günter oberdorster_how to assess the risks of nanotechnology?
DESCRIPTION
Plenary session 1TRANSCRIPT
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The Responsible Development of Nanotechnology:
Challenges and Perspectives
Ne3LS Network International Conference 2012
November 1-2, 2012, Montréal, Canada
Plenary Session 1:
How to assess the risks of nanotechnology?
Analysis and discussion of the various risk facets
Günter Oberdörster Department of Environmental Medicine
University of Rochester
November 1, 2012
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OUTLINE
Introductory remarks
Nanoparticle characteristics
Dosing the respiratory tract
Nanoparticle Biokinetics
Nanoparticle – protein interactions
Hazard/Risk characterization
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Introductory Remarks
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Nanoscale Materials
Gold
Nanoshell
Nanometers
10-1 1 10 102 103 104 105 106 107 108
Carbon
Nanotube
Bucky-ball ZnO Nanorods
Water Glucose Antibody Virus Bacteria Cancer Cell A Period Tennis Ball
Nano-onion
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NANOTECHNOLOGY
THE BRIGHT! and THE DARK?
Multiple Applications/Benefits Consumer Fears/Perceived Risks
• Structural Engineering
• Electronics, Optics
• Food and Feed Industry
• Consumer Products
• Alternative Energy
• Soil/Water Remediation
• Nanomedicine: – therapeutic – diagnostic – drug delivery – cancer – nanosensors – nanorobotics
• Safety: Potential adverse effects
• Environmental Contamination
• Inadvertent Exposure (inhalation, dermal, ingestion)
• Susceptible Subpopulation
• Societal Implications
• Nanotoxicology:
Safety Assessment of engineered Nanomaterials and of Nanotechnology enabled Applications
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Some Headlines in the Popular Press:
Nanoparticles (NPs)
kill workers
cause cancer
damage DNA
soften your brain
cause lung damage
cause genetic damage
in sunscreen cause Alzheimer’s?
are carbon nanotubes the next asbestos?
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All NPs are “toxic”
Appreciation of Reality
Effects and Biokinetics
of UFP (1990s)
Nanotoxicology - Hype Cycle
Increasing Insight of
Nanotox Concepts
Time
Haza
rd Realistic Assessment of Hazard and Risk
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From: Slikker Jr., et al. 2004
Conceptual Depiction of Factors for Considering
Dose-dependent Transitions in Determinants of Toxicity
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…
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…
Nano TiO2 repeated bolus instillation into mouse:
7.5 mg into mouse = 17.5 grams into human nose!
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17.5 g TiO2 (P25)
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DPPC/Alb-Dispersed Mitsui Multiwalled Carbon
Nanotubes (MWCNTs)
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Induction of mesothelioma in p53+/- mouse by intraperitoneal
application of multi-wall carbon nanotube
Takagi et al., J. Toxicol. Sci. 33 (No. 1): 105-116, 2008
Carbon nanotubes introduced into the
abdominal cavity of mice show asbestos-like
pathogenicity in a pilot study CRAIG A. POLAND, RODGER DUFFIN, IAN KINLOCH, ANDREW MAYNARD, WILLIAM A. H. WALLACE, ANTHONY SEATON, VICKI STONE, SIMON BROWN WILLIAM MACNEE, AND KEN DONALDSON
Nature Nanotechnology/Vol. 3/July 2008
Induction of mesothelioma by a single intrascrotal administration
of multi-wall carbon nanotube in intact male Fischer 344 rats Sakamoto et al, J.Tox. Sci., 34, 65-76, 2009
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MWCNT in Subpleural Tissues, Visceral Pleura and Pleural Space of Mice Following Oro-Pharyngeal
Aspiration (80 µg) From: Mercer et al., 2010
VP: visceral pleura; Mac: alveolar macrophage; Mo: monocyte; Ly: lymph vessel; PS: pleural space
Day 28
Day 56
Day 28
Day 56
VP VP Mac
VP
VP
Ly
Mo
PS
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Many Challenges in Nanotoxicology
Which testing strategy to assess environmental and
human safety (EHS) concerns?
