Nanoparticles and Health

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Nanoparticles and Health

• Michael T. Kleinman
• Department of Community and Environmental
  Medicine
• University of California, Irvine

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Definitions- Particle Size

• Nano Ultrafine lt 100 nm (Conventional)
• Nano lt10 nm (suggested by unique quantum and
  surface-specific functions)
• Fine 100 nm - 3 ?m
• Respirable (rat) lt 3 ?m (max 5 ?m)
• Respirable (human) lt 5 ?m (max 10 ?m)
• Inhalable (human) 10 - 50 ?m

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Much of our thinking about nanoparticles stems
from our knowledge of traffic-related particulate
matter (EPA, 2004)

• The four polydisperse modes of traffic-related
  ambient particulate matter span approximately 4
  orders of magnitude from below 1 nm to above 10
  µm.
• Nucleation and Aitken mode particles are defined
  as ultrafine particles (lt100 nm).
• Source-dependent chemical composition is not well
  controlled and varies considerably.
• In contrast engineered nanoparticles (1-100 nm)
  have well controlled chemistry and are generally
  monodispersed.
• The particles lt 10 nm have surface properties
  that are quantum dominated and may represent a
  separate class of materials.

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NPs Deposit Very Efficiently in the Alveolar
Region
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Interparticle Forces And Surface Chemistry Will
Be Influenced By Size And Whether Particles Are
Individual or Aggregates Agglomerates
Mechanical interlocking
Single particle
Capillary (surface tension)
Van der Waals (cohesive force a 1/d2)
Chemical bonds
Equivalent dia. 2 x Settling velocity 3-4 x
Equivalent diameters of 10-1000x are common
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These properties influence lung deposition as
well as toxicity.

• Ultra-fine or nanoparticles may deposit as
  aggregates due to high Van Der Waals forces,
  rather than discrete particles.
• If an inhaled particle with a diameter of 50100
  nm forms an aggregate of 510 particle types, in
  terms of deposition it may have the properties of
  a 200500 nm particle
• Inhaled agglomerates may dissociate when in
  contact with lung surfactants.

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Engineered Nanoparticles

• There are four basic categories of nanoscale
  materials that are being sold as commercial
  products and materials that may need to be
  regulated.
• Metal oxidesceramics from oxides of zinc, iron,
  cerium, and zirconium
• chemical polishing agents from semi-conductor
  wafers
• scratch resistant coatings for glass and
• cosmetics and sunscreens which are the biggest
  group of current commercial nanomaterials.
• Nanoclaysnaturally-occurring plate-like clay
  particles
• improve strength, hardness, heat resistance and
  flame retardancy of materials
• produce barrier films in plastic beverage
  bottles, paper juice cartons, and tennis balls.
• Nanotubes and spheresused in coatings
• to dissipate and minimize static electricity in
  fuel lines and hard disk handling trays
• can also be found in electrostatically paintable
  car exterior components, flame-retardant fillers
  for plastics, and field emitter sources in flat
  panel displays.
• Quantum dotsused in exploratory medical
  diagnostics and therapeutics and self assembly of
  nanoelectronic structures.

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Engineered nanoparticles will have a variety of
applications in the environment and in people

• Nanoscale sensors are being investigated for
  detection of biological compounds such as algal
  toxins in the marine environment or mycobacteria
  present in drinking water.
• Fluorescent dendrimers displaying spatially
  resolved microdomains on polymer beads can detect
  different algal (or other) toxins.
• The binding of different toxins results in
  specific fluorescence wavelengths, depending upon
  the spatial resolution of the dendrimers on the
  polymer beads.

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NANOTECHNOLOGY, HUMAN HEALTH, AND MEDICINE
Nanoparticles are far to useful NOT to enter the
human environment! Once an early biomarker of a
disease or dysfunction is identified, then
scientists can use targeted pharmaceutical or
gene therapy to correct the faulty
components. Kenneth Olden
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INTERACTIONS WITH BIOLOGICAL SYSTEMS

• The challenge that nanomaterials pose to
  environmental health is that they are not one
  material.
• It is difficult to generalize about them because,
  similar to polymers, they represent a very broad
  class of systems.
• Many engineered nanomaterials have precisely
  controlled internal structures, which are
  structures of perfect solids.
• Over a third of the atoms in a nanoparticle are
  at the surface, and these are extremely reactive
  systems, which in some cases can generate oxygen
  radicals
• Nanoparticles can also be tied up very tightly in
  covalent bonds and wrapped with a polymer.
• Because of the size of nanostructures, it is
  possible to manipulate the surface interface to
  allow for interactions with biological systems.
• With the correct coating, particles below 50 nm
  can translocate into cells relatively easily and
  are able to interact with channels, enzymes, and
  other cellular proteins.
• Those particles above 100 nm, based primarily on
  size of the particles, have more difficulty.
• Through the interactions with cellular machinery,
  there is potential for medical uses, such as drug
  delivery and cellular imaging.

