Examination of Witnesses (Questions 260
- 277)
TUESDAY 5 MAY 2009
Professor Ken Donaldson, Dr Qasim Chaudhry, Dr Jonathan
Powell and Professor Michael Depledge
Q260 Lord May of Oxford:
There does seem to me, and I may be wrong, that it is a subject
which is inherently at the interface between the physical and
the life sciences, so that it does require a certain amount of
willingness to cross boundaries that not everyone is good at.
Professor Donaldson: That is absolutely right.
It is an interdisciplinary undertaking. To study the environmental
and human health consequences of particles, you have to understand
the particle and you have to understand the toxicology and the
toxicity, so you definitely have to have a multidisciplinary team.
Professor Depledge: I think that is right; it
has to be a multidisciplinary activity. I think in the UK the
ecotoxicological investigations of nanomaterials are again punching
above their weight. There are a number of groups around the country,
but I would point out that I think the amount of resource available
for undertaking research on the effects of nanomaterials on the
environment and human health is extremely small compared with
the amount of money that is being invested in the development
of new nanotechnologies, in new materials. It is tiny in comparison
with the investment. It is also to me very interesting that we
have some of the research councils in the UK providing resources
to look at the impacts on the environment and human health, whereas
other research councils are actually promoting the development
of new nanotechnologies and new applications, so you have one
chasing the other. This is happening at a grand scale in Europe
where in the Framework 7 programme, the environment and climate
part, there is relatively limited resource available for looking
at the impacts of nanomaterials on the environment and human health,
but in other programmes within the EU there are vast amounts of
money available for stimulating European industries to adopt nanotechnology
methodologies, and indeed there is a suggestion that one-third
of all industrial manufacture in Europe will involve nanotechnologies
within 10 to 15 years.
Dr Powell: Just to add very quickly concerning
your specific remit here, I think there is little or no work,
either in the UK, Europe or even on the world scale, in terms
of the gut, foods and nanoparticles. Most of what we know about
comes from the work, as Ken Donaldson said, from the lung, a little
bit from the skin and the tiny amount that has been done in the
gut. In terms of what is going to happen, I believe that there
is now access to certain research grants. What needs perhaps to
be done is to try and enhance the interest so that more work around
the gut is undertaken around foods and I think, again as Ken has
said, in the UK we should be fairly well placed at the global
level to be leaders in this area.
Q261 Chairman:
If we focus that question very specifically on the regulatory
requirements for risk assessments, if you had to summarise in
a few sentences what would be the top research priorities for
risk assessment of nanotechnologies, nanomaterials in food and
packaging in relation to regulation, what would you pick out?
Dr Powell: I would argue that because of where
we are currently at, that is to say we have nanoparticulates coming
through already, if not in this country I am sure soon to come
and certainly in other countries, and yet we do not have regulations
and knowing how slow the latter are compared to the former, we
need to do something fairly quickly. For me therefore the priority
would be a logic model, and that logic model would unfold in a
fairly simple way, starting with the question of: are these particles
degraded in the lumen—ie do they reach the cells? If they
do not, then we consider them one way. If they do reach the cells,
are they degraded in the cell? Do they bind constituents of the
gut lumen? Then, if they do not get degraded within the cells,
where do they go thereafter and what are the basic cellular aspects;
are there concerns for toxicity. I would like to see a fairly
rapid logic model develop because I think it will address the
gap.
Q262 Chairman:
Once the model is developed, can it be populated or do you need
new research to populate those different stages?
Dr Powell: I think the model I would try to
run with would use current techniques and current technologies
that are fairly easily available. That is not to say it is foolproof
because it will not be but I do believe it will address to a large
extent our concerns and it will at least get us to a point where
we can say that there is no logical reason to worry about this
particle or, yes, there is a logical reason to worry this particle.
The second very quick point to make is that we need to consider
how necessary are these particles. So we have titanium dioxide,
we have heard about earlier, which is completely unnecessary—it
makes food whiter or brighter, which is not necessary—versus
particles which might contribute to food safety in this country,
which clearly is very necessary. So I think that would be an important
part of this model.
Professor Donaldson: You could do a lifetime
feeding studying rats of some selected nanoparticles. All right,
there is a problem to choose which ones but you might choose some
of the ones that are most commonly used in foods. You could start
with titanium dioxide, I would suggest. A lifetime feeding study
in rats, including toxicokinetics, to their full life span, could
be undertaken, just to see if you find any adverse effects in
these animals. Also, there are a number of genetic models you
get nowadays, and is there a mouse model for an inflammatory bowel
condition that could be used, Professor Powell?
