Download Measurement Methods to Evaluate Engineered Nanomaterial

Measurement Methods to Evaluate Engineered
Nanomaterial Release from Food Contact
Materials
Gregory O. Noonan, Andrew J. Whelton, David Carlander, and Timothy V. Duncan
Abstract: This article is one of a series of 4 that report on a task of the NanoRelease Food Additive project of the Intl.
Life Science Inst. Center for Risk Science Innovation and Application to identify, evaluate, and develop methods that
are needed to confidently detect, characterize, and quantify intentionally produced engineered nanomaterials (ENMs)
released from food along the alimentary tract. This particular article focuses on the problem of detecting ENMs that
become released into food indirectly from food contact materials. In this review, an in-depth analysis of the release
literature is presented and relevant release mechanisms are discussed. The literature review includes discussion of articles
related to the release phenomenon in general, as experimental methods to detect ENMs migrating from plastic materials
into other (nonfood) complex matrices were determined to be relevant to the focus problem of food safety. From the
survey of the literature, several “control points” were identified where characterization data on ENMs and materials may
be most valuable. The article concludes with a summary of findings and a discussion of potential knowledge gaps and
targets for method development in this area.
Keywords: characterization, detection, food contact materials, food safety, measurement methods, migration,
nanotechnology, release
Introduction
This article is the second in a series of 4 articles related to a task
of the NanoRelease Food Additive (NRFA) project of the Intl.
Life Science Inst. Center for Risk Science Innovation and Application to identify, evaluate, and develop methods that are needed
to confidently detect, characterize, and quantify intentionally produced engineered nanomaterials (ENMs) released from food along
the alimentary tract. A full description of the project’s charge and
scope, as well as an executive summary of the project’s findings, is
presented in the first article in this series (Szakal and others 2014).
The focus area of the present article is measurement methods, including theoretical methods, to detect the release of ENMs into
foods from food contact materials. The 3rd and 4th following articles in this series, respectively, describe methods to characterize
and detect ENMs in foods (including sample preparation) (Singh
and others 2014) and describe methods to characterize, detect,
MS 20140332 Submitted 28/2/2014, Accepted 4/3/2014. Author Noonan is
with Center for Food Safety and Applied Nutrition, United States Food and Drug
Administration, 5100 Paint Branch Parkway, College Park, MD 20740, U.S.A.
Author Whelton is with Dept. of Civil Engineering, Univ. of South Alabama, 150
Jaguar Drive, Shelby Hall, Suite 3142, Mobile, AL 36688, U.S.A. Author Carlander is with Nanotechnology Industries Assoc, 101 Avenue Louise, 1050 Brussels,
Belgium. Author Duncan is with Center for Food Safety and Applied Nutrition,
United States Food and Drug Administration, 6502 South Archer Rd, Bedford Park,
IL 60516-1957, U.S.A. Direct inquiries to author Timothy V. Duncan (E-mail:
[email protected]).
and study the behavior of ENMs introduced into the alimentary
tract through food ingestion (Alger and others 2014). While the
present article is capable of standing alone, due to the fact that
some experimental methods may have utility in multiple areas relevant to the project’s overall scope, some methods discussed within
this article may have additional descriptive detail offered in other
articles in this series.
Background Concepts and Goals of the Article
General considerations of contaminant release from food
contact materials
The general risk that a chemical poses to human health is
dependent on 2 factors: (1) the capacity of the chemical to do
physical harm if an individual is exposed to it (in other words, its
toxicity) and (2) the likelihood of exposure, which in the case of
oral exposure from food includes how much of the toxicant is in
the food to begin with as well as its pharmacological properties
(in other words, how easily it is absorbed by the alimentary tract).
Regarding ENMs as the potential toxicants, the chief concern
is whether their small size increases their toxicity (due to unique
chemistry) or increases their bioavailability (due to a purported
ability to pass more quickly through natural biological barriers).
In the case of ENMs added directly to foods, exposure assessments
should be relatively straightforward in the sense that it will be
known with certainty that the consumed particles will be introduced to the alimentary tract. Bioavailability and the chemical
fate of ENMs in the (admittedly complex) gut environment are
Published 2014. This article is a U.S. Government work and is in the public domain in the USA.
doi: 10.1111/1541-4337.12079
Vol. 13, 2014 r Comprehensive Reviews in Food Science and Food Safety 679
Measuring nanomaterial release . . .
the primary aspects that need to be understood. In addition, such
particles are specifically engineered to exist in food matrices, so
their exact morphologies and other physical characteristics in
such environments should already be reasonably known.
Assessing the risks of nanotechnology-enabled food contact materials introduces the additional question of whether the particles
can become released into the food in the first place and, if they
can, what the characteristics of such particles are once they are
released into an environment for which they were not specifically
designed. In the limiting situation that ENMs in food contact applications always remain attached to or dispersed within the host
material under the intended conditions of use, the potential adverse toxicological properties they possess in the free state may be
irrelevant. If, however, the embedded ENMs are able to diffuse
through the material and then partition into the external environment during the packaging’s use or storage (this 2-part process
is formally termed migration), then the risks that such migrated
materials pose to consumers need to be evaluated.
Determining whether a prospective migrant, ENM or otherwise, can become released into a contacted food matrix requires robust, standardized experimental methods, including sample preparation methods and chemical analytical methods, which
can identify and quantify the presence of the migrant in the contacted matrix as a function of time. This enables risk assessors to
estimate a typical consumer’s likely exposure to the substance per
unit time based on assumptions about consumption rate, total dietary intake of all food, and so on. While such methods are fairly
well established for conventional (small-molecule) migrants, an
additional complication arises in the case of migrating ENMs. An
exposure assessment requires information related to the following
2 questions: To how much is the consumer likely to be exposed?
To what is the consumer likely to be exposed? Neither question is
always straightforward to answer for an ENM.
Molecular structure is the sole piece of information required
to uniquely identify a small molecule. For instance, every bisphenol A or furan molecule is chemically equivalent and uniquely
identified by its relative quantities and physical arrangement of
specific atoms. Thus, the “To what is the consumer likely to be
exposed?” question is usually self-evident and the preservation of
molecular identity before and after migration of a small molecule
is easily confirmed by conventional analytical techniques like gas
chromatography–mass spectrometry (GC-MS). ENMs, however,
are not so easily identified or classified. For example, although all
AgNPs may have the same general core composition (and even
here we must be careful), they can vary vastly in their physical
characteristics (size and shape), surface features (charge and ligand sphere), aggregation/agglomeration or dissolution state, and
level of intrinsic purity. Along this wide spectrum of properties,
which are also prone to evolve over time in complex ways, the
toxicological and pharmacological behavior of ENMs can change
dramatically. Unlike a molecular name, the term silver nanoparticles
is thus not sufficiently descriptive to identify to what a consumer
is likely to be exposed in the event ENM release into a food item
occurs, even if the characteristics of the pristine particles (prior to
incorporation in the food contact material) are perfectly known.
As a result, estimating consumer exposure to ENM-based migrants from food contact materials requires new methods that can
both: (1) identify and quantify the migration of the ENMs into
surrounding matrices over time and (2) simultaneously provide
the type of characterization data necessary to understand how the
properties of the migrated ENMs are likely to change between the
time the material is made and the time the food is consumed.
The purpose of this article is to review existing methods that
can help risk assessors acquire this necessary information so they
can better understand release of ENMs from nanotechnologyenabled food contact materials. In particular, it is important to be
able to detect particles that have already migrated into foods, as
well as predict ahead of time the types of ENMs that are most
likely to migrate and the conditions under which migration is
most likely to occur. This will ensure that the development of
nanotechnology-enabled food contact materials can be appropriately targeted toward endpoints that are least likely to pose a threat
to human health. Therefore, this article focuses on methods and
tools specifically dedicated to understanding the process of migration itself, including postrelease behavior and dynamics, rather
than on methods that might be used simply to detect or quantify particles that have already migrated into complex matrices.
The latter group would be largely identical to a larger body of
experimental methods that can be used to detect nanoparticles
intentionally added to food matrices, which are reviewed in the
next article in this series (Singh and others 2014).