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SIZE ISNT EVERYTHING

• In most cases, nanoscale systems will alter in
  physical size upon interaction with an aqueous
  system.
• For example, it is very common for many
  nanostructures to adopt a different chemical form
  simply through relatively minor interactions
  consequently, size is not a constant factor in
  biological interactions.
• The surface area can make up a sizeable fraction
  of these materials.
• they can be derived to make many different
  biomedical systems.
• by changing surface coatings the nanomaterial
  toxicity can almost be completely altered.
• For example, changing the surface features of the
  materials can change a hydro-phobic particle into
  a hydrophilic one.
• Hypothetically, surface coats could, for
  instance, make it possible to eat nanoscale
  mercury if it has the right surface coating,
  while it may be dangerous to eat nanoscale table
  salt if the surface coating was not correct.
• The scientists typical view of toxicology, which
  is driven by the composition of an inorganic
  particle, may have to be modified for nanoscale
  materials, because surface characteristics are
  going to affect different dimensions of
  environmental and health effects

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Carbon Nanotubes Will Be Used In Electronics
Applications

• Transistors and diodes
• Field emitter for flat-panel displays
• Cellular-phone signal amplifier
• Ion storage for batteries
• Materials strengthener

Source Scientific American- Illustration
RICHARD E. SMALLEY, Rice University
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Manufactured Nanotubes are Similar to
Combustion-Generated Nanotubes

• Assays on a murine lung macrophage cell line to
  assess cytotoxicity of commercial, single wall
  carbon nanotubes (ropes) and two different
  multiwall carbon nanotube samples utilizing
  chrysotile asbestos nanotubes and black carbon
  nanoaggregates as toxicity standards.
• These nanotube materials were characterized by
  transmission electron microscopy.
• and observed to be aggregates ranging from 1 to
  2 microm in mean diameter, with closed ends.
• The cytotoxicity data indicated a strong
  concentration relationship and toxicity for all
  the carbon nanotube materials relative to the
  asbestos nanotubes and black carbon.
• These results implicate NPs as triggers of
  asthma and related respiratory or other
  environmental health effects.
• Indoor number concentrations for multiwall carbon
  nanotube aggregates is at least 10 times the
  outdoor concentration
• Virtually all gas combustion processes are
  variously effective sources of Nanotubes.
• These results also raise concerns for
  manufactured carbon nanotube aggregates, and
  related fullerene nanoparticles.
• From Mur et al., Cytotoxicity assessment of some
  carbon nanotubes and related carbon nanoparticle
  aggregates and the implications for anthropogenic
  carbon nanotube aggregates in the environment
  (2005).

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Nanoparticles and CV Disease
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Electron micrographs demonstrating effects of
different sized particles in RAW 264.7 cells
treated with USC-Jan 02 CAPs for 16 hr. (A) and
(B) Untreated RAW 264.7 cells. (C) and (D) RAW
264.7 cells exposed to coarse particles. (E) and
(F) RAW 264.7 cells exposed to fine particles.
(G) and (H) RAW 264.7 cells exposed to UFPs.
Notice damage to cristae as well as the presence
of particles (P) inside mitochondria (M) in UFP-
or fine UFP-exposed cells.
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USE OF QUANTUM DOTSQDs can be used for long-term
tracking of primary liver cells without
compromising liver-specific function
Hepatocytes were labeled by endocytosis of
EGF-coated red QDs
A B Labeled Hepatocytes on Day 1. C D
Hepatocytes were reorganized by Day 7 but still
identified by label. D Albumin production
(marker for hepatocyte function) same as
controls.
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THE ENVIRONMENT CAN INFLUENCE THE TOXICOLOGY OF
NANOMATERIALS

