Ethics of Research involving animals
Other issues - continuation II
Testing for toxicity
15.81 Current trends in society suggest that there is an increasing intolerance to risk, although some commentators believe we are now over-zealous in testing requirements.45 We described the types of procedures typically undertaken in toxicology research in paragraphs 9.9–9.25. In view of the severity that some toxicity testing can entail, we endorse the recommendation of the House of Lords Select Committee Report on Animals in Scientific Procedures (2002) that ‘the government and the scientific community should engage more in a systematic and visible search for methods involving the Three Rs in toxicology. The Government should nominate one department to take the lead in this.’ We recommend that the Inter-Departmental Group on the Three Rs should coordinate this work.
15.82 With regard to international initiatives the Working Party is concerned about the potential impact of recent EU legislation for new and existing chemicals testing (REACH), which is likely to be implemented by 2006. According to some estimates, had the initial proposal been implemented, up to 12.8 million animals could have been involved for the testing of approximately 30,000 existing chemicals (see Box 9.2).46 The conclusion that the scale of testing and use of animals did not appear to justify the additional protection afforded to society has been widely supported, and discussions about the actual implementation were still in progress at the time of writing. Whatever its final form, REACH will greatly increase animal testing across the EU. While we make no detailed recommendation in this area, it is crucial that new approaches to risk assessment that implement the Three Rs most effectively should be explored, particularly by making maximum use of data sharing (paragraphs 15.68 and 15.70), and using computational and in vitro tissue culture methods where possible.
15.83 There has been particular concern about toxicity testing of what many perceive to be trivial products, such as cosmetics and toiletry products, or medicines which are very similar to those already on the market.47 All members of the Working Party who, in principle, can accept some forms of research involving animals, agree that unnecessary testing must be avoided. However, they were not able to agree on specific recommendations because it is not always straightforward to define a trivial use or a form of unnecessary testing. In the case of medicines, improvements are sometimes made in small increments, and although new medicines may differ only slightly from products already marketed, they may in fact be safer or more effective for particular people (see paragraphs 3.13 and 14.40). In the case of cosmetics or toiletry products there is the possibility that some people have sensitivities or allergies towards ingredients such as colorants which different manufacturers use in addition to the active ingredient. Some would therefore argue that a range of apparently identical products can be justified, since the different compositions help to take into account the variability in sensitivities among different people.
The international context of animal research
Problems in harmonising international test guidelines
15.84 Many tests involving animals are conducted to provide safety or efficacy data for regulatory authorities, in compliance with national or international legislation (see paragraphs 9.4 and 13.49–13.52). Thus, if various authorities require testing to be carried out using different study designs, a single chemical that is marketed in a number of countries might need to be tested several times. Harmonisation of test guidelines, so that a single study design is acceptable to regulatory authorities in many countries, is a very valuable means of reducing the use of animals in safety and efficacy testing. The ICH has managed to improve mutual acceptance for the pharmaceutical industry, but much still needs to be done to extend this approach to other product areas.
15.85 In theory, the adoption of guidelines on toxicity testing by the OECD should allow national or supranational regulatory authorities (such as the EPA (Environmental Protection Agency) or FDA (Food and Drug Administration) in the USA, or the European Commission) to incorporate them with minimal change into their own testing requirements. But in practice this has not always been the case. While, the European Commission incorporated new in vitro methods for skin corrosivity more than a year before their final review and approval by the OECD, the EPA made changes to the protocols for the three new in vivo methods for acute oral toxicity and also to a new OECD-approved in vivo method for predicting skin sensitisation (the mouse local lymph node assay). Thus, the EPA delayed acceptance for some time after their adoption by OECD and, in addition, the EPA’s requirements for acute oral toxicity and skin sensitisation are no longer harmonised with those of other OECD Member States.
15.86 The lack of stringent international harmonisation poses problems. In the UK, the Home Office may only grant a project licence for safety assessment according to the use of procedures that are less severe to the animals involved than those described in a relevant OECD test guideline. This approach means that any company intending to register a product such as an agrochemical formulation in the USA is unable to conduct in the UK a substantial number of the tests required by the EPA. In addition, as most companies have policies for animal welfare that encourage the conduct of a single set of safety tests for global registration, the more severe protocols required by the EPA48 are usually used and, in the case of UK-based companies, some or all of the testing has to be exported to other countries. There are many other examples of individual countries having different safety requirements.49 Increased efforts must be made to standardise and harmonise testing requirements, in order to ensure that the minimum number of animals is used at the global level. We therefore recommend that the UK through its National Coordinators at the OECD makes it a priority to identify areas in which harmonisation continues to be difficult and initiates steps to increase adoption of scientifically valid protocols that entail the least adverse welfare costs to the animals involved. We also note that under the Inter- Departmental Concordat on data sharing, regulatory authorities aim to ‘press for agreement on behalf of the UK Government for fullest provisions and procedures which enable data sharing when negotiating, updating and transposing relevant European Directives and when taking part in other international harmonisation processes’. In order to support the proposed initiative by the National Coordinators at the OECD, we recommend that the UK Inter-Departmental Group on the Three Rs should produce or commission a report on cases where less severe protocols are not recognised internationally, whether for scientific or other reasons, and make suggestions for improving acceptance.
