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Nano Occ Med


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Nano Occ Med

  1. 1. Occupational Medicine Implications of Exposure To Engineered Nanoscale Particulate Matter American Chemical Society Meeting Safety in Nanotechnology Research Rick Kelly, MS, CIH Lawrence Berkeley National Laboratory
  2. 2. THE MOLECULAR FOUNDRY Nanoscale Science Research Center and User Facility
  3. 3. Free Engineered Nanoscale Particulate Matter–“Nanoparticles” • Not firmly attached to a surface • Not part of a bigger item (e.g., microchip, cell wall) •  an result in exposure via C inhalation, skin absorption or ingestion (or other nanospecific routes of exposure!)
  4. 4. Primarily Talking About Inorganic Nanoparticles Bucky Ball (C60) Nanoflowers Single Wall Carbon Nanotube Silica Whiskers Rods, Wires, Shapes Quantum Nanodots
  5. 5. Goals of Occupational Medicine 1.  Prevent injury and illness —  Workplace (exposure) monitoring •  Comparison to safe exposure limits —  Engineered, administrative and personal protective controls •  Ventilation, respirators, gloves, training etc. 2.  Detect early signs & symptoms of injury or illness —  Medical surveillance 3.  Intervene in disease process —  Removal from exposure —  Treatment
  6. 6. Why Are We Concerned?
  7. 7. Potential for Novel Toxicity •  Properties of nanoscale materials may be fundamentally different from bulk materials of same composition •  Among the new properties of nanoscale materials may be: —  ew toxicological N properties not seen in bulk material
  8. 8. Particle Size Dependent Occupational Toxicity •  Free crystalline silica —  ost toxic when <10 µm M •  Alveolar deposition •  Probably surface area effect as well
  9. 9. Nanoparticles Have Been Produced Commercially for Decades •  arbon black C •  umed silica F • ron oxide I •  itanium dioxide T •  luminum oxide A •  irconium oxide Z •  sbestos A
  10. 10. Ambient Ultrafines Are Associated With Worsening of Disease •  Ambient fines and ultrafines are associated with increased cardiovascular and respiratory events, including death, in susceptible populations Particulate Air Pollution and Risk of ST-Segment Depression During Repeated Submaximal Exercise Tests Among Subjects With Coronary Heart Disease Juha Pekkanen et al 2002 Reflects myocardial ischemia
  11. 11. Nanoparticle Surface Area is Huge! 1 8 •  1/2 the size = 2x the surface area and 23 = 8x the number or particles •  Approaches 100% of atoms on the surface 64 512 • w
  12. 12. Surface Area May Be Critical Metric •  Toxicity of ultrafine TiO2 appears much higher than fine TiO2 per unit mass •  Toxicity is equivalent when surface area is the exposure metric Measured polymorphonuclear neutrophils in lung lavage fluid, an index of inflammation Oberdorster, Int Arch Occup Environ Health. 2001 Jan; 74(1):1-8.
  13. 13. Nanotubes Look A Lot Like Chrysotile Asbestos Two similar appearing nanofibers •  Chrysotile asbestos (left) •  Multiwall carbon nanotube (above) Similar toxicity? Asbestos and macrophage
  14. 14. Fiber Toxicology: Dose, Dimension & Durability •  Key factors contributing to toxicity: • Diameter < 1000 nm • Length >5,000 nm: • High biopersistance • Poor pulmonary clearance • Carbon nanotubes can fall into this size range • 80% of raw CNTs retained in lung at 60 days
  15. 15. Distribution Across Anatomical Barriers •  Nanoparticles may go where other particles Sally Tinkle, NIEHS can not! — Through intact skin — Through the GI epithelium — Through the respiratory tract epithelium — Through the bloodstream — Up along nerve axons from the nose to brain — Across the placenta — Through the blood-brain barrier?
