Animal Welfare and the 3Rs

The 3Rs: Replacement, Reduction, and Refinement, are important from a legal, ethical and scientific standpoint. All research using animals in the US, for example at universities and pharmaceutical companies, is regulated by the Animal Welfare Act (AWA), which is administered by the Animal and Plant Health Inspection Service (APHIS) of the US Department of Agriculture (USDA). The 3Rs are implicit in the AWA and any scientist planning to use animals (except rats, mice, and birds, which are not included in the AWA) in their research must first demonstrate why there is no alternative; and that the number of animals used, and any suffering caused, will be kept to a minimum.

The 3Rs are also important from an ethical standpoint, as research using animals has the potential to cause pain, suffering or distress – this can arise from the experiments themselves or from the way that animals are housed. In any humane society there is clearly a moral obligation to ensure that any harm caused is kept to an absolute minimum. Indeed, opinion polls have shown that the public only accepts research using animals where this is the case. Minimizing suffering is the responsibility of all those involved in the use of animals in research, including the research institutions and the people of that carry out the studies. All research establishments are required to have an Institutional Animal Care and Use Committee (IACUC) which reviews all research projects to ensure all that the 3Rs are being implemented.

Finally, and very importantly, there are strong scientific reasons for implementing the 3Rs. The way animals that animals are housed, handled and used in scientific research can affect their physiology, immunology and behavior. For example, even something as simple as holding an animal can affect its blood pressure and the level of some hormones. This, in turn, can affect the validity and reproducibility of any data obtained. Minimizing the impact of the research on the animals is therefore very important for science and animal welfare.

Replacement:

The vast majority of scientific and medical research does not involve the use of animals. However, the use of animals is an important aspect in some areas of research and, in an ideal world, alternatives would be available. Although difficult, some progress on replacement has been made by scientists. Animals have been replaced, for example by the use of cell culture systems, human volunteers, computers and new imaging techniques. There a number of sophisticated examples of replacements including in vitro models of skin, which can be used for drug discovery research as well as for testing new chemicals and products, and computer models to study how the heart works or to select potential new medicines.

A lot of scientific effort has been devoted to developing new, non-animal techniques which can be used in experiments instead of animals. There have been some notable successes, but overall, progress has been slow.

Insulin is a lifeline for millions of diabetics, but it is essential they give themselves the correct dose – either too high or too low a dose can be harmful. Each batch of insulin has to be tested to measure how active it is so that the correct dosage can be calculated. Previously, this was done by injecting the insulin into mice. Now that insulin is produced by bacterial culture rather than being extracted from pig and cow pancreases, it contains fewer impurities. A new technique has been developed which uses a machine called a chromatograph which can provide information about purity, replacing the need to use animals to test for the purity and activity of batches of insulin.

Many non-animal techniques have been designed to replace the animal tests used in safety testing, but these new techniques do not always work well enough. A great amount of scientific work has been devoted to the search for an in vitro test to replace the Draize eye irritation test, which was once viewed as a relatively simple animal test to replace. This test studies whether a chemical irritates the eye by dropping a dilution of it directly onto the eye of an animal, usually a rabbit. Over the past couple of decades several different in vitro tests have been been assessed to see if they accurately predict whether a substance will irritate the eye. Unfortunately, none of them worked well enough to be used to replace the existing animal test. However as pre screening tests they help prevent many chemical irritants from reaching animal testing stages and have lead to a dramatic reduction in the number of animals used in the Draize test. New in vitro methods that may be able to completely replace the Draize test are currently being evaluated in Europe and the USA.

Another aspect of replacement is the use of “lower” species of animals wherever possible. If we can use a dog instead of a primate and hope to achieve the same quality results, then it must be done. If we can use a rabbit instead of a dog, or a mouse instead of a rabbit, then we must similarly apply this principle of using the lowest suitable species for the research. This, in part, explains why most research is done on mice and rats.

(1) http://www.nc3rs.org.uk/downloaddoc.asp?id=348&page=7&skin=0

(2) http://www.rds-online.org.uk/pages/page.asp?i_ToolbarID=4&i_PageID=45

Reduction:

Keeping the number of animals used to a minimum is extremely important. However, when thinking about ways to reduce the number of animals used, researchers also have to ensure that the design of their experiment is robust. If by reducing animal numbers, researchers end up with data that have no statistical significance, they would have wasted animal lives, which would be unacceptable.

The number of individual animals used is important, but what really matters is what actually happens to the animals and how much they suffer. At times there can be a conflict between applying the principles of reduction and refinement. For example, some researchers may have to face the ethical dilemma of deciding whether it is better to use 10 rats in an experiment that will involve suffering or to use 100 rats in the same experiment but involving little or no suffering. A specific example is the use of female mice in the production of genetically modified mice. Females are used to provide fertilized eggs for microinjection. In order to reduce the number of females used it is common practice to give hormones, to increase the number of eggs released per animal – a process called superovulation. However, superovulation requires that each animal is given an injection into its abdomen and this may cause pain. A choice has to be made between reduction and refinement.

http://www.nc3rs.org.uk/downloaddoc.asp?id=348&page=7&skin=0

Refinement:

Although replacement is the ultimate goal, as long as animals are used in research, refinement is the ‘R’ with the greatest and widest potential impact. Refinement not only improves the life of every animal used in research, it also improves the quality of the science. This is illustrated by a study of genetically modified mice with similar mutations to those found in people with Huntington’s disease – a disease that causes difficulties in movement and memory. If the Huntington’s disease mice are provided with a complex cage environment that provides opportunities to hide, nest, gnaw and forage, the disease progresses much more slowly than in mice kept in barren cages, and in fact the mice mimic the progress of the human disease more closely. Thus, by providing a better environment for the mice, researchers have a more realistic ‘model’ of Huntington’s disease that they can use to try to understand how to treat the disease. Of course the mice are happier too.

An obvious way to improve animal welfare it to provide an environment that meets the animals’ specific needs (see Barley, 2005). So, for example, rats and will remain less stressed if they are put in cages with a solid floor, this is a cheap and effective method of improving animal welfare for better scientific results. Research at the University of Oxford is trying to determine the optimal cage cleaning regimen, since a very dirty cage is bad for animal welfare, however too frequent cleaning will disrupt the urine odors that mice used to maintain social hierarchies and mark territory – thus stressing the animal unnecessarily.

Stress minimization through better training for animal technicians, and ensuring pain relief is quickly administered whenever necessary are two more ways of improving animal welfare.

Barley, J. (2005) Balancing the needs of animals and science. School Science Review, 87(319)

http://www.nc3rs.org.uk/downloaddoc.asp?id=348&page=7&skin=0

Further Reading: