In 1959, William Russell and Rex Burch published their book, The Principles of Humane Experimental Technique [1], in which they proposed the concept of the three Rs (3Rs) reduction, refinement, and replacement - in relation to the humane treatment of experimental animals. Their concept was little recognized outside the United Kingdom for about 20 years, until the animal welfare movement, the general public, some committed politicians and, finally, the international scientific community, raised concerns about the suffering of experimental animals. The 3Rs concept has become the generally accepted scientific basis of institutions serving the development of alternatives to animal experiments. In 1989, ZEBET (Zentralstelle zur Erfassung und Bewertung von Ersatz- und Erganzungs-methoden zum Tierversuch = National Centre for Documentation and Evaluation of Alternative Methods to Animal Experiments) was established at the Federal Health Institute (BGA) as the first government agency promoting the development and validation of non-animal testing procedures. In 1993, the European Union (EU) followed this example by establishing the European Centre for the Validation of Alternative Methods (ECVAM) at the Joint Research Centre (JRC) in Ispra (Italy); in 1997, the federal government agencies of the USA formed ICCVAM (Interagency Coordinating Center for the Validation of Alternative Methods); and in 2005, the Japanese government established JaCVAM (Japanese Centre for the Validation of Alternative Methods) at the National Institute of Health in Tokyo.

The activities of these institutions focuses on replacing regulatory animal tests that must be conducted in order to identify the toxic properties of chemicals to which humans or the environment are exposed, when the chemicals are used in a specific product or for a specific purpose. These tests have been criticized, since the exposure of test animals to hazardous chemicals may lead to considerable suffering and even death of the animals. In Europe, these activities were driven by the cosmetics and chemicals policies which are aimed at replacing the animal tests within the next decade by advanced non-animal testing procedures. The German Ministry for Education and Research (BMBF, Bundesminsiterium für Bildung und Forschung) has, for the past 20 years, provided substantial funding to research aimed at replacing testing in animals for regulatory purposes. Since 1990 the European Commission has sponsored research according to the 3Rs in several of its framework programs. Within the program of policy supporting research, the European Commission has more recently assigned a substantial amount of funding in the life sciences to research on the development and validation of alternative methods for regulatory safety testing of drugs, cosmetics, pesticides and other chemicals.

The 3Rs concept has proven successful in reducing the suffering of laboratory animals used in regulatory safety testing. At the international level, the harmonization of test guidelines has proven successful in reducing safety testing in animals for regulatory purposes. However, it is still a scientific challenge to replace a given regulatory animal test by a non-animal test that must provide sufficient information for the safety assessment of chemicals. Meanwhile, there are a few examples which prove that regulatory animal tests can indeed be replaced when the mechanistic basis of the specific area of toxicology is well understood and an appropriate in-vitro model is available. Using the validation of the 3T3 NRU in-vitro phototoxicity test as an example, it will be illustrated how the first non-animal toxicity tests were experimentally validated for several years and accepted for regulatory purposes by EU Member-States, and in the year 2004, even at a worldwide level, by the OECD. Examples will also be provided as to how animal tests in the pharmacopoeia were replaced by advanced non-animal methods.

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