House of Lords - Animals In Scientific Procedures

Select Committee on Animals In Scientific Procedures Report

CHAPTER 4: THE EFFICACY OF ANIMAL EXPERIMENTS

4.1 We consider the efficacy of animal experiments in two general areas of use, research and toxicology. Within each area we raise the questions:

Do experiments on animals provide valuable information?
Are there other practicable means of discovering that information which do not use animals?

FUNDAMENTAL AND APPLIED RESEARCH

4.2 Scientists who use animals argue that research involving animals has been vital to the understanding of disease and in the development of possible cures. Research scientists do not solely work on animals, but use animal research as one method among many. Scientists say that they prefer not to use animals, both because of the potential suffering caused to the animals, and also because of the high costs involved in both time and money. Animal use, they argue, continues only where it is absolutely necessary.

4.3 Other witnesses to the Committee argue that animal experimentation as a method for protecting human health is at best flawed, at worst pointless. They consider that, for this purpose, it is inaccurate and often misleading, as results in animals cannot be "read across" to humans. They also claim that non-animal methods have not been as well-funded as animal research, so the relative efficacy of the two approaches has not been fairly tested. They argue that animal research continues only because it has always been done, and scientists have had to conform to this expectation or risk being isolated.

4.4 The main criticisms levelled against the use of animals in research are:

research on animals is unethical. Harm should not be caused to any animal unless it is for the ultimate benefit of that particular animal;

research on animals is ineffective. Diseases manifest themselves in different ways in animals than in humans. New compounds (for example, new pharmaceutical products) may be beneficial to certain animals, but have no effect on humans. Similarly, compounds which might have been beneficial to humans have in the past been ruled out because they have produced negative results in animals;[67]
animal research is harmful to human health, because it diverts money away from non-animal research, and some drugs have serious side-effects which are not discovered until the drug is administered to patients. A number of witnesses argued that animal research provides misleading information, and is responsible for the growing trend in drug-related doctor-induced illness ("iatrogenesis");[68]
there is a record of failure in modelling disease. Induced conditions, such as artificially induced Parkinson's Disease caused by chemical or physical lesions in the brains of mice, are not good models of naturally occurring conditions.[69] Equally, drugs which have been effective in combating stroke in animals have been ineffective in humans;[70]
some animal research is trivial;[71] some is used to develop products which duplicate existing ones;[72] and some is of little relevance —retrospective analyses show that some animal research is never cited in the literature;[73]
animal use continues largely through habit, scientific inertia, and the availability of funding from pharmaceutical companies and research councils. If the same amount of money and intellectual effort had been invested in non-animal methods over the years, scientists would have discovered similarly effective drugs.

4.5 Scientists and industry have countered that animal research is effective. The Department of Health, which spends approximately £6 billion each year on pharmaceuticals, asserts unequivocally that:

"Properly regulated animal research is absolutely essential to the discovery of new treatments as well as to the assessment of safety and efficacy of medicines".[74]

