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![Page 1: Considerations for Characterizing the Potential Health Effects from Exposure to Nanomaterials David B. Warheit, PhD. DuPont Haskell Laboratory Newark,](https://reader036.fdocuments.us/reader036/viewer/2022070323/56649d9f5503460f94a8ac22/html5/thumbnails/1.jpg)
Considerations for Characterizing the Potential Health Effects from
Exposure to Nanomaterials
David B. Warheit, PhD.
DuPont Haskell Laboratory
Newark, Delaware, USA
NNI-NIST Workshop
Gaithersburg, MD
September 13, 2007
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Outline• Particle characterization as it relates to
• particle deposition, macrophage interactions, particle translocation
• Particle characterization for 5 studies
• Fine/Ultrafine TiO2 particle types;
• Fine/Nanoscale Quartz particle-types;
• Summary - Recommendations
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Rat Lung Microdissection
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Rat Lung Tissue Dissected to Demonstrate the Junction of the Terminal Airway and Proximal Alveolar Region
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Iron Particle Deposition at Bronchoalveolar Junction
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Iron Particle () Deposition in the Lungs of Exposed Rats
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Iron Particle Deposition at Bronchoalveolar Junction
(Backscatter Image)
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Alveolar Macrophage Clearance of Inhaled Iron Particles
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Alveolar Macrophage Clearance of Inhaled Iron Particles
(Backscatter Image)
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Alveolar Macrophage Migration to Iron Particle Deposition and Phagocytosis
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Alveolar Macrophage Migration to Iron Particle Deposition and Phagocytosis
(Backscatter Image)
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Macrophage phagocytosis of TiO2 particles
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Two Alveolar Macrophages (M) Sharing a Chrysotile Asbestos Fiber () with an Alveolar Epithelial Cell (E)
MM E
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TEM demonstrating pathways for possible translocation of particles
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Translocation of chrysotile asbestos fibers from airspace to epithelium
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1) Pulmonary Instillation Studies with Nanoscale TiO2 Rods and Dots in Rats: Toxicity is not dependent upon
Particle Size and Surface Area. Toxicol Sci., 2006
• Material characterization employed in this study:• synthesis method• crystal structure • particle size • surface area • composition/surface coating • aggregation status • cryo TEM • crystallinity • purity (TGA)
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2) Pulmonary bioassay studies with nanoscale and fine quartz particles in rats: Toxicity is not dependent upon particle size but on surface characteristics. Toxicol Sci.
2007
• Material characterization employed in this study:
• synthesis method • crystal structure/crystallinity (XRD)• median particle size - particle size (range) • purity (% Fe content)– ICP-AES • surface area • TEM • aggregation status• purity• surface reactivity (erythrocyte hemolysis)• reactive oxygen species (ESR) •
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3) Pulmonary Toxicity Study in Rats with Three Forms of ultrafine-TiO2 Particles: Differential Responses
related to Surface Properties Toxicology, 2007
• Material characterization employed in this study:• crystal phase• median particle size and size distribution in water and
PBS• pH in water and PBS• surface area (BET)• TEM • aggregation status, • chemical (surface) reactivity – (Vitamin C assay) • surface coatings/composition, purity
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4) Assessing toxicity of fine and nanoparticles: Comparing in vitro measurements to in vivo pulmonary toxicity
profiles. Toxicol Sci. 2007.• Particle-types utilized in this study:• Fine-sized carbonyl iron• Fine-sized crystalline silica• Fine-sized amorphous silica• Nano ZnO• Fine ZnO
• Particle characterizations conducted both in the “dry state” and “wet state”
• Material characterization employed in this study:• Particle characterization in the dry state• particle size - surface area – density - crystallinity• calculated size in dry state (based on surface area
determinations) • purity
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4) Assessing toxicity of fine and nanoparticles: Comparing in vitro measurements to in vivo pulmonary toxicity
profiles. Toxicol Sci. 2007. (cont)
• Particle characterization in the wet state• particle size in solutions – PBS, culture media, water
• average aggregated size in solutions,
• % distribution
• surface charge
• aggregation status
•
• Conversion and comparisons of in vitro and in vivo doses for dosimetric comparisons
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5) Comparative Pulmonary Toxicity Assessments of C60 Water Suspensions in Rats: Few Differences in Fullerene
Toxicity In Vivo in Contrast to In Vitro Profiles. Nano Lett. 2007.
