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									Engineered Nanoparticles:
The Next Asbestos or the
  Next Best Thing Since
      Sliced Bread

                       Pam Greenley, CIH
                   Associate Director MIT EHS
                       Greenley@mit.edu

 Acknowledgements: Marilyn Hallock and Andy Kalil, MIT Industrial
                          Hygienists




                                                                    1
     Engineered Nanoparticles
• What is it and where is it
• Potential Routes of Exposure
• Common types – define, potential uses, tox info
    –   Carbon nanotubes
    –   Graphene
    –   Quantom dots
    –   Polymers for drug delivery
•   Controls
•   Air sampling and Exposure Limits
•   Assessing exposure risk for your patients
•   Hot topics highlight and Information Sources




               Definition of Nano
• A nanometer (nm) is 1/1,000,000,000 of a
  meter
• Nanoparticles are a specific type of nano-
  object, with all three external dimensions
  at the nanoscale.
• Nanofibers are defined as
  fibers with diameters less
  than 100 nanometers.




                                                    2
             WHAT IS NANOTECHNOLOGY?
      Working at the atomic, molecular and supramolecular levels, in the length scale of
      approximately 1-100 nm range, in order to understand and create materials, devices and
      systems with fundamentally new properties and functions because of their small structure.
      Definition on http://nano.gov




Dr. Kane and Dr. Hurt
Brown University




                Market ~ $1.6 trillion in 2013
                   ~ 1,300 manufacturers
        nAg > carbon nanomaterials > metal oxides
 Zn0 and Ti02 NPs are widely used in cosmetics, sunscreens,
          construction industry, and photovoltaics

McIntyre R.A. Common nano materials and their use in real world applications.
                    Science Progress 95: 1-22, 2012




                                                                                                  3
           Nano in Consumer Products
                                …
    Est. total amount in commerce: few thousand tons
Product                  “Nano Inside”                     Value Added

                        Active Ingredient:
                           Nanoscopic                    Transparency
                             TiO2/ZnO


                         Lined with Ceramic                    Gas
                            Nanoparticles                 Impermeability



                         Silver Nano Particles             Antimicrobial




               Different Types of
                Nanomaterials
     Naturally            Human Origin                  Human Origin
     Occurring             (Incidental)                 (Engineered)
Forest fires            Cooking smoke                Metals

Sea spray               Diesel exhaust               Quantum dots
Mineral composites      Welding fumes                Buckyballs/Nanotubes
Volcanic ash            Industrial effluents         Sunscreen pigments
Viruses                 Sandblasting                 Nanocapsules


                     Nanotechnology
                                      From OSHA Course: Introduction to Nanomaterials
                                                             and Occupational Health




                                                                                        4
   “It is a mistake for someone to say nanoparticles
  are safe, and it is a mistake to say nanoparticles are
        dangerous. They are probably going to be
   somewhere in the middle. And it will depend very
                 much on the specifics.”
          Vicki Colvin, Director of Center for Biological and
         Environmental Nanotechnology at Rice University,
              quoted in Technology Review, April 2003



    HIGH UNCERTAINTY DOES NOT EQUAL HIGH RISK
    HIGH UNCERTAINTY EQUALS HIGH PRECAUTION




Engineered Nanoparticles Can Be More Toxic Than
     Bulk Material : MSDS May Be Misleading

                        Old Inhalation Toxicology:
                             -Particle type is key for toxicity
                            • Particulate mass causes lung disease
                            •Crystalline Silica is toxic, TiO2 is not toxic

                        New Nanotoxicology:
                           - Nano is more toxic than bulk material
                           - Nano TiO2 is as toxic as crystalline silica
                           - Particle count and surface area may be
                               more important than mass




                                                                              5
  Routes of Exposure: Dermal
              Available data are limited and often conflict;
        Skin cannot be ruled out as a potential route of exposure

 • Several studies show little to no
   penetration of nanoscale oxides
   beyond surface skin layers
 • Polysaccharide and metal
   nanoparticles have been shown
   to penetrate flexed, damaged or
   diseased skin
 • Quantum dots were found to
   penetrate intact pig skin within
   8-24 hours at occupationally
   relevant doses



                                                                 From OSHA Course:
                              What Workers Need to Know about Nanomaterial Toxicology




Nanoparticles: Possible Skin Penetration (?)