• in vitro – in vivo design/methodologies
• acute – chronic toxicities
• dose, dosimetry, dosemetric related issues
• correlations between phys.chem. properties and toxicity
• nano-bio interactions: corona formation
• risk extrapolation: laboratory animals to humans
• human exposure assessment
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ENM Synthesis Sources
Exposure
Pathways
Receptor
Interactions
Risk Assessment
Predictive
Models
Characterization – Properties
Life Cycle Releases
From Cradle to Grave
Dispersion, Transformation
Air, Water, Soil, Sediment
Exposure Assessment
Environment; Human
Hazard Characterization
Eco/Human Toxicity
Risk Characterization
Bioinformatics
Predicting nanostructure- induced responses
Safety Assessment of Engineered Nanomaterials
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Nanoparticle Characteristics
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What is different: Nanoparticles vs Larger Particles (respiratory tract as portal-of-entry)
Nanoparticles (<100 nm) Larger Particles (>500 nm) General characteristics:
Ratio: number/surface area/volume high low
Agglomeration in air, liquids likely (dependent on medium; surface) less likely
Deposition in respiratory tract diffusion; throughout resp. tract sedimentation, impaction, inter- ception; throughout resp. tract
Protein/lipid adsorption in vitro very effective and important for bio- less effective kinetics and effects
Translocation to secondary target organs: yes generally not (to liver under “overload”)
Clearance
— mucociliary probably yes efficient
— alv. macrophages poor efficient
— epithelial cells yes mainly under overload
— lymphatic yes under overload
— blood circulation yes under overload
— sensory neurons (uptake + transport) yes not likely
Proteinl/lipid adsorption in vivo yes some
Cell entry/uptake yes (caveolae; clathrin; lip. rafts; diffusion) yes (primarily phagocytic cells)
— mitochondria yes no
— nucleus yes (<40 nm) no
Effects (caveat: dose!) :
at secondary target organs yes (no)
at portal of entry (resp. tract) yes yes
— inflammation yes yes
— oxidative stress yes yes
— activation of signaling pathways yes yes
— genotoxicity, carcinogenicity probably yes some
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Fine, 250nm
Ultrafine, 25 nm
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Physico-chemical NP Properties of Relevance for Toxicology
Size (aerodynamic, hydrodynamic)
Size distribution
Shape
Agglomeration/aggregation
Density (material, bulk)
Surface properties:
- area (porosity)
- charge
- reactivity
- chemistry (coatings, contaminants)
- defects
Solubility/Sol-Rate (lipid, aqueous, in vivo)
Crystallinity
Biol. contaminants (e.g. endotoxin)
Properties can change
-with: method of production
preparation process
storage
-when introduced into
physiol. media, organism
Key parameter: Dose!
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Particle Number and Particle Surface Area per 10 pg/cm3 Airborne Particles
(Unit density particles)
Particle Diameter Particle Number Particle Surface Area
nm N/cm3 µm2/cm3
5 153,000,000 12,000
20 2,400,00 3,016
250 1,200 240
5,000 0.15 12
Small size, high number per mass, and surface chemistry
confer both desirable and undesirable properties.
Detailed Physico-chemical characterization of NP is essential.
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0%
10%
20%
30%
40%
50%
60%
1 10 100 1000 10000
Dp [nm]
Ns/NNs/N
Surface Molecules as Function of
Particle Size
From Fissan, 2003
Diameter (nm)
% S
urf
ace
Mo
lecu
les
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0 500 1000 1500 20000
10
20
30
40
50ultrafine TiO2 (20nm)pigment grade TiO2 (~200nm)saline
Particle Mass, ug
% N
eu
tro
ph
ils
0
10
20
30
40Fine TiO2 (~250nm)
UltrafineTiO2 (~20nm)
108 10 9 1010 1011 10 12 1013
Particle Number
% N
eu
tro
ph
ils
Percent of Neutrophils in Lung Lavage 24 hrs after Intratrachael Dosing of Ultrafine and Fine TiO2 in Rats
Particle Mass vs Particle Number
▲ Fine TiO2 (200nm) ■ Ultrafine TiO2 (25nm) ● Saline
Which Dose-Metric?
