Select Committee on Animals In Scientific Procedures Minutes of Evidence

Examination of Witnesses (Questions 880-899)



  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-induced—there 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 benefit assessment.

  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 advance.

Baroness Warnock

  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 used.

  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 end point.

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.

Lord Lucas

  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.

Lord Taverne

  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 examples?
  (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 else?
  (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 approach—that 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 technique—in other words, replacement—if 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 animals—in other words, if fewer animals could be used—and 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.

Baroness Warnock

  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 research.

  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.

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