15.87 International guidelines also have a crucial role with regard to welfare standards of animals involved in research. There is evidence that relevant OECD guidelines do not use important concepts such as what defines a maximum tolerated dose, severe distress, obvious pain or a moribund condition consistently (paragraph 9.35).50 Several of the existing OECD test guidelines could also be improved with regard to issues such as environmental enrichment, and conditions of housing, as, for example, some do not specify the requirement for group housing where this would be possible.51 All these factors can act as potential sources of avoidable suffering for the animals, and we recommend that the OECD reviews and revises relevant guidelines to achieve greater consistency and to contribute to a wider application of the Three Rs in view of current knowledge.
UK researchers commissioning or undertaking research abroad
15.88 There are a number of scientific, Three R-related and logistical reasons why researchers may collaborate with overseas scientists, outsource research work or obtain animals or animal-derived products (such as monoclonal antibodies) from other countries. This interaction can provide a useful means of disseminating good practice developed within the UK. But there is also a need to ensure that the international nature of research is not used to introduce double standards. We note the position statement by the Wellcome Trust, which, as a general rule, we endorse: ‘International research supported by the Trust is expected to be carried out in the spirit of the UK legislation as well as being compliant with all local legislation and ethical review
procedures.’52
15.89 Further to the requirement implied in this statement, some members of the Working Party would like to see formal provisions in place which ensure that research and testing, both nationally and internationally, are always carried out in accordance with the least-severe protocols, in order to minimise harm to animals used in research. They would also welcome the introduction of regulations that would prevent UK researchers from importing or outsourcing research or research products that it would not be possible to obtain in the UK.
Since the extent to which this may be occurring is uncertain, they would like to recommend that Ministers request the APC to undertake a systematic study to clarify the matter, exploring perhaps also whether a system of certification or voluntary codes of conduct would be suitable devices to ensure that UK-based researchers adhere to the same standards abroad as in the UK. From their point of view, whenever UK researchers are involved in international collaborations they should seek to adopt protocols that meet the highest international standards of best practice. As a minimum they should meet UK requirements, which in most cases are likely to be stricter than those of other countries. The group would also like to recommend that multinational companies that undertake part of their research in the UK should enforce a single global policy on animal care and welfare that meets the highest international standards of best practice.
15.90 However, other members of the group, while welcoming the aspiration behind such proposals, have reservations about their appropriateness and feasibility. They argue that because of the differences in regulatory systems it would be very complicated to ensure that research facilities abroad, or products sourced from outside of the UK met with Home Office approval. If such approval could not be attained, there would be a risk that research and testing facilities in the UK would be disadvantaged, since the exchange of products such as antisera, passaged tumours or GM lines is crucial to collaboration in fundamental research. Accordingly, they do not see a need to recommend that the APC be asked to undertake a study to advance the debate. Similarly they point out that practical problems may prevent multinational companies from implementing a single harmonised policy on animal care and welfare, both in the medium and long term.
15.91 Members also briefly discussed, but were not able to agree on, the question of whether UKbased research might be driven abroad because of the current, or likely future, regulatory provisions and practice. During our fact-finding meetings and discussions we heard conflicting evidence about this possibility. Some researchers observed that several research projects, and some laboratories, have been moved abroad while others, more frequently pharmaceutical companies, consider that the attractiveness of scientific talent in the UK generally outweighs any regulatory burdens. A range of views was represented among members of the Working Party, with some agreeing with the evidence presented during the fact-finding meetings, and others disagreeing. The latter group found arguments against regulation unhelpful especially in view of the fact that those wishing to relax regulations often point to the strictness of the regulatory framework in order to allay concerns, for example, by members of the public. Despite these disagreements, all members of the Working Party emphasise that maintaining high standards in the UK has the potential to continue to influence regulations positively elsewhere. At the same time, the provisions of the A(SP)A and their implementation also need to be reviewed regularly in the context of national and international developments in policy and public debate.
Footnotes45 For example, Durodie B (2003) The true cost of precautionary chemicals regulation Risk Anal 23(2): 389–98.
46 Institute for Environment and Health (2001) Testing requirements for proposals under the EC White Paper – Strategy for future
chemicals policy available at: http://www.le.ac.uk/ieh/webpub/webpub.html. Accessed on: 21 Apr 2005.
47 These medicines are sometimes also referred to as me-too medicines.
48 For example, the use of higher dose levels in the acute oral toxicity tests and additional animals in the local lymph node assay.
49 For example, certain non-OECD countries can still demand an LD50 test, and Japan requires additional safety pharmacology
tests (both in vitro and in vivo) of active ingredients for pesticides.
50 Koeter HBWM (1999) The OECD Test Guidelines Programme and animal welfare concern: how to avoid major animal suffering,
in Humane Endpoints in Animal Experiments for Biomedical Research, Hendriksen CFM and Morton DB (Editors) (London: Royal
Society of Medicine Press), pp13–14.
51 Combes RD, Gaunt I and Balls M (2004) A scientific and animal welfare assessment of the OECD health effects test guidelines
for the safety testing of chemicals under the European Union REACH system ATLA 32: 163–208.
52 The Wellcome Trust Policy on the use of animals in medical and veterinary research, available at
http://www.wellcome.ac.uk/doc%5Fwtd002764.html. Accessed on: 21 Apr 2005.