4.6 In particular those in favour of animal research argue that:

animals are used to develop an understanding of normal, healthy biological systems;
animals are used as models for humans.[75] Animal research helps scientists to understand the mechanisms of diseases and compounds, as well as their specific effects. Humans would of course be better models and human volunteers are always used in later stages during clinical trials. Experimenting on humans at the early stages of drug development is unacceptable, so the best available models — animals — should be used instead;
many mammals are physiologically very similar to humans: they have similar vital organs — brain, heart, lungs, liver, kidneys — and process toxins in the liver in similar, though not identical, ways. General scientific opinion argues that "similarities in mammalian physiology are such as to justify limited extrapolation across species."[76] For example, work on new forms of oral contraceptives can be undertaken on rodents or sheep, as the pituitary gland, which is responsible for the release of reproductive hormones, is similar in all mammals including humans;[77]
the usefulness of animal models is illustrated by the similarity of the veterinary and human pharmacopoeias, and the same drugs are often used to treat the same diseases;[78]
research on animals is often carried out for the overall benefit of other animals;
animals are required for the manufacture of each batch of certain medical preparations. It is not simply a question of using animals for the initial research phase. In particular, there are a number of vaccines, including the polio vaccine, where each new batch needs to be tested on animals to ensure efficacy and safety;[79]
the unpredictable nature of discovery reinforces the need for fundamental research, as well as applied research closely targeted to specific diseases: new discoveries, though sometimes unforeseen, are the result of carrying out "good science" in a particular research field;[80]
animal research is needed because systemic effects can be investigated only in whole body systems. Scientists agree that research in vitro is, where possible, preferable, as experimental conditions can be more easily controlled, and the results are more repeatable and reliable. But such research can only examine certain effects of a drug on a particular type of cell. To understand how different organs in the body interact under the effects of a drug, a whole organism — an animal — is needed; and
animal experiments continue to be used because they have produced, and continue to produce, extensive and beneficial advances in science: "Virtually every medical achievement of the last century has depended directly or indirectly on research in animals".[81]

4.7 Research scientists argue that there are already strong incentives to use non-animal methods. They are sensitive about subjecting animals to scientific procedures. Animal experiments are expensive compared to in vitro alternatives, while using non-animal methods involves less bureaucracy and avoids the delays associated with the current licensing system. Scientists recognise that animal models are more variable than in vitro models. Scientists therefore say that they have every incentive not to use animals where possible.

4.8 On balance, we are convinced that experiments on animals have contributed greatly to scientific advances, both for human medicine and for animal health. Animal experimentation is a valuable research method which has proved itself over time.

4.9 What cannot be ascertained, however, is whether many of these advances could have been made by other methods. We have been told that certain procedures and approaches which use animals, and which can subject them to considerable suffering, have been pursued over long periods of time with apparently limited success.[82] It seems to us that non-animal methods have not always been given sufficient consideration.

4.10 There is no doubt that considerable reduction in the use of animals has taken place. Nearly a million fewer animals were used in scientific procedures in 2000 than were used in 1987, just after the 1986 Act was introduced.[83] Since the introduction of the Act a "culture of care" has been established.[84] In the last 15 years great progress has been made in the introduction of non-animal methods. Since 1995, procedures for toxicological testing have fallen by nearly one third.[85] The internet has made the retrieval of relevant data far easier. Replacement methods have been developed in fields such as computer modelling (in silico methods) and in vitro assessment, while refinements have been developed in areas such as the establishment of humane endpoints and telemetrics.[86] Reduction in the number of animals used has been achieved through better statistical training and better experimental design. The acute oral LD50 test has been largely replaced by the Fixed Dose Procedure, leading to a reduction in animal use.[87] Refinement methods, including the better understanding and application of humane endpoints, are now routinely used. Scientists have led this great improvement in animal welfare, but new methods rapidly become the standard methods, such that it is soon forgotten that any improvement has taken place.[88]

4.11 Like members of any profession, scientists become accustomed to particular methods of working. Animal experimentation is such a standard part of fundamental biological research that it might be hard for an individual to gain recognition and funding if he or she persisted in using only non-animal methods.

4.12 Scientific status also derives from discovering the new. Lord Sainsbury, the DTI Minister, said that scientists were motivated primarily by discovery (Q. 1699). Replacements, refinements and reductions are not discoveries of the kind for which scientists generally strive. The status of those who work to develop replacements or refinements to animal experiments is questionable.[89] There are, for example, no specific university posts in the Three Rs. The Home Office Minister, Angela Eagle, speaking of the development of reductions, refinements and replacements, said, "I do not get the impression…that it is one of the most exciting and sought after areas of scientific endeavour" (Q. 538). The development and use of non-animal methods has always taken place, but it has had a low profile. We consider that there is merit in providing additional impetus for the development and use of the Three Rs.

4.13 In considering the use of animals in fundamental research, we have therefore reached two basic conclusions.

4.14 There is at present a continued need for animal experiments both in applied research, and in research aimed purely at extending knowledge.