Dr Powell: There are a number of mouse models,
yes.
Professor Donaldson: That could perhaps be coupled
with some studies in these mouse models where they have an inflammatory
gut condition. Looking at toxicokinetics in these I think would
go a long way to allay people's fears, if a couple of these studies
came up showing nothing very much, and, if they did come up with
something, then that should raise some warning flags.
Professor Depledge: I wholeheartedly agree with
those two comments. The other thing that I think that is important
is to build into the design of some of these materials ways of
getting them to biodegrade, for example in the pH of the gut into
harmless forms. A great deal more could be done with the design
of these materials to ensure that they do not have a protracted
lifetime.
Dr Chaudhry: I agree with the comments made
by Dr Powell and Professor Donaldson that long-term studies are
needed but also they need to be linked with histopathology. We
do not know which new targets in the model might arise because
of nanoparticles, so not only long-term studies but also linked
with histopathology to find if there are any novel targets for
these particles.
Q263 Lord Haskel:
We are learning that nanotechnology is a huge field. Are there
any other areas of research in nanotechnology which can help research
into nanotoxicology? Do we learn from any other areas?
Dr Powell: I think certainly in terms of imaging
and analysis there is a very good cross-over between the two areas
and really our success in detecting these particles in tissue,
the histopathology that Dr Chaudhry has referred to, has on many
occasions relied on physics and such technicological advances
to allow us to look at them. To my mind, and we do a lot of work
in the imaging and analysis area, that has been wholeheartedly
down to advances technologically on the physics and the engineering.
Dr Chaudhry: Another area which has a cross-over
is nanomedicines and nanomedicines are being developed for oral
intake and they are supposed to leave the gut and take the medicines
and deliver them to specific tissues and organs. A lot can be
learnt from that mechanism about how particles can translocate
out of the gut and where they go and where they end up.
Q264 Lord Haskel:
What about nanomedicines? Professor Depledge has mentioned nanomedicines
a couple of times. Is there anything we can learn from that?
Professor Depledge: Yes, I think there is a
great deal we can learn from that because we can study the design
of nanomedicines where we are trying specifically to deliver nanomaterials
or drugs or coatings or whatever to particular parts of the body.
So I do think that that is important. Clearly in nanomedicine
imagining techniques are being driven forward in that area too.
It is also interesting—and whether it is possible to do
it I am not sure—that the military have a wide variety of
applications for nanomaterials and are also developing techniques
for measuring nanoparticles in the environment. There may be some
cross-over there in appropriate circumstances.
Q265 Lord Haskel:
There are more and more nanomaterials being used in our clothing.
Is there anything that we can gather from that about the toxicology?
Professor Depledge: I think there is a great
deal that can be gained from that but again it spills over into
where do these materials end up. We are talking about measurement
techniques. It is hard enough to visualise nanomaterials in tissues
and in organs in humans, but imagine the problem of detecting
nanomaterials actually in the environment because there is a background
of nanomaterials around that are just naturally produced and to
actually identify engineered nanomaterials against that background
is a terrific problem. Nanomaterials are one of the few kinds
of materials that we put into the environment about which we do
not know how much is there, how long they persist, what they transform
into, where they go. We do not know the answers to those questions.
Professor Donaldson: I think there is an informative
example also from nanomedicine. The nanomedical people have designed
a nanoparticle that crosses from the blood into the brain. The
blood-brain barrier is usually a very tight barrier and most things
do not pass over. The brain is very privileged and protected.
The nanomedical people have designed particles that cross the
blood-brain barrier, so there should be something that tells us
if somebody came up with a particle having a similar surface as
that one, then it should not be used for any other purpose. You
do not want these things locating to the brain unless you want
them to locate to the brain. I think there are lessons to be learnt
generically about a big picture of what it is about particles
generally that makes them do anything. Just a big structure activity
relationship for particles is what we need. If you had that, you
would be home and dry really, but that is not going to happen
tomorrow.
