OSH and Nanotechnology: Knowns and unknowns

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Nanotechnology and Risk John Howard,
M.D. Director Emeritus National Institute for
Occupational Safety and Health Washington, D.C.
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Nanotechnology Turning fiction to
realityScience fiction
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Nanotechnology Turning fiction to
realityScience fact Smart Dynamic Nanoplatorms
Nanoclinics
PEBBLEs (Probe Encapsulated By Biologically
Localized Embedding)
Raoul Kopelman and Martin Philbert, University of
Michigan
20 nm 600 nm in diameter
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Theres Plenty of Room at the BottomRichard
Feynman, 1959
The principles of physics, as far as I can see,
do not speak against the possibility of
maneuvering things atom by atom. It is not an
attempt to violate any laws it is something, in
principle, that can be done but in practice, it
has not been done because we are too big.
A full transcript of the lecture can be found at
www.its.caltech.edu/feynman/plenty.html
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Nanotechnology

• Definition includes all three features
• Research and technology development at the
  atomic, molecular, or macromolecular levels, in
  the length scale of approximately 1-100 nm.
• Creating and using structures, devices, and
  systems that have novel properties and functions
  because of their small and/or intermediate size.
• Ability to control or manipulate on the atomic
  scale.
• www.nano.gov

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Particle Sizes and Shapes
NCI
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Size Comparisons
Eukaryotes
Bacteria
Molecules
Viruses
Nanoparticles
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Different Shapes of Nanoparticles
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Nanotechnology Particles lt 100 nm, Natural and
Anthropogenic Sources

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Nano Applications

• Electronics
• Magnetics
• Optics
• Informational Technology
• Material Devices
• Medicine

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Early nano-enabled consumer products are on the
market now
Gibbs, 2006
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Nanomedicine Basics

• Biological processes occur at the nanoscale
• Nanotechnology allows access to internal milieu
  of living cells
• Smart nanodevices are the future of medicine
• Bridge between aerosol physics, engineering and
  molecular biology
• Paradigm of cancer diagnosis, treatment and
  prevention will change.

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Early Detection Monitor Complex Biologic Changes
NCI
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Early Detection -- Cantilevers
NCI
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Therapeutics -- Nanoshells
NCI
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Molecular Imaging Nanoparticles (Brain)
NCI
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Nanotechnology development and implementationPrim
ary nanomaterial complexity
Adapted from Roco, MC (2004) AIChE J. 50 (5)
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Defining the IssueNanotechnology and Risk

• Nanotechnology - The Motivation
• Purposely engineered nanostructured materials and
  devices demonstrate new, unique and
  size-dependent properties and behavior.
• Nanotechnology - The Challenge
• Does the nature of engineered nanostructured
  materials and devices present new safety and
  health risks?
• How can the benefits of nanotechnology be
  realized while proactively minimizing the
  potential risk?

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Concern Over the Potential Impact of
Nanotechnology
ETC Group 2005
Woodrow Wilson Center 2006
NGO Coalition 2007
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Concerns Over the Potential Impact of
Nanotechnology
Washington Post 2005
THONG, 2005
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Opportunities Avoid damage to human and
environmental health

• Risk assessment and risk management in parallel
  with product and technology development
• Perceived vs. Real Risk
• Asbestos
• Genetically Modified Foods

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Risk Challenges Knowledge Base and
Instrumentation
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What we know What we
dont know

• Nature and extent of hazard
• Nature and extent of exposure
• Nature and extent of risk
• What measures to use
• Limitations of controls
• Limitations of protection
• What limits are appropriate
• Content of medical surveillance

• Some potential hazard
• Some exposure occurs
• Some risk may exist
• Nanoparticles can be measured
• Nanoparticles can be controlled
• Filters and respirators should protect
• There are no specific exposure limits
• There is no recommended medical surveillance
  guidance

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Toxicity

• Size
• Shape
• Surface

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Size inflammatory response varies inversely
with sizeTiO2 Instillation in Rats
Diameter 25 nm
Inflammatory Response ( PMN)
Diameter 250 nm
Particulate Mass (µg)
Oberdörster, G., Phil. Trans. Roy. Soc. London
Series A 358 (1775), 2719-2740, 2000
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AgglomerationHow does it affect particle
biological activity?
0.18 0.32 ?m aerodynamic diameter
CNT agglomerates
compact carbon particle
dense nanotube rope
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Particle Shape?Tubes, spheres, fibers, ropes,
rings, planes, dots
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Particle Shape Should we study every
shape?Zinc Oxide Nanoparticles
Materials Today June 2004. Zhong Lin Wang,
Georgia Institute of Technology
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Surface AreaHow to Assess Biologic Activity of
Nanoparticles?
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Surface AreaHow to Assess Biologic Activity of
Nanoparticles?