• Material characterization employed in this study:• particle size and size distribution• surface charge • crystallinity • TEM • composition • oxidative radical activity (ESR measurements) • surface reactivity (erythrocyte hemolytic potential)
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Recommendations for Minimal Essential Material Characterization for Hazard
Studies with Nanomaterials
• Particle size and size distribution (wet state) and surface area (dry state) in the relevant media being utilized – depending upon the route of exposure;
• Crystal structure/crystallinity;• Aggregation status in the relevant media;• Composition/surface coatings;• Surface reactivity;• Method of nanomaterial synthesis and/or
preparation including post-synthetic modifications (e.g., neutralization of ultrafine TiO2 particle-types);
• Purity of sample;
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Studies to Assess Pulmonary Hazards to Nanoparticulates
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Ultrafine TiO2 Studies
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Pulmonary Toxicity Study in Rats with Three Forms of ultrafine-TiO2
Particles: Differential Responses related to Surface Properties
Toxicology 230: 90-104, 2007
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Characterization of Ultrafine TiO2 Particle-types - 1
uf-3
C
300 nm
uf-2
B
300 nm
uf-1
A
300 nm
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Characterization of Ultrafine TiO2 Particle-types - 2
SampleCrystalline
phase
Median size and width distribution
(nm) Surface area
(m2/g)
pHChemical reactivity
in water* in PBSdeionized water
in PBS
delta b*
F-1 rutile382.0± 36%
2667.2 ± 35% 5.8 7.49 6.75 0.4
uf-1 rutile136.0± 35%
2144.3± 45% 18.2 5.64 6.78 10.1
uf-2 rutile149.4± 50%
2890.7± 31% 35.7 7.14 6.78 1.2
uf-380/20
anatase/ rutile
129.4± 44%
2691.7± 31% 53.0 3.28 6.70 23.8
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Protocol for ultrafine TiO2 Pulmonary Bioassay Study
Exposure Groups• PBS (vehicle control)• Particle-types (1 and 5 mg/kg)
o rutile-types uf-1 TiO2
o rutile-type uf-2 TiO2
o anatase/rutile-type uf-3 TiO2
o rutile-type F-1 fine TiO2 (negative control)o α-Quartz particles (positive control)
Instillation Exposure
24 hr 1 wk 1 mo 3 mo
Postexposure Evaluation via BAL and Lung Tissue
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RESULTSBiomarkers
Pulmonary InflammationPulmonary CytotoxicityLung cell Proliferation
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Pulmonary Inflammation
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BAL Fluid LDH Values (cytotoxicity)
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Pulmonary Cell Proliferation Rates
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Lung Sections of Rats exposed to uf-1 (A); uf-2 (B); or F-1 (C)- 3 months pe
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Lung Section of Rat exposed to uf-3 3 months postexposure
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Lung Section of Rat exposed to Quartz particles - 3 months postexposure
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Nanoscale Quartz
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Pulmonary Bioassay Studies with Nanoscale and Fine Quartz Particles
in Rats: Toxicity is not Dependent upon Particle Size but on Surface
Characteristics
Toxicol Sci. 95:270-280, 2007
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Nanoscale Quartz Particles
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Characterization of Nanoscale Quartz Particles
Sample
Average size (nm)
Size range
(nm)
Surface area (m2/g) Crystallinity
ICP-AES (% Fe content)
Nanoquartz I 50 30-65 31.4 α-Quartz 0.080%
Nanoquartz II 12 10-20 90.5α-Quartz
0.034%
Fine quartz 300 100-500 4.2α-Quartz
0.011%
Min-U-Sil 534 300-700 5.1α-Quartz
0.042%
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Pulmonary Inflammation – Nanoscale Quartz study
Percent Neutrophils in BAL Fluids of Rats exposed to Fine and Nano-sized Quartz Particles (Study #2)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
5 mg/kg 1 mg/kg 5 mg/kg 1 mg/kg 5 mg/kg 1 mg/kg 5 mg/kg
PBS CarbonylIron
particles
Min-U-Sil quartz particles Nano quartz II particles Fine quartz particles
Exposure Groups
% P
MN
s
24 Hour 1 Week 1 Month 3 Month
**
*
***
*
*
***
*
*
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BAL Fluid LDH Values – Nanoscale Quartz study
BAL Fluid LDH Values in Rats exposed toFine and Nano-sized Quartz Particles (Study #2)
0
100
200
300
400
500
600
700
800
0.5 mls 5 mg/Kg 1 mg/Kg 5 mg/Kg 1 mg/Kg 5 mg/Kg 1 mg/Kg 5 mg/Kg
PBS CarbonylIron
particles
Min-U-Sil quartz particles Nano quartz II particles Fine quartz particles
Exposure Groups
BA
L f
luid
LD
H v
alu
es
(u/L
)
24 Hour 1 Week 1 Month 3 Month
*
*
*
*
**
*
*
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Lung Parenchymal Cell Proliferation– Nanoscale Quartz study
Lung Parenchymal Cell Proliferation rates of rats exposed to Nano-Quartz and other particulates
0.00%
0.20%
0.40%
0.60%
0.80%
1.00%
1.20%
5 mg/kg 1 mg/kg 5 mg/kg 1 mg/kg 5 mg/kg 1 mg/kg 5 mg/kg
PBS CarbonylIron
Min-U-Sil quartz particles Nano quartz II particles Fine quartz particles
Exposure Groups
Pe
rce
nt
Pro
life
rati
ng
Ce
lls
24 Hour 1 Week 1 Month 3 Month
*
*
**
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Lung Tissue Sections – Control (A); Min-U-Sil (B); NanoQ II (C); Fine Quartz (D).
