The Dynamics of Engineered Nanomaterials in
the Mammalian Alimentary Canal Environment
Following Release from Food Matrices
16 April 2013 Webinar
NanoRelease Food Additive
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Task Group 2 – Charges
…the gastrointestinal tract is complex, composed of numerous cell
types and environments…
AIM
Discussing the potential dynamics of nanoparticle interactions
within the GI tract
TG2 in the NanoRelease Food Additive Project
TG2 white paper aim to inform and provide input to TG3
(Modelling) and TG4 (Measurement Methods)
TG2 – Alimentary Canal Environment
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Task Group 2 – Charges
1.
Review physical, chemical, physiologic and anatomic context of the
GI tract
2.
Anatomy and physiology in relation to nanomaterial uptake
likelihood (e.g. villi, Peyers patches, M-cells etc)
3.
Physico-chemical factors of the gut that affect
aggregation/agglomeration and dissolution transitions of
nanoparticles (e.g. pH, redox, temperature, enzymes, surfactants,
etc).
4.
Lumen content and composition (e.g. insoluble fiber, bacteria, large
particles, etc) that may influence nanoparticle characteristics and
properties (opsonization, corona formation and dynamics)
5.
Human variation in physiological state, age, disease, hormonal
status, phenotypic variation…
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TG2: Alimentary Canal Environment
MEMBERS
Susann Bellman (COCHAIR)
TNO Netherlands
David Carlander (COCHAIR)
Nanotechnology Industries Association
John Milner (advisor)
Brian Lee
Human Nutrition Research Ctr. (USDA)
MassGen Hospital (Gastroenterology, Nutrition,
Mucosal Immun.& Biology)
GE Global Research
Bruce Hamaker
Purdue University
David Lefebvre
Health Canada
Dora Pereira
MRC Human Nutrition Research
Dragan Momcilovic
US Food and Drug Admin.
James Waldman
Ohio State University
Joseph Scimeca
Cargill, ILSI North America
Jozef Kokini
Univ. of Illinois
Lourdes Gombau
Leitat Tech. Center
Alessio Fasano
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Task Group 2 – White Paper Chapters
1.
Introduction
2.
Alimentary canal anatomy and mucosal cell types involved in
the exclusion or absorption of nanomaterials
3.
Gastrointestinal luminal factors affecting nanomaterials
4.
Impact of physiological variability
5.
Conclusions
This presentation focuses on the main findings from the chapters above
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Q: What can
Chapter 1: Introduction
be measured
to understand
‘Setting the scene’
uptake
• The human gut has been exposed to particles of varying sizes for likelihood?
millennia, either exogenous from the diet (for example ferritin) or
endogenously formed (for example calcium phosphates).
•
The properties of the atoms on the surface of nanomaterials affect
their dynamics. The surface can bind reversibly or irreversibly bind
molecules from their environment. The resulting corona also affects
behaviour.
•
Size is an important characteristic
•
The physicochemical surface properties of the nanomaterials can
affect release from the food matrix, solubility, stability, interactions
with mucus, interactions with the apical cell membrane and
absorption
•
The fraction of material which is not absorbed, or which has been
secreted back into the lumen via enterohepatic circulation, is
excreted in the faeces. Is there recirculation and toxicity in the
enterohepatic pathway?
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Q: What can
Chapter 1: Introduction
be measured
to understand
uptake
• Nanomaterials can have complex dynamics during their transit
likelihood?
along the gastrointestinal tract due:
•
changing pH in the various segments (buccal cavity, stomach, gut, colon)
•
digestive enzymes (in the buccal cavity, stomach and gut)
•
bacteria (in the buccal cavity and colon).
•
Opsonization/corona formation
• Reversible dynamics can occur e.g.:
•
reversible agglomeration(and/or aggregation?) during transit through the
lumen
•
re-formation of nanomaterials in the lumen or in cells from ions.
• It can be challenging to separate the detection of administered
engineered nanomaterials from the natural nanomaterials
present in food and living tissues.
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Q: What can
Chapter 2: Alimentary canal anatomy and mucosal cell be measured
to understand
types involved in the exclusion or absorption of
uptake
nanomaterials
likelihood?
• If a given class of nanomaterials quickly dissolves or digests
following release from the food matrix, the buccal cavity may be
the only tissue with limited exposure to the nanomaterial.
• The dissolved material may be considered equivalent to the
standard ionic form.
• If a nanomaterial class forms permanent aggregates, the material
could be studied in comparison with bulk materials.
Test methods and models: Buccal/gastric dissolution models?