• Particle number and particle surface area per
  constant 10 µg/m3 concentration

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Surface AreaHow to Assess Biologic Activity of
Nanoparticles?
Surface atoms
Core atoms

• Fraction of atoms on the surface for a simple
  cubic lattice with 1 Å bond length

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Surface ChemistryHow do surface species affect
bioactivity?

• Surface chemistry vs. activity for C60 fullerenes

Fullerene species concentration (ppb)
C.M. Sayes et al. NanoLett. 2004, 4, 1881
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Current Research Results Single-Walled Carbon
Nanotube Toxicity to Respiratory Tract
Rat lung cells cannot digest and clear long
carbon nanotubes. D. Brown, Napier Univ. and I.
Kinloch, Univ. Manchester
V. Castranova, NIOSH
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Ultrafine and Nano-particlesClearance
Translocation Reactivity
Alveolar type
Alveolar type
I
I
C
II
EN
surfactant
alveolar air space

surfactant
M
I
C
EN
I
Macrophages
Blood-air barrier 200 nm thick
Simeonova, 2006
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Current Research Results Carbon Nanotube
Toxicity to Respiratory Tract
Pharyngeal aspiration of SWCNT elicited acute
inflammation combined with early progressive
fibrosis and granulomas in mice.
1 day post exposure 40 mg/mouse SWCNT
28 days post exposure 40 mg/mouse SWCNT
A.A. Shvedova et al, Am. J. Physiol. Lung Cell.
Mol. Physiol., 2005
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Current Research Results Carbon Nanotube
Toxicity to Respiratory Tract
Whole body inhalation exposure to SWCNT elicited
acute inflammation combined with early
progressive fibrosis and granulomas in mice.
A.A. Shvedova et al, Am. J. Physiol. Lung Cell.
Mol. Physiol., 2008
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3 Days Post-Exposure Transmission Electron
Micrograph of Carbon Nanotubes in Lung
Interstitium
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Medical Surveillance for Nanomaterials?

• Radiographic -- HRCT
• Serum Biomarkers of Lung Inflammation
• Neopterin
• In chronic beryllium disease, serum neopterin has
  high positive predictive value (Harris, Am J Ind
  Med, 1997)
• KL-6
• One of the MUC1 antigens, strongly expressed on
  Type II alveolar cells, correlates with
  interstitial pneumonia
• Exhaled Breath Condensate (EBC) (Jackson, Am J
  Res Crit Care Med, 2007)
• 8-Isoprostane
• Elevated and correlated with progressive COPD
  (Makris, Respiration, 2008)
• Elevated levels in sarcoidosis (Piotrowski,
  Chest, 2007)
• TNF-alpha

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CNT vs. asbestos

• Direct exposure of the mesothelial lining of the
  body cavity of mice by intraperitoneal injection
  (50 µg dose)
• Acute (24h and 7 days) response
• Long (gt 20 µm) straight MWCNT produced
  inflammatory response and formation of granulomas
  similar to asbestos fibers

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CNT vs. asbestos
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CNT vs. asbestos
www.cdc.gov/niosh/blog/nsb052008_nano.html
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Current Research Results Translocation Titanium
Dioxide
Translocation is a function of particle size (G.
Oberdorster, EHP, 1992, 97, 193)
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Nanotoxicology Practical Findings from a New
Field

• Biological activity depends largely on particle
  surface chemistry. Nanoparticles can be designed
  to be non-toxic.
• TiO2 studies suggest that particle surface area
  for particles of different sizes but of the
  same chemistry is a better dose metric than is
  particle mass or particle number. NIOSH Current
  Intelligence Bulletin on TiO2 (www.cdc.gov/niosh/r
  eview/peer/Tio2/)
• Fine TiO2 1.5 mg/m3
• Ultrafine TiO2 0.1 mg/m3
• Our gravimetric environmental sampling paradigm
  may not work to measure nanoparticles with little
  mass.

