • Take home key issues


Desirable applications of nanotechnology
Desirable Applications of Nanotechnology Nanomaterials

1. “Smart” therapeutics

2. Targeted molecular imaging agents

3. Biological sensors/

diagnostic tools

4. Tissue engineering

5. Nano-enabled products


Nano at niehs
Nano at NIEHS Nanomaterials

  • Funded by NIEHS

    • 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

Dept of Health

and Human Services (DHHS)

NIH

CDC

FDA

NIEHS

NIOSH

NCTR

DERT

DIR

NTP


Early fears
Early fears Nanomaterials

  • 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
“Early” studies on showing toxicity of nanotubes Nanomaterials

  • 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



Safety lack of risk risk hazard x exposure
Safety = lack of risk Nanomaterials Risk = hazard x exposure

  • Exposure assessment

  • Hazard identification

  • Hazard characterisation

  • Dose-response



Nano sized is already part of our knowledge base
“Nano-sized” is already part of our knowledge base Nanomaterials

Physical

Atomic

100 pm

1nm

10nm

100nm

1um

10um

100um

Dendrimers

Metal oxides

H2

C60

Nanosilver

H20

Quantum dots

Organic molecules

Gold Nanoshells

Grain of salt

Nanotubes

Proteins

Human cell

polymers

Dust Particles

Thickness of a cell membrane

Bacteria

Viruses



Diversity of nanomaterials
Diversity of nanomaterials Nanomaterials

Anatase Ti02

Fullerene C60 aggregates

Multiwalled Carbon Nanotubes

Rutile Ti02



General concerns over nanoscale vs microscale materials
General concerns over nanoscale vs microscale materials Nanomaterials

  • 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 ?



Contexts for use and exposure to nanoscale materials
Contexts for use and exposure to nanoscale materials Nanomaterials

  • 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
Increased uptake of nanoscale vs microscale particles Nanomaterials

  • 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




Effects may be related to surface area based dose
Effects may be related to surface area based “dose” Nanomaterials

  • 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
Surface area metrics: A key consideration Nanomaterials

Mass-based

Surface area-based

  • 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



Nanomaterial characterization requires new skills sets

Chemical: Nanomaterials

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

Nanomaterial characterization requires new skills sets


Nanotoxicology assessing the health hazards of engineered nanomaterials

“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


Nanotoxicology assessing the health hazards of engineered nanomaterials

New properties lead to new mode of action 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.”


Protein fibrillation in vitro induced by nanoparticles
Protein fibrillation in vitro induced by nanoparticles 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.”

  • 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


Nanotoxicology assessing the health hazards of engineered nanomaterials

Strategies and pitfalls 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.”


Nanotoxicology assessing the health hazards of engineered nanomaterials

Biological levels and hazard evaluation strategies 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.”


We have experimental strategies to detect hazards
We have experimental strategies to detect hazards 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.”

  • 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
Carbon-based NSMs 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.”

  • Fullerenes

    • eg C60 “Buckyballs”

  • Nanotubes”

    • Single walled (SWNT)

    • Multi walled (MWNT)

  • Nanofibres/nanofibrils

Source: J Nucl Med 48: 1039


Technegas
Technegas 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.”

  • 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
Pulmonary toxicity evaluation of Fullerene-C60 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.”

  • 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


Multiwalled nanotubes
Multiwalled nanotubes 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.”

  • Ma-Hock et al 2009

    • Nanocyl NC 7000

      • 5–15 nm x 0.1–10 µm, 250–300 m2/g

    • Exposure: head-nose exposed for 6 h/day, 5 days/week, 13 weeks

    • No systemic toxicity.

    • Increased lung weights, multifocal granulomatous inflammation, diffuse histiocytic and neutrophilic inflammation, and intra-alveolar lipoproteinosis in lung and lung-associated lymph nodes

      • 0.5 and 2.5 mg/m3.


Asbestos like activity of long mwcnt
“Asbestos like” activity of “long” MWCNT 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.”

  • Poland et al 2008

    • Nature Nanotech 3:423

  • Injection to C57Bl6 mice

    • 50ug or vehicle into peritoneal cavity

    • Evaluation at 7 days

  • Pathology

    • Inflammation

    • Foreign body Giant Cells

    • Granulomas

  • Long MWCNTs and long fibre amosite (LFA) gave similar responses

  • Tangled MWCNT gave different responses


No asbestos like activity of short tangled mwcnt
No “asbestos like” activity of short/tangled MWCNT 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.”

  • Muller et al 2009

    • Toxicol Sci 110; 442–448

  • 20 mg IP injection – male Wistar rats

    • 24 month followup

    • MWCNT +, MWCNT-, 11nm x 0.7um

    • Crocidolite asbestos 330 nm x 2.5um

  • Clear carcinogenic response with crocidolite but not MWCNT

  • Authors note

    • Model may not be responsive to short fibres

    • Consistent with Poland et al 2008


Key issues for the field of nanotoxicology
Key issues for the field of “nanotoxicology” 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.”

  • “Are nanomaterials safe?” = “Are chemicals safe?”

    • There is no single type of nanomaterial

  • Effects can scale with surface area

    • Paradigm shift in how we estimate “dose” for assessing risks relative to other agents.

  • Lack of adequate characterization of what a given “test article” is

    • Major obstacle to developing structure-activity relationships

  • Nanoscale phenomena occurs at the interface between chemical space and physical space.

  • Very limited information on exposures



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