Q266 Chairman:
I know that at least two of you are authors on this large report
that we have recently received called EMERGNANO produced by the
Institute of Occupational Medicine in Edinburgh. I have to confess
to not having read it page by page, line by line—I am sure
you have all read it—but the bottom line seems to be that
there are still major gaps in the knowledge base with regard to
characterisation, exposure of toxicology of nanoparticles and
nanomaterials. In terms of us drafting our report, would you recommend
us to take this as an assessment of the current state of knowledge
on health risks and risk assessment?
Professor Donaldson: Not really; it is not a
review of literature but a review of ongoing, research funding
by government at European level. It is not a review of the literature.
It is quite important to appreciate that it is research that is
going on and us saying that the research is not looking in this
and that place. It is quite well focused (for instance nanotubes
get quite a lot of attention) but it does show the kind of flightiness
of research that is very dependent on fashion. When you look across
the research, you can see that nobody seems to be interested in
the gut but everybody wants to look at nanotubes for example.
It is a problem.
Q267 Chairman:
Would you say, as a follow-up to that, and one of the issues we
have been talking about is gaps in knowledge as far as risk assessment
is concerned, that one of the issues is the capacity in the UK
or elsewhere in terms of toxicological experts working on absorption
through the gut? Is that one of the limiting factors? I think
we have heard previously from Dr Powell that he collaborates with
others in Germany but not with others in the UK, presumably because
there are not other groups doing gut absorptive nanoparticles?
Dr Powell: I think the joined-up-ness between
the two groups is going to be very important. I have seen a number
of early studies, either started or proposed, not in this country
but elsewhere, which in terms of the gut and in terms of the dietary
aspects have schoolboy errors in them. They have been undertaken
by toxicologists. I am sure the toxicology downstream would be
fantastic. I am sure were we to try to address toxicology alone,
we similarly would make errors, and therefore it is important
that the two sides get together, people such as ourselves who
have expertise in particles and the gut and diet and those who
have expertise with the toxicological outcomes. I do not think
that has happened and that probably needs to happen.
Professor Donaldson: I think we are reaping
what we sowed. If we look at the Royal Academy/Royal Society report,
there was a really important paragraph that there should be a
central core-funded chunk of research and expertise brought together
to design a programme that would look systematically at nanoparticle
toxicology, and that was ignored. We had response mode funding
where people just put forward what they wanted to do, so what
you get is piecemeal. There is no cohesive approach to trying
to understand particles as a whole. Until we have a proper structure
function view of all particles, then there will we will not be
home and dry. The only way you can do that is to have a central
core-funded programme that looks at all the different aspects
and target organs and brings people together to try and drive
forward such a programme. You do not get it from response mode
funding; you get the kind of expertise that is already out there
multiplied up. People who do work on the lung, all put money in
for work on the lung and there is nobody doing work on the gut,
so nobody puts forward research on the gut. If you had a programme
that recognised the gaps and saw the big picture, then you would
go down all these pathways. We are reaping what we sowed.
Q268 Chairman:
The view is that that recommendation has not been effectively
taken up?
Professor Donaldson: No, it was not taken up.
Q269 Chairman:
Is it being taken up in any other country?
Professor Donaldson: The best is America probably.
Professor Depledge: The US is taking it up and
they have set up a number of centres. They started off with just
one or two centres. One of the biggest was at Rice University,
but now they have set up some other centres as well and they are
trying to bring together diverse groups of scientists. Just going
back to what we were saying, I think the point that there is a
lack of toxicologists and ecotoxicologists in the UK and also
across Europe is being widely recognised now.
Q270 Baroness Neuberger:
We have been talking about the need for, if you like, a strategic
programme of research. If you were looking at what industry should
do, and you have already said that there is a need for an independent
industry-wide body, Dr Chaudhry, what health and safety research
would you expect industry to be doing now and what methodologies
would you expect them to be looking for when they are looking
at a new food product containing nanoparticles to make sure that
it is safe for the consumer?
Dr Chaudhry: First of all, I think detection
technologies are missing in the whole scenario. People can detect
nanoparticles in neat solutions and in isolated cells and all
that. When it comes to very complex matrices like food and varieties
of foods, then it suddenly becomes very difficult. This is being
taken up at the European Commission level and at the Seventh Framework
Programme they are going to fund some of the projects specifically
designed to develop and validate methodologies for that purpose.