TEM micrograph of a single TiO2 nanocrystal. V.
Colvin, Nature Biotech, 2003, 21, 1166.
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Control Strategies
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Approaches to Safe Nanotechnology in Research and
Manufacturing

• Engineering controls
• Total enclosure of the process
• Partial enclosure with local exhaust ventilation
• Local exhaust ventilation
• General ventilation

http//www.cdc.gov/niosh/topics/nanotech/safenano/
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Approaches to Safe Nanotechnology

• Work practices
• Controlled access
• Reduction in periods of exposure
• Regular cleaning of process areas

http//www.cdc.gov/niosh/topics/nanotech/safenano/
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Particle Penetration through Filters
Penetration
Inertial/impaction
Particle size
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Particle Penetration through Filters
Penetration
Inertial/impaction
Particle size
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Particle Penetration through Filters
Penetration
Diffusion
Particle size
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Particle Penetration through Filters
Penetration
Diffusion
Particle size
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Particle Penetration through Filters
Penetration
Thermal rebound
Particle size
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Particle Penetration through Filters
Penetration
Thermal rebound
Particle size
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Particle Penetration through Filters
Inertial/impaction
Thermal rebound
Diffusion
Penetration
Particle size
1 nm (?)
200 nm
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NIOSH Approaches to Safe NanoPersonal Protective
Equipment Respirators

• Use of respiratory protection for nanomaterials -
  professional judgment and hazard assessment

n 5 error bars represent standard
deviations Flow rate 85 L/min NIOSH Approved N95
Brownian Motion Comes to the Rescue!
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Particle Penetration Through Clothing

• Some fabric swatches behave like filter media
• Particle penetration driven by pressure
  differences
• Particle penetration is a function of the air
  permeability of the fabric
• NIOSH research project

10 cm diameter circular swatch Single layer of
needle-punched Aramid material Face velocity
0.63 cm/sec Flow rate 1L/min Data courtesy of
Dr. Zhong-Min Wang (NPPTL)
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Approaches to Safe NanotechnologyPersonal
Protective Equipment Clothing

• ASTM standard F1671-03 specifies the use of a 27
  nm bacteriophage to evaluate the resistance of
  protective clothing materials to penetration by
  blood-borne pathogens.
• No guidelines exists on the selection of clothing
  for the prevention of dermal exposures.

Nanoscale alumina on cotton fabric (M.
Ellenbecker)
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Risk Management Government

• EPA -- Toxic Substances Control Act (TSCA)
• January, 2008 -- EPA launched Nanoscale Materials
  Stewardship Program (epa.gov/oppt/nano). August
  22, 2008 22 organizations, 93 nanomaterials
• EPA does not require a separate registration for
  nanosized substances of existing bulk substances
• EPA has received and reviewed a number of new
  chemical notices for nanosized materials
• EPA -- Federal Insecticide, Fungicide and
  Rodenticide Act (FIFRA)
• Any company marketing a product using silver
  nanoparticles to kill bacteria must provide
  scientific evidence that particles do not pose an
  environmental health risk (Federal Register on
  September 21, 2007 EPA-HQ-OPP-2007-0949
  FRL-8149-4)
• ATEN Technology/IOGEAR fined 208K for selling
  unregistered pesticides and making unproven
  claims about their effectiveness nanoshield
  coating on mouse and keyboard (March 7, 2008)
• OSHA -- Occupational Safety and Health Act
• Control Banding initiative with NIOSH
• FDA Nanotechnology Task Force report (July 25,
  2007)
• Nanoscale materials present challenges similar to
  other emerging technologies

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EPA Nanotechnology Research Strategy

• Describes initiation of and guides in-house
  nanotechnology research program within EPAs
  Office of Research and Development
• Describes key research questions under four
  themes
• Sources, Fate, Transport, and Exposure
• Human Health and Ecological Research to Inform
  Risk Assessment and Test Methods
• Risk Assessment Methods and Case Studies
• Preventing and Mitigating Risks
• Draft released in January, 2008
• http//es.epa.gov/ncer/nano/publications/nano_stra
  tegy_012408.pdf

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Organization for Economic Cooperation and
Development

