Examination of Witnesses (Questions 880-899)|
TUESDAY 15 JANUARY 2002
880. Did I get the impression from what you
said that there are other causes for emphysema and chronic lung
disease? For instance, air pollution? Is it possible to carry
out experiments in this country on animals creating an artificial,
polluted atmosphere and do you need to?
(Professor Page) One of the causes that is considered
to be a major precipitating event for some types of emphysema
is certain industrial pollutants, for people working in certain
occupational environments. One of the big problems we have at
the moment is, if you have 1,000 people who smoke, only a certain
percentage will get emphysema and we do not really understand
which group will get it and which group will not. If we did, we
could take preventive measures in all sorts of ways. Air pollution
is now considered a major issue, both for respiratory health in
general and also contributing to Chronic Obstructive Pulmonary
Disease (COPD). It is easier here at the moment. I have certainly
held grants from the Wellcome Trust to study the impact of air
pollution and whether or not air pollution is causing the number
of people with allergy to go up, for example, because we have
no understanding of why. We were doing that sort of experiment
but that is because in some ways the perception of air pollution
and of tobacco smoke being horrible and self-inducedthere
is less need to justify it because we all recognise that you cannot
get away from diesel fumes and we are interested to know what
that does to help.
881. You can get licences?
(Professor Page) With air pollution, yes.
Lord Hunt of Chesterton
882. What is worrying about your reply is you
keep using the word "sensitivity" as if the decision
is taken by some bureaucrat or official reading The Daily Express.
There is a political sensitivity that is not so worryingly unobjective
in the way it is done. Dr Festing earlier said that fundamental
research often leads to very practical, useful answers. One of
the things that is not clear to us is this: do you always, when
you are wanting to do animal experiments of a fundamental nature,
have to produce some medical benefit in the application for the
research. The impression I had was that you do have to. Simply
to say up front, "This is pure research. We have no idea
whether it is going to be useful or not" would not enable
you to do the experiments.
(Dr Matfield) I think we used the term "public
sensitivity", not "political sensitivity". At the
end of the day, the civil servants and ministers who are making
decisions about which licences to award are doing it on behalf
of the public, so I think it is quite legitimate that public sensitivities
are reflected in that. Can I turn to my colleague to answer your
second part about the fundamental research?
(Dr Festing) I am not sure if you are referring to
funding of the assessment by the funding agencies or the cost
883. Supposing you said, "This is a fundamental
experiment but I have no idea whether this will be useful or not"
openly. As I understand it, you would have difficulty getting
permission to do such an experiment.
(Dr Festing) The advancement of knowledge in itself
is an allowed reason. In the assessment of benefit from severity,
the chief inspector says that the benefit is the importance of
the objectives times the probability of the achievement. The importance
of the objectives is about the general attributes. Is it original?
Is it realistic? You do not have to give a clear, precise medical
884. This is going back to the concern about
smoking beagles. In assessing the cost in that case I am not clear
how far down the road of getting collapsed lungs the beagles would
have to get. Is there any way in which the experiments might be
brought to an end with knowledge having been gained and the animals
put down before the actual, final effects of emphysema on these
animals came about?
(Dr Matfield) The smoking beagles case was a long
time ago but I think the point of using them was to develop tobacco
alternatives which was perceived as a trivial purpose. There has
been a huge change in the way that we do animal experiments, particularly
where we allow them to end. There is now the concept of humane
end points. It is a major way of improving the welfare of laboratory
animals. For example, if one were doing a toxicity test to see
whether a certain substance caused cancer, do you need to wait
until the cancer is massive and obvious or do you wait for the
first pin-prick nodule of a tumour? The minimum distress to the
animal possible is the touch-stone. The first reliable sign that
you can use as the end point to the experiment must be the one
885. In the case of tobacco, any breathlessness
or difficulty would be the point at which the work would be brought
to an end and the animal destroyed?
(Professor Page) Yes.
886. The cost to the animal need not be so high
as a total collapse of its lungs?
(Professor Page) No, and I think it is fair to say
that most people would use smaller animals than dogs because there
is a direct expense of using laboratory dogs as opposed to a smaller
animal. In all cases, what you are trying to do is induce a change
that you can detect, either in the function of the lung or histology
of the lung. As soon as you see that, you would use that as the
Earl of Onslow
887. Let us assume animal A starts coughing
slightly. You know that this stuff is going to make it cough.