As this article will show, the body of literature related to the
detection of ENMs that have migrated from nanotechnologyenabled food contact materials (primarily in the form of polymer
nanocomposites [PNCs]) is relatively small. In light of this fact,
and because methods to trace the release of nanoscale fillers from
PNCs likely have general applicability, we will also consider methods and procedures that have been used to understand release of
ENMs from PNC materials intended for nonfood applications. In
addition, because some of the tools we discuss rely on chemical
and physical theory, both as the basis of predictive models and to
put empirical results into context, we view it as a useful exercise to
first review some of the basic principles of diffusion and migration
as they relate to molecular species, as well as to provide a brief
overview of current regulatory thinking regarding the appropriate
way for packaging manufacturers to measure migration. The article will conclude with a brief discussion of current challenges with
respect to detection and modeling of ENM migration as well as an
overview of new methods that may become useful in the future.
Mathematical diffusion models and prediction of migration
rates
The best way to determine likely consumer exposure to a substance added to a food contact material is to experimentally measure its concentration in a food that has been stored in the material
under prescribed conditions. However, this is not always practical
because migration experiments are not trivial to perform, and it is
also difficult to generalize results. For example, if an experiment
performed for a certain contact material yields migration data for
that material in the presence of 1 food type, and a manufacturer
decides to use the same material to store a new food with very different physical or chemical properties, the experiment may need
to be performed again to ensure that the migration rate for the
new intended use is low enough to meet safety standards. For
a material with a number of specific intended applications, the
experimental workload can quickly become unwieldy.
While there are a number of experimental shortcuts that may
be taken to assist in the generalization of empirical results (for
example, the use of food simulants), mathematical modeling of
migration is also a valuable tool. Being able to predict the migration rate for a given combination of food contact material,
external environment type, and use condition (temperature, pressure, and storage time) is desirable because it alleviates the need for
cumbersome experiments and can also help manufacturers predict
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Measuring nanomaterial release . . .
Nevertheless, migration models have historically tended to focus
on estimating diffusion constants, since diffusion is the kinetic process that is usually rate-limiting. The partition aspect of migration
is usually treated as a partition coefficient, K, which scales the expected amount of migrated substance at equilibrium based on the
relative solubility of the migrant in the polymer and the external
matrix. Predicting partition coefficients has received less attention
in the literature, and stock values for limiting “very soluble” (K =
1) and “insoluble” (K = 1000) cases are often used in conjunction with the predicted diffusion constants to estimate migration
levels (Begley and others 2005). Experimentally determined partition coefficients may be used for more precise predictions of the
total migration. However, because the determination of partition
coefficients requires the measurement or estimation of solubility (a parameter that has ambiguous meaning for an ENM), it is
not particularly clear how best to specify partition coefficients for
nanoscale migrants.
Even beyond the difficulties in formulating semiempirical models
to estimate diffusion rates (or partition coefficients) for ENMs, the
unfortunate truth is that semiempirical models are only as good
as the data that support them. Even in the case of small molecule
diffusion, the polymer-specific parameters are constantly being
fine-tuned in light of new migration data and may need adjustment for nonpolyolefinic polymers such as PET or nylon or for
temperatures below glass transition points. In particular, existing
semiempirical models have been formulated for small molecules
and whether they will yield accurate predictions of nanoparticle
diffusion constants is unclear. Molar mass (molecular weight) certainly has little precisely defined meaning for nanoparticles and,
in any case, the body of data for nanoparticle diffusion is fragmentary at best. Therefore, there are numerous challenges at this
time that must be overcome before mathematical modeling becomes a viable tool set to understand nanoparticle migration. The
biggest area of need may thus be the acquisition of sufficient migration rate data from well-controlled experimental model systems
to build semiempirical models for ENM diffusion (or to verify that
existing diffusion models are appropriate to use for ENMs). Acquiring such data is predicated, of course, on the availability of
reliable experimental methods that cannot only measure ENM
release rates (presumably by identifying ENMs that are released
into the external environment over time), but can also provide
information on what has diffused. This is particularly challenging
10454
because migration rates of ENMs are expected to be slow and
∗
4
2/3
D p = 10 exp Ap − 0.01351M + 0.003M −
(1)
released quantities are anticipated to be miniscule, which places a
T
burden on currently available experimental methods.
This model relates the “upper bound” (95% confidence limits,
units of square centimeter per second) diffusion constant, D∗p , to a Experimental measurement of diffusion
polynomial function of only 3 parameters: temperature, molecular
Determining diffusion constants in polymers is not an easy task,
weight of the diffusant, and a polymer-specific parameter, Ap . Ap even for small-molecule migrants, and there are several methods
values for various polymers are set by considering experimental that are generally employed, depending primarily on the characdiffusion data (diffusion constants and diffusion activation energies) teristics of the migrant (molecular weight, volatility, and so on).
for a variety of small molecules and are adjusted such that the An experiment can be performed in an actual food package if
predicted diffusion constants are statistically likely to be greater available (for example, a plastic beverage bottle) or by taking a
than those measured experimentally. A more thorough explanation representative section of a polymer film and assessing whether the
of this process is provided in the cited literature (Begley and others migrant of interest can pass through it under a certain set of con2005).
ditions. In the latter experiment, a specially designed migration or
It deserves mention here that models such as that described permeation cell is usually used (Figure 1). In this particular experiabove are diffusion models and are not necessarily migration mod- ment, a solution of the prospective migrant in a suitable test matrix
els. Although the terms are often mistakenly used interchange- is first loaded into the donor chamber and the receptor chamber is
ably, migration involves additional processes beyond diffusion that charged with neat matrix. The cell is brought to the desired temneed to be considered in order to reliably predict the amount perature (usually chosen to represent the conditions to which food
of a substance released into a food from a polymer over time. packaging materials are likely to be subjected during use/heating
the safety of a new material early in the development cycle. Risk
assessors are therefore using theoretical or in silico approaches to
support experimental determinations of migration (Oldring and
others 2009; Hearty and others 2011).
In the case of migration of an unknown substance from the interior of a polymer to the external environment under a specific set
of conditions, it is usually sufficient to know the diffusion constant
(related to the rate at which the migrant can move about throughout the polymer) and the relative solubilities of the substance in
the polymer and the external environment (related to the degree
to which a migrant can partition into the external matrix). With
this information, it is, in principle, possible to predict the extent
of migration at equilibrium via use of classical physical descriptions of mass transfer, such as Fick’s laws of diffusion. Complete
knowledge of the molecular state of any system yields absolute
predictive power over its macroscale properties; thus, in principle,
one should be able to calculate a priori the diffusion constant and
partition coefficient of any food contact material based on the
molecular structures of the migrant and polymer as well as relevant structural information such as polymer density, crystallinity,
and so forth. However, in practice, estimating the diffusion coefficient or partition coefficient from first-principles approaches
is difficult given the number of factors involved. Moreover, from
a risk assessment standpoint, a good predictive model should allow for enough conservatisms to ensure that any deviations of
an experimentally determined diffusion value from the predicted
value should err as frequently as possible on the side of caution
(in other words, models should slightly overestimate the extent of
migration). It is difficult to build such a degree of conservativeness
into first-principles models, which again limits their usefulness to
manufacturers of food contact materials.
Although predictive models based on elementary physical and
chemical principles have limited use in the context of risk assessment, semiempirical models (which are based largely on experimental data) can be conveniently formulated to predict an output
value based on a limited number of parameters and can also be
formulated with any degree of conservativeness required. Several
such models to predict diffusion constants of small molecules in
polymer matrices exist, the most popular of which was devised by
Otto Piringer and coworkers from the Fraunhofer Inst. (Brandsch
and others 2002):
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Figure 1–Schematic of a static liquid permeation cell, 1 potential experimental setup to measure migration rates of small-molecule migrants through
polymer films. Reproduced from Song and others (2013), with permission from Taylor and Francis.
or storage) and aliquots are removed from the receptor chamber
periodically and assayed for the migrant concentration using an analytical method of choice (LC-MS, GC-MS). The rate of permeation of the migrant through the film is determined by plotting the
amount of migrant that appears in the receptor chamber as a function of time. Most migration experiments such as this make use of
host substances that mimic the chemical properties of food rather
than actual foods, and these food simulants can include substances
such as water, dilute acetic acid (acidic foods), olive oil or coconut
oil (fatty foods), and various concentrations of aqueous ethanol.
