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Thurkish Thoracic Society – 12 th Annual Congress

Thurkish Thoracic Society – 12 th Annual Congress. Adverse E ffects of N anoparticles in the R espiratory T ract and their B iokinetics in the whole B ody Manuela Semmler-Behnke, Wolfgang G. Kreyling Helmholtz Center Munich – Research Center for Environmental Health

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Thurkish Thoracic Society – 12 th Annual Congress

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  1. Thurkish Thoracic Society – 12th Annual Congress Adverse Effects of Nanoparticles in the Respiratory Tract and their Biokinetics in the whole Body Manuela Semmler-Behnke, Wolfgang G. Kreyling Helmholtz Center Munich – Research Center for Environmental Health Institute of Lung Biology and Disease (iLBD) D-85764 Neuherberg / Munich, Germany manuela.behnke@helmholtz-muenchen.de HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  2. Medicine Nanotechnologies - Basics for future Science + Technologies Per se sustainable: Save resources + energy Associated risks? HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  3. Paradigm of Risk Assessment of NP exposure assessment hazard identification hazard characterization risk characterization NP Dosimetry HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  4. ~2 m² Heart Alveolar wall 1 mm Gehr,1988 140 m², erythrocyte, 7 µm 400 m² • Nanoparticles (NP): Access to blood circulation Alveolar epithelium HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  5. t=0 t1 t2 t3 Biokinetics Radio-NP administration 100% balanced sampling: organs + tissues + remaining carcass + total excretion no further sample preparation Gamma-spectroscopic radio-analysis Application + analysis of radio-labeled NP Inhalation (INH) Intra-tracheal instillation (IT) Intravenous (IV) injection HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  6. Ir 85Kr-neutral ____ 50 nm • Intratracheal intubation-ventilation of Ir-NP Neutron activation of Ir electrodes Kreyling et al.,2002 HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  7. WKY rat, 192Ir NP, 1 hr exposure 15 nm CMD, 107 cm-3, 0.2 mg/m³ Kreyling et al., 2002 1.0 n o i t c Fraction (* 10-²) 0.8 a r f WKY rats (n = 4) d e Liver Spleen Brain Kidneys Heart n 0.6 i a t e r lung r 0.4 o d e t e cumm. feces r 0.2 c x e Days after inhalation liver 0.0 0 6 8 2 4 days Systemic translocation of Ir NP towards 2ndtarget organs Long-term translocation kinetics same exposure Semmler et al., 2004 Same for: spleen, heart, kidneys, brain There is little but persistent accumulation of Ir-NP in secondary target organs Ir NP mass < 1 ng, but number > 108 NP per organ HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  8. Translocation of iridium + carbon NP towards 2ndtarget organs WKY rat, Ir or carbon UFP + 192Ir label, 1-hr inhalation exposure 20 or 80 nm CMD, 107 cm-3, 0.1 mg/m³ carbon 192Ir agglom. 192Ir labeled carb. agglom. Szymczak et al. 2006 • Strong dependency of translocation on NP material: iridium vs. carbon NP of same size • Size dependency of translocation of iridium NP (20 vs. 80 nm) HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  9. Ventilation-inhalation system of TiO2 NP • Morphological characterisation of NP distribution in the lungs HelmholtzZentrum münchen German Research Center for Health and Environment Institute of Lung Biology and Disease (iLBD)

  10. 90 V(v) UFP TiO2 1h 80 24h mean 70 60 50 Particle profiles (% of total lungs) 20 Volume density V(v) of lung compartment vessel 15 Epith. cell 10 UFP 5 TiO2 0 500 nm endoth. cell Intracellular, epithelium Air spaces on epithelium Connective Capillary tissue ___ 50 nm 5 nm • Morphometry of inhaled TiO2 nanoparticles in rat lungs Intubated ventilated WKY rat, TiO2 NP, 1 hr exposure 22 nm CMD, 107 cm-3, 0.1 mg/m³ morphometry 0 + 24 h after inhalation • Rapid translocation of ~ 20% NP fraction • Volume proportional re-distribution: by which mechanism? M. Geiser et al., EHP 2005 Microscopic view Amorphous TiO2 Red blood cell in lung capillary tissue HelmholtzZentrum münchen German Research Center for Health and Environment Institute of Lung Biology and Disease (iLBD)