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0 50 100 150 200 250 0
10
20
30
40
50
ultrafine TiO 2 (~25nm) fine TiO 2 (~200nm) saline
Percent of Neutrophils in BAL 24 hrs after Instillation of TiO 2 in Rats
Correlation with Particle Surface Area
Particle Surface Area, cm 2
% N
eu
tro
ph
ils
Which Dose-Metric?
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Dosing the Respiratory Tract
Impact of Dose-Rate
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Tracheobronchial
Nasal Pharyngeal
Laryngeal
Alveolar
TOTAL
0.0001 0.001 0.01 0.1 1 10 100 0.0
0.2
0.4
0.6
0.8
1.0
Diameter (µm) D
ep
osi
tio
n F
racti
on
Dep
osi
tion
Mech
an
ism
s
Diffusion
Sedimentation
Impaction
Total deposition
Fractional Deposition of Inhaled Particles in the Human Respiratory Tract (ICRP Model, 1994; Nose-breathing)
Thoracic Respirable Inhalable
< 100um < 30um < 10um
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High
more material; d– as dry powder aerosol; liquid aerosolization methods likely require addition of dispersant
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High
more material; d– as dry powder aerosol; liquid aerosolization methods likely require addition of dispersant
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From: Morello et al., 2009
Intratracheal Instillation of Particle Suspension, Rat
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Comparing Responses when the same Lung Dose of TiO2 Nanoparticles
is administered by Inhalation or intratracheal Instillation
4 Groups of Rats:
1. Controls (instillation of saline)
2. 200 µg TiO2 (25 nm) instillation into lungs
3. Four hour inhalation to deposit 200µg TiO2 into lungs
4. Four days of 4 hour daily inhalation to deposit 200µg TiO2 into lungs
24 hours after dosing lungs were lavaged and inflammatory cellular and biochemical parameters determined
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Dose-Rate matters as Determinant of Hazard
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Biokinetics andTranslocation
of Inhaled Nanoparticles
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Exposure Media
Uptake Pathways
Translocation
and Distribution
Excretory
Pathways
Air, water, clothes Air Food, water
Skin
Respiratory Tract
GI-tract
Blood Liver
Lymph
Bone Marrow Spleen
Urine Feces
Deposition Ingestion Inhalation
Other sites (e.g. muscle, placenta)
(platelets, monocytes, endothelial cells)
Breast Milk
Heart
Sweat/exfoliation
Drug Delivery
Injection
Confirmed routes
Potential routes
Lymph
trach- nasal bronchial alveolar
CNS
PNS
Exposure and Biokinetics of Nanoparticles
Kidney
(Modified from Oberdörster et al., 2005)
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Exposure Media
Uptake Pathways
Translocation
and Distribution
Excretory
Pathways
Air, water, clothes Air Food, water
Skin
Respiratory Tract
GI-tract
Blood Liver
Lymph
Bone Marrow Spleen
Urine Feces
Deposition Ingestion Inhalation
Other sites (e.g. muscle, placenta)
(platelets, monocytes, endothelial cells)
Breast Milk
Heart
Sweat/exfoliation
Drug Delivery
Injection
Confirmed routes
Potential routes
Lymph
trach- nasal bronchial alveolar
CNS
PNS
Exposure and Biokinetics of Nanoparticles
Kidney
(Modified from Oberdörster et al., 2005) Translocation rates are very low!