That will be done or it is being addressed. The other issues are
in terms of safety; what are the long-term effects. We are not
talking about short-term or acute types of effect because maybe
you need very high doses for that, which may not be present in
food products which contain nanoparticles. We are talking about
long-term effects and again long-term studies coupled with histopathology
to find out what is going on in the body—animal models,
in vitro tests. Some of the in vitro tests can show,
for example, initial indications of mutagenicity. Particle exposure
may lead to mutagenicity. This is what industry needs to do so
that if they are going to use nanomaterials for a specific purpose
or a composition, they can ensure that all the safety aspects
are being addressed.
Q271 Baroness Neuberger:
Do you expect them to have done that for a new product?
Dr Chaudhry: This has been debated for some
time by industry and by some other quarters. Industry's view was
that these are not new materials. Because the regulations did
not at that time recognise them as new materials, then they thought:
We are already using titanium, why should we worry about nanotitanium;
if we are using iron, why should we be worried about iron and
things like that. But now there is a realisation and there are
proposals to change some of the legislation so that it is clear
in the word of the law that if someone is going to use food additives,
even if they are already approved but someone starts making a
nano form of them, then they will be recognised as having been
made by a different process; i.e. a new material. That means that
the company is going to have to produce safety data to show that
these are safe to be put in food. Also, if someone is developing
a normal food with nanotechnology, the wording of the law was
a bit unclear and it did not clarify whether any food produced
using nanotechnology would automatically be qualified to be considered
as novel food, but now there is a proposal which will go into
European legislation to make it clear. In the next few years hopefully
we will see lots of clarification at a legalistic level. That
will then trigger companies to ensure that they do not put anything
into the food which they assume is already approved.
Q272 Baroness Neuberger:
There is a real issue, is there not, coming back to Lord May's
point, that if this is something that was widely known—and
we are waiting for the law to clarify before people have to be
seen to do be doing those kinds of health and safety studies—it
is not very satisfactory for the consumer, is it?
Dr Chaudhry: Our food laws come under national
legislation. They are made in Europe and then filtered through
down to national level. This is now being taken up at European
level and then it will come down to national level.
Q273 Baroness Neuberger:
Coming down to national level, do you think the FSA or some other
body ought to be responsible for holding a whole register somehow
of health and safety research by industry to ensure that the work
that is done is fit for purpose and that the lessons learnt and
the methodologies can be shared, which I think was your point
about having an industry-wide body?
Dr Chaudhry: To be fair, government has done
quite a lot. They have founded the Nanotechnology Research Co-ordination
Group (NRCG) which is headed by Defra; the FSA and other agencies
are part of that. It deals with across-the-board issues and then
every agency is responsible for its own remit. In that sense,
the FSA are responsible for the food area. Usually what happens
is that a new technology emerges and regulation and technology
feed each other and that is how the system goes, but this technology
has taken everyone by surprise. It emerged out of lab benches
and suddenly people thought: let us put these materials into products—cosmetics,
food, paints and coatings, and variety of other things. The production
volume certainly started to increase from milligrams to grams
to kilograms to multi-tonne and now we are talking about thousands
of tonnes of some materials. It has taken everyone by surprise.
To be fair, regulators are doing what is needed. They may have
been a bit slow but everything is being done, in my view as much
as possible.
Dr Powell: I just want to make a couple of very
quick points. We do of course have at least one example which
has been mentioned a couple of times here from the USA where one
particular particle that was passed as safe to use by the FDA
was never in any way intended to be in nanoparticulate form and
never was but, as legislation did not prevent that, it suddenly
came into being in a nanoparticulate form. I do believe that there
are fairly simple procedures and tests that could be undertaken
and, if not within the industry itself, certainly they could be
outsourced reasonably cheaply. That would in the short to mid
term, whilst we are getting our act together in terms of understanding
and legislation, provide I think a fairly rational approach to
determining nanoparticulate safety in the foods I talked about.
Q274 Baroness Neuberger:
Do you think that would be a relatively easy thing to do?
Dr Powell: Yes. As I said earlier, I do not
think it is going to provide 100 per cent proof but, in terms
of effectiveness for 80 to 90 per cent, this would really be a
pretty quick, cheap and easy way to proceed. These are not complicated
assays that I am talking about.
Q275 Chairman:
Could you just clarify what you are talking about?
