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T h e e t h i c s o f r e s e a r c h i n v o l v i n g a n i m a l s cases, for example for cosmetics and cosmetic ingredients, testing requirements are not specified in regulations but there is a general requirement for safety, which could be met by the use <strong>of</strong> animal or non-animal tests. National authorities in the EU issue guidance on how the provisions laid out in the Directives should be met, which, due to preferences <strong>of</strong> regulators, usually means that data from established animal tests must be provided. So as to maximise returns, many chemicals are marketed worldwide, and testing must then conform to the requirements <strong>of</strong> other regulatory bodies, particularly those <strong>of</strong> the USA and Japan. 9.4 Current testing regimes have evolved significantly over the past three decades. Existing practices have changed and new methods have been added. A major influence on these developments has been the Test Guidelines Programme <strong>of</strong> the Organisation for Economic Cooperation and Development (OECD), which has developed standardised methods <strong>of</strong> testing that are accepted in principle by all 30 OECD Member Countries 3 through an agreement on the mutual acceptance <strong>of</strong> data. 4 <strong>The</strong> OECD approach has largely removed the need for testing according to different protocols to satisfy regulatory authorities in different countries, and has thus substantially reduced the total number <strong>of</strong> <strong>animals</strong> used for certain standard tests. It also provides a focus for the introduction <strong>of</strong> new methods that replace, reduce or refine animal use. Change and revision have been slow but there are many current initiatives, within both the scientific and regulatory communities, that challenge present practice with the aim <strong>of</strong> providing the same or even better levels <strong>of</strong> human safety while using fewer <strong>animals</strong> (see Box 2.4 and paragraph 11.10). <strong>The</strong> International Conference on Harmonisation <strong>of</strong> Technical Requirements for Registration <strong>of</strong> Pharmaceuticals for Human Use (ICH) also seeks to standardise the approach to testing <strong>of</strong> pharmaceuticals (see paragraphs 12.8, 13.50 and 15.84). Box 9.2: <strong>The</strong> EU REACH Initiative: Registration, Evaluation and Authorisation <strong>of</strong> Chemicals Registration, Evaluation and Authorisation <strong>of</strong> Chemicals (REACH) refers to the new EU regulatory framework for chemicals proposed by the EC in October 2003. At the time <strong>of</strong> writing, the proposal is being considered by the European Parliament and the <strong>Council</strong> <strong>of</strong> the EU. <strong>The</strong> legislation is intended to bring 30,000 chemicals manufactured within or imported into the EU under a single regulatory regime. REACH aims to make manufacturers responsible for the chemicals that they produce and to make it easier for highly toxic chemicals to be removed from the market. Under the new system, businesses that manufacture or import more than one tonne <strong>of</strong> a chemical substance each year would be required to register it in a central database.* <strong>The</strong> European Commission has stated that new legislation is necessary due to the inadequacy <strong>of</strong> the current legislative framework for chemicals. A particular problem concerns the arbitrary cut-<strong>of</strong>f date in 1981, which provides the distinction between ‘new’ and ‘existing’ chemicals. At present, ‘new’ chemicals that have been placed on the market after 1981 must be tested if their production exceeds 10 kg per year, whereas there are no such provisions for ‘existing’ chemicals. <strong>The</strong>refore, it is argued, the current legislation encourages the continued use <strong>of</strong> untested existing chemicals because it is easier and cheaper.† REACH has proved controversial, not least because its requirements will result in a substantial increase in the number <strong>of</strong> animal experiments. Many chemicals have been in use for decades and there is concern that some tests may duplicate those already performed by private companies. <strong>The</strong> UK Government is advocating a policy <strong>of</strong> ‘one substance-one Registration’, as a means <strong>of</strong> minimising animal testing and reducing costs and bureaucracy. This means that companies would be required by law to share data on tested substances, in the hope that universally available data will avoid duplicate testing <strong>of</strong> that substance.‡ * See EC Enterprise and Industry (2005) <strong>The</strong> New EU Chemicals Legislation – REACH, available at: http://europa.eu.int/comm/enterprise/reach/overview.htm.. Accessed on: 3 May 2005. † EC (2003) Q and A on the new chemicals policy REACH, available at: http://europa.eu.int/rapid/pressReleasesAction.do? reference=MEMO/03/213&format=HTML&aged=0&language= EN&guiLanguage=en. Accessed on: 27 Apr 2005. ‡ See House <strong>of</strong> Commons Science and Technology Committee (2004) Within REACH: <strong>The</strong> EU’s New Chemicals Strategy (London: TSO), available at: http://www.publications.parliament.uk/pa/cm200304/ cmselect/cmsctech/172/172.pdf. Accessed on: 3 May 2005. 3 Member Countries include the UK and other European Countries, Japan and the USA, a list is available at: http://www.oecd.org/document/58/0,2340,en_2649_201185_1889402_1_1_1_1,00.html. Accessed on: 26 Apr 2005. 4 OECD (2001) Mutual Acceptance <strong>of</strong> Data (MAD), available at http://www.oecd.org/document/41/0,2340,en_2649_201185_1890473_1_1_1_1,00.html. Accessed on: 26 Apr 2005. 156