A B
C D
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The hemolytic potential of the four -quartz samples used in the study. The samples, including:
These samples show a similar trend as the inflammation, cytotoxicity, and cell proliferation data.
Hemolytic Potential of -Quartz Samples
nano-quartz II = Min-U-Sil > fine-quartz > nano-quartz I
Hemolytic potential is a measure of surface reactivity.
• Min-U-Sil• fine-quartz• nano-quartz I• nano-quartz II
Nano-quartz II (NQ-2) 12 nm
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Blank PBS TritonX100
15.000 7.500 3.750 1.875 0.938 0.469 0.234 0.117 0.059
Concentration (mg/mL)
AB
S @
540
nm
Nano-quartz I (NQ-1) 50 nm
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Blank PBS TritonX100
15.000 7.500 3.750 1.875 0.938 0.469 0.234 0.117 0.059
AB
S @
540 n
m
Fine-quartz (FQ-1) Silica 300 nm
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Blank PBS TritonX100
15.000 7.500 3.750 1.875 0.938 0.469 0.234 0.117 0.059
AB
S @
54
0 n
m
Crystalline Silica (Min-U-Sil) 534 nm
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Blank PBS TritonX100
15.000 7.500 3.750 1.875 0.938 0.469 0.234 0.117 0.059
AB
S @
54
0 n
m
Crystalline Silica (Min-U-Sil 5) 534 nm
Fine Quartz 300 nm
Nano Quartz I 50 nm
Nano Quartz II 12 nm
Concentration (mg/mL)
AB
S @
540
nm
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Summary of α-Quartz Results
Endpoint Min-U-Sil Nanoquartz I Nanoquartz II Fine quartzParticle size ++++ ++ + +++
Surface area + +++ ++++ ++
Fe content ++ +++ ++ +
Crystallinity ++++ ++++ ++++ ++++
Radical content ++++ ++ +++ -
Hemolytic content +++ + +++ ++
Lung inflammation +++ ++ +++ ++
Cytotoxicity +++ ++ +++ +
Airway BrdU ++ N/A ++ +
Lung parenchymal BrdU
++ N/A ++ +
Histopathology +++ N/A ++++ ++
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Fullerene Water Suspensions Characterization
Nano-C60 C60(OH)24
FWSSize and Size Distribution
Surface Charge Crystallinity
nano-C60 160 ± 50 nm - 36 mV simple hexagonal
C60(OH)24 <2 nm 0 not crystalline
OHOH
OH
OH
HO
HO
OH
OHHO
HO
HOOH
OHHO
OHOH
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200 nm
Nano-C60 characterization
50 100 150 200 2500
50
100
150
200
Pop
ulat
ion
Size (nm)
Fullerene Water Suspensions Characterization
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Recommendations for Minimal Essential Material Characterization for Hazard
Studies with Nanomaterials
• Particle size and size distribution (wet state) and surface area (dry state) in the relevant media being utilized – depending upon the route of exposure;
• Crystal structure/crystallinity;• Aggregation status in the relevant media;• Composition/surface coatings;• Surface reactivity;• Method of nanomaterial synthesis and/or
preparation including post-synthetic modifications (e.g., neutralization of ultrafine TiO2 particle-types);
• Purity of sample;
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Acknowledgments• This study was supported by DuPont
Central Research and Development. • Tom Webb and Ken Reed provided the
pulmonary toxicology technical expertise for the study. Dr. Christie Sayes – postdoctoral fellow. Denise Hoban, Elizabeth Wilkinson and Rachel Cushwa conducted the BAL fluid biomarker assessments. Carolyn Lloyd, Lisa Lewis, John Barr prepared lung tissue sections and conducted the BrdU cell proliferation staining methods. Don Hildabrandt provided animal resource care.