If you stop giving it that stuff, will it stop coughing or will
it go on like my godfather, Tony Murray-Smith, who coughed like
anything and smoked 60 cigarettes a day?
(Professor Page) It depends on the extent of damage
but it could well carry on coughing.
888. Could it recover? Is it non-regenerative?
(Professor Page) That is correct. The real problem
with emphysema is, for example, if you have asthma or other types
of obstruction, the muscle that surrounds your airway tubes constricts.
We can take drugs to relieve that and you feel better immediately.
The big problem and the reason we have people sitting in wheelchairs
with oxygen attached to them and they cannot walk from here to
the other side of the room as a result of smoking cigarettes all
their lives, is that the structures for gas exchange in the periphery
of the lung are destroyed. If you have just been in the sunshine
you can get changes to your skin's elasticity. Once we destroy
the elastic fibres in the skin, we age. If you do the same thing
in the lung which you accelerate with smoking, it is impossible
to reverse that.
889. In the course of your working life, have
you ever developed alternatives to the use of animals in experiments?
Is it realistic to expect people like you to be the mainstay of
such developments or would it be best done by people who are dedicating
themselves to that principally?
(Professor Page) As a working scientist, in my own
laboratory, I have cell culture, the use of organ tissue taken
from experimental animals, or from people, cell lines and all
of the so-called alternatives are developed by the scientific
community. We are the people developing these alternatives. Most
good laboratories will have an approach to their scientific problem
that works across a range of different techniques, including animal
experimentation. You would use animal experimentation only as
the last experiment you would do and you would certainly use alternatives
if they were available.
890. I think smoking forced on animals is the
first example we have had about substantial severity of procedures
which you cannot do in this country. Can you give us any other
(Professor Page) Off the top of my head, no. I use
that example from my own working life.
891. Could you write in if you think of anything
(Professor Page) Yes.
892. What evidence is there that regulatory
toxicity testing is scientifically necessary? Are there any animal
experiments which are required by European or international regulations
that you consider to be unnecessary?
(Professor Page) The animal tests used for regulatory
testing provide direct information about the effects of potentially
toxic substances on a range of organs and tissues. These tissues
and organs are biologically very similar in all mammals, including
humans. To check against the possibility that an animal may be
showing an unusual response, it is required that you study at
least two species. In some cases you would study three species,
rodents and then maybe a dog or even a primate. If the same result
is found in all of them, it can be assumed the result is likely
to be normal across mammals, including ourselves. I can illustrate
this by describing the testing of a drug that I found recently,
coming back to your question about the cough, because cough is
another medical need. This was a drug that had previously been
discovered by a Swedish pharmaceutical company. It had been given
intravenously to animals, including man, to see if you could use
this drug for treating a heart condition. From the science that
I was involved in, we recognised that how this drug worked may
have application in the lung but to deliver it to the lung without
having an adverse effect on the rest of the body we wanted to
try and give this drug directly to the lung by inhalation with
an inhalation device. Because this drug had never been given by
that route of administration, we had to do the necessary toxicology
in the rat and the dog, giving the drug deliberately to the dogs
every day for 14 days. We found an adverse effect on the lung
at a very high dose. That allowed us to determine how much we
could safely give to normal, healthy people. I was one of the
first people to take it. When we increased the dosage, we got
no adverse effects in the human lung. When we eventually reached
a high dose and started to see the same things which we had seen
in the animals, we knew then to stop. That allowed us very safely
and with confidence to go into a patient population with much
more sensitive airways. We think these tests are scientifically
necessary in order to not take the risk of, in this case, going
straight to the patient and asking them to be your guinea pig.
(Dr Matfield) If I may respond to the second part
of the question: are there any animal experiments for regulatory
toxicity testing we consider unnecessary? There are two fairly
well known examples of this, discussed frequently in the pharmaceutical
industry and amongst scientists. The first is what we call harmonisation.
Different countries often have significantly different testing
requirements to get approval for drugs to be prescribed to patients
in that country. A country may say they only want to test it against
the risk of causing cancer for one year in rodents or two years
in rodents and so forth. There is a danger that if every country
was just allowed to have all these different requirements, there
would have to be a new set of tests for every different country
where the drug was to be given to patients. To get around that
problem, there has been a major project by the pharmaceutical
industry and the international regulators for many years now on
international harmonisation of these requirements. The ultimate
goal, which is still some way off, would be one set of testing
requirements that, could be sufficient for regulatory approval
in every country. However, I think it has been estimated at the
last International Harmonisation Conference that the number of
animals has already been reduced in regulatory testing by something
like 50 per cent for some classes of medicine. The second example
that comes to mind is what is sometimes called the "tick
box" approach to regulatory testing. An immediate example
here is a recent proposal by the European Commission that all
the chemicals in industrial use which are produced at a high volume
but have not had adequate toxicity testing should be retested.