• We do not have testing procedures equivalent to
  drug delivery devices in place for some NP
  applications (Eva Oberdörster, Southern Methodist
  University).
• Coating or modifying the outer surfaces of
  nanomaterials can alter the toxicity of most
  particles. TOPO (trioctylphosphine oxide) is used
  to control the magnetic and electronic properties
  of nanoparticles.
• Questions remain about the effects of
  environmental conditionsas opposed to laboratory
  conditions.
• Drefus et al. (2004) suggests that air exposure
  and nanoparticle dose are important for cytotoxic
  effects.
• Toxicity of CdSe quantum dots in a liver culture
  model changes when they are exposed to air or
  ultraviolet light.
• LESSON LEARNED Nanomaterials may be safe under
  laboratory conditions but not under some
  environmentally relevant conditions.

(A) Hepatocyte viability assessed by
mitochondrial activity of QD-treated cultures vs.
untreated controls. Thirty minutes of exposure to
air while TOPO-capped renders QDs highly toxic at
all concentrations tested. Ultraviolet light
exposure increases toxicity with increasing time
and QD concentration
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POTENTIAL MECHANISM

• Surface oxidation leads to release of cadmium
  ions.
• (A) Proposed mechanism of Cd release from the QD
  surface via either TOPO-mediated or UV-catalyzed
  surface oxidation.
• (B) Inductively coupled plasma optical emission
  spectroscopy (ICP/OES) measurements of free
  cadmium in 0.25 mg/mL solutions of QDs,
  indicating higher levels of free cadmium in all
  oxidized samples.
• Increasing Cd levels with UV exposure time,
  correlate with cytotoxicity observed in previous
  figure

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Exposure to carbon nanotube material Aerosol
release during the handling of unrefined SWCNT-
Andrew Maynard et al.

• Laboratory study and field-based study
• Field study assessed airborne and dermal
  exposure to SWCNT while handling unrefined
  material.
• Lab studies SWCNT can release fine particles
  with sufficient agitation.
• Field studies concentrations generated while
  handling material were very low- always lt 53
  ?g/m3.

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Handling nanotube material
Raw single walled nanotube material
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Characteristics of airborne nanotube particle
Expected Morphology
Predominant Morphology (Field Samples)
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Preliminary Study at Rice University SiO2
Nano-SiO2 is less inflammatory than Min-U-Sil
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TiO2 Nanoscale Rods
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Toxicity of TiO2
Pigmentary Nano-TiO2 are not different
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Are Nanoparticles More Toxic Than Projected From
Studies of Larger Particles?

• Some current hypotheses suggest that
  nanoparticles are more toxic (inflammatory,
  tumorigenic) than fine-sized particles of
  identical composition.
• This concept is based on a systematic evaluation
  of only three particle types titanium dioxide,
  carbon black, and diesel particles.
• Thus, the current hypotheses are based on a
  paucity of data.

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TiO2 Inflammatory Responses May Be Size Dependent
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On the hopeful side----

• Nanotechnology is a revolutionary scientific and
  engineering concept that will have a large impact
  on our life.
• A core piece of this technology is the production
  of nanomaterials for electronic, chemical,
  medical, pharmaceutical, and environmental
  applications.
• Natural and modified natural nanomaterials would
  be good reference points for comparison of the
  functionality, cost, and potential ecological
  implications of synthetic nanomaterials.
• While the environmental impact and health effects
  of synthetic nanomaterials are essentially
  unknown and their use is of concern, natural
  nanomaterials have been part of human existence
  since antiquity.
• Many of these NPs do not appear to pose much risk
  either to the physical environment or to human
  health.

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On the other hand, there are many unanswered
questions

• Where are the impacts of products that have
  nanomaterials in them?
• Where in the life cycle are their impacts going
  to fall?
• Are there any impacts in the use stage like
  automobiles the disposal stage, like electronic
  equipment or the extraction stage like some of
  our mining endeavors?
• How will the move to nanotechnology change a
  materials flow within a particular sector?
• What is the correct metric for nanoparticles?

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PERHAPS AN HOLISTIC APPROACH COULD BE USED TO
HELP US UNDERSTAND THE POTENTIAL HEALTH
IMPLICATIONS
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WHERE DO WE STAND?

• Most of the initial reports (in the media) have
  been positive however, we should not forget that
  given the nature of nanoparticles, not all
  nanomaterials will be benign.
• Kenneth Olden

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Recent Review Article