Regulatory bodies typically issue documents intended to inform
manufacturers what they view is the best way to perform these
types of measurements. The U.S. Food and Drug Administration
version of this document includes information on simulants to
use, how to design a diffusion cell, conditions (temperatures and
times) under which migration is most appropriately measured, the
appropriate size and thickness of test films, how to ensure that
the experiment assesses a “worst case scenario” for diffusion, how
to properly validate tests and measure concentrations of test substances, and so forth (U.S. Food and Drug Administration 2002).
This document also describes migration models that may be appropriate to use and where to find preexisting datasets to support
these models, as well as additional useful information about conducting exposure assessments, proper ways to report data, how
to identify an intended technical effect, and so on. In the European Union, the European Food Safety Authority (EFSA) and the
European Commission have issued similar guidance documents.
Despite this prodigious amount of information related to migration of small molecules from food-contact polymers, it is yet
unclear to what extent these guidelines apply to the assessment
of nanomaterial migration. Most of the above-described procedures were formulated from years of accumulated migration data.
These data are simply not available for nanoscale migrants; thus,
it is unknown whether conventional test conditions, food simulants, and migration metrics are directly applicable to the migration of nanomaterials. There are also lingering questions regarding
whether conventional migration testing procedures are compatible with nanomaterials in the first place. For instance, to increase
the surface area for migration and achieve better sensitivity, many
laboratories manually cut test films into small pieces and submerge
them in a stacked orientation into a vessel filled with the food simulant, and then measure the amount of migrant that leaches out
from the surface of the cut films over time. In conventional migra-
tion experiments using thin films, the release of the migrant from
the edges (as opposed to the comparatively larger surface area of
the faces) is assumed to be small for thin films of sufficient diameter
(Crank 1979), but whether this assumption holds for nanoparticles, which may be more likely to be manually dislodged by the
cutting process and are likely to have low signal-to-background
levels due to anticipated slow nanoparticle diffusion, is still an issue
that needs to be resolved.
Strategy for addressing the goals of this article
The previous sections presented an overview of theoretical and
experimental assessment of migration and established that there are
many questions to be answered with respect to proper methodology to measure release of ENMs from food contact plastics.
The remainder of this article focuses on the body of ENM release literature, paying particular attention to both sampling and
instrumental methods currently used to assess migration. This discussion includes a review of nanoparticle release studies related
to materials that do not have direct relevance to food because
they offer insight into sampling/instrumental procedures and fundamental release mechanisms that are relevant to those materials
that are intended for food-related applications. We also note that
in the context of this work, the term food includes drinking water, including tap water, and the term food contact materials, while
predominantly packaging, also includes other materials that touch
food such as potable water infrastructure, food processing equipment, cutting boards, eating utensils, appliance liners, gloves, and
so forth. By broadening the scope in this way, we hope to maximize the relevance of this work as well as draw upon as many
sources as possible to fully understand nanoparticle release and
best survey current and emerging detection and characterization
methodologies.
Literature Review of Experimental Methods
Potential ENM release mechanisms
In order to construct a predictive framework that can be used to
predict the quantity and form of ENMs released into external
media in any given situation, or at least to put acquired release
data into proper context, it is necessary to understand the potential mechanisms by which ENMs could potentially be released as
a function of ENM characteristics and external conditions. Once
we have identified all potential mechanisms, we can begin to build
a comprehensive system of knowledge related to ENM release as
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Figure 2–The 4 “D” engineered nanomaterial release pathways.
a generalized phenomenon that is supportive of thorough and reliable risk assessment. The ultimate goal is a predictive framework
that can be used to say “If this type of ENM is put into this type
of polymer and it is subjected to these kinds of conditions, this is
the likely result after a certain amount of time has elapsed.” Such
an expansive picture of ENM release cannot be generated, however, without a sufficiently developed body of experimental data
and this, in turn, requires a sufficiently developed tool set that can
be used to distinguish between the potential release mechanisms
identified and their potential endpoints (characteristics and quantity of released ENMs). With this in mind, the task group analyzed
the existing body of ENM release literature with the aim of identifying possible release mechanisms, in the hope that this would
enable the task group to identify the kind of tool set needed to
support the predictive framework envisioned. By comparing the
target tool set to the existing tool set, the task group hoped to
identify and prioritize targets for method development.
Our survey of the release literature has revealed 4 “D” ENM
release phenomena during the life cycle of any nanocomposite
material: desorption, diffusion, dissolution, and degradation of the
matrix (Figure 2). (In practice, multiple processes for nanomaterial
release may simultaneously occur, but these processes are treated
separately herein.) The main distinctions between these phenomena pertain to where the ENM is located, the extent to which
it interacts with the media (in other words, liquid and vapor), its
ability to migrate through the host matrix material, and whether
the particle remains an ENM or is transformed into ions (particle
characteristics). It is important to note here that some of these
mechanisms may be more or less important depending on the intended application of the nanocomposite; therefore, some mechanisms may be more or less important, generally, for food contact
materials. Some of these distinctions will be pointed out below.
Desorption. Desorption pertains to ENMs located on the material or substrate’s surface. Here, ENM adhesion is controlled
by electrostatic interactions between the ENM and the substrate. Desorption would be most likely for nanocomposites in
which the nanoelement is restricted to the interfacial region between the nanocomposite and the external medium (coatings, in
C 2014 Institute of Food Technologists®
other words). The textile industry, for example, has embraced
this production method by dipping fabrics into a solution of
suspended silver nanoparticles. Unfortunately, the actual bonding processes/interface between ENMs and substrates has been
poorly characterized to date. External stimuli that would likely
affect ENM–material surface bonds include liquid characteristics
(pH, ionic strength, and presence of contaminants that promote
bonding), temperature, fluid velocity, physical abrasion, and vibration. These external stimuli could dislodge ENMs from the
food contact material surface and enable them to enter the contact medium (that is, the food). It is crucial to point out that in
desorption, unlike in the diffusion mechanism described below,
mobility of the ENMs within the matrix is not a limiting factor
for release; therefore, particle morphology and size may not be
major considerations here. Note that the fate of ENMs that are
covalently bound to the material’s surface may be better described
by the “degradation of the matrix” phenomena described below.
Diffusion. Much of the existing food contact discussion surrounding nanomaterials pertains to the perceived risk that ENMs
will migrate or diffuse out of polymer contact materials into the
food substance, primarily because many of the nanocomposite materials currently under development for food contact applications
are those in which the ENM elements are dispersed throughout the interior of the host matrix, rather than deposited on the
surface. Diffusion has been used for decades to describe contaminant transport through materials (for example, polymers) into the
contact medium (for example, water, air, or food). ENM diffusion would be expected to closely resemble molecular diffusion of
other commonly studied infrastructures and food packaging additives, although if the molecular-scale interactions between ENMs
and the matrix are sufficiently strong, diffusion may no longer be
appropriately modeled as following Fick’s laws, upon which many
migration models are based. If the principles of contaminant diffusion hold for ENMs, ENM diffusivity would be influenced by
the ENM’s physicochemical properties (for example, polarity, size,
and shape), the concentration gradient between the food contact
material and food itself, as well as matrix properties (for example,
density, polarity, and additives), and environmental conditions (for
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Measuring nanomaterial release . . .
example, pressure and temperature) (Comyn 1985). Note, however, the ENMs initially localized in the interior of the host matrix
must migrate to the interfacial region before they are released into
the external medium. Whether this partitioning process is identical
to the desorption process described above remains an open question. Thus, if migration experiments are performed on a PNC,
care must be taken to differentiate true diffusion and release from
superficial desorption of ENMs remaining on the polymer surface
after initial processing. It is also worth pointing out that ENMs
are large compared to most conventional molecular-scale migrants
and are therefore larger than anything that has been successfully
subjected to successful diffusion models or migration experiments.
Dissolution. Numerous publications in the peer-reviewed literature describe the influence of nanocomposites on metal ion
levels in a contact liquid. These studies can be classified as ENM
dissolution. Dissolution involves the transformation of an ENM
from its native, particulate physical form into its ionic constituents.