• Ladderman et al (1999): nm TiO2 penetrated stratum
  corneum and deeply into hair follicles
• Tinkle et al (2003): Size dependent penetration of
  dextran particles (0.5 and 1 um) through mechanically
  “flexed” skin into epidermis and dermis
• Monteiro-Riviera et al (2006): Quantum dots penetrated
  into dermis in pig skin bioassay
• Zang et al (2008): Quantum dots did not penetrate into
  intact mouse skin unless skin was abraded (different
  shape particles used in this study)




                                                                                        6
Routes of Exposure: Inhalation
• Airborne NPs can be
  inhaled and deposit in
  the respiratory tract
• NP penetration into           <30 microns
  the lung depends on
  size                            <10 microns
• Size depends on
  aggregation state
                               <2 to 3 microns
• Inhaled NPs may              2000 nm
  enter the blood and      Image: http://upload.wikimedia.org/wikipedia/commons/3/36/Respiratory_Tract.png


  translocate to other
  organs                                                      From OSHA Cours
                           What Workers Need to Know about Nanomaterial Toxicolog




      Nanoparticle Lung Deposition
          (Maynard and Kuempel, 2005)




                                                                                                             7
Nanoparticle Cellular Uptake and Translocation in Body
                       and Brain




100 nm particles, intercellular space        10 nm particles, inside cell
       • Some nanoparticles translocate to liver and other
         organs after inhalation (Oberdorster et al 2002)
       • 13C labeled carbon translocated into brain via
         olfactory nerve (olfactory bulb, cerebrum,
         cerebellum) (Oberdorster et al 2004)
       • Manganese oxide reached brain after inhalation
         (Elder et al 2006)
       • Nano TiO2 intranasally instilled in mice: oxidative
         damage and neuron degeneration in some areas of
         brain (Wang et al 2008)




                Carbon Nanotubes
                     Characteristics:
                          Allotrope of carbon with cylindrical structure
                          Diameter: 1-100 nm; Length: 10 nm to
                             microns
                          Single walled or multiwalled
                          Six times stronger than steel with very
                             unusual properties; conducting
                     Potential Uses:
                          Structural composites (aerospace,
                            automotive)
                          Many Electronic Applications (computer
                            circuitry, energy storage)
                          Drug Delivery




                                                                            8
         Carbon Nanotubes
               • Activities with Airborne Exposure Potential:
                 Furnace Activties: Growth, Removal, Cleaning
                 Weighing on open balances
                 Machining or Grinding
                 Sonication
                 Incorporating into other products
               • Toxicity: non-biodegradable fiber
                  Animal inhalation studies have shown persistent inflammation,
                     granulomas, fibrosis; as toxic as silica
                  Long, rigid MWCNT at high doses have shown asbestos-
                     like effects
                  Recent NIOSH REL (2013): 1 ug/m3 based on subchronic
                     animal studies (less than crystalline silica)
                  Cardiovascular effects: can produce oxidative stress in aortic
                     mitochondria; can increase plaque formation in mouse
                     atheroscelorosis model




  Long MWCNTs: Recent Toxicology Studies
       Suggest Asbestos-Like Effects

• Recent Intraperitoneal and Instillation Studies
  – Takagi et al (2008): single injection of 3 mg/ animal
    MWCNT caused mesothelioma tumors like asbestos
    at 6 months
  – Poland et al (2008): single injection of 50 ug/animal
    produced asbestos-like changes at 7 days
  – Hubbs et al (2009): MWCNT instilled into rat lungs
    penetrated through lungs into pleural space
  – These studies used high doses; MWCNT were long
    (10-20 um); short MWCNT did not show these effects




                                                                                   9
                Quantum Dots
                  Characteristics: nanocrystals made of
                    semiconductors materials
                      Size: 5-50 nm
                      Materials: cadmium selenide, indium
                         phosphide, copper-indium sulfide,
                      Coatings: often zinc sulfide
 Quantum Dots     Potential Uses:
                      Nanocrystals exhibit much brighter and long-
                        lasting fluorescent properties than organic
                        dyes
                      Currently used for animal imaging studies of
                        cell function; can do real time tracking of
                        cell activities
                      Future optical and electronic uses:
                        photovoltaic devices, light emitting diodes,
                        lasers, medical imaging




          Quantum Dots- QD
                Airborne Exposure Potential:
                   Many types synthesized in solution using
                     colloidal chemistry. Precursors dissolved in
                     solvents and heated until solution is
                     supersaturated. Nanocrystals self-assemble
                     and precipitate out of solution.
                   Exposure from manipulation of solutions:
Quantum Dots         sonication, vortexing, injections, pouring,
                     spills.
                Toxicity:
                   Cadmium Selenide quantum dots are cytotoxic
                     (cell death
                   Toxicity partially reduced by ZnS coatings..
                   Some of toxicity is related to release of
                     Cadmium ions. Cadmium is known human
                     carcinogen.