4.15 There is scope for the scientific community to give a greater priority to the development of non-animal methods, and more consideration could be given to the pursuit of the Three Rs.

TOXICOLOGICAL RESEARCH[90]

4.16 In toxicology, in vivo tests (tests carried out in live animals) form only part of a complex process of risk assessment that takes account of other sources of information, including analysis of chemical structure and in vitro tests. The purpose of toxicological risk assessment is to evaluate the likelihood of harmful effects resulting from exposure to specific doses or concentrations of particular chemicals, and thus to inform the risk management process (actions such as prohibition of the use of a chemical, the specification of maximum recommended doses, or the provision of advice on safety precautions).

4.17 In the development of new pharmaceutical compounds, testing in animals is similarly only one stage of a much larger process. Pharmaceutical companies have told us that, of half a million compounds initially considered, preclinical lead optimisation screening (selecting the most likely candidate compounds using in vitro and in silico methods) reduced the number tested in animals to ten.[91] Of this ten, seven were rejected, three went on to clinical trials in humans, and just one would eventually be released onto the market.

4.18 Many of those opposed to the use of animal experiments were particularly critical of in vivo toxicological tests. Their principal arguments were:

species differences mean that tests in animals are inapplicable to humans. Aspirin, for example, is a teratogen[92] in many animals, but not in humans.[93] Aspirin also has beneficial effects in humans (for example, in helping to prevent strokes) which are not reproduced in animals.;
animal-based toxicology has failed to protect human health. Adverse drug reactions have risen 10-fold between 1990 and 2000.[94] Some witnesses cited the thalidomide tragedy as an example of the failure of in vivo toxicity testing;
tests on new drugs which are shown to be toxic in animals are sometimes later or concurrently carried out in humans anyway, so why are the tests done in animals in the first instance?[95] Animal tests are done in order to give legal protection to pharmaceutical companies if their products are later found to be toxic;
many new drugs are "me too" drugs — versions of drugs which are already on the market. Animals should not be used to test drugs which are not medically necessary, but simply aim to provide profits for pharmaceutical companies;
regulators are too inflexible — toxicity assessments should not be carried out on a "tick the box" approach. Not enough use is made of existing data from humans and animals, and many substances have an extensive history of use which should be taken into account when assessing toxicity. The EU Chemicals White Paper, which proposes to back-test many thousands of chemicals, would require millions of unnecessary animal deaths in order to satisfy regulators, rather than to improve safety standards;
the validation requirements for non-animal tests are in marked contrast to the almost total lack of formal validation of animal test methods.[96] Standards of validation required by regulatory bodies for new non-animal tests are more stringent than the standards of validation required for animal tests. Results from animal methods are still held to trump results from other methods.

4.19 Scientists argue that the use of two species and the existence of historical data enable toxicologists to use animal tests to contribute to the overall assessment of hazard. All our witnesses agreed that in vivo toxicological tests were imperfect; scientists argued that despite their imperfections, animal tests are often still the best available. In particular, scientists argued that:

the whole toxicological process, taking into account known species differences, and allowing for variation within species, can provide an acceptably accurate assessment of what level of dose of a given compound is likely to be safe;
in vivo toxicology is necessary to obtain whole organism toxicity responses, rather than the responses of individual cell-types which can be assessed in vitro;[97]
poisons in humans are processed by the liver, and the liver is where most adverse effects are found. Scientists, however, cannot yet artificially replicate the functions of the liver, and are currently left with no choice but to continue to use animals in toxicological testing where liver function is important.[98]
the use of two species in a toxicological assessment is a compromise which provides some reassurance that important toxic effects have not been missed. The two most commonly used species, the rat and the beagle, are well calibrated models — so much research has been carried out in the past that similarities and differences between them and humans can be assessed with a reasonable degree of confidence;
doses given to test animals are at a much higher level than those given to human patients, in order to allow for both inter-species and intra-species variation;
the thalidomide tragedy in the UK occurred because the animal testing was incomplete. More extensive testing on pregnant rabbits, as was done in the US where the drug was not licensed, revealed the devastating side effects;[99]
improvements in toxicology are taking place all the time. Increased use is made of: in vitro methods;[100] computer modelling;[101] and data extracted from human and animal patients.[102] All these non-animal methods are used wherever possible, especially for the preliminary screening of drugs. In many cases, though not all, animal toxicity tests "provide valuable information, not available from any other source, for assessing human health effects";[103]
adverse drug reactions are usually the result of poor prescribing practice and over-dosing. Rare effects, in a small sub-group of the human population, are very difficult to predict using laboratory tests, or even using clinical trials in humans.

