Memorandum by the Medical Research Council
Human Nutrition Research Unit
MRC Collaborative Centre for Human Nutrition
Research (hereafter HNR) was established in 1998 to advance
knowledge of the relationships between human nutrition and health
by providing a national centre of excellence for the measurement
and interpretation of biochemical, functional and dietary indicators
of nutritional status and health. HNR conducts basic research
in relevant areas, focusing on optimal nutritional status and
nutritional vulnerability in relation to health, including the
development of innovative methodologies. HNR responds to the strategic
priorities of the wider scientific community by conducting research
projects, within the scope of HNR's activities, in collaboration
with, and on behalf of: other MRC establishments and groups, Government
departments, industry, national and international agencies, universities,
research foundations and charitable organisations. HNR also acts
as an independent, authoritative source of scientific advice and
information on nutrition and health in order to foster evidence-based
nutrition policy and practice. In light of the work carried out
at HNR and the expertise of our staff, our comments are confined
primarily to the role of nutrition in securing good health for
the whole population.
The Micronutrient Status Research section at
MRC Human Nutrition Research, Cambridge, led by Dr Jonathan Powell,
has a long history of research interests in mineral based nano—and
micro-particles in the gastrointestinal tract in terms of exposure,
uptake and potential cellular effects. We study both endogenously-formed
mineral particles (mineralised calcium) and exogenous mineral
particles (eg dietary ferritin or food additives such as silicates
and titanium dioxide) and we use a range of approaches from synthetic
chemistry and basic cellular thought to whole-animal studies (human
and murine).
INTRODUCTORY CONCEPTS
We consider a nanoparticle to be a non-living
nano-scaled entity. Traditionally such particles would be considered
ultra-fine, fine or coarse, depending upon size, and there is
an increasing consensus that the ultra-fine fraction is equivalent
in meaning to nanoparticulate, which would be of < 100 nm
diameter. Biologically this makes sense because, as a rule of
thumb, particles below 100 nm diameter tend not to trigger
active uptake mechanisms (ie macro-pinocytosis and phagocytosis)
but instead tend to be taken up through more constitutive endocytic
mechanisms. Nonetheless we wish to point out that the gut is heavily
exposed to fine particles (ie particles > 100 nm diameter)
and that these should be considered in the overall picture. Additionally,
the different mechanisms of uptake, determined by particle size,
will affect intracellular exposure and outcomes.
The gastrointestinal tract is a unique environment.
Unlike any other tissue the gut has specific mechanisms for the
purposeful uptake of nanoparticles as well as the inevitable inadvertent
pathways that nanoparticles are able to access. The major pathways
are as follows:
1. Epithelial cell endocytosis. This is for true
ultra-fine particles and, for example, is the route of uptake
of dietary ferritin.
2. Paracellular uptake of small ultra-fines,
which may be enhanced through disease processes or drugs, or dietary
agents that enhance this pathway.
3. Persorption, which will allow the uptake of
fine and ultra-fine particles. This is a mechanism of inadvertent
permeation where an enterocyte leaving the villous tip leaves
a hole through which particles can permeate.
4. M-cell uptake overlying intestinal lymphoid
aggregates. This is the classical route for the uptake of fine
particles and is efficient but it is likely that ultra-fines also
access this route.
A further aspect of the unique gut environment
is that it contains many luminal toxins and antigens and, due
to entropic forces, particles will bind these in the lumen with
relatively high affinity. This will change the overall properties
of the particle surface and the cellular effects of the antigen
or toxin. It should be noted that there are recent data showing
that prion infectivity is greatly increased when prions are ingested
with particulates.
Immune cells from the gut will migrate to other
organs and, therefore, there is a systemic route for distribution
of particles from the gut as well as the obvious routing through
venous and lymphatic channels.
Gut diseases may potentially increase permeability
of nanoparticle uptake.
STATE OF
THE SCIENCE
AND ITS
CURRENT USE
IN THE
FOOD SECTOR
— What are the main potential applications
and benefits of nanotechnologies and nanomaterials in the food
sector, either in products or in the food production process?
— What is the current state of the market
for, and the use of, food products and food production processes
involving nanotechnologies or nanomaterials, either abroad or
in the UK?
— What might the "next-generation"
of nanotechnologies and nanomaterials look like? How might they
be applied in the food sector, and when might they enter the market?
— What is the current state of research
and development in the UK regarding nanotechnologies and nanomaterials
which have or may have an application within the food sector?
How does it compare to research and development in other countries?
— What are the barriers to the development
of new nano-products or processes in the food sector?
We wish to make clear to the Committee that
nanoparticles are not a new phenomenon, they occur naturally and
that the gut has been exposed to them presumably throughout evolution.
However, due to marked technological advances over the last five
to 10 years, we are able to characterise nanoparticles so
much better than before, which is at least one reason for their
recent appearance on the scientific horizon. The main areas pertinent
to the G.I tract are as follows:
1. Enhanced delivery of nutrients: nano-encapsulation
or micellar protection of micronutrients and antioxidants to prevent
them from degradation during manufacture and storage or under
gastrointestinal conditions. These products are already in the
marketplace, for example, Novasol is a product range of supplements
from Aquasol which consists of pH-resistant micelles that deliver
vitamins and antioxidants. Another example is Canola Active oil,
produced by Shemen Industries, that delivers phytosterols to inhibit
the transportation of cholesterol from the digestive system into
the bloodstream.
