The ethics of research involving animals - Nuffield Council on ...
The ethics of research involving animals - Nuffield Council on ...
The ethics of research involving animals - Nuffield Council on ...
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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<br />
Repeated-dose toxicity studies<br />
9.16 <str<strong>on</strong>g>The</str<strong>on</strong>g>se studies have three main objectives (i) to identify toxicity that develops <strong>on</strong>ly after a<br />
certain length <str<strong>on</strong>g>of</str<strong>on</strong>g> c<strong>on</strong>tinuous exposure to the chemical, (ii) to identify the organs most<br />
affected and (iii) to determine the doses at which each effect occurs.<br />
9.17 Repeated-dose studies are c<strong>on</strong>ducted for various periods <str<strong>on</strong>g>of</str<strong>on</strong>g> time. <str<strong>on</strong>g>The</str<strong>on</strong>g> 28-day (sub-acute)<br />
study is most comm<strong>on</strong>, but studies <str<strong>on</strong>g>of</str<strong>on</strong>g> 90 days to <strong>on</strong>e year are also regularly carried out. Rats<br />
and mice are generally used but for certain classes <str<strong>on</strong>g>of</str<strong>on</strong>g> chemicals, such as agrochemicals and<br />
pharmaceuticals, the tests may also be c<strong>on</strong>ducted in n<strong>on</strong>-rodent <str<strong>on</strong>g>animals</str<strong>on</strong>g> such as the beagle<br />
dogs, pigs, marmosets or macaques (see paragraphs 9.26 and 9.30). <str<strong>on</strong>g>The</str<strong>on</strong>g> test data allow an<br />
assessment <str<strong>on</strong>g>of</str<strong>on</strong>g> the highest dose without significant effects (the ‘no observed adverse effect<br />
level’, or NOAEL). This is used in risk assessment and risk management, by limiting the<br />
acceptable exposure <str<strong>on</strong>g>of</str<strong>on</strong>g> humans to a fracti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the NOAEL. For example, in the case <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
agrochemicals and food additives, these studies are used to assign a reference dose to which<br />
safety factors are applied to give an acceptable daily intake (ADI) that is typically a<br />
hundredfold less than the observed NOAEL. This can be defined as the dose level to which<br />
humans may be exposed, through residues <strong>on</strong> foodstuffs and in drinking water, with the<br />
practical certainty that no adverse health effects will ensue.<br />
9.18 Repeated-dose studies are also used to give an insight into any species differences in toxicity<br />
that could be relevant to the assessment <str<strong>on</strong>g>of</str<strong>on</strong>g> risk in human health. Depending <strong>on</strong> the use and<br />
physico-chemical properties <str<strong>on</strong>g>of</str<strong>on</strong>g> a chemical, different routes <str<strong>on</strong>g>of</str<strong>on</strong>g> administrati<strong>on</strong>, such as oral, by<br />
inhalati<strong>on</strong> or dermal c<strong>on</strong>tact, may be used to give a more appropriate risk assessment. For<br />
pharmaceuticals, results <str<strong>on</strong>g>of</str<strong>on</strong>g> these studies support investigati<strong>on</strong>s requiring the first<br />
administrati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the test substance to humans.<br />
Carcinogenicity<br />
9.19 For the assessment <str<strong>on</strong>g>of</str<strong>on</strong>g> carcinogenicity, rats and mice are dosed for up to two years (the typical<br />
lifespan for these species) and the incidence and type <str<strong>on</strong>g>of</str<strong>on</strong>g> the tumours that develop is<br />
evaluated (see paragraph 9.33). This knowledge is used to assess the risk <str<strong>on</strong>g>of</str<strong>on</strong>g> cancer inducti<strong>on</strong><br />
by the chemical in exposed humans. In practice, the assessment <str<strong>on</strong>g>of</str<strong>on</strong>g> repeated-dose studies and<br />
carcinogenicity is <str<strong>on</strong>g>of</str<strong>on</strong>g>ten combined into a single study in rodents thus reducing the use <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
experimental <str<strong>on</strong>g>animals</str<strong>on</strong>g>.<br />
Genotoxicity<br />
9.20 Short-term studies investigating interacti<strong>on</strong>s with genetic material (DNA and chromosomes)<br />
are widely used to screen chemicals for the potential to cause cancer or heritable mutati<strong>on</strong>s.<br />
Most <str<strong>on</strong>g>of</str<strong>on</strong>g> these studies involve the use <str<strong>on</strong>g>of</str<strong>on</strong>g> in vitro assays for mutati<strong>on</strong> in bacteria or isolated<br />
mammalian cells that have been shown to predict the potential for a substance to be<br />
carcinogenic or mutagenic through interacti<strong>on</strong> with DNA. In the pharmaceutical industry tests<br />
are performed as high-throughput screens (see paragraphs 8.9 and 8.21), both early in drug<br />
discovery and also to support drug registrati<strong>on</strong>. Animal studies, usually in the mouse, are used<br />
<strong>on</strong>ly when <strong>on</strong>e or more <str<strong>on</strong>g>of</str<strong>on</strong>g> these in vitro tests has given a positive result, and with the purpose<br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> dem<strong>on</strong>strating that the chemical can or cannot reach a sensitive tissue and cause genetic<br />
changes in the intact animal. In practice, very few chemicals that have been c<strong>on</strong>firmed to be<br />
mutagenic in vitro are tested any further in <str<strong>on</strong>g>animals</str<strong>on</strong>g>. However, in the case <str<strong>on</strong>g>of</str<strong>on</strong>g> pharmaceuticals,<br />
regulatory requirements demand that an in vivo test be completed before the start <str<strong>on</strong>g>of</str<strong>on</strong>g> Phase<br />
II clinical studies in humans.<br />
9.21 In vivo tests include the rodent b<strong>on</strong>e marrow micr<strong>on</strong>ucleus test, which is an early predictor <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
carcinogenic activity. A single dose <str<strong>on</strong>g>of</str<strong>on</strong>g> compound is administered to rats or mice which are<br />
killed either 24 or 48 hours later for examinati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> chromosomal changes in b<strong>on</strong>e marrow<br />
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