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The 3Rs principle

You'll find hereunder a detailed presentation of the 3Rs : Replacement, Reduction and Refinement.

Alternative methods are all methods that can lead to the 3Rs principle, which means it replaces, reduces and refines the use of animals for research. Contrarily to what the names suggest there're not only replacement methods.

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REPLACEMENT

Replacement methods replace in vivo methods in certain studies, therefor avoiding the use of living animals.

For product security regulation, eight Replacement in vitro methods have been approved by the OECD, the referent international organism on the subject. Amongst them, six are linked to skin and eye toxicity (corrosion, irritation), one to photo-toxicity and one to skin absorption. These methods replace animal testing but only for skin and eyes. We don't yet know how to evaluate in vitro toxicity for other organs or full organisms.

For the regulations on the control of organic products (vaccines, toxins), researchers have managed to develop physicochemical methods that are slowly replacing in vivo methods, still necessary to insure the control on batches of certain organic medicines. It's the case for example for the test of botulinic toxins (BOTOX ND) developed by Allergan and approved by the FDA in June 2011.

In medical research, future drugs are classified thanks to in vitro screening tests before tests on animals. Before discovering these tests, screening was essentially done on rats and mice. The impact of this discovery was so important that we can today attribute to it most of the 40% decrease of animals used in France since the 90'.

The in silico (medical software programs) replacement methods are only used in non-regulated fields. These models simulate a product’s outcome in an organism (metabolism, diffusion, elimination). They can help avoid studies on animals by an effective selection of products. In silico models of toxicity prediction also exist but their liability is still limited.

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REDUCTION

The number of animals necessary for a study is always chosen on the basis of a statistical study. We always try to use the fewest animals possible for a research study, while keeping in mind that a representative panel of animals is necessary. Using too few animals could invalidate the result. It's important to highlight that in the case of regulatory studies (for example medicine security studies) the minimum number of animals is set.

Reduction is an organic principle of animal research.

Thus the constant standardization of breeding methods, the attention put to the good health of the animals and the harmonization of the accommodation are factors of reduction that structure daily animal research (for more information, click here).

The growing control on genetics can also decrease the number of animals per study. Hence, the use of stems from intermarried rats or mice – with ewtremely low genetic variability - give us a typical sample with only a small amount of animals.

Using distance recording technologies (telemetry) through implanted systems enables recording (electrocardiograms for example) for months on the same animal, without it being bothered by tests. This means we no longer need to use different animals for each study, and thus reduce the number of animals used for these types of studies.

It was possible to preserve a vast number of animal lives by avoiding the repetition of similar studies in different countries thanks to the International harmonization of regulatory studies for drugs. It's Pierre Joly, then director of Roussel-Uclaf in France and President of the International Federation of Medicine Industries, who in 1990 started the initiative to have countries and labs found the International Conference on Harmonization (ICH). It aims to internationally harmonize regulatory studies on drugs, starting with those using animals. This harmonization thus guarantees international recognition of national studies, avoiding repetition.

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REFINEMENT

Refinement, or optimization, aims to decrease constraints on animals being tested. It is taught in regulatory trainings and is also part of an additional specialized training.

Refining animal accommodation

Constraints linked to animal accommodation are today low thanks to the changes in accommodation conditions, which impose on labs to make a substancial effort for animal comfort.

Constraints linked with the studies

Constraints linked with the studies are often present. Certain references classify and try to quantify these constraints. They can be of three different kinds:

- contention during a recording phase
- manipulation by technicians
- strong or chronicle pain due to a particular interventions

To each type of constraint, there’s an answe:

- discomfort due to immobilization is reduced by improving the materials and accommodations
- stress linked to manipulation is reduced or eliminated by taming
- pain is eliminated with analgesics or anaesthetics. These are systematically used during surgical interventions.

In the event of chronicle pain (for example with arthritis) accommodation is adapted (better surveillance, additional litter).

Pain

It's not possible to remove all pain in the case of diseases such as cancer or inflammatory diseases. It's also the case with some regulatory studies. To respond to this problem researchers have created the notion of anticipated stop points (see the French Guide of Grice). An anticipated stop point (or premature stop criteria) is a clinical sign that predicts a painful evolution in an animal on which it's impossible to intervene (veterinary interventions, ceasing treatment, euthanasia) without invalidating the study. We then avoid outbreaks of pain. This notion was introduced in the February 2013 update of the French Rural code. The requirements for early cessation can be loss of weight or of appetite, change of attitude or of blood consistency. It depends on the model and must be scientifically approved, at the risk of invalidating the study. There isn't yet a criterion for early cessation for all models but it's an active research field and publications on the subject are abundant (for more information click here, here and here).

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