2. Safety: nanosensors for pathogen and contaminant
detection. Raflatac have recently released, commercially, a hydrogen
sulphide indicator label for fresh poultry products, where the
generation of hydrogen sulphide indicates spoilage. This label
contains a nano-layer of silver that changes colour once it reacts
with hydrogen sulphide
3. Smart packaging: Packaging that reacts to
stimuli such as materials with self-healing properties when perforated
or an intelligent ripeness indicator that responds to aroma as
fruit ripens.
4. Reducing spoilage: nanoclays in food packaging
prevent the permeation of oxygen to slow the ageing process of
food or slow the ripening of fruits and vegetables. Honeywell
are marketing an oxygen barrier based on nanoclays and a nylon
resin that scavenges oxygen to extend the shelf-life of beer (Aegis®
OX barrier).
5. Interactive food: foods and beverage products
that can be personalized to fit the tastes, nutritional needs,
or allergies of individual consumers. Kraft are one of the leaders
in this field of research.
6. Taste or texture improvement: reduce consumption
of fat, sugar and salt through the enhancement of taste characteristics.
Slim Shake Chocolate is a product already in the market, which
the manufacturer (RBC), claims to contain 4-6 nm silica nanoparticles
that are coated with cocoa components ("cocoa clusters")
and due to their high surface area provide a satisfactory sensory
experience in a low fat and low sugar product. Another example
comes from Unilever which aims to reduce the fat content in ice-cream
from 16 per cent to about 1 per cent by decreasing the size of
emulsion particles that give ice-cream its texture.
7. Equipment coating: application of nano-coating
in food processing equipment to prevent the growth of biofilms
that can lead to food spoilage and contamination. Many commercially
available food containers are already coated with nano-silver,
or anti-sticking nano-composites, and some refrigerators are coated
with nano-silver. Zinc oxide is also being studied as a cheaper
anti-microbial agent to replace nano-silver, and applications
are expected in the near future.
8. Removal of unwanted chemicals or pathogens
from food.
9. Food processing: nanosensors that can withstand
extreme conditions (eg temperature, pressure, viscosity) and provide
real-time data on processing conditions.
Further examples can be found in the presentation
given by Dr Dora Pereira of the MSR section at MRC-HNR (Appendix,
page 3) [not printed] to an audience of the Cambridge Science
festival on 13 March. We would like to add that although the range
of nanotechnologies that can be applied to food, or food production,
is vast, and many different strategies are being developed or
are already in the market, the perception of safety will determine
public acceptance and may limit the growth in several areas.
HEALTH AND
SAFETY
— What is the current state of scientific
knowledge about the risks posed to consumers by the use of nanotechnologies
and nanomaterials in the food sector? In which areas does our
understanding need to be developed?
— Is research funding into the health
and safety implications of nanotechnologies and nanomaterials
in the food sector sufficient? Are current funding mechanisms
fit for purpose?
— Can current risk assessment frameworks
within the food sector adequately assess the risks of exposure
to nanotechnologies and nanomaterials for consumers? If not, what
amendments are necessary?
— Are the risks associated with the
presence of naturally occurring nanomaterials in food products
any different to those relating to manufactured nanomaterials?
Should both types of nanomaterials be treated the same for regulatory
purposes?
Gastrointestinal exposure to nanoparticles may
be natural, due to inadvertent environmental exposure or due to
purposeful environmental exposure. Examples of naturally occurring
nanoparticles are dietary ferritin, which is about 13 nm
in diameter but when digested releases iron oxide particles of
around 2 to 3 nm and the endogenous calcium phosphate
particles that are formed within the gut lumen and appear to have
diameters of 20 to 200 nm. It is likely the majority
of natural nanoparticles to which the gut is exposed are mineral
based. Inadvertent environmental exposure comes through soil,
dust, exhaust fumes etc. In contrast, purposeful, man-made exposure
is mainly through food additives and excipients or congeners that
are used in supplements and medicines etc.
We believe that traditional toxicology models
are not likely to capture much information when it comes to nanoparticle
adverse effects. This is because any effects are likely to be
mediated immunologically and, therefore, identified through chronic
exposure and by interaction with individual genotypes. It may
first be useful to categorise particles as fine or ultra-fine
to identify their likely route of cellular uptake and thereafter
to establish their chemical stability to predict cellular processing.
It may thus become possible to develop assays that will predict
nanoparticle toxicity.
Several companies are developing nano-delivery
systems that enhance the absorption of antioxidants known to provide
health benefits. However, many of these antioxidants are normally
poorly absorbed and may not be well tolerated at higher levels,
which may result in "too much of a good thing" scenarios.
Therefore, prior knowledge based on normal delivery of nutrients
should be ignored and these nano-delivered nutrients should be
treated as novel chemical entities. However, the use of naturally
occurring nanomaterials (eg ferritin) may be fast-tracked in future
regulatory processes providing that there is evidence of their
consumption over periods of time long enough to guarantee their
safety, and that their administration is not substantially above
what would be found in an average diet. MRC-HNR is working on
the synthesis and commercialisation of ferritin-core mimetics
as novel iron supplements.
REGULATORY FRAMEWORK
— Is the regulatory framework for nanotechnologies
and nanomaterials fit for purpose? How well are imported food
products containing nanotechnologies and nanomaterials regulated?
— How effective is voluntary self-regulation
either in the UK or EU or at an international level? What is the
take up by companies working in the food sector?
— Will current regulations be able adequately
to control the next generation of nanotechnologies and nanomaterials?
— Is there any inter-governmental co-operation
on regulations and standards? What lessons can be learned from
regulatory systems in other countries?
Currently, legislation does not account for
the nano-scaling of current approved excipients and additives.
An example of this is noted above, namely that amorphous silica
is an approved particulate which recently has been nano-sized
by RBC in their Slim Shake Chocolate product and thus has "inherent"
FDA approval although the original toxicity testing is likely
to have been carried out on particles of tens of micrometres in
diameter. We, therefore, believe that the regulatory process should
be based on a case-by-case approach.
PUBLIC ENGAGEMENT
AND CONSUMER
INFORMATION
What is the current level of public awareness
of nanotechnologies, and the issues surrounding the use of nanotechnologies
and nanomaterials in the food sector? What is the public perception
of the use of such technologies and materials?
We have not carried out any surveys to consider
the level of public awareness or perception of nanotechnologies
in the food sector.
How effective have the Government, industry and
other stakeholders been in engaging and informing the public on
these issues? How can the public best be engaged in future?
Efforts to inform the public have not kept pace
with the growth of this new technology area. This increases the
risk that a false alarm over safety or health consequences could
undermine public confidence, engender consumer mistrust, and,
as a result, damage the future of nanotechnology, before the most
exciting applications are realised.
In the latest national MORI Survey for the Office
of Science and Technology (2005) a large proportion of those surveyed
said that they wanted to hear about new developments in science
and technology before they happen, not afterwards; and 49 per
cent said that they receive too little information about science
(more than twice the proportion than in 1999-2000). The Wellcome
Trust document "Engaging Science: Thoughts, deeds, analysis
and action report" (2006) recognises the value of a well
informed public debate "to enable a wide range of opinions
to feed into policy-making discussions."
If the public is to trust, debate and value
scientific progress, we need a society engaged with contemporary
science. Scientists themselves need to be encouraged, trained
and supported in communicating their work. Stimulating public
interest in science, its potential applications, misapplications
and impacts, as well as the nature of science itself can be achieved
through the development of a clear public engagement strategy
with specific audiences identified, measurable objectives and
outputs.
What lessons can be learned from public engagement
activities that have taken place during the development of other
new technologies?
The value of public engagement within the fields
of science and nutrition is increasingly recognised but, to date,
under-utilised. A report prepared for the Research Councils UK
and the Department for Innovation, Universities and Skills highlights
that "direct dialogue with the public should move from being
an optional add-on to science-based policy making and to the activities
of research organisations and learned institutions, and should
become a normal and integral part of the process" (People
Science and Policy Ltd/TNS 2008). Moreover it notes that the public
increasing want more information; 8 out of 10 people
agreed that "science is such a big part of our lives we should
all take an interest."
The Nutrition and Health Communications team
at MRC HNR has a strong track record in engaging with a variety
of different audiences to drive improvements in public health.
Our aim is to build bridges between our scientists and people
of all ages and from all walks of life to consider, question and
debate the key issues in relation to diet and health and to stimulate
their awareness and enthusiasm for science in society.
Public engagement has many different levels
and mechanics and is a key part of the MRC Corporate Communications
Strategy. At HNR our activities tend to focus on issues directly
relevant to our own research or broad nutrition and health messages
about a healthier diet. Our key learnings are:
— Develop a communications plan with agreed
key messages appropriate to the audiences.
— Provide an in depth briefing to journalists
at an early stage and keep them regularly informed.
— Encourage and train scientists to engage
with the public.
— Make scientists accessible to the media
throughout the communication process.
— Engage leading medical research and scientific
bodies to make a positive and proactive contribution to the debate,
not just defensive responses.
Given our particular research interest in the
area of nanoparticles we are at the start of a scoping exercise
to identify how we might contribute to the debate across a variety
of audiences, including the public. We shall observe the progress
of this Inquiry in some detail and would welcome the opportunity
to discuss public engagement opportunities in more detail.
Should consumers be provided with information
on the use of nanotechnologies and nanomaterials in food products?
Public attitudes towards new technologies play
an increasingly crucial role in supporting their development and
application. The public should be provided with information on
the use of nanotechnologies and nanomaterials in food productions
because public opinion has the potential to influence the public
policy and regulatory environment in either positive or negative
directions, with recent examples including biotechnology and genetically
modified crops. It also impacts on the investment environment,
with investors influenced by actual and potential community and
shareholder concerns.
12 March 2009
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