In The Principles of Humane Experimental Technique, W.M.S. Russell and R.L. Burch saw replacement as the ultimate goal for laboratory animal based research, education and testing.
Replacement alternatives can be defined as "methods or strategies which do not involve the use of protected animals in regulated procedures" (as defined in national or international laws, such as the Animals [Scientific Procedures] Act 1986 in the UK, and Directive 86/609/EEC in the European Union).
Replacement alternatives include:
the collation and use of information already gained
the use of physical and chemical analysis techniques
the use of mathematical and computer models (including molecular modelling, structure-activity relationship [SAR] approaches, and physiologically based pharmacokinetic [PBPK] modelling)
the use of in vitro systems (including sub-cellular fractions, short-term maintenance cultures, and cells and tissues maintained in culture for longer periods)
the use of human-oriented post-marketing surveillance and epidemiological approaches, and the ethical use of human volunteers
the use of organisms not classed as protected animals
the use of early developmental stages of protected animals species, before the regulations apply to them.
There are two main types of replacement:
For example, when in vitro human skin preparations are used instead of in vivo tests on guinea-pigs or rabbits)
For example, when the pyrogen test in rabbits is replaced by the Limulus amoebocyte lysate (LAL) assay or a test based on whole human blood).
Replacement can be total or partial
One kind of total replacement involves the decision not to require an animal test any more, since the information it provides does not justify its continued performance. A recent example is the decision of the European Pharmacopoeia not to require the Abnormal Toxicity Test for certain kinds of vaccines.
Another kind of total replacement is where information which is needed can be gained without recourse to the existing animal procedures, as in the case of the batch testing of hormones such as insulin and somatotrophin, and in the replacement of the rabbit pyrogen test.
A third kind of total replacement occurs when production via laboratory animal procedures can be replaced by in vitro production (for example, monoclonal antibody production in vitro in place of the in vivo ascites method).
There are also various kinds of partial replacement. For example, animal use by the pharmaceutical industry in the discovery of potential new medicines has been greatly reduced by the use of computer-based studies and in vitro systems as screens.
A second kind of partial replacement involves the use of physicochemical tests, SAR approaches and/or in vitro systems to identify highly toxic substances, so that any subsequent animal studies will be conducted either to confirm lack of toxicity or to identify mild or moderate effects. For example, scientifically validated in vitro methods are now available for identifying chemicals likely to be corrosive to the skin, and progress can be expected in the near future with in vitro methods for skin irritation.
This kind of hierarchical or stepwise testing strategy is now widely used by industry as a means of reducing both animal numbers and animal suffering, and is recognised in a number of OECD test guidelines (which form the internationally recognised system for the regulatory testing of chemicals and certain kinds of products). They are a good example of one way in which the Three Rs of Russell & Burch - reduction, refinement and replacement - can be achieved simultaneously as a result of the application of good and humane science.
More information on replacement can be found by going to the external links or papers listed in the submenu to this page or by searching the paper database.