Dr Powell: Yes. I am thinking firstly about
simply in vitro assays, test tube assays that will allow
us to ask the question: under simulated conditions of digestion,
is this nanoparticle persistent or does it get broken down? Secondly,
if we take two simple cell types, the one that lines the gut (the
epithelial cell) and the underlying immune cells and we challenge
those with the nanoparticles in the presence and absence of some
bacterial toxins that are found in the gut, do we then see effects
on those cells in terms of maybe three simple outcomes that are
quite well established—reactive oxygen species, cytokines
and cell surface markers—and look at degradation of the
particle. If we see no effects there and we see degradation of
the particle, I would be fairly well reassured that that is likely
to be safe. If however we see effects on the cells, or we do not
see degradation of the particles, I might then suggest that we
look into just how necessary is that particle to bring into the
food environment at the moment.
Q276 Chairman:
Are there any other points that any of you as witnesses would
like to make? We have reached the end of our questioning but there
may be a point that you feel we have not covered or issues you
would like to raise at this stage. No. Of course, if at a later
stage you feel that there are points you would like to write in
about again, and already a number of you have submitted written
evidence, please feel free to do so to the committee clerk sitting
on my left. Also, I should remind you that there will be a transcript
of this session and you will have a chance to comment on it before
it is finalised. Just in closing and in thanking you for coming
to give evidence to us, I would like to revert back to an earlier
question to be absolutely clear. In the early part of this morning's
discussion, you all in different ways emphasised the heterogeneity
of what might be considered to be nanoparticles and considered
issues like whether they were persistent or not, their reactivity
or lack of reactivity on the nanoscale. I just wanted to go back
to cases that we have heard about of potential application which
are really of nanoengineering of items that are already in the
diet. For example we have heard about the notion of nanosized
salt particles to increase the surface area and therefore the
saltiness so you can have less salt in food. Another example was
a mayonnaise with a nanoemulsion with I think fat droplets enclosed
in water droplets, or maybe the other way round, I cannot remember
how it was. I want to ask you whether the concerns that you expressed
in relation to unknowns about risk assessment would apply to those
engineered, naturally occurring, already existing components of
food or whether it was more to the components that are not already
existing or naturally occurring.
Professor Donaldson: Obviously with something
soluble like sodium chloride, like salt, all that would happen
in a nano form is that it would be much more rapidly soluble.
I cannot see that changing the toxicity or lack of toxicity in
general that salt has at all. Likewise, changing the size of micelles,
lipid micelles, I do not think would have a big effect. Our concern
here is, for want of a better word, about hard particles or things
that are added in. That is my feeling.
Dr Powell: I completely agree with that. I would
also just add however one small caveat. It is still possible to
take naturally occurring soluble molecules and make them nanoparticulate
but not make them rapidly biodegradable. Just because they have
naturally occurring components does not immediately transfer to
safety.
Dr Chaudhry: This is the area, going on from
Dr Powell's comment on nanoparticles naturally occurring but made
into less degradable ones, that is the basis of a nano delivery
system, so that they take materials out of the gut. Although they
may be composed of naturally occurring molecules, they may take
things out of the gut into other cells and tissues.
Professor Depledge: My concerns are the materials
that are added to food that are designed to be toxic in one way
or another, perhaps to bacteria or those kinds of things. I also
emphasise again that contaminant nanoparticles in food are important,
things that are designed to be toxic but somehow or other end
up contaminating food. With later generations of nanomaterials,
in the third or fourth generation where they combine with other
systems, synthetic biology systems and so on, for the future there
needs to be even greater care taken.
Professor Donaldson: If I can I say one word
in closing, it is not to be too hung up on the 100 nanometre cut-off
and to be concerned at things of 200. I do not know where the
cut-off is to say that things are fairly close to the size that
nature makes, maybe 500 per micron, but certainly we should not
be too struck on the idea that 100 nanometres means harmfulness
beneath it and harmlessness above it.
Q277 Chairman:
That is a very helpful comment and one we have heard before.
Dr Powell: I am sorry but there is just one
brief point, which is that I would like to re-emphasise something
we probably have not said enough about today and that is that
the gut lumen is a very unusual environment; it is full of bacterial
toxins and ingested particles really have the ability to bind
to their surface these kinds of toxins and other molecules and
can, at least in theory, and we now have evidence for this, carry
them across into the gut mucosa. You are dealing with quite a
complex situation.
Chairman: You did mention that earlier
but it is useful that you remind us of it. I would like to draw
the session to a close and thank all of our witnesses for an excellent
session. You have answered our questions patiently and very clearly
and been very helpful to us. Thank you all very much indeed.
| 
