Ethics of Research involving animals
Reduction - continuation I
Harmonisation of international test guidelines
12.7 We have noted that 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 13.48). If different authorities require testing to be carried out using their own specific study designs, a single chemical that is marketed in a number of countries might need to be tested several times for toxic effects. 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 number of animals used in safety and efficacy testing worldwide. Harmonisation has many advantages: it can reduce the need for repeat testing; eliminate the requirement for redundancy in testing (where more than one test provides the same information); minimise group sizes (e.g. by agreement to use a single sex) and lead to the adoption of shortened protocols, reduced animal numbers and less-severe treatments and procedures.
12.8 A relatively high level of harmonisation of test methods for chemicals has been achieved by the Test Guidelines Programme of the OECD. Similarly, in the area of pharmaceuticals, the ICH has achieved a substantial decrease in the numbers of animals used globally in the preclinical safety assessment of new pharmaceuticals (about a 50 percent reduction overall for a typical package of tests).11 Examples of reduction in regulatory testing include:
- As discussed in Chapter 9, the ‘classical’ LD50 test was used for many years to estimate the oral toxicity of a single dose of a chemical (paragraph 9.14). Although a few LD50 tests are still used in some circumstances, widespread and enduring opposition to this test on animal-welfare grounds led to the development of several alternative methods in which fewer animals were dosed, in a stepwise manner.12
- Tiered testing strategies have been employed to reduce the use of animals in several areas of toxicity testing. For example, the irritancy of chemicals for the skin and eye was previously assessed by using rabbits, without any prior testing. The currently recommended procedure involves assessing the chemical properties of the test materials and the use of in vitro methods as a first stage. Assessment of skin irritancy is undertaken before the eye test. Only if none of the previous assessments indicate irritancy is the eye test performed on live rabbits.13
- Vaccines that are produced from living organisms (e.g. viruses and bacterial toxoids) are tested for safety and/or efficacy at a number of points during manufacture, and batches are usually tested more than once to ascertain their efficacy (Box 8.5). These tests involve the use of large numbers of animals, and often involve infecting both vaccinated and unvaccinated animals with the relevant pathogen, leading to severe suffering in some unprotected animals.14 Some of these ‘challenge tests’ for vaccine potency can be replaced with serological methods in which the presence of specific antibodies in the blood of immunised animals is used to demonstrate protection against challenge by the pathogen. A major success of this approach has been the development and validation of serological methods for the potency testing of tetanus vaccines, which have reduced the number of animals required.
- Prompt deletion of obsolete or redundant tests from testing requirements is a high priority for avoiding unnecessary use of animals. For example, tests for abnormal toxicity, which were general tests for adverse effects of vaccines, have been deleted from most monographs of the European Pharmacopoeia. Also, two types of animal test that were previously required for toxicity testing of diphtheria and tetanus vaccines have been eliminated. Substantial reductions in the number of animals used per batch have been achieved by modifications to five other tests on diphtheria, tetanus and pertussis vaccines.15
Footnotes
9 The Group is led by Home Office officials and has members from the Department of Health, the Department for the
Environment, Food and Rural Affairs, the Department of Trade and Industry, the Office of Science and Technology, the Food
Standards Agency, the Health and Safety Executive, the Medicines and Healthcare Products Regulatory Agency and other
agencies. Its terms of reference are ‘to improve the application of the 3Rs and promote research into alternatives, reducing
the need for toxicity testing through better sharing of data, and encouraging the validation and acceptance of alternatives.’
See http://www.homeoffice.gov.uk/docs2/interdept3rs.html. Accessed on: 3 May 2005.
10 Home Office (2002) The Inter-Departmental concordat on data sharing, available at:
http://www.homeoffice.gov.uk/docs/dataconcordat.html. Accessed on: 3 May 2005; see also Animal Procedures Committee (2003) Review of the cost-benefit assessment in the use of animals in research (London: HO), p52-6.
11 The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH) brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration. The purpose is to make recommendations on ways to achieve greater harmonisation in the interpretation and application of technical guidelines and requirements for product registration, in order to reduce the need to duplicate the testing carried out during the research and development of new medicines; Lumley CE and van Cauteren H (1997) Harmonisation of international toxicity testing guidelines for pharmaceuticals: contribution to refinement and reduction in animal use EBRA Bulletin November: 4–9.
12 The Fixed Dose Procedure (FDP) uses approximately one quarter of the animals required by the LD50 test. FDP avoids the
death of the animals as an endpoint, recording signs of "evident toxicity" instead. The Up-and-Down Procedure (UDP) is a
stepwise approach where one animal receives the dose thought to be the best estimate of the LD50 dose. Depending on the
outcome (death/life), the dose for the next animal is adjusted. After reaching the reversal of the initial outcome (i.e. the
point where an increasing or decreasing dose pattern is reversed by giving a smaller or higher dose) four additional animals
receive the dose, to replicate the finding. UDP requires more time than the previous methods and is more expensive, but
uses fewer animals; See Test Guideline No 420: Fixed Dose Method and Test Guideline No 425: Up-and-Down Procedure in
OECD (2001) Guidelines for Testing of Chemicals (Paris: OECD).
13 Guideline 405 Acute eye irritation/corrosion in OECD (2001) Guidelines for Testing of Chemicals (Paris: OECD).
14 Associate Parliamentary Group for Animal Welfare (2005) The use of animals in vaccine testing for humans, available at:
http://www.apgaw.org/userimages/Vaccinetesting.pdf. Accessed on: 9 May 2005.
15 Associate Parliamentary Group for Animal Welfare (2005) The use of animals in vaccine testing for humans, available at:
http://www.apgaw.org/userimages/Vaccinetesting.pdf. Accessed on: 9 May 2005.
16 Refinement is sometimes referred to incorrectly as ‘the refinement of experiments to get more data’. This is clearly an important goal, but it is not an interpretation of Refinement as originally defined in the Three Rs.