At present, there is debate as to whether nanoparticles migrate to
the surface and then are dissolved into their ionic constituents, or
whether the ions desorb from ENM surfaces while the ENMs are
still dispersed throughout the nanocomposite matrix. Unfortunately, this is a question that cannot be answered with inductively
coupled plasma mass spectrometry (ICP-MS), an elemental analysis method, but it will hopefully be elucidated in the coming
years as the detection and quantification measurement methods
improve. Experiments have shown that dissolution is a significant
contributor to the fates of AgNPs and zinc oxide nanoparticles in
the environment (Liu and Hurt 2010; Scheckel and others 2010).
Available data demonstrate that nanoscale zinc oxide is much less
stable in water than AgNPs. In addition, water pH, redox potential, ionic strength, particulate matter, temperature, and dissolved
oxygen level are also reported to influence dissolution rates.
Degradation of the matrix. In the event that ENMs are rigidly
fixed to the polymer matrix (either because they are too large to
be mobile or they are covalently attached to polymer molecules),
ENMs could still be released if something were to happen to
the integrity of the matrix itself. For example, ENMs embedded
in the matrix could be exposed as the material mechanically or
chemically decomposes. Decomposition could be caused by external stimuli such as physical abrasion, heating, UV exposure,
and hydrolysis. Hydrolysis could change the gross properties of
the polymer, thereby enabling ENM release. This aspect of matrix
degradation may be particularly applicable to foods in the event
that food contact materials are water- or acid-sensitive, as in the
emerging class of nanocomposites fabricated from biocompatible
polymers. Many foods contain water, and this water could influence polymer packaging properties (and hence diffusion rates)
during long exposure times by acting as an effective plasticizing
agent. Finally, matrix degradation could also be accelerated due
to the physical properties of the embedded ENMs. For example,
photoactive ENMs (such as TiO2 ) can generate reactive oxygen
species in response to UV light exposure and thus degrade the
localized area near the ENM (Wang and others 2011). This could
be a desirable characteristic for degradable food contact material.
ENMs released from the product could be present as individual nanoparticles or as composites, bound/surrounded by organic
binders from the parent material.
What release mechanisms tell us. It is important to be clear that
the release mechanisms presented above are not islands unto themselves. Interrelationships do exist and some of these were alluded to
above. Diffusion may not be able to proceed without desorption;
dissolution and diffusion are intertwined because particles that
dissolve (partially or wholly) must still diffuse through the host
medium to become released. In the case of complex (core–shell,
for example) ENM architectures, some components may dissolve
more readily than others; various forms of matrix degradation will
impact all of the mechanisms because the basic polymer or ENM
properties become attenuated and so on. Moreover, more work
needs to be done to understand the conditions under which these
various mechanisms are most likely to occur and, even more importantly, how the release mechanism will relate to postrelease
processes like agglomeration/aggregation, particle dissolution,
size changes via Ostwald ripening, and/or surface characteristic
modifications.
Most critical of all is a need for high-quality analytical methods
that can distinguish between these mechanisms so that they can
be better understood and inform safety assessments and decisionmaking. An analysis of the release mechanisms and the available release literature (see below) reveals that our ability to distinguish between dissolution and diffusion is the most significant and widely
recognized gap in the current tool set. ICP-MS and ICP-OES
(optical emission spectrometry) are the primary techniques utilized to monitor ENM release from nanocomposite materials, and
because all information about nanoparticle characteristics is lost
when test samples are fed into the plasma for analysis (indeed,
information on whether the source came from a particle at all is
lost), ICP-MS and ICP-OES simply cannot distinguish between
these 2 mechanisms. This deficit is certainly important because
although many studies have shown residual signatures of metallic
ENM components, it is not known whether the eventual consumer will be exposed to ENMs or ionic salts, which potentially
may have different pharmacological and toxicological profiles.
Robust methods that can measure ENM–polymer surface interactions, polymer matrix integrity, and ENM characteristics, both
before and after release, are crucial to understanding release mechanisms and postrelease processes. In particular, standardized sample
preparation techniques for TEM imaging of ENMs while they are
embedded in polymer films are needed to better study how the
characteristics of ENMs change during PNC processing. Much of
the release literature is based on uncharacterized or poorly characterized test materials fabricated from polymers and/or ENMs with
unknown properties, which lessens their usefulness in studying release mechanisms because structure–function relationships remain
largely undisclosed.
Methods used to assess release of ENMs from nanocomposites in the environment (nonfood)
Purpose and scope. Because of the limited information available
pertaining specifically to ENM release from food contact materials into foods, we reviewed the literature that describes ENM
release from solid materials into the environment. ENMs are used
in a variety of infrastructure and building-construction technologies, vehicles, consumer products, and medical applications, and
a number of the release considerations for ENMs in food contact
applications are shared with these other applications. Theoretically, ENM release has the potential to occur during food contact
material use and disposal due to weathering or routine contact and
cleaning. Airborne emission is also possible, but will not be discussed at great length here due to the dissimilarities between food
contact applications and air emissions. The task group primarily
focused on studies related to the release of ENMs from polymeric
substrates into directly contacted liquid media, as they are expected
to have the most relevance to release from food contact materials.
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Measuring nanomaterial release . . .
Table 1–Capture and detection techniques that have been used to measure characteristics of ENMs released from materials in aqueous nonfood
applications.
Method description
Capture
Centrifugation
Size fractionation by filtration
Direct identification
ICP-MS particle number technique
Laser granulometer and mastersizer
TEM EDX microscopy
TEM high angle angular dark field (HAADF)
detector and EDX microscopy
SEM EDX microscopy
X-ray absorption near edge spectroscopy (XANES)
Indirect identification
ICP-MS acid digestate analysis
ICP-OES acid digestate analysis
Ion selective electrode (ISE)
ENMs
Sample integrity
Ag, ZnO
Ag
Wet
Wet
(Kaegi and others 2010; Scheckel and others 2010)
(Benn and Westerhoff 2008; Benn and others 2010;
Farkas and others 2011)
Ag
TiO2
Ag, TiO2 , CNT, SiO2
Wet
Wet
Dry
Ag
Dry
(Farkas and others 2011)
(Golanski and others 2011)
(Kaegi and others 2008; Liu and Hurt 2010; Farkas and
others 2011; Nguyen and others)
(Kaegi and others 2008; Kaegi and others 2010)
Ag, TiO2
Dry
Ag, ZnO
Dry
Ag, TiO2
Wet
Ag, ZnO
Wet
Ag
Wet
The majority of published ENM environmental-focused studies
that the task group analyzed described the fate of individual ENMs
in air and water media (Chen and Elimelech 2009; O’Brien and
Cummins 2010; Arvidsson and others 2011; Petersen and others
2011; Zhang and others 2011; Mudunkotuwa and others 2012;
Nowack and others 2012). Using these data, modeling of predicted
ENM environmental concentrations has also been carried out and
will likely continue as more data become available (Gottschalk and
others 2009; Arvidsson and others 2011; Gottschalk and others
2011). Through experimentally based air/water studies, investigators have discovered that some ENMs are stable in water and bind
with other constituents in the water (such as organic materials),
whereas other ENMs decompose into ions rendering them classic
ionic constituents. This underscores the true complexity of ENM
release.
Methods supporting the study of ENM release into aqueous environments (nonfood). To assess ENM release from polymeric ma-
terials into aqueous but nonfood environments, a combination of
particle size separation techniques, total metal quantitation methods, and microscopic identification procedures have been applied
(Table 1). Application of these methods has enabled researchers to
confirm release for certain ENM–material pairings and to elucidate the role of some solution, material abrasion, and environmental properties on ENM release potential. It is somewhat difficult
to compare results of these studies and make generalized conclusions because there are no standardized methods to understand the
form of ENMs that are released. For a limited number of studies in
which nanocomposites contact liquids, only liquid metal ion levels
were reported (via ICP-MS), and ENM release was implied but
not confirmed. Absence of standardized methods also inhibits application of fundamental scientific principles to document ENM
release (such as diffusion coefficients through polymer matrices
into water).