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Exposure Media
Uptake Pathways
Translocation
and Distribution
Excretory
Pathways
Air, water, clothes Air Food, water
Skin
Respiratory Tract
GI-tract
Blood Liver
Lymph
Bone Marrow Spleen
Urine Feces
Deposition Ingestion Inhalation
Other sites (e.g. muscle, placenta)
(platelets, monocytes, endothelial cells)
Breast Milk
Heart
Sweat/exfoliation
Drug Delivery
Injection
Confirmed routes
Potential routes
Lymph
trach- nasal bronchial alveolar
CNS
PNS
Exposure and Biokinetics of Nanoparticles
Kidney
GI-tract and kidney as major excretory organs (Modified from Oberdörster et al., 2005)
?
Respiratory Tract
GI-tract
Blood Liver
Urine
(platelets, monocytes, endothelial cells)
Lymph
trach- nasal bronchial alveolar
CNS
PNS
Kidney
Translocation and Elimination Pathways from Respiratory Tract
<~6 nm
GI-tract and kidney as major excretory organs
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FROM RESPIRATORY TRACT TO BRAIN:
POTENTIAL TRANSLOCATION PATHWAYS OF NANOPARTICLES
CSF: Cerebrospinal Fluid
BBB: Blood-Brain Barrier
CSBB: Cerebrospinal Brain Barrier
Inh
aled
Na
no
pa
rticles
Nose Olfactory Mucosa Nasopharyngeal Mucosa
Lymph CSF
Brain Olfactory Bulb Trigem. Ganglion
Blood BBB
Lower Respirat.
Tract
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0.0
0.2
0.4
0.6
0.8
1.0
Unexposed Exposedright nostril occluded
Rat, Right Nostril Occlusion Model: Accumulation of Mn in Right and left Olfactory Bulb 24 Hours after Exposure to Ultrafine (~30nm) Mn Oxide Particles (n=3-5, mean+/-SD)
left olfactory bulb right olfactory bulb
ng
Mn
/mg
w
et
weig
ht
Elder et al, 2006
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Mn concentration in lung and brain regions of rats following 12 days ultrafine Mn-oxide exposure (mean +/- SD)
0.0
0.5
1.0
1.5
2.0
Control 12 days
Lung Olfactory Trigeminal Striatum Midbrain Frontal Cortex Cerebellum Cortex
*
*
* *
*
ng
Mn
/mg
we
t w
t
(465 µg/m3; 17x106 part./cm3; CMD: 31 nm; GSD: 1.77)
Elder et al, 2006
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Inflammation in the Brain Regions where
Mn Signal was Found
0
1
2
3
4
5
6
7
8
Neurogenin
MnSOD
NCAM
Na-K-Cl co-trans.
ATP-rel. K-channel
TNF-a
MIP-2
GFAP
Olfactory
Bulb
CerebellumStriatumMidbrainFrontal
Cortex
Controls
Rel
ati
ve
Inte
nsi
ty,
fold
in
crea
se
0
10
20
30
40
Rel
ati
ve
Inte
nsi
ty, fo
ld i
ncr
ease
Olfactory
Bulb
CerebellumStriatumMidbrainFrontal
Cortex
mRNA Levels TNF- Protein
Elder et al, 2006
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Protein Adsorption on Nanoparticles
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NP physicochemical properties: •Size
•Surface size and chemistry
•Charge
•Surface hydrophobicity
•Redox activity
•Others
Body compartment media: •Respiratory tract lining fluid
•Gastrointestinal milieu
•Plasma proteins
•Other mucosal membranes
•Intra/extracellular fluid
protein/lipid adsorption and desorption patterns
biodispersion across barriers and in target tissues/cells
determine
determine
“Concept of Differential Adsorption” Modified from Müller and Heinemann, 1989
Altered plasma composition in disease state is likely to change adsorption pattern
+
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Two Layers of Proteins of the “Core” Nanoparticle :
An outer “weak” layer of protein corona And an inner “hard”layer of stable, rapidly exchanging with free proteins slowly exchanging corona of proteins (red arrows)
From: Walczyk et al., 2010
Nano – Bio Interactions Schematic drawing of the structure of NP-protein complexes in plasma:
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kDa
Albumin
Adsorption of Proteins (FBS) Is Inhibited by Surfactant Coating (Pluronic F127) (SDS PAGE)
(Dutta et al., 2007)
Casein Proteins
Hemoglobulins
Lactoglobulin
SWCNT BET surface 274 m2/g
Silica NP (10 nm) BET surface 212 m2/g
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From: Dutta et al., 2007
Cytotoxicity of 10 nm SiO2 in RAW264.7 Cells (18 hr. incubation)
Is Inhibited by Surfactant Treatment (Pluronic F127)
+
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Hazard and Risk Characterization
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Adverse NP Effect: at portal of entry and remote organs
Experimental Animals
Humans
Biological Monitoring (markers of exposure)
Occupational/ Environmental Monitoring
Public health/social/ economical/political consequences
Regulations Expos. Standards
Prevention/Intervention Measures Biomed./Engineering
Exposure-Dose- Response Data
In Vivo Studies (acute; chronic)
In Vitro Studies (non-cellular) (animal/human cells) (subcellular distribution)
Risk Calculation
Susceptibility Extrapolation Models (high low) (animal human)
Mechanistic Data
Risk Assessment and Risk Management Paradigm For Engineered Nanoparticles (NPs)
Inhalation Ingestion, Dermal
Biokinetics!
Dose-Metric!
Physico-chemical
Parameters!
Modified from Oberdörster et al., 2005
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Adverse NP Effect: at portal of entry and remote organs
Experimental Animals
Humans
Biological Monitoring (markers of exposure)
Occupational/ Environmental Monitoring
Public health/social/ economical/political consequences
Regulations Expos. Standards
Prevention/Intervention Measures Biomed./Engineering
Exposure-Dose- Response Data
In Vivo Studies (acute; chronic)
In Vitro Studies (non-cellular) (animal/human cells) (subcellular distribution)
Risk Calculation
Susceptibility Extrapolation Models (high low) (animal human)
Mechanistic Data
Risk Assessment and Risk Management Paradigm For Engineered Nanoparticles (NPs)
Inhalation Ingestion, Dermal
Biokinetics!
Dose-Metric!
Physico-chemical
Parameters!
Modified from Oberdörster et al., 2005
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in vivo Humans Workplace Laboratory Consumer
in vitro Bolus; ALI Target cells,
Tissues Dose-Response
in vivo Animals
Biokinetics (translocation;
corona formation) Dose-Response
Phys-chem. Properties Target Organs Respirability
NOAELs; OELs; HECs
Phys-chem. Properties Endpoints; Ref. Material Hi-Lo Dose; Relevancy
Mechanisms Reproducibility
Exposure (assessment) Hazard (characterization)
Risk Assessment
Considering Exposure and Hazard for Risk Assessment
Concepts of Nanomaterial Toxicity Testing:
Inhal/ Bolus ( )
Long-term
In silico models
Dose - Response Exposure – Dose - Response
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Dosimetric Extrapolation of Inhaled Particles from Rats to Humans
Rat Human
Exposure [mg(m3)-1] Exposure (HEC) [mg(m3)-1]
Inhaled Dose [mg(kg)-1] Inhaled Dose [mg(kg)-1]
Deposited Dose µg(cm2)-1;
µg(g)-1
Deposited Dose µg(cm2)-1;
µg(g)-1
Retained (Accumulated) Dose [µg(g)-1; µg(cm2)-1]
Effects
Assumption: If retained dose is the same as in rats and humans, then effects will be the same
Breathing
Minute
Volume
Tidal Volume, Resp. Rate Resp. Pause
Particle characteristics Anatomy
Clearance Retention
Regional Uptake (Metabolism, T½)
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Two Subchronic MWCNT Inhalation Sudies in Rats