Considerations for Characterizing the Potential Health Effects from Exposure to Nanomaterials David B. Warheit, PhD. DuPont Haskell Laboratory Newark,

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Presentation transcript:

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

Outline Particle characterization as it relates to particle deposition, macrophage interactions, particle translocation Particle characterization for 5 studies Fine/Ultrafine TiO 2 particle types; Fine/Nanoscale Quartz particle-types; Summary - Recommendations

Rat Lung Microdissection

Rat Lung Tissue Dissected to Demonstrate the Junction of the Terminal Airway and Proximal Alveolar Region

Iron Particle Deposition at Bronchoalveolar Junction

Iron Particle (  ) Deposition in the Lungs of Exposed Rats

Iron Particle Deposition at Bronchoalveolar Junction (Backscatter Image)

Alveolar Macrophage Clearance of Inhaled Iron Particles

Alveolar Macrophage Clearance of Inhaled Iron Particles (Backscatter Image)

Alveolar Macrophage Migration to Iron Particle Deposition and Phagocytosis

Alveolar Macrophage Migration to Iron Particle Deposition and Phagocytosis (Backscatter Image)

Macrophage phagocytosis of TiO 2 particles

Two Alveolar Macrophages (M) Sharing a Chrysotile Asbestos Fiber (  ) with an Alveolar Epithelial Cell (E) M M E

TEM demonstrating pathways for possible translocation of particles

Translocation of chrysotile asbestos fibers from airspace to epithelium

1) Pulmonary Instillation Studies with Nanoscale TiO 2 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)

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 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)

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

4) Assessing toxicity of fine and nanoparticles: Comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Sci 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

4) Assessing toxicity of fine and nanoparticles: Comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Sci (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

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 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)

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;

Studies to Assess Pulmonary Hazards to Nanoparticulates

Ultrafine TiO 2 Studies

Pulmonary Toxicity Study in Rats with Three Forms of ultrafine-TiO2 Particles: Differential Responses related to Surface Properties Toxicology 230: , 2007

Characterization of Ultrafine TiO 2 Particle-types - 1 uf-3 C 300 nm uf-2 B 300 nm uf-1 A 300 nm

Characterization of Ultrafine TiO 2 Particle-types - 2 Sample Crystalline phase Median size and width distribution (nm) Surface area (m 2 /g) pH Chemical reactivity in water*in PBS deionized water in PBS delta b* F-1rutile ± 36% ± 35% uf-1rutile ± 35% ± 45% uf-2rutile ± 50% ± 31% uf-3 80/20 anatase/ rutile ± 44% ± 31%

Protocol for ultrafine TiO 2 Pulmonary Bioassay Study Exposure Groups PBS (vehicle control) Particle-types (1 and 5 mg/kg) o rutile-types uf-1 TiO 2 o rutile-type uf-2 TiO 2 o anatase/rutile-type uf-3 TiO 2 o rutile-type F-1 fine TiO 2 (negative control) o α-Quartz particles (positive control) Instillation Exposure 24 hr1 wk1 mo3 mo Postexposure Evaluation via BAL and Lung Tissue

RESULTS Biomarkers Pulmonary Inflammation Pulmonary Cytotoxicity Lung cell Proliferation

Pulmonary Inflammation

BAL Fluid LDH Values (cytotoxicity)

Pulmonary Cell Proliferation Rates

Lung Sections of Rats exposed to uf-1 (A); uf-2 (B); or F-1 (C)- 3 months pe

Lung Section of Rat exposed to uf-3 3 months postexposure

Lung Section of Rat exposed to Quartz particles - 3 months postexposure

Nanoscale Quartz

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: , 2007

Nanoscale Quartz Particles

Characterization of Nanoscale Quartz Particles Sample Average size (nm) Size range (nm) Surface area (m 2 /g) Crystallinity ICP-AES (% Fe content) Nanoquartz I α-Quartz0.080% Nanoquartz II α-Quartz 0.034% Fine quartz α-Quartz 0.011% Min-U-Sil α-Quartz 0.042%

Pulmonary Inflammation – Nanoscale Quartz study

BAL Fluid LDH Values – Nanoscale Quartz study

Lung Parenchymal Cell Proliferation– Nanoscale Quartz study

Lung Tissue Sections – Control (A); Min- U-Sil (B); NanoQ II (C); Fine Quartz (D). ABC D

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 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) 540 nm

Summary of α-Quartz Results EndpointMin-U-SilNanoquartz INanoquartz IIFine quartz Particle 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++++++

Fullerene Water Suspensions Characterization Nano-C 60 C 60 (OH) 24 FWS Size and Size Distribution Surface ChargeCrystallinity nano-C ± 50 nm- 36 mVsimple hexagonal C 60 (OH) 24 <2 nm0not crystalline

200 nm Nano-C 60 characterization Fullerene Water Suspensions Characterization

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;

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.