Available data for release of ENMs into aqueous environments
(nonfood). Inorganic ENMs have been the most heavily scru-
tinized materials; of these, AgNP products have received the
greatest attention. Release of AgNPs into water from laboratorymanufactured and commercial off-the-shelf (COTS) materials (for
example, fabrics, dust masks, medical cloths, toothpaste, and building construction products) has been studied. ENM desorption has
C 2014 Institute of Food Technologists®
References
(Benn and others 2010; Kulthong and others 2010;
Golanski and others 2011)
(Impellitteri and others 2009; Scheckel and others 2010)
(Kaegi and others 2008; Kaegi and others 2010; Farkas
and others 2011)
(Benn and Westerhoff 2008; Kaegi and others 2008;
Benn and others 2010; Kaegi and others 2010;
Scheckel and others 2010)
(Farkas and others 2011)
been documented from fabrics in distilled water, tap water, and
simulated washing machine conditions (for example, tap water,
biocides, and surfactants) (Geranio and others 2009; Impellitteri
and others 2009; Benn and others 2010).
Matrix degradation has been linked to AgNP release from
COTS toothpaste, building exterior paints that contain nanofiller,
and abraded PNCs that released AgNPs, metal oxide nanoparticles
(silica and titania), and multiwalled carbon nanotubes (CNTs)
into liquids and air (Kaegi and others 2008, 2010; Golanski
and others 2011; Schlagenhauf and others 2012). Many of the
same techniques that have been used to detect ENM release
from PNCs into liquid environments (vide infra) have also been
applied to confirm whether ENMs remained encapsulated in the
matrix during and following environmental aging. For example,
ICP-MS has been used to quantify metals and TEM to visually
detect ENMs in digested polymers and environmental samples
(Kaegi and others 2008, 2010). High-resolution SEM with
energy-dispersive X-ray (EDX) has been applied for elemental
analysis (Kaegi and others 2008, 2010; Nguyen and others 2011;
Wohlleben and others 2011; Schlagenhauf and others 2012).
Other techniques utilized in this area are perhaps more uniquely
suited to study the specific release phenomenon of matrix
degradation. For instance, abrasion-induced release of nanoscale
particles into liquid has been investigated using a laser granulometer to indirectly identify particle sizes (Golanski and others 2011),
and attenuated total reflectance Fourier transform infrared (ATR
FTIR), X-ray photoelectron spectroscopy (XPS), and secondary
ion mass spectrometry (SIMS) have been applied to monitor
composite surface chemistry to identify changes in chemical
signatures that could indirectly confirm ENM release or polymer
degradation (Nguyen and others 2011; Wohlleben and others
2011). Combinations of an aerodynamic particle sizer (APS), fast
mobility particle sizer (FMPS), laser aerosol particle (LAP) size
spectrometer, and scanning mobility particle sizer (SMPS) devices
have also been used to describe the particle size distribution of
nanosized particles in air during abrasion. While no studies were
found that reported ENM release due to hydrolysis of matrix
materials (such as polyesters), this is also a likely release pathway
and experimental methods that can study this process should be
identified.
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Measuring nanomaterial release . . .
The dissolution of ENMs embedded within nanocomposites
has not been directly studied, but some literature data imply that
dissolution is significant. We identified a number of studies in
which researchers exposed nanocomposites to aqueous environments and observed relevant metal ion concentrations to increase
(Kumar and others 2005; Kumar and Munstedt 2005; Damm
and Münstedt 2008). Ag and Zn ion release from AgNPs and
nanoscale ZnO medical PNC devices (Yang and others 2008) into
water has been documented by ICP-MS. No studies were found
that reported ENM diffusion through nonfood materials into water. This is likely because metrologies needed for characterizing
diffusion (or distinguishing it from other release mechanisms) are
lacking and there is a limited understanding of ENM interaction
and dissolution within matrices (see above).
Control points for characterization and identification of
ENMs in food contact materials and experimental hurdles
As stated previously, the number of studies evaluating migration
of ENMs from food contact materials is relatively small. Presently,
the development of nanotechnology-enabled food contact materials has primarily utilized ENMs with inorganic core compositions,
including those composed of metals, metal oxides, and clays (aluminosilicate nanoplatelets). The majority of these materials utilize
polymers that are either embedded or coated with ENMs and are
often referred to as nanocomposites. In addition to the synthetic
(or bioderived) PNCs, there are a number of reports on the development of nanomaterial-modified papers (Gottesman and others
2011) and carbohydrate-based “fabrics” such as cellulose nonwoven materials that function as pads at the bottom of meat or
produce storage containers (Fernandez and others 2010a,b). Although no commercial product or application has been identified
for the nanomaterial-modified papers, antimicrobial effects have
been evaluated and food safety is often a targeted application.
Before the current literature related to ENM release into foods
from these materials is presented, it is worth reflecting first on
where and when analytical methods should be employed during
their life cycle. After consideration of the literature, the task group
suggests that there are a number of control points during the production and use of a nanocomposite where characterization could
be performed to gain a greater understanding about the physicochemical characteristics of the nanomaterial/nanocomposite and
evaluate its potential risk as a food contact material. In principle, if a complete body of information on the characteristics and
identities of ENMs at each of these points is obtained, we can
fully specify the life cycle of the ENMs and, importantly, fully
understand the 4 “D” mechanisms described earlier, which will
ultimately broaden our understanding of the quantity and type of
ENMs that may enter the alimentary tract via the food contact
material route of exposure. Therefore, methods development experts should focus on generating a tool set that is well adapted to
studying ENM properties at each of these control points.
This section reviews these 3 control points (termed CP-1, CP2, and CP-3) and subsequent sections present methods that have
been used to evaluate ENM characteristics and migration at these
various points.
Control point 1: the raw or pristine ENM. For manufacturers
or researchers who are synthesizing their own nanocomposites,
characterization of the raw/pristine nanomaterial (in other words,
prior to addition to the polymer) is often a critical first evaluation
point. Electron microscopy (for example, transmission electron
microscopy [TEM] and scanning electron microscopy [SEM]),
particle sizing, elemental composition (ICP, AAS, and EDS), and
X-ray diffraction (XRD) (in the case of nanoclays) are the most
commonly used characterization methods. The limited matrix
interferences allow for fairly straightforward analysis of the nanomaterial although the researcher needs to be aware of techniquedependent differences in the determination of particle size. For
example, microscopic techniques such as TEM measure the physical dimensions (often different if the particle is nonspherical) of
the electron-dense core, whereas light scattering techniques such
as dynamic light scattering (DLS) estimate size based on the rate of
movement through a fluid medium, and thus, measure a “hydrodynamic radius,” which includes the core (or its spherical abstraction
if it is nonspherical), any directly attached organic ligands, and any
loosely associated solvent molecules that impact the particle’s rate
of movement. Some of the challenges of pristine particle analysis,
as well as the importance of solving them toward measuring the
properties of ENMs in more complex media, are discussed in the
1st article in this series (Szakal and others 2014).
Control point 2: the polymer-distributed ENM. After production of the nanocomposite, characterization of the nanomaterial
becomes more difficult and the sample matrix limits the available
analytical techniques. Electron microscopies (SEM and TEM) are
usually utilized for imaging the materials and acquiring such information as aggregation state and dispersion morphology; however,
small particle sizes or low particle concentrations can limit the
effectiveness of microscopy methods, especially SEM. In addition, sample preparation remains a challenge. For SEM, material
coatings can inhibit identification of the nanomaterial within the
composite. Conventional microtoming of samples for TEM analysis can be difficult for many glassy polymers or thin films such as
LDPE bags, in which fixing agents do not adhere well to the polymer and the materials may be too soft (at room temperature) to get
adequate shear for sectioning. It does not help that microscopic
analysis of fabricated nanocomposites reported in the literature
is often outsourced to contract laboratories, and so experimental
procedures are often poorly documented, vague, or absent, which
makes standardization of sample preparatory techniques difficult.
