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 />
cells. It is expected that the highest dose level used will show evidence <str<strong>on</strong>g>of</str<strong>on</strong>g> adverse effects if<br />
the substance is genotoxic, and the MTD is normally used to set this dose level.<br />
Effects <strong>on</strong> reproducti<strong>on</strong> and development<br />
9.22 Studies within this category are intended to determine the effects <str<strong>on</strong>g>of</str<strong>on</strong>g> compounds <strong>on</strong> various<br />
aspects <str<strong>on</strong>g>of</str<strong>on</strong>g> the reproductive capacity <str<strong>on</strong>g>of</str<strong>on</strong>g> the adult, and <strong>on</strong> the development <str<strong>on</strong>g>of</str<strong>on</strong>g> the <str<strong>on</strong>g>of</str<strong>on</strong>g>fspring.<br />
<str<strong>on</strong>g>The</str<strong>on</strong>g> most comprehensive test method for reproducti<strong>on</strong> (the two-generati<strong>on</strong> reproducti<strong>on</strong><br />
study) involves repeated oral doses to young rats through the period <str<strong>on</strong>g>of</str<strong>on</strong>g> sexual maturati<strong>on</strong><br />
into young adulthood when the <str<strong>on</strong>g>animals</str<strong>on</strong>g> are mated to treated females. <str<strong>on</strong>g>The</str<strong>on</strong>g> females are dosed<br />
throughout pregnancy and until the <str<strong>on</strong>g>of</str<strong>on</strong>g>fspring are weaned. <str<strong>on</strong>g>The</str<strong>on</strong>g> pups are dosed until<br />
adulthood and mated and the sec<strong>on</strong>d-generati<strong>on</strong> young evaluated. <str<strong>on</strong>g>The</str<strong>on</strong>g>se tests provide<br />
informati<strong>on</strong> <strong>on</strong> fertility, mating behaviour, parental behaviour and development <str<strong>on</strong>g>of</str<strong>on</strong>g> the<br />
ne<strong>on</strong>ate to adulthood. <str<strong>on</strong>g>The</str<strong>on</strong>g> results are used in hazard classificati<strong>on</strong> and in risk assessment.<br />
More-limited informati<strong>on</strong> <strong>on</strong> fertility and reproductive performance can also be obtained<br />
from a <strong>on</strong>e-generati<strong>on</strong> study or a screening test, which combines reproductive investigati<strong>on</strong>s<br />
with a 28-day repeated-dose toxicity test.<br />
9.23 Studies <strong>on</strong> developmental toxicity provide specific informati<strong>on</strong> <strong>on</strong> the potential hazards to<br />
the unborn that may arise from exposure <str<strong>on</strong>g>of</str<strong>on</strong>g> the mother to a particular substance during<br />
pregnancy. Typically, groups <str<strong>on</strong>g>of</str<strong>on</strong>g> pregnant rats or rabbits are treated orally for up to the whole<br />
period <str<strong>on</strong>g>of</str<strong>on</strong>g> gestati<strong>on</strong>, and the uterine c<strong>on</strong>tents are then examined and evaluated just prior to<br />
parturiti<strong>on</strong>. An evaluati<strong>on</strong> is made <str<strong>on</strong>g>of</str<strong>on</strong>g> maternal toxicity relative to that in n<strong>on</strong>-pregnant<br />
females, embryo or fetal death, altered growth and structural changes in the fetus. Rabbits<br />
are used in additi<strong>on</strong> to rats and mice because rodents do not generally resp<strong>on</strong>d, or resp<strong>on</strong>d<br />
variably, to the effects <str<strong>on</strong>g>of</str<strong>on</strong>g> potent human teratogens such as thalidomide (see Box 8.4). <str<strong>on</strong>g>The</str<strong>on</strong>g><br />
results <str<strong>on</strong>g>of</str<strong>on</strong>g> both tests are used in classificati<strong>on</strong> by hazard and in risk assessment.<br />
CHAPTER 9 ANIMAL USE IN TOXICITY STUDIES<br />
Safety pharmacology<br />
9.24 In the development <str<strong>on</strong>g>of</str<strong>on</strong>g> pharmaceutical products, additi<strong>on</strong>al tests are needed to detect<br />
exaggerated intended or unintended pharmacological resp<strong>on</strong>ses. Pharmacology studies to<br />
evaluate safety are generally c<strong>on</strong>ducted in the dog (for cardiovascular endpoints) and in the<br />
rodent (for assessment <str<strong>on</strong>g>of</str<strong>on</strong>g> the effect <strong>on</strong> the whole body). Some examples <str<strong>on</strong>g>of</str<strong>on</strong>g> the types <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
studies performed in <str<strong>on</strong>g>animals</str<strong>on</strong>g> are described briefly below (see Box 9.4).<br />
■<br />
■<br />
Dog telemetry: dogs are implanted with radio-transmitters for c<strong>on</strong>tinuous m<strong>on</strong>itoring <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
blood pressure, heart rate, body temperature and electrocardiogram (ECG, see paragraph<br />
4.56). <str<strong>on</strong>g>The</str<strong>on</strong>g>se parameters can be m<strong>on</strong>itored from the c<strong>on</strong>scious dog, and allow the<br />
measurement <str<strong>on</strong>g>of</str<strong>on</strong>g> the effects <str<strong>on</strong>g>of</str<strong>on</strong>g> test compounds <strong>on</strong> the cardiovascular system in vivo. Dogs<br />
are usually reused in multiple studies, subject to veterinary and regulatory approval by the<br />
Home Office. <str<strong>on</strong>g>The</str<strong>on</strong>g>y are euthanised at the end <str<strong>on</strong>g>of</str<strong>on</strong>g> the studies.<br />
Haemodynamics <str<strong>on</strong>g>of</str<strong>on</strong>g> anaesthetised dogs: this type <str<strong>on</strong>g>of</str<strong>on</strong>g> <str<strong>on</strong>g>research</str<strong>on</strong>g> is undertaken as a followup<br />
to dog telemetry. Under terminal anaesthesia, multiple systems may be investigated<br />
including, for example, blood pressure, heart rate, ECG and peripheral blood flows (also<br />
cor<strong>on</strong>ary and renal blood flows).<br />
■<br />
Absorpti<strong>on</strong>, distributi<strong>on</strong>, metabolism and excreti<strong>on</strong> studies (ADME): although not strictly<br />
toxicity studies, these investigati<strong>on</strong>s (typically undertaken in rodents and dogs) are used to<br />
assess the amount <str<strong>on</strong>g>of</str<strong>on</strong>g> chemical or pharmaceutical that is absorbed into the animal, where<br />
it is distributed within the body, how it is changed by metabolism, the time-course for<br />
these events and how, and at what rate, the material is eliminated from the body (see<br />
paragraph 9.31). This informati<strong>on</strong> is used to select dose levels for toxicity studies and<br />
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