                                                                       10
Graphene
 Characteristics:
    Allotrope of carbon with two dimensional
       structure arranged in hexagon pattern
       like graphite
    One layer of atoms thick (0.3 nm)
    Other dimensions 0.3nm to 10 um
    Can compress and become more
       particle-like
 Potential Uses:
    Very strong, light-weight, nearly
      transparent, excellent conductor of
      heat and electricity
    Computer circuitry: integrated circuits,
      transistors, electrodes, solar cells,
      additives to coolants, energy storage




Graphene
Airborne Exposure Potential:
   Can behave as a sheet, particle, or fiber;
     chips may break off from edges
   Exposure from manipulating powder or
     powder in solution: weighing, transfer,
     sonication, machining
Toxicity: very few studies
  Cellular studies show membrane damage
  and cell toxicity
   One animal study (IV injection) showed no
      toxicity; another study showed
      inflammation in lung, liver, and other
      organs
   Inhalation toxicity not evaluated but is
      needed




                                                11
Nano Polymers for Drug
       Delivery
       Characteristics:
           Dendritic polymers in the nano size range
              (<100 nm in diameter)
           Many different types: PLA (polylactide), PGLA
              (polylactide glycolide), PEG (polyethylene
              glycol) based dendrimers, polystyrene
           Highly branched dendritic molecules permit
              receptors and drugs to be attached to target
              drug delivery to specific tissues
       Potential Uses:
           Many different forms of drug delivery
           Long term delivery systems for insulin, anti-
             cancer drugs, growth factors, gene therapy
           New biodegradable polymers that can be
             absorbed by body;




Nano Polymers for Drug
       Delivery
       Airborne Exposure Potential:
           Most types synthesized in solution by self
             assembly of precursors
           Exposure from manipulation of solutions:
             sonication, vortexing, injections, pouring,
             spills
       Toxicity: will depend upon polymer type
           Many polymers in micron size range are
             considered GRAS (Generally Recognized
             as Safe) by FDA
           FDA recently recommended (2012) that nano
             compounds should have additional testing
             because they can have different properties.
             This is a recommendation, not requirement
             at this point.
           Some nano polymers show pulmonary
             inflammation and release of inflammatory
             factors.




                                                             12
   Prevent Inhalation Exposure: Use Fume
        Hoods for Nanoparticle Work
 • Carbon Nanotube Furnace in Fume Hood


Flammable
gas
hazards
too!




       •Follow good practices when using fume hoods: equipment
       set up 6” behind sash, sash below chin, remove arms slowly
       •Face Velocity of 80 to 100 fpm better than higher face velocity




      Prevent Inhalation Exposure: Other
       Types of Exhausted Enclosures
 • Biosafety Cabinets: only Class II
   Type B1 or B2 BSCs which exhaust
   into building ventilation can be used.
   Some air is recirculated in a BSC:
   only low levels of solvents and
   particulate can be used
 • Nanomaterials Enclosure:
   developed for weighing balances
   and handling of particulate that is
   easily disrupted by air currents.
   Attached to HEPA filters. Solvents
   can’t be used unless also connected
   to house exhaust.




                                                                          13
       Nilfisk HEPA Vacuum Filters




   Use HEPA Respirators for Spill
    Cleanup Outside Fume Hood

Moldex P100 Disposable and MSA Comfo
 Elite with HEPA Cartridges




                                       14
   Recent Development of Occupational
         Exposure Limits (OELs)
• NIOSH recommends that exposures to CNT and CNF be kept below
  the recommended exposure limit (REL) of 1 μg/m3 of respirable
  elemental carbon as an 8-hr TWA. (NIOSH, April 2013)
   – Recommended air sampling method is collection on filter and analysis by a
     thermal optical analyzer for elemental carbon.


• Nano sized TiO2 (<100 nm): OEL set at 300 ug/m3 (NIOSH,
  proposed 2005; adopted 2011) OEL for micron size TiO2 is 1.5
  mg/m3
• Fullerenes: OEL recommended at 390 ug/m3 (Shinohara et al 2011)

• Comparison to existing OELs for materials known to be highly toxic
  to humans: Crystalline silica 25 ug/m3, Cadmium 2 ug/m3, Beryllium
  0.05 ug/m3




   NIOSH recommends Method 5040 to quantify
   exposure to airborne carbon nanotubes*


   • 37-mm quartz-fiber filter
   • Flow rate of 2 to 4 liters per minute
   • Size selective samplers may be
     needed
   • Reported as elemental carbon


      * NIOSH Draft Current
                                                                    37-mm
      Intelligence Bulletin, 2010                               quartz-fiber filter
                                                                                      3-30




                                                                                             15
                                       Measurement tools for
                                            Research


                 FMPS (Fast Mobility
                 Particle Sizer): measures
                 particle number in 30 size
                 ranges from 5 nm to 550
                 nm to give particle size
                 distribution