Even if a microscopist is successful in preparing a sample and
acquiring an image, the information obtained is still predominantly qualitative and may not be representative of the entire material. Therefore, other characterization techniques are required to
supplement microscopy methods; however, there are few widely
available options available at this point. One researcher attempted
to avoid the difficulties in preparing samples for SEM and TEM by
ashing the nanocomposite and then evaluating the ash for nanoparticles (Huang and others 2011). While this clearly avoids difficulties in sample preparation, it raises additional questions about the
de novo formation of particles under extreme sample preparation
conditions. Elemental analysis is also still used, but the elemental
concentrations are determined after digestion of the nanocomposite samples and represent total elemental concentrations and
not nanomaterial-specific data. Although methods of nanoparticle
extraction from the PNC might allow for single-particle ICP-MS
(SP-ICP-MS) analysis, successful extraction techniques have not
been developed and such a method would in any case provide little
information about the nature of ENM dispersion.
Control point 3: the released ENM. The final control point after nanocomposite characterization is to determine the amount
and form of migration of the nanomaterial from the nanocomposite. Although foods can be used to determine migration, food
simulants are usually used to simplify an experimental setup and
reduce matrix interferences (see above). Elemental analyses (ICPMS, AAS) are often the first methods used to assess the migration
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Measuring nanomaterial release . . .
of the nanomaterial. While these methods are extremely sensitive,
researchers generally must digest the sample prior to analysis; thus,
while they afford information on total elemental concentrations,
they provide no information on physical characteristics of migrated
ENMs (size, for instance) or even whether whole ENMs migrated
in the first place. EM or light scattering techniques would be the
obvious choice to distinguish whole migrated nanoparticles from
diffused ions, but migrated ENM concentrations are expected to
be incredibly small, which is a serious problem for these techniques. SP-ICP-MS may address some of these gaps, but given
the current limitations in size sensitivity as well as the fact that the
technique is not widely available, there is a need for new methods
to help support our understanding of ENM migration from PNC
food contact materials.
Methods used to assess release of ENMs from
nanocomposites into foods
Theoretical modeling of ENM diffusion. As mentioned previously, diffusion or migration models assist in the prediction of
migration of a substance from a food contact material to the contacted food and, in principle, theoretical modeling can be a tool
adapted for each of the above-described control points. Although
our understanding of the physical principles of migration for small
molecules is quite advanced, there have been very few studies focused on the modeling of the diffusion of ENMs through polymer
matrices, to say nothing of migration to the external environment,
either in a theoretical framework or to aid in the interpretation of
experimental data. Šimon and others (2008) are some of the few
researchers who have attempted to do so, and presented a diffusion
model using the Stokes–Einstein equation for the diffusion of a
spherical particle through a fluid with lamellar flow properties.
Using this approach, they presented a simple relationship between
particle size and predicted migration level as a function only of
temperature, the polymer’s dynamic viscosity, and the available
surface area for release. For example, the authors predicted that
for LDPE embedded with 10 nm AgNPs at 1 kg/m3 with an
exposed surface area of 0.2 m2 , the total amount of migrated silver
in the surrounding medium after 1 y of storage at 25 °C would
be 260 µg. Šimon and others (2008) did recognize that a number
of assumptions made for the model may not be entirely applicable and contended that the calculated diffusion coefficients most
likely represent the highest limits and an overestimation of migration. The model also made no accounting for the chemistry of the
surrounding medium and only considers the diffusion mechanism
presented above.
Although we can scrutinize the assumptions of any model at
length, even a model based upon seemingly perfect assumptions
is useless unless we have confidence that it makes accurate predictions. Such confidence is, of course, impossible to have without
experimental data that can be compared with values predicted by
the model. Therefore, although the lack of theoretical models of
ENM diffusion certainly qualifies as a knowledge gap to be addressed in the long term, spending too much energy on this at the
present moment may be premature. Until experimental methods are
sufficiently developed to generate reliable ENM migration data,
theoretical methods will have only academic relevance.
Methods to assess migration of nanosilver from food contact
materials. Although silver has been incorporated into polymers
and other textiles for some time, its application to food contact materials is relatively new. A number of early reports of
the use of AgNPs did not incorporate the silver into a polymer
film/nanocomposite, but created materials in which AgNP was on
C 2014 Institute of Food Technologists®
the polymer surface. For example, del Nobile and others (2004)
produced a coating of silver islands of about 90 nm in polyethylene oxide on the surface of a polyethylene film by plasma-based
vapor deposition. They imaged the starting materials using EM
and quantified the concentration of silver in the films by XPS. Ag
concentrations in a variety of solutions (water, malt extract broth,
and apple juice) that had been placed in contact with the materials were determined using ICP-OES. Similarly, Fernandez and
coworkers synthesized AgNPs in situ in the presence of cellulose,
forming silver nanoparticles at the surface of cellulose fibers (Fernandez and others 2010a,b). These authors imaged their ENMs (in
the nanocomposite stage) with TEM and quantified silver content
in the meat or fruit exudates (but not in the meat or fruit itself)
by graphite furnace atomic absorption spectrometry (GFAAS).
While these experiments were important in determining the extent of Ag transport, they do not represent migration of silver;
rather, they demonstrate simple surface desorption or dissolution
or a combination thereof (see Figure 2). Unfortunately, neither
of the studies attempted to determine the form (ionic compared
with particle) of the silver in the solutions. Due to the in situ style
of ENM generation, characterization at the CP-1 stage (pristine
state) was not possible. Sample preparation for TEM analysis in
both of these cases was not particularly well documented.
In 2010 and 2011, there appeared a number of publications
evaluating the use of silver in nanoscale form as an additive
to polymeric food contact materials (Busolo and others 2010;
Emamifar and others 2010; Huang and others 2011; Lin and
others 2011; Song and others 2011). The materials utilized
by Emamifar and Busolo did not contain AgNPs, but rather
employed Ag-modified ZnO nanoparticles and Ag-modified
clay platelets, respectively. The remaining researchers evaluated
commercially available AgNP/PNCs. In all cases, except for that
by Song and others (2011), who performed no imaging analysis
of their test films, the characteristics of the particles in the host
materials were evaluated to some extent by TEM or SEM imaging
(with or without EDX-based confirmation of particle identity) to
determine distribution patterns or aggregation extent. In the study
by Busolo and others (2010), wide-angle X-ray scattering was
used to determine the extent of clay exfoliation (separation of clay
platelets), and differential scanning calorimetry (DSC) was used to
examine the effect of ENM distribution on the thermal properties
of the material. The migrated silver concentrations in aqueous
media (water, food simulants, or orange juice) were determined in
all cases as total silver (and zinc, in the case of the study by Emamifar and others 2010) either by elemental analysis techniques (ICP
and AAS) or voltammetry, although the amount of detail provided
regarding preparation of samples for migration experiments varied
significantly (in 1 case, no information at all was provided about
sample preparation or even the analytical technique used). In cases
in which sample preparation information was provided, films
or simulant were generally treated to microwave acid digestion
prior to elemental analysis. It should be noted that all of the
researchers detected silver content in the substance contacting
the test materials, regardless of whether the silver was used as an
additive to larger particles or alone. However, with the exception
of Huang and others (2011), who used SEM/EDX to analyze
the food simulant postmigration and reported the observation
of whole AgNPs, none of these studies reported the detection
of ENMs in the migration solvents, suggesting either that silver
ions were the primary end point of silver migration or that the
analytical tools used were inadequate to measure what was actually
occurring.
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Measuring nanomaterial release . . .
In a departure from the approach of measuring AgNP migration through ICP or AAS analysis, von Goetz and others (2013)
recently evaluated silver migration from commercially available
AgNP nanocomposites, but they used SP-ICP-MS in an attempt
to determine whether any of the migrated silver was in nanoparticulate form as opposed to diffused silver cations. The authors
also conducted a CP-2 level analysis on the nanocomposite test
materials using laser ablation directly into an ICP-MS instrument,
which afforded information about the geometric distribution of
the AgNPs inside the polymer that is typically lost when samples
are processed by acid digestion and solution nebulization. Atomic
force microscopy (AFM) was used to analyze the surface topography of the materials. From this combination of techniques, the
researchers observed silver migration (into water, ethanol, acetic
acid, and olive oil, to varying degrees) and concluded that most
of the Ag migration could be accounted for by Ag ion migration.
Nevertheless, they did report the presence of AgNPs in some
of the migration solutions, which was confirmed by TEM/EDS
analysis of residues left after the simulants were evaporated.