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Q: What can
Chapter 2: Alimentary canal anatomy and mucosal cell be measured
to understand
types involved in the exclusion or absorption of
uptake
nanomaterials
likelihood?
•
If primary nanoparticles are stable and remain single particles, the
small intestine would be an important segment to study with regard
to absorption.
•
Absorptive enterocytes are important since they are the most
abundant cell type.
•
•
M cells in the Peyer’s patch epithelium make up less than 1 % of the alimentary
canal surface area, but are the cell type most specialized for the uptake of
particulate matter.
Mucus secreted by Goblet cells coats the gut mucosa. Mucosa may
be a barrier to the absorption of some nanomaterials or may
enhanced absorption by mucoadhesive properties that increase
residence time in the intestinal wall and consequently absorption
Test methods and models: Intestinal wall models with enterocytes and
goblet cells?
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Chapter 3: Gastrointestinal luminal factors
affecting nanomaterials
Q: What can
be measured
to understand
uptake
likelihood?
• In the upper gastrointestinal tract nanoparticles may aggregate
(so that their behaviour during at least part of the exposure
process is more typical of large particles even though their single
unit is as a small particle) or dissolve (so that they then behave like
their soluble constituents) and then lower down the GI tract those
that aggregated may dissolve and vise-versa.
• E.g. iron oxide particles that can become solubilized in the acidic
environment of the stomach but then agglomerate together with other
dietary constituents (such as low molecular weight ligands) forming
nanoparticles when released into the near neutral environment of the
small intestine.
Test methods and models: De- and Agglomeration/Aggregation models in
various GI environments?
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Chapter 3: Gastrointestinal luminal factors
affecting nanomaterials
Q: What can
be measured
to understand
uptake
likelihood?
• Nanoparticles are rarely seen by cells in their ‘native form’. Most
nanoparticles readily adsorb to their surface molecules and ions
from their environment. In the gut, particle surfaces may be
‘cleared’ in the acid and enzyme-active area of the stomach but readsorb material further down the GI tract. In this environment,
bacterial proteins and carbohydrates are especially common. The
formation of protein corona is a special consideration.
• The way nanoparticles are presented to the gut-lining cells will
depend on their mobility through mucus, on their interaction with
bile salts and other luminal contents, pH gradients, presence of
electrolytes and local ionic strength, fasted and fed state
conditions.
Test methods and models: ‘Standardised’ corona models in various GI
environments?
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Chapter 3: Gastrointestinal luminal factors
affecting nanomaterials
Q: What can
be measured
to understand
uptake
likelihood?
• Even though M-cells are not one of the most abundant cell types
in the GI tract they are very specialized for the uptake of particles
and therefore provide a significant route of uptake of particles in
the GI tract, and the only one significant for larger particles.
• Transcellular vs paracellular pathways. Other routes include
endocytosis through enterocytes or persorption through gaps in
the tight junctions. Both of these mechanisms are more significant
for smaller nanomaterials.
• Little is known about the interactions between food related nano
particles and the gut flora, adherence of gut bacteria to nano
particles can result in biofilm formation and subsequent
persistence of nano particles
Test methods and models: M-cell models? Endocytosis/persorption models?
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Chapter 4: Impact of physiological variability
Q: What can
be measured
to understand
uptake
likelihood?
•
High doses of some unique classes of nanomaterials may have an
impact on intestinal permeability, which could be a confounding
effect in studies.
•
The alimentary canal of individuals with certain diseases can have a
tendency for higher permeability to particulate matter.
•
The present white paper only briefly described natural physiological
variability and disease states.
•
There is a data gap with regard to studies on the quantification of
nanomaterials in the alimentary canal of individuals with states of
altered physiology. Risk assessment sometimes uses inter-individual
uncertainty factors to account for this.
•
Bioavailability (the proportion of material which is absorbed) is an
important parameter to study in both the healthy and diseased state
Test methods and models: Models with altered physiology? Bioavailibility models?
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Chapter 5: White Paper Conclusions
• While current food risk assessment guidelines, some of which
include studies in animal models, capture and ensure the safety of
nanomaterial products, there is currently a gap in the availability
of validated alternative models for the study of nanomaterial
dynamics such as bioavailabililty.
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Additional considerations
• Continue to address and discuss behaviour of the three categories
of materials identified in TG1:
•
Category 1: Soft/lipid-based nanomaterials
•
Category 2: Solid non-lipid non-metal nanomaterials
•
Category 3: Solid metalloid/metal-based nanomaterials
• Fate and behaviour (systemic toxicity) of NM after intestinal
barrier translocation is outside scope of this NanoRelease Food
Additive Project
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On behalf of TG2
Thank you for your attention!
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