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Wednesday, October 3, 2001, 12:00 p.m. EDT
U.S. scientists are reducing the number of rodents in chemical safety testing to a fraction of the 50 to 200 animals used in the old LD50 test for toxicity, but the use of human or animal cell lines could immediately reduce the number of animals further -- as much as 30 percent more -- the National Institute of Environmental Health Sciences said today in releasing two new federal interagency reports on alternative testing methods.
The old LD50 test (which stands for lethal dose 50 percent) rated the toxicity of chemicals by finding the dose that killed half the test animals. As now being modified by three more humane alternatives, only eight to 12 rodents are needed to estimate the lethal dose. The tests at issue determine if a chemical or product will cause illness or death in animals after ingestion of a single dose. Restrictions, warning labels and special packaging, such as child-proof containers, are based on the results.
The two new reports suggest that cell lines may eventually replace much animal testing but that even today cells (which are grown in cultures and reproduce indefinitely) can be used to screen chemicals for their relative toxicity, thereby further reducing the need for animals by nearly a third.
The reports say effective testing - including some requiring animals - remains necessary to reduce the risks of death, disfigurement and injury facing adults and children from chemicals in the workplace and in the home. Some 2.2 million human poisonings were reported to U.S. poison control centers in 1999 alone, with 873 deaths and 13,500 cases involving life-threatening symptoms or significant residual disability or disfigurement.
Today's statements on reducing animals used for testing were made with the release to the scientific community of the Report of the International Workshop on In Vitro Methods for Assessing Acute Systemic Toxicity (NIH Publication 01-4499) and an accompanying Guidance Document on Using In Vitro Data to Estimate In Vivo Starting Doses for Acute Toxicity (NIH Publication 01-4500). NIEHS and the National Toxicology Program, which is headquartered at NIEHS, and the U.S. Environmental Protection Agency co-sponsored the workshop, which produced these documents and was attended by more than 100 scientists from eight countries.
So the effort has been to find tests that are as good, or better, than the older animal-intensive tests, and that may provide information more helpful in diagnosing and managing patients who become sick from ingesting toxic materials. Currently:
- On Aug. 21, in a meeting set up by the National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods, U.S. scientists agreed on final adjustments to a U.S. test called the Up-and-Down Procedure so that it can replace the LD50 test. Although it takes longer, the Up-and-Down test gives good results with as few as six to nine rats.
- Two other alternative tests, each using only eight to 14 rodents, have been developed in Europe. The Fixed Dose Procedure, first suggested by the British Toxicological Society in 1984, is based on dosing at a series of fixed dose levels, with 5 animals dosed at each level. The approach avoids the use of death as an endpoint, instead relying on the observation of clear signs of toxicity. The Acute Toxic Class Method, developed in Germany, is a stepwise procedure with the use of 3 animals per step. It is based on biometric evaluations of the results of fixed doses ( the same series of dose levels in the FDP), which are adequately separated to enable a substance to be ranked for hazard classification purposes.
- The Organization for Economic Cooperation and Development, an international trade group that includes several European countries, Japan and the United States is removing the old LD50 test from its guidelines. Within a year of final OECD approval, the older animal-intensive LD50 method can be replaced by the regulatory agencies of the member governments with less animal-intensive tests such as the three above. This official, international switch to the new tests is expected in the latter months of 2002.
- U.S. regulatory agencies are also moving to accept the new, substitute test results.
Much of the work to reduce animal test requirements has been fostered by the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) and the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) which was organized by NIEHS in 1997 to evaluate new test methods. ICCVAM is composed of representatives from 15 federal agencies - the Agency for Toxic Substances and Disease Registry, Environmental Protection Agency, Consumer Product Safety Commission, Food and Drug Administration, Department of Agriculture, National Institutes of Health, Department of Defense, National Cancer Institute, Department of Energy, NIEHS, Department of the Interior, National Institute of Occupational Safety and Health, Department of Transportation, National Library of Medicine and the Occupational Safety and Health Administration. ICCVAM's work gets staff and other support from the National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods, or NICEATM, which organized the workshops from which the two reports released today were developed.
Other alternatives which have gone into general use under ICCVAM's auspices have substituted for more animal-intensive tests for allergic contact dermatitis and for the corrosiveness of chemicals on the skin.
About the National Institute of Environmental Health Sciences (NIEHS): NIEHS supports research to understand the effects of the environment on human health and is part of the National Institutes of Health. For more information on NIEHS or environmental health topics, visit www.niehs.nih.gov or subscribe to a news list.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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