The authors acknowledged that they were unable to determine
whether the AgNPs migrate via the diffusion mechanism, as
depicted in Figure 2, or whether they are released from the surface
(desorption mechanism) or are formed postdissolution during
sample-handling. The latter process may be indicated because the
detected AgNPs in the simulant residuals were composed of AgCl
and AgS, in agglomerated form. Methods and experiments that
can distinguish between migration of particles and formation of
particles from ions after the fact are sorely needed.
Methods to assess migration of nanoclay residuals into foods.
The 1993 publication by Kojima and coworkers is one of the
earliest reports of improvement in mechanical and thermal characteristics of polymers after the addition of clay (Kojima and others
1993). The initial studies with clay PNCs were interested in the use
of clays as flame/fire retardants (Lewin 2003; del Nobile and others
2004). In these applications, a number of researchers have evaluated the migration of clays to the surface of the polymer composite
(Zammarano and others 2006; Tang and Lewin 2007). Generally,
in monitoring clay migration, the researchers utilized elemental
constituents of the clays (Mg, Al, and Si) and analyzed for these elements. Much like the case of AgNPs, this method does not provide
information on the migration of individual clay particles, which,
when fully dispersed, are highly anisotropic (a mere 1 nm thick,
but often hundreds to even thousands of nanometers in each lateral
dimension). In the use of clay/polymer materials as fire retardants,
there is clearly an increased surface concentration measured for
these elements after testing. Whatever the mechanisms responsible
for this migration of clay particles to the surface, the conditions under which it occurs represent extreme temperatures, often above
the melting point of the polymer, which are not applicable to
evaluating the migration of clays in food contact applications.
The methods used to assess the presence of clays in the clay
nanocomposites or to evaluate migration into foods and food simulants are generally similar to the methods used for Ag and other
metal oxide materials. Microscopy (TEM and SEM) and elemental
analysis (ICP-MS, AAS, and EDX) are the most commonly used
techniques. In addition, XRD has been used in a number of studies
to acquire information about the dispersion of the clay within the
polymer matrix (for example, interplatelet separation/degree of
exfoliation). FTIR spectroscopy, usually with the benefit of ATR,
and XPS have also been used to study changes in clay concentration in the surface region of the nanocomposite during annealing.
As with AgNP nanocomposites, these independent techniques do
not necessarily offer any direct information about the form of the
migrant, but they would be considered a critical component of the
CP-2 level described above. Most commonly, elements present in
the clay (Al, Si, Mg, and Fe) are detected by ICP-AES or ICPMS analysis, methods that usually cannot also provide information
about the form of the migrated species. In addition, due to the
common occurrence of many of the elements found in clays (Si,
Al, and Mg), background interferences can be difficult to avoid
or to correct for, making careful sample preparation important.
Often, the use of clean-room facilities and expensive nonglass instrument components is required, which can make these analyses
inaccessible to less well-equipped or less well-funded facilities.
Several recent examples of clay migration studies are worth
mentioning here. Mauricio-Iglesias and others (2010) fabricated
their own montmorillonite/wheat gluten composite films and analyzed silicon and aluminum content in various simulants after
extended storage times at 40 °C using ICP-OES. Their ICP-OES
analysis was outsourced to a contract laboratory, so experimental
conditions for the analysis (like sample digestion parameters) were
not provided. Notably, the authors observed different results depending on whether silicon or aluminum was the target analyte,
suggesting a need for standardized procedures and choice of analyte
for clay migration analysis. In a follow-up study, Mauricio-Iglesias
and others (2011) also used FTIR to analyze the clay structure in
the film and provided information on differences in migration levels they observed during high-pressure processing of the test films.
These authors did not perform any other significant analyses on
clays prior to dispersion in the polymer or in the dispersed state
(other than the FTIR analysis), indicating that they were primarily
interested in a CP-3 level analysis.
Avella and others (2005) dispersed montmorillonite clay into
thermoplastic starch and analyzed release of clay residuals onto
vegetables. They used magic angle spinning nuclear magnetic resonance (MAS NMR) to analyze the clay dispersion in their composite films, SEM for imaging of surface features, and a materials
testing machine (Instron) to measure mechanical properties like
tensile strength. They employed both flame and graphite furnace
AAS for elemental characterization of the foods postmigration
although they replaced aluminum with iron and magnesium as
analytes, in addition to silicon.
Schmidt and others (2011) investigated migration of magnesium
aluminum double hydroxide clays from polylactide films and used
ICP-MS to measure total aluminum migration, as well as TEM
for both film characterization and characterization of the clay
migrates. They also used gel permeation chromatography (GPC)
to analyze the polymeric materials before and after the migration
experiments, as well as SEM to characterize the clays prior to
incorporation into films (a rare example of a CP-1 level analysis
in the nanoclay area).
Finally, Farhoodi and others (2014) prepared composites of
montmorillonite in polyethyelene terephthalate (PET) by meltblending and processed these materials into bottle form by blowmolding. They analyzed the extent of clay dispersion in the films
(CP-2 level analysis) by XRD, tapping mode AFM (by generating phase contrast images that are sensitive to viscoelasticity and
chemical composition), and TEM; they also determined migration levels into common food simulants using an American Society
for Testing and Materials (ASTM) standard migration cell and by
monitoring both aluminum and silicon levels in the simulant with
ICP-OES. As is often the case, the CP-3 level analysis in this study
was limited to measurement of ionic or atomic residuals, which
provided no information on the form of migrated clays.
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Measuring nanomaterial release . . .
Using a slightly different attempt at obtaining CP-3 level information about the nature of clay migrates, Schmidt and others
(2009) used a combination of asymmetric field flow fractionation (aFFF) with multiangle light scattering (MALS) and ICP-MS
to characterize particle size and composition of migrants from
a 5% montmorillonite/polylactide nanocomposite. Using aFFF
with MALS, they detected the presence of 50- to 800-nm particles in 95% simulant after the migration experiment was completed; however, the ICP-MS component of the analysis failed to
show that the migrated particles included elements characteristic
of clays, suggesting that the detected nanoparticles were not associated with migration of the clay additives. Although this study
presented a null result, it nevertheless demonstrated the benefit
of in-line separation and characterization of ENMs. This combined technique cannot rule out the formation of nanoparticles
after migration, but it does differentiate between different sizes
and composition of material.
One other recent approach that may assist in monitoring the clay
migration profile has been to covalently label the clay particles with
fluorescent tags (Diaz and others 2013). Not only does this allow
monitoring of the migration experiment via fluorescence spectroscopy or microscopy (both of which are very-low-background
optical techniques), but it also avoids the need to prepare samples
for ICP-MS/AES or TEM/SEM analysis. Ideally, the fluorescent
tag would remain covalently bound to the clay, maintain fluorescent properties, and allow in situ continuous monitoring during
migration. The results of this particular study implied that migration of clays on experimental time scales was occurring because
fluorescence was observed in the external media after storage and
heating; however, the effect of sample preparation (for example,
cutting of the film) on such release is unclear. While this approach is certainly clever and may yield valuable information about
nanoparticle release from polymers as a general phenomenon,
it may be less useful to evaluate migration in commercial
clay/PNCs that have already been extruded without fluorescent
labels.
Discussion of food contact material release literature and current challenges. One of the most difficult challenges evident from
the current literature is determining the form of the nanomaterial that is migrating, that is, distinguishing between diffusion and
dissolution as the release mechanism (Figure 2). Based on current migration models used for molecular species, migration of
nanomaterials from nanocomposites should be quite slow: slow
enough, at least, that the number of particles migrating during a
1-, 2-, or 10-d test will likely fall below the limit of detection for
techniques typically used to count particles. The use of ICP-MS
or other elemental analysis techniques to monitor elemental concentrations can assist with the evaluation, but information about
the form of the migrant is lost when the sample passes through the
6000 K (or higher) inductively coupled plasma. SP-ICP-MS can,
in some instances, help address the technical challenges; however,
even with this highly sensitive technique, the size of the migrated
particle may be too small to detect because of the omnipresent
ionic background. Even if detection of ENMs is possible, there is
often the concern that the particles formed de novo or otherwise
changed their characteristics after the migration occurred. Therefore, appropriate controls, using ionic solutions and/or ENMs that
do not form under simulant conditions, may be necessary to fully
evaluate ENM migration.