        Comparison of Source Concentration (inside Fume Hood) and
Breathing Zone Concentration During Transfer of 300 nm Amorphous Silica




                                            Silica 300 Aerosol Monitoring 011006'-
                                           Source Conc. vs. Breathing Zone Conc.
                       4.00E+04
                                                                                        Source Conc.
                       3.50E+04                                                         Transferring Silica

                       3.00E+04
  dN/dlog Dp [#/cm3]




                                                                                        Source Conc. Stirring
                       2.50E+04                                                         Silica- Close Sash
                       2.00E+04

                       1.50E+04                                                         Breathing Zone Conc.
                                                                                        Stiring Silica- Close
                       1.00E+04                                                         Sash

                       5.00E+03
                                                                                        Ambient Background
                       0.00E+00                                                         Conc.
                                   1         10                    100           1000
                       -5.00E+03
                                                  Channel Dp[nm]




                                                                                                                16
                          Air Monitoring for Carbon Nanotubes Around Furnace
                                During Growth and Purge Cycles (at MIT Lab)


                                          Aerosol Monitoring of CNT Furnace 011006'
                     6.00E+03

                     5.00E+03
                                                                                                    Background
dN/dlog Dp [#/cm3]




                     4.00E+03
                                                                                                    Moving detection
                     3.00E+03

                                                                                                    Fix tubing detection
                     2.00E+03
                                                                                                    Open chamber
                     1.00E+03

                     0.00E+00
                                 1         10                        100                     1000
                     -1.00E+03
                                                 Channel Dp [nm]




                             Field Instruments - Measurement of
                                         NanoParticles

                • Use multiple instruments to
                  cover particle size range
                • Take a background reading first
                  if not a clean area may not be
                  able to distinguish background
                  from NP release
                • Are the counts I am seeing
                  Engineered NP?
                          – Use Transmission Electron
                            Microscopy (TEM) to ID what is is
                            (carbon or carbon nanotubes)
                • Costly, not easy
                                                                                      TSI Condensation
                                                                                      Particle Counter




                                                                                                                           17
       EPA Regulation of Nanomaterials
• Toxic Substance Control Act
  – Carbon nanotubes are “New Chemicals”
  – R&D exemption for new chemical registration
  – Significant New Use Rule (SNUR) for MWCNTs
• Clean Air Act
  – Not yet Criteria Air Pollutant but covered under PM2.5
• Clean Water Act
  – Total Suspended Solids (TSS) limits in permits
• Aquatic, developmental and ecotoxicity
  –   Nanosilver in wastewater treatment sludge (9/2010)
  –   QD soil degradation study (7/2011)
  –   Coating NPs alters toxicity (1/2012)
  –   Drosophila fecundity and silver NPs (5/2011)




 Key Questions for your Patients
• What type of Engineered Nanoparticles
• Where are they on the Inhalation Exposure Gradient
   -solid material with embedded nanostructure
  -solid material with nanostructure bound to surface
  -wet liquid suspensions of nanoparticles
  -free nanoparticles (dry, dispersible single particles or agglomerates,
  gaseous phase)
• What type of engineering controls – fume hoods, BSC’s,
  HEPA vac work
• What type of PPE – Gloves, labcoat or coverall, HEPA cartridge
  respirator
• How are spills and maintenance Activities




                                                                            18
                  Hot Topics
• Engineered Nanoparticles in Consumer
  Products
• Tox studies – lots in the works but
  diversity of materials will keep us in the
  realm of the unknown
   – Olfactory nerve delivery to brain
   – MWCNT and mesothelioma
   – NIOSH epidemiology study of CNT workers
• Regulatory – OHS ahead of environmental
  and consumer




             Information Sources
• HTTP://icon.rice.edu Internation Council on
  Nanotechnology; email notifications; ESH database on
  nanomaterials (can search by particle type and time
  period)
• http://www.ncbi.nlm.gov/entrez National Center for
  Biotechnology Information (NCBI) Pub Med [can search
  for articles on nanoparticle toxicity]
• www.safenano.org UK site: very current and good blog
• www.cdc.gov/niosh/topics/nanotech/ Nanotechnology
  Topics page at NIOSH; also NIOSH eNews
• http://www.nnin.org/ National Nanotechnolgoy
  Infrastructure Network (NNIN) – nano research funding




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    MIT Information Sources
• EHS Web Site
  -Potential Risks of Nanomaterials
  http://web.mit.edu/environment/ehs/topic/n
  anomaterial.html
  -Best Practices for Handling
  Nanomaterials in Laboratories
  -Checklist for Nanomaterials Standard
  Operating Procedures




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