4.20 The scientific position was summarised by Dr Robert Coleman:

"we have a moral and a legal obligation with new compounds to do our very best to ensure that anybody who takes them is not going to come to harm. Part of that process is testing in animals and if we get it wrong, we get it wrong, but more often than not we will get some information that will be valuable to us. Some compounds slip through the net. I do not really see how we can overcome it. It does not mean to say that [animal testing] does not have a value." (Q. 1574)

4.21 The effectiveness of in vivo toxicity tests is difficult to assess, due to the ethical constraints on testing chemicals in human subjects which have shown adverse findings in animals. Only in the case of pharmaceutical substances, administered in doses judged to be safe, or after accidental exposure to chemicals, can the results of animal tests be checked against actual human experience.

4.22 The scientifically most valid method for assessing toxicology, as all our witnesses agreed, would be to test directly in humans — but this could involve an unacceptable risk to those involved, and it is said that insufficient volunteers would be forthcoming.[104]

4.23 Recently, the International Life Sciences Institute (ILSI) undertook a study of a series of pharmaceutical compounds that had shown toxicity in human clinical trials.[105] This study found that in 71% of cases, the effects seen in people were foreshadowed in the animal tests carried out prior to the clinical trials. Moreover the efficacy of the animal tests for the direct purposes for which they were intended was still higher. Of the 29% of effects not detected in animal tests, the majority were of a type that the animal tests were not designed to detect, or were intrinsically undetectable in this type of test, for example, headache, dizziness, and certain skin reactions.

4.24 The Department of Health argue that the current system has proved itself through use: "the current test battery, based on a mixture of in vitro and in vivo tests, has been shown to be extremely effective in terms of predicting human toxic responses".[106]

4.25 We consider that toxicological testing in animals is at present essential for medical practice and the protection of consumers and the enviroment, as it often provides information that is not currently available from any other source.

THE DEVELOPMENT OF NON-ANIMAL TOXICOLOGICAL TESTS

4.26 The current system of toxicological testing may be effective in most instances, but there is little doubt that it could be improved. About two thirds of the compounds which are approved for clinical trials in humans are not subsequently licensed for general use. Of those drugs which do make it to market, some are subsequently withdrawn when previously undiscovered toxic effects come to light. It has been argued that the toxicity of at least some of these compounds could have been determined by better use of in vitro methods (Q. 1568).

4.27 The science underpinning the current system is also unsophisticated. The dose shown to be safe in animals, the "No Adverse Effect Level", is typically divided by 10 to take account of differences between animals and humans, and by 10 again to take account of differences in individual susceptibility.[107] These factors are highly approximate, and Professor Purchase observes that "the current default value for one component of the 'interspecies' factor may be too small".[108]

4.28 Dr Gill Langley, of the Dr Hadwen Trust, argued that many of the standard toxicological animal tests have never undergone formal validation, or have failed retrospective validation.[109] Professor Combes, from FRAME (Fund for the Replacement of Animals in Medical Experiments) was particularly critical of the carcinogenicity bioassay (Q. 458). In giving oral evidence with the Department of Health, Sir John Pattison acknowledged that "There is a dearth of research in this area" (Q. 1485). All sides of the debate on the use of animals acknowledge that there are problems with animal toxicity testing.