Also evident from the literature is that there are various approaches to measuring migration and, although the data for a
specific product or material may be novel, the variation in exper
C 2014 Institute of Food Technologists®
imental strategies complicates the comparison of results and the
development of a general understanding of nanomaterial migration. The extent of migration of an ENM will be influenced by
the composition and form of the ENM, the characteristics of the
polymer matrix, the composition of the simulant, the time and
temperature under which the experiment was carried out, and
the use of single- or double-sided migration cells. The extent of
migration may also be influenced by the way the sample material
was prepared due to physical abrasion of particles during cutting or
tearing. Unfortunately, available migration studies not only vary
significantly in the sample preparation methods used, but also in
the level of description provided of how these methods were carried out. In some extreme cases, this information is completely
absent. A number of regulatory authorities have recommended
(US FDA) or required (European Commission) migration conditions that, while developed for additive migration, could easily be
applied to ENM migration. However, even if the exact conditions
specified in these recommendations/requirements are not utilized
in ENM migration experiments, the migration conditions should
be appropriate for food contact materials and the polymer matrix
should be evaluated based on a realistic intended use of the polymer. Additionally, evaluations of ENM migration should include
sequential exposures of the test material to simulant in order to
differentiate between surface desorption and migration.
Finally, with respect to the above-identified control points, the
task group found that many studies were focused primarily on
CP-3 level analysis (actual migration experiments) with considerably less effort spent on CP-2 (test materials) and especially CP-1
(pristine materials) level analyses. It is true that in some cases,
the CP-1 level analysis may be less important (for nanoclays, for
example, in which attributes like particle size and shape are less
defined) or even impossible (for ENMs incorporated into host
matrices in situ, for instance, or in the case of commercial materials that were acquired from 3rd-party sources). Even so, the value
of characterizing ENMs at earlier control point stages should not
be discounted: A comprehensive predictive framework of ENM
migration cannot be developed without a robust understanding of
how the pristine ENM or host material properties, as well as their
properties in the resultant nanocomposite, impact the downstream
quantity, and form of migrated ENMs. Without such a framework,
it will be difficult to have confidence in CP-3 level evaluations
of commercial materials. Therefore, the task group recommends
that significant attention be given to developing standardized tools
and sample preparation methods for all identified control points,
and the task group especially suggests that researchers involved
in migration work characterize their starting materials with these
available tools to the maximum extent possible.
Summary and Recommendations
This article presented some of the difficulty surrounding evaluation of the release of ENMs from food contact materials into
aqueous media. Such evaluations are necessary, however, to make
precise assessments of likely exposure of consumers to ENMs from
dietary sources, especially in light of the fact that most public perception surveys indicate that food contact materials, and particularly food packaging, are the most likely food-related applications
of ENMs to be accepted by consumers in the near future.
While many of the detection issues related to assessment
of ENM release from food contact materials are likely to be
similar to those encountered for detection of ENMs intentionally
introduced into foods (as discussed in the next article in this series
by Singh and others 2014), some differences in these areas justified
Vol. 13, 2014 r Comprehensive Reviews in Food Science and Food Safety 689
Measuring nanomaterial release . . .
separate articles on these topics. First, the focus here has been on
the prediction of exposure assessment, not the direct detection of
ENMs in foods. Second, the type of ENMs likely to be encountered in food contact and in direct-food applications is likely to
overlap only marginally, with the former category being primarily
inorganic ENMs and the latter being more organic in nature (for
example, liposomes, encapsulates, and so on). This will impact
the analytical methods needed for detection. Third, the front-end
sampling issues are different: the use of food simulants in the
case of food contact applications as compared to the use of more
complex matrices in real food analysis, as well as the need to characterize plastic materials for exposure assessments discussed above.
Finally, ENMs in food contact materials are not usually intended
to be released into food, so interactions with food matrices are not
always known. These differences introduce unique challenges—
and unique solutions—to the problem of ENM release
evaluation.
An evaluation of the ENM release literature revealed significant deficiencies. One of these deficiencies is the available tool
set itself. While there are numerous potential candidates, most
notably SP-ICP-MS, no optimal method to distinguish between
the various potential methods of ENM release has been identified,
particularly one that can determine whether ENMs migrate as
whole particles or as dissolved ions. Even in cases in which whole
particles are observed, there is still a question of whether such particles were released in a particular manner or whether they were
formed from ions during postmigration handling. As a result, a
majority of release studies simply ignore this question altogether
and present a total migration amount by simple elemental analysis
of the simulant using ICP-MS. The value of such studies toward a
true understanding of the phenomenon of ENM release remains
an open question.
The other major deficiency uncovered by our literature analysis
was a general lack of interest in thorough characterization of test
materials, particularly of particles and host polymers in the pristine
state. While it is true that such analyses have no obvious value with
respect to a safety evaluation of a particular material, in which only
the quantity and characteristics of the migrant need to be known,
from a broader standpoint, the lack of such information means that
existing studies shed little light on important structure–function
relationships, which are necessary to understand if a predictive framework for ENM migration is to be developed. Even in studies that
do undertake evaluations of their ENMs, polymers, and nanocomposite materials prior to migration experiments, the sheer variety
of sample preparation techniques, analytical approaches, and style
of data presentation make it difficult to compare 1 study to another,
and so again development of a more expansive understanding of
ENM migration is hindered.
As a result of these considerations, we conclude that the following should be regarded as research priorities in this area:
r Targeted development of new analytical tool sets capable of
differentiating between the various release mechanisms described here.
r Efforts to research the effect of sample preparation methods on
measured migration levels, particularly nanoparticulate forms.
r Development of model systems, particularly those that use
well-characterized reference materials, to better understand
important structure–function relationships.
r Formulation of standardized analytical techniques, sample
preparation methods, test materials, and data reporting strategies to increase consistency in the published literature.
Allocating resources to these priorities will lend confidence to
theoretical models and also experimental efforts, as well as support efficient research and development of safe nanotechnologyenabled food contact materials at the commercial level.
Acknowledgments
The authors of this report are grateful to the following individuals for their expert input and support for this effort (alphabetically
listed): Maurizio Avella, Joe Hotchkiss, Anil Patri, Ruud Peters,
Jonathan Powell, Vicki Stone, Scott Thurmond, Jim Waldman,
Stefan Weigel, and Jun Jie Yin. Experts were convened and initial
framing concepts were developed for this article by the NRFA
Steering Committee (http://www.ilsi.org/ResearchFoundation/
RSIA/Pages/FoodAdditiveSteeringCommittee.aspx and http://
www.ilsi.org/ResearchFoundation/RSIA/Pages/NRFA_
TaskGroup1.aspx), which operates as an independent public–
private partnership. Project management and editing support was
provided to the NanoRelease project experts by Richard Canady,
Lyubov Tsytsikova, Christina West, Molly Bloom, and Elyse
Lee of the ILSI Research Foundation. This phase of the project
was funded by the Pew Charitable Trusts, the US Food and
Drug Administration, Health Canada, ILSI North America, the
Coca-Cola Co., the Illinois Inst. of Technology’s Inst. for Food
Safety and Health, and the ILSI Research Foundation. Substantial
in-kind support was provided by the Nanotechnology Industries
Assoc. Furthermore, this material is partly based upon work
supported by the USDA Natl. Research Initiative Agriculture
and Food Research Initiative, the US Environmental Protection
Agency, and the Natl. Science Foundation.
This article has been reviewed in accordance with the US FDA’s
peer and administrative review policies and approved for publication. The statements made in this report do not necessarily represent the official position of the US FDA or affiliated organizations.
Mention of trade names or commercial products does not constitute an endorsement or recommendation for use by the US
FDA.
Author Contributions
Carlander serves as the task group chairperson and coordinator.
Duncan serves as the task group chairperson and coordinator, provided text to the manuscript, and performed general document
editing. Noonan provided text to the manuscript. Whelton provided text to the manuscript. The ordering of noncorresponding
authors is alphabetical and does not reflect quantity of contribution
to this article.
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