There has been a high degree of concern about this because it
appears that this would involve a great number of animal experiments.
An argument has been made against the tick box approachthat
being the idea that every test should be done for every chemical.
If you apply a bit of scientific thinking to this, you find that
a lot of these chemicals have been in routine exposure to humans
for a long time, and we have some good human exposure data about
their toxicity. Other chemicals may be produced in high volume
but are they ever exposed to humans? It turns out that some have
not. By using a more scientific, analytical approach to toxicity
testing and not just the tick box approach, there is potential
to substantially reduce the requirement for animal testing. I
believe this point is currently being put by scientists and some
of the Member States to the European Commission.
Earl of Onslow
893. Let us assume that you do a toxicity test
and it does not have any poisonous effect on the dog. What happens
then? Is it there for another test later on?
(Dr Matfield) Most certainly not.
894. It has to be bumped off even if it has
not been poisoned?
(Dr Matfield) The principle is that animals should
not be reused in experiments. There are very limited exceptions
allowed by the Home Office, where it is clear that reuse would
produce overall less deficit to animal welfare. In the case of
regulatory toxicity testing, for many tests, the only way you
can get an indication about whether there has been, for example,
early stage tissue damage is at autopsy. It is a necessary part
of the experiment. There is another mandatory requirement which
is if an animal in an experiment has undergone anything which
might leave it with lasting harm it must be put down at the end
of the experiment, just in case. The whole principle is you do
not allow a continuing welfare deficit.
Lord Hunt of Chesterton
895. The question is about regulatory toxicity
testing but we did have a very candid reply earlier on from somebody
who was talking about the commercial aspect of it. Obviously,
companies do not want to tell everybody what they are all doing
and therefore the argument was that, because medicine progresses
through commercial competition, it does mean that one has a level
of duplication of animal testing as part of that process. Would
you like to comment?
(Dr Matfield) That is a common misconception. Any
duplication would be extremely unusual because all pharmaceutical
companies work on different compounds. They patent them at a very
early stage to prevent competitors working on the same compounds.
Although they may be in a similar drug class, they are different
pharmacological compounds being tested. It is not duplication.
(Professor Page) By definition, if you own a composition
of matter patent, you own that chemical class. If another company
is doing experiments with another chemical class, there is not
duplication. They may have a similar biological effect or pharmacological
effects but they are, by definition, different.
896. The answer given before was that the market
almost imposes duplication of animal testing and you are saying
the market reduces duplication for the reasons you have given.
(Dr Matfield) I find that a surprising answer that
you were given earlier.
897. We will sift through that later. I wonder
if the AMRC team would like to begin on this question: are there
any animal experiments you would consider unjustified, whatever
the likely benefits to human health, or not?
(Dr Layward) The way in which we would consider animal
experiments to be unjustified is if they did not fulfil the three
Rs: replacement, refinement and reduction. It would be unjustified
if we were using a higher animal than was necessary in order to
answer a particular question. It would also be unjustified if
the answer could be obtained using another techniquein
other words, replacementif you could answer the same thing
using cell culture or other techniques that did not involve animals.
Thirdly, it would be unjustified if people were using excessive
numbers of animalsin other words, if fewer animals could
be usedand also if there could be a less stressing intervention,
if you were using an intervention that was highly stressing and
there was an alternative that was less stressing. Under those
conditions, animal experiments would be considered to be unjustified.
898. Would there be any other considerations?
Leaving aside the three Rs, and particularly the numbers of animals,
supposing you could use a fairly small number of animals but the
nature of the procedure was to cause the animal intense pain or
suffering. Would there be any cases where, on the cost benefit
analysis, the cost would be too great?
(Dr Matfield) Yes; any such research purpose would
have to have the potential to provide quite important information.
There is a principle under the 1986 Act that severe and lasting
pain which cannot be alleviated is simply not allowed. Severe
pain of the type you are talking about would only be permitted
if there were some very substantial benefit to come out of the
899. Such as findings about the nature of pain
and so on?
(Dr Matfield) My understanding of pain research is
that there is usually no need to inflict overt pain on animals.
You can use low levels and measure the nerve response.