R&D toxicity test to be eliminated

In a rare collaboration between animal rights organizations and scientists, the US has joined a growing worldwide movement to eliminate the use of a toxicity test called the lethal dose–50 (LD₅₀) test, and embrace alternative methods that require fewer animals. Animal rights groups estimate that about 5 million animals per year have been used in LD₅₀ tests in the US alone.

The LD₅₀ determines the dosage of a chemical that kills half the animals in a test group—the bigger the dose required, the lower the chemical's toxicity. Test groups typically comprise 50–200 animals, often rats. The test is being phased out internationally and will no longer be used by regulatory agencies for classification and labeling of drugs and chemicals.

The International Organisation for Economic Co-operation and Development (OECD), an international trade organization that includes the US, Japan and several member states of the European Union, intends to eliminate the LD₅₀ from its test guidelines by September 2002. After that time, data generated by the old method can be rejected by government authorities and less animal-intensive studies used instead.

Officially, the test is not required by the US Food and Drug Administration (FDA) to evaluate new medicines and is no longer used by many biomedical researchers and drug companies. “The FDA usually requires different information,” says veterinarian Bill Stokes, director of the National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods (ICCVAM). “They want to know the LD₁₀ [the dose at which 10% of animals die]—they're more interested in knowing when you start getting toxic effects.”

Replacing LD₅₀ will be one of three measures of toxicity that use as few as 14 animals. In the 'up-and-down' method, animals are exposed to incremental doses of a substance every 48 hours, and the dose that kills the animals is observed. This method takes more time but uses as few as 6–9 rats. Stokes explains, “If an animal dies, you reduce your dose by that same factor and continue until you've had three deaths, or three survivals.” This method was reviewed in July 2000 by an ICCVAM panel, which asked that a computer software program be developed to establish test doses. This software has now been created by the US Environmental Protection Agency and ICCVAM announced on 21 August that it was fine-tuning the technique, which uses only eight rats per compound tested.

The 'fixed-dose procedure', first proposed by the British Toxicological Society in 1984, is another stepwise analysis—this one based on dosing at a series of fixed dose levels, with five animals dosed at each level. This approach avoids the use of death as an endpoint, instead relying on the observation of signs of toxicity. The 'acute toxic class method' uses three animals per step and is based on biometric evaluations of fixed doses.