  16. 16. Cardiovascular Toxicity of CNTs Instilled In The Respiratory Tract •  Li Zheng of NIOSH, March 2007 - Intrapharyngeal dosing of SWCNT in mice resulted in oxidative stress in aorta and heart tissue and damaged mtDNA in aorta - Accelerated atherosclerosis
  17. 17. The Devil Is In The Details! • Factors shown to influence CNT toxicity •  Dose •  SWCNT vs. MWCNT •  Length/aspect ratio •  Manufacturing method (CVD, HIPCO, laser ablation, carbon arc) •  Catalyst residue (Ni, Y, Co, Fe) •  Degree of aggregation and methods of dispersion •  Oxidation •  Functionalization (increase or decrease toxicity) •  Species, dosing method, cell type •  CNTs may disrupt a number of standard assays of cell viability, stress and function, giving false positive or negative results
  18. 18. Pulmonary Toxicity: All Published Instillation/Aspiration Studies Year Author Species Granuloma Inflamm Diffuse Fibrosis 2001 Huczko Guinea pig – No – 2004 Warheit Rat Yesa Yesb No 2004 Lam Rat Yes Yes – 2005 Muller Rat Yes Yes Yes 2005 Huczko Guinea pig Yes Yes Yes (Grubek- Jaworska) 2005 Shvedova Mouse Yes Yesb Yesd 2006 Mangum Rats Yes No Yes 2006 Carrero Mice Yes Yes – Sanchez 2007 Shvedova Mice Yes Yes Yes A = non-uniform, b = transient, c = by choking, d = progressive
  19. 19. Inhalation Studies • No good published CNT inhalation studies to date! • NIOSH has completed an inhalation study but has not released the results, pending publication
  20. 20. What is the Real Occupational Exposure Potential? Air sampling when handling raw carbon nanotubes Maynard, 2004 Raw single walled carbon nanotube material HiPCO Process
  21. 21. CNT Clumps In Air Sample Raw nanotubes consist mostly of clumps and bundles of nanotubes on the micro scale, very few free nanoscale structures
  22. 22. Nanotube Exposure Summary Highest Nanotube mass concentration estimated from metals analysis is relatively low So what is an appropriate exposure limit for CNTs?
  23. 23. Are CNTs Just Graphite Toxicologically? Redacted! •  ctual MSDS for A CNTs (May, 2007) •  uoted PEL is for Q graphite!
  24. 24. Anna Shvedova from NIOSH, 2005 “…if workers are exposed to respirable SWCNT particles at the current PEL (for graphite particles) they may be at risk of developing some lung lesions.” •  ranulomatous lesion G resulting from exposure to CNTs at a level ~ 20 days of inhalation at the permissible exposure limit for graphite.
  25. 25. Where Do We Stand for Nanoparticles? 1.  Prevent injury and illness —  Workplace (exposure) monitoring •  No widely accepted methods, tools and analysis expensive and experimental, high background level •  No accepted workplace exposure limits —  Engineered, administrative and personal protective controls •  Ventilation systems, HEPA filters, respirators, gloves all work 2.  Early detection of signs or symptoms of injury or illness —  Medical surveillance •  No accepted protocols specific to nanoparticles •  Technical basis limited 3.  Intervene in disease process —  Removal from exposure •  Might be helpful —  Treatment •  Unknown
  26. 26. Prudent Approach 1.  Prevent injury and illness —  Workplace (exposure) monitoring •  Use simple screening tools, control banding approach —  Engineered, administrative and personal protective controls •  Treat all engineered nanoparticles as toxic, use prudent practices to control exposure 2.  Early detection of signs or symptoms of injury or illness —  Medical surveillance •  Implement optional general health awareness exams •  Register and track employees with significant exposure •  Stay abreast of new toxicological findings, implement specific health screening protocols as appropriate, perhaps on an experimental basis 3.  Intervene in disease process —  Removal from exposure •  Very sensitive as it impacts employability —  Treatment •  Unknown