T h e e t h i c s o f r e s e a r c h i n v o l v i n g a n i m a l s 9.5 Toxicity has two main components: the effect caused and the level <strong>of</strong> exposure (dose) at which the effect is observed. Some tests are designed specifically to detect a particular effect (such as skin and eye irritancy, skin sensitisation and mutagenicity studies). Other tests (such as sub-chronic and chronic studies) are designed to detect a wider range <strong>of</strong> less-specific effects on organs or body systems and the dose range over which the effect develops. 9.6 Information from toxicity tests is first used to provide a classification for a chemical, for example to assign appropriate warning labels for containers, and, where necessary, for selecting measures, such as protective equipment, during manufacture, exposure and use. Data from tests that characterise the relationship between dose and toxicological response are integrated with information on human exposure to produce a risk assessment, and to identify control measures necessary to manage and reduce any identified risk. Tests on species such as fish and amphibians are used in a similar way to assess the potential environmental effects <strong>of</strong> chemicals. For pharmaceuticals, results from animal tests are used in combination with data on the efficacy <strong>of</strong> a potential medicine to decide whether the beneficial effects <strong>of</strong> the treatment would outweigh the risks <strong>of</strong> adverse side effects, and to establish a safe dose for use in clinical trials (see paragraphs 8.26–8.28). <strong>The</strong>y may also indicate potential side effects that must be monitored carefully. 9.7 <strong>The</strong> prediction <strong>of</strong> the likely effects <strong>of</strong> chemical exposure on human health is based primarily on the results <strong>of</strong> tests <strong>involving</strong> experimental <strong>animals</strong>. <strong>The</strong> number <strong>of</strong> <strong>animals</strong> involved in these tests varies. A full complement <strong>of</strong> toxicity tests for a successful pharmaceutical compound that proceeds to the market, <strong>involving</strong> single dosing, repeat sub-chronic and chronic dosing, reproductive testing, genotoxicity and carcinogenicity testing, can involve between 1,500 and 3,000 <strong>animals</strong>. <strong>The</strong> actual numbers required will depend on the need for further tests according to the nature <strong>of</strong> the test substance and also its toxic properties. <strong>The</strong> numbers <strong>of</strong> <strong>animals</strong> used to test other types <strong>of</strong> chemical are generally lower, but in some cases, where there is particular controversy about the safety <strong>of</strong> a chemical, tests may be repeated, with modifications, resulting in the use <strong>of</strong> even more <strong>animals</strong>. CHAPTER 9 ANIMAL USE IN TOXICITY STUDIES 9.8 Large numbers <strong>of</strong> <strong>animals</strong> are also used in several other tests. For example, a carcinogenicity bioassay generally involves 800 <strong>animals</strong> in total (400 <strong>of</strong> each sex) and may be conducted on both rats and mice. Adult <strong>animals</strong> (typically at least 80 <strong>animals</strong> <strong>of</strong> each sex per study), <strong>of</strong>fspring and fetuses are used in reproductive and development studies. Rats and mice are most commonly used (74 percent), but in some cases testing is carried out on other <strong>animals</strong> such as rabbits (four percent), guinea pigs (three percent), dogs (one percent) or primates (less than one percent). 5 <strong>The</strong> interpretation <strong>of</strong> the results for assessing human safety depends on a number <strong>of</strong> assumptions. First, unless there is specific knowledge <strong>of</strong> species differences in the test response, it is assumed that the effects detected in rodents or other species are the same as those that would be induced in humans. Secondly, it is assumed that the sensitivity <strong>of</strong> the test <strong>animals</strong> represents, at best, the average sensitivity <strong>of</strong> the highly heterogeneous human population and that for some members <strong>of</strong> the human population the health risk could be much higher (see paragraph 8.39, Box 9.3 and paragraph 10.33). We consider next a range <strong>of</strong> examples to illustrate the different kinds <strong>of</strong> toxicity tests which are currently used. 5 Figures refer to percentages <strong>of</strong> procedures started in 2003 and carried out for the purpose <strong>of</strong> toxicology or safety and efficacy evaluation. See Home Office (2004) Statistics <strong>of</strong> Scientific Procedures on Living Animals Great Britain 2003 (Norwich: HMSO). 157
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The ethics
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The ethics
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Foreword The issue
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Table of contents
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Stages 1-2: discovery and selection
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Conclusions and recommendations ...
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Terms of reference
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T h e e t h i c s o f r e s e a r c
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Chapter 1 Introduction
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Chapter 2 The cont
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Chapter 3 Ethical issues raised by
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Section 2 Use of <
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Chapter 5 The use
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Chapter 14 Discussion of</s
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Appendices
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Genetic screening: ethical issues P
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