4.29 Partly for this reason, and partly because toxicology assesses clearly defined end-points, greater progress has been made in finding non-animal methods in toxicity than in pure or applied research (Q. 459). The European Centre for the Validation of Alternative Methods (ECVAM), is shortly to publish a report on "Alternative (non-animal) methods for chemicals testing: current status and future prospects".[110] While progress has been made, the Minister, Angela Eagle MP, warned that "the easy ways of replacing animal use have been attained already" (Q. 540).[111]

4.30 The development of replacement tests for existing animal tests is difficult. The problem was explained by Herman Koeter of the OECD.[112] He said that toxicological assessment was like a jigsaw puzzle, with many different tests all interlocking. Replacing individual tests was difficult, and unlikely to result in the saving of many animal lives. What was needed was not the gradual replacement of individual pieces of the jigsaw, but a whole new system of toxicology — a paradigm shift of significant magnitude.

4.31 We recognise that this is a difficult process. Angela Eagle said that "We are at the stage where it is much harder to see how some of the experiments currently being done could be replaced but that does not mean that some of our most creative, finest scientific brains out there ought not to turn their minds to it" (Q. 540). We agree.

4.32 During the conference we held in the House of Lords on 21st May 2002, delegates considered that the replacement of 90% of animal experiments in toxicology would take at least 20 years.[113] The development of non-animal toxicological methods therefore needs sustained investment and research over a period of time. Any serious undertaking to develop non-animal tests needs substantial Government backing, and a sustained and co-ordinated, international effort.

4.33 We consider that the development of scientifically valid non-animal systems of research and testing is important, not just to improve animal welfare, but to provide substantial benefits for human health.

TOXICOLOGY AND THE LAW

4.34 Many toxicological tests are required by law.[114] In the UK, the Medicines Control Agency demands proof of safety before it will license a new drug. Similarly, the Health and Safety Executive demands the toxicological assessment of industrial chemicals and various other products, which requires information "some of which can only be obtained from animal testing".[115]

4.35 Regulations on toxicity testing for new compounds have now largely been harmonised internationally. This is clearly beneficial in terms of animal use. For example, instead of three very similar sets of tests being carried out for a new drug to be licensed in the European Union, the United States and Japan, only one set of tests needs to be carried out which is accepted by the regulatory authorities in all three jurisdictions.

4.36 For new drugs and medicines, the harmonisation body is the ICH — the International Conference on Harmonisation. There are four members — regulators from the US, from Japan, and from the European Union, and representatives from the global pharmaceutical industry. Better harmonisation has already led to a reduction in animal use (Q. 892), and the ICH plays "an important quasi-legal role in drug development".[116]

4.37 For new chemical compounds, the harmonisation body is the OECD — the Organisation for Economic Co-operation and Development. There are 39 member states. Adoption of non-animal toxicological tests is slow, as the OECD requires consensus from all member states before new test guidelines are adopted.[117]

4.38 It is important for regulatory authorities to keep abreast of technological developments, and to be aware of new non-animal testing methods which these may allow. We recognise that decisions on whether individual animal tests can be replaced or refined cannot be taken unilaterally by the UK Government, but there appears to be no reason why the UK Government should not take the initiative for moving the agenda forward.

4.39 One area where the Government could take the initiative is in welfare standards in toxicological testing. Currently, rats involved in many toxicological experiments are kept in wire-bottomed cages. These are easier to clean than solid-bottomed cages, and the lack of nesting material means that no extraneous substances can interfere with the test. Such cages potentially have a welfare cost, as rats not only have no nesting material, but the wire floor can cause prolonged physical discomfort. It is possible that these wire-bottomed cages seriously compromise the welfare of hundreds of thousands of animals each year. We learnt from the Organisation for Economic Co-operation and Development that no government had yet even asked the OECD to consider including in OECD Test Guidelines the recommendation to use solid-bottomed cages, nesting materials, and other relatively uncontroversial environmental enrichments.

4.40 We recommend that the Government should take greater steps to promote the adoption of replacements and the incorporation of refinements into animal test guidelines issued by the International Conference on Harmonisation and the Organisation for Economic Cooperation and Development.

4.41 A number of witnesses have highlighted the importance of the need for co-ordinated international action has been highlighted by the recent European Commission White Paper, Strategy for a future Chemicals Policy.[118] This proposes carrying out toxicity tests on thousands of chemicals which have been in use for some time. The Institute for Environment and Health, in a report prepared for the DTI in April 2001, estimated that at least 12 million vertebrates would be required for the testing proposed.[119]

4.42 The White Paper on Chemicals has already been the subject of an Inquiry by the House of Lords European Union Select Committee.[120] We note and endorse their conclusion relating to animal testing that "the very success of any chemicals strategy depends on the public being reassured that a serious effort is being made to develop alternatives to animal testing" (para. 191).

4.43 We also consider that there is very little political will to reduce the need for animals in toxicology. At the European level, the funding for ECVAM is under constant pressure.[121] In the United Kingdom, our questioning of different Government departments has revealed that no department is prepared to take responsibility for the issue of animals in science in general, and for the need for animals in toxicology in particular. We therefore note and endorse the further observation of the House of Lords European Union Select Committee that "there is a lack of resources and of political will in the EU to bring non-animal tests into use" (para. 197).

4.44 The Government and the scientific community should engage in a systematic and visible search for methods involving the Three Rs in toxicology. The Government should nominate one department to take the lead on this.

4.45 The UK Government should use their influence to urge the EU to make the development and validation of replacements for animal experiments a priority, particularly in toxicology.

POTENTIAL OF DEVELOPING TECHNOLOGIES

4.46 There is considerable potential for companies specialising in the Three Rs. We have taken evidence from Dr Robert Coleman, the Director of Pharmagene in the UK, and have met Dr Paul Silber, the Director of In Vitro Technologies in the US. Both companies illustrate the commercial potential for non-animal technologies, particularly in screening compounds in the relatively early stages of drug development.

4.47 Dr Coleman said that there were problems with the availability of human tissue for use in in vitro studies.[122] It is important that the events at Bristol Royal Infirmary and Alder Hey do not provoke a reaction which prevents the provision of human tissues to appropriate companies.

4.48 We also note that recent developments in computer modelling in the UK have potential for use in toxicology. The Food and Drug Administration in the United States is in discussions about how a particular computer model can be incorporated into current regulation.[123] Such replacement technologies are likely to be increasingly important in the future. In parts of Europe, there is a move away from animal-based research, particularly in toxicology. The UK should act now to be in the forefront of new developments.

4.49 The promotion of the commercial advantages of the Three Rs needs a clear lead from a nominated department within Government.

67 The point that animals are different from humans and that the results of the research on animals are therefore not applicable to humans is made by almost every opponent of vivisection, including the BUAV, the NAVS, PETA, Professor Vernon Coleman, Doctors and Lawyers for Responsible Medicine and many members of the public who submitted written evidence. Back

68 Professor Vernon Coleman (Q. 1276) and Doctors and Lawyers for Responsible Medicine (Qs 1721-24). See also paragraph 4.17. Back

69 BUAV (p. 89). The MRC disagree (p. 221), as do the Parkinson's Disease Society of the UK (p. 251). Back

70 FRAME and Dr Hadwen Trust (Q. 462). Professor Rothwell said that a treatment for stroke had been developed (Q. 651), but this statement was criticised by Dr Pandora Pound (p. 317). Back

71 The BUAV cite the development of sucralose (p. 98). Back

72 BUAV (p. 81). Back

73 PETA (p. 255). Back

74 DoH (p. 163). Back

75 See in particular Dr Michael Festing, 'The Use of Animals as Models of Humans in Biomedical Research', (p. 140). Back

76 Mr Smith, Royal Veterinary College (Q. 1752). Back

77 Goodman, S. & Check, E. 'The great primate debate', Nature, vol. 417 (2002), 684-87; see also the Society for the Study of Fertility (p. 321). Back