• Produces internationally agreed instruments,
  decisions and recommendations to promote rules of
  the game in areas where multilateral agreement is
  necessary for individual countries to make
  progress in a globalized economy (30 members, 70
  observers).
• In November 2007 OECD Working Party on
  Manufactured Nanomaterials established a
  NIOSH-led project to raise awareness about- and
  harmonize approaches for- exposure measurement
  and mitigation for nanomaterials.
• OECD Workshop on Exposure Assessment Exposure
  Mitigation led by NIOSH on October 20, 2008 in
  Frankfurt, Germany.

www.oecd.org
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International Organization for StandardizationTC
229 Nanotechnologies

• Technical Report on Health Safety practices in
  occupational settings relevant to
  nanotechnologies
• Encyclopedic report focusing on best practices in
  occupational settings that are currently being
  utilized globally hazard characterization,
  exposure assessment, risk assessment, control
  methodologies.
• Based on NIOSH Approaches to Safe
  Nanotechnology and developed with NIOSH
  leadership.
• Experts from 13 countries (lead by NIOSH)
  participated in the development 39 participating
  and observing members reviewed the report during
  development.
• Approved for publication as ISO/TR-128852008 in
  May, 2008 release by ISO September, 2008.

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British Standards Institute PD6699-22007 Guide
to safe handling and disposal of manufactured
nanomaterials
www.bsi-global.com/en/Standards-and-Publications/I
ndustry-Sectors/Nanotechnologies/
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Risk Management Private Sector
Woodrow Wilson Center 2006
Woodrow Wilson Center 2007
ED-DuPont 2007
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The National Nanotechnology Initiative 2008
Strategic Plan

• Goals
• Advance a world-class nanotechnology research and
  development program
• Foster the transfer for new technologies to
  products for commercial and public benefit
• Develop and sustain educational resources, a
  skilled workforce, and the supporting
  infrastructure and tools to advance
  nanotechnology and
• Support responsible development of nanotechnology.

Available at http//www.nano.gov/NNI_Strategic_Pla
n_2007.pdf
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The National Nanotechnology Initiative EHS
Strategy

• Identify and prioritize EHS research for
  nanomaterials
• Analyze the current research portfolio of the
  seven federal agencies funding EHS research
• Perform an analysis to determine areas requiring
  emphasis for further research
• Develop a strategy to address identified areas
  for research
• NIOSH is a coordinating agency for Human Health
  and Environmental Exposure Assessment research
  category

Available at http//www.nano.gov/NNI_EHS_Research_
Strategy.pdf
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The National Nanotechnology Initiative EHS
Strategy

• National Nanotechnology Initiative Human and
  Environmental Exposure Assessment workshop.
• Sponsored by National Institute for Occupational
  Safety and Health Consumer Product Safety
  Commission Nanoscale Science, Engineering, and
  Technology Subcommittee
• Workshop site CPSC conference facility, 4330
  East West Highway, Bethesda, MD
• Date February 24-25, 2009
• Workshop goal to provide an open forum to
  facilitate effective communication among
  stakeholders about progress achieved in Human and
  Environmental Exposure Assessment research
  category and about path forward for addressing
  research needs in this category by
• Bringing stakeholders together to build dialogue
  and to facilitate collaborations
• Discussing State of the Science to compare the
  progress of ongoing research to research needs
  and to identify gaps and emerging trends
• Relating progress and next steps to adaptive
  management of the research needs strategy.

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Government Accountability Office EHS Review

• Effective coordination of agency activities
  related to EHS risks of nanotechnology
• 20 of research projects reported as EHS-focused
  were in application area
• Projects are consistent with agency priorities
  and NEHI research categories
• Available at http//www.gao.gov/cgi-bin/getrpt?GAO
  -08-402

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NIOSH ResourcesNanotechnology Topic Page
www.cdc.gov/niosh/topics/nanotech/
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NIOSH Nanotechnology ProgramField Research Team
2007-2008

• Field Research Team for partnerships in studying,
  assessing nanotechnology processes
• exposures,
• work practices,
• control procedures,
• medical monitoring

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CNF Air Sampling Results as Total Carbon (µg/m3)
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Controlling technology impactThe accepted model?
with nanotechnology, we still have the chance to
make a difference before the train leaves the
station
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In the long term, nanotechnology will demand a
revolutionaryre-thinking of occupational health
and safety