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Section C
Factors Involved in the Toxicity of Nanoparticles
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Physiochemical Determinants of Particle Toxicity
! The widely accepted physicochemical determinants in
traditional particle toxicology are:
- The form of the particle: for example, fibers more
potent toxicant than isometric particles; spiky fractured
crystals more potent than smooth round-ish particles)
- The chemical composition and related surface
reactivity: free radical-generating surface sites, poorly
coordinated and easily removable metal ions, strong
adsorption and modification of endogenous
antioxidants or of proteins
- The time of residence in a given body compartment
generally defined as biopersistence—a property
related to both chemical factors, such as solubility,
adsorption potential, and to the cellular and tissue
response to it
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Physiochemical Properties Relevant to
Nanoparticle Toxicity
! Nanosize
- Surprisingly, the smaller the particle, the greater the
toxicity!
! Extremely large specific surface (that is, surface exposed
per unit mass)
! High ratio of surface to bulk atoms, leading to higher
surface reactivity
! Specific reactivity arising at the nanolevel
! Chemical structure linked to nanosize (absence of any
larger counterpart)
! Strong interparticle forces leading to aggregation
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Possible Components in a Carbon Nanotube
Sample
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Chemical Reactivity on the Surface of
Nanoparticles
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Toxicokinetics
! Toxicokinetics: considerations for the biodistribution of
nanoparticles
- How do we best characterize “internal dose” and
“biologically effective dose?”
- Half-lives have been determined in animal models for
some nanoparticles
- Physiological barriers exist
! Such as opsinization and subsequent clearance
by the liver
- Anatomical barriers exist
! Such as tissue epithelium (can nanoparticles
penetrate the epithelium?)
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Toxicokinetics
! Toxicokinetics: considerations for the biodistribution of
nanoparticles
- Cellular uptake processes: pinocytosis and
phagocytosis
! Other transport mechanisms?
- Is there localization to specific tissues?
- Ability to enter the central nervous system
! Penetrate the blood-brain barrier?
! Olfactory nerve endings
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Distribution of Nanoparticles in Experimental
Animals
The biodistribution of 40% C18PGA particles coated with 0.1% polysorbate 80 three
hours after injection into mice (open columns) and rats (filled columns). [40% C18PGA
poly (glycerol adipate) with 40% of pendant hydroxyl groups substituted with C18 acyl
groups.]
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Hazard Assessment
! Some considerations for the toxicodynamics of
nanomaterials
- Nanoparticles have been shown to enter cells in
culture as well as intact organisms
- In a variety of in vitro systems, the following have been
observed
! Cytotoxicity
! Genotoxicity
! Altered gene expression
- What do these observations mean?
- How should they be used to develop practical
toxicological screening methods?
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Hazard Assessment
! Some considerations for the toxicodynamics of
nanomaterials
- What underlying biologic mechanisms drive
nanomaterial-induced toxicity?
- What adverse health outcomes should we measure (at
the sub-cellular, cellular, organ-system, and organism
levels)?
- What role does synergism play?
! It is likely that nanomaterials will adsorb other
chemicals or biological agents, and these
combinations could behave in novel ways
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NM Effects as the Basis for Pathophysiology
and Toxicity
Source: (2006). Science. 311: 622,
2006.
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Man-Made Nanoparticles
! Mechanistically, are man-made nanoparticles similar to
particles derived from combustion?
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Issues Relevant for Human Toxicology and
Epidemiology
! What are the relevant patterns and pathways of human
exposure to man-made nanomaterials?
! How should we best characterize “exposure,” and what
analytic methods need to be developed and validated to
do so?
! What are the most relevant adverse human health
consequences?
! What prospective cohorts of potentially exposed persons
should be identified (prior to exposure) and monitored
over time following exposure?
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Putting Nanomaterials into the Toxicological
Paradigm
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Lecture Evaluation
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