  11. O N anesthetized 2 2 sample intubated rats 2 nm DMPS CPC ventilated in M U plethysmographs H tube furnace Kr-85 -30 Pa Ti Ti Control spark generator - 1500 Pa O (0.1%) Ar 2 25 nm ________ • Ventilation-inhalation system of 48V labeled TiO2 NP • Biokinetics of NP distribution in the lungs 48V labeled after proton irradiation HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  12. Inhaled 20 nm NP of different materials ~20 nm NP • Only 5 % NP translocate to blood, similar to Ir NP, but more than carbon black (EC) • Almost all TiO2 NP are retained in the epithelium + interstitium as Ir NP did during 6-months study HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  13. Administered Gold NP All gold NP were neutron activated prior to administration to achieve 198Au radio-label HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  14. 198Au colloid 18 nm 198Au55 cluster 1.4 nm Translocation of gold nanoparticles: Effect of particle size • Intratracheal instillation in WKY rats • 1-10 µg 198Au particles in 50 µL saline, negative ionic surface charge • # of particles: 1 1014 (1.4 nm cluster) 2 1011 (18 nm colloid) • G. Schmid, Univ of Essen, Germany • Mass fractions of gold nanoparticles in different organs after 24 h 1.4 nm 18 nm Indeed, size matters!! Semmler-Behnke et al., Small, 2008 HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  15. translcation within 24 h y y Variation of size + surface charge after lung instillation • Strong NP size dependence below 10 nm • Significant dependency on positive versus negative ionic surface charge of 2.5 nm NP Relative to administered lung dose HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  16. Epithelial lining layer blood erythrocyte Complementary morphometric + biokinetics studies Combination of morphometric + biokinetics TiO2 NP study + long-term Ir NP study provides new insight into NP transport Courtesy P. Gehr interstitium Ir NP: Semmler-Behnke et al., 2007 • Translocation into blood is a minor transport mechanism • But relocation from the epithelial surface to into the epithelium and interstitium is a prominant transport mechanism including re-entrainment of NP back to the epithelial surface + macrophage-mediated clearance towards the larynx HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  17. NP-protein complex Receptor binding Y Y Y Y Epithelial lining layer endocytosis blood erythrocyte • NP interactions + relocation on lung epithelium surfactant Courtesy P. Gehr HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  18. Epithelial lining layer blood erythrocyte • NP-protein-complexes mediate NP crossing the air-blood-barrier • Evidence : • Different NP bind selectively to proteins in lung lining layer and serum in vitro • Different NP accumulate selectively in different organs in vivo depending on NP properties like size, material, surface modifications, etc. • When crossing the air-blood-barrier the same NP accumulates in a different pattern of organs compared to IV injection Courtesy P. Gehr HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  19. 0.3% 0.002% Immune system Alveolar epithelium 6% 94% brain liver heart AM kidneys fetus urine Y Y • Nanoparticle (NP) translocation via different routes Courtesy: Furong Tian HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  20. Perspectives • Understanding the underlying mechanisms of NP accumulation in different organs and the dynamics of NP-protein-complexes • Determine quantitative biokinetics of other relevant engineered NP (TiO2, Ag, CNT, CB, etc.) • Identify proteins which distinctively bind to certain NP • Identify NP-protein-complexes accumulating in a selected organ • From the rather small translocated fractions in 2nd target organs after a single short-term exposure we don’t expect any adverse health effects; • However, after chronic or multiple exposures retained NP in 2nd target organs may accumulate to an extent leading to adverse health effects; a scientific area not yet studied in sufficient detail!! HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  21. Acknowledgements Focus Network: Nanoparticles & Health HMGU-Inst. f. Inhalation Biology: Wolfgang G. Kreyling Jens Lipka Winfried Möller Shinji Takenaka Furong Tian Steffi Fertsch Otmar Schmid Tobias Stöger Holger Schulz HMGU-Inst. Radiation Protection Wilfried Szymczak, Klaus Wittmaack HMGU-Inst. Epidemiology Annette Peters, Achim Heinrich, H-Erich Wichmann HMGU-Inst. Toxicology Andreas Stampfl Univ. of Berne:Marianne Geiser, Peter Gehr Univ. of Essen:Günter Schmid Univ. of Aachen:Ulrich Simon Univ. of Marburg:Wolfgang Parak, Ralph Sperling Univ. of Leipzig: Tilman Butz LMU Experim. Medicine: Fritz Krombach, André Khandoga Harvard School of Public Health:Akira Tsuda Univ. of Edinburgh: Vicky Stone, Lang Tran, Ken Donaldson Univ. of Rochester: Günter Oberdörster EU Joint Research Center, Ispra: Neil Gibson, Christoph Klein, Hermann Stamm DFG:NanoHale + NanoBioResponseUBA: Toxicokinetics of TiO2 NP EU-FP7: AntiCarb CNT as drug carriers NeuroNano: NP effects in brain? InLiveTox: In vitro µ-fluidic: NP + membranes ENPRA: NP risk assessment HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

  22. Thank Yor For Your Attention!!! HelmholtzZentrum münchen German Research Center for EnvironmentalHealth Institute of Lung Biology and Disease (iLBD)

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