Federal agencies respond to test method recommendations
By Debbie McCarley and Cathy Sprankle
U.S. federal agencies, including NIEHS, have agreed with recommendations for use of a method that requires fewer animals and enables pain-free testing to categorize chemicals and products that are likely to cause allergic contact dermatitis in humans as strong skin sensitizers.
The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) evaluated the scientific validity of the proposed method, the murine local lymph node assay (LLNA), and recommended how it could be used for regulatory testing and safety decisions. Regulatory agencies, including the U.S. Food and Drug Administration, U.S. Environmental Protection Agency, Consumer Products Safety Commission (CPSC), and Occupational Safety and Health Administration, have indicated that they will take actions in response to the ICCVAM recommendations to encourage use of the LLNA for this purpose where appropriate.
“Based on the ICCVAM evaluation, the LLNA can be used to identify those chemicals likely to pose the greatest hazard of allergic skin reactions for consumers and workers,” noted William Stokes, D.V.M., director of the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), which administers ICCVAM. “The LLNA will also provide important animal welfare benefits compared to historical testing methods by eliminating animal discomfort during testing and using 40 to 50 percent fewer animals.
Protecting consumers and workers from allergic contact dermatitis
Allergic contact dermatitis (ACD) is a skin reaction characterized by localized redness, swelling, blistering, or itching after direct contact with a skin allergen. Poison ivy is a well-known cause of ACD, but the condition also develops in people exposed to skin-sensitizing chemicals and products in the home or workplace. These substances include chemicals such as formaldehyde, formulations such as pesticides, and metals such as nickel. Occupational skin diseases, including ACD, are the most common type of occupational disease, with government estimates of the annual costs exceeding $1 billion.
To protect workers and consumers, U.S. regulatory agencies require the testing of chemicals and products to determine their potential to cause ACD. For more than 10 years, the LLNA has been accepted worldwide as a valid alternative to traditionally used guinea pig test methods for assessing ACD hazard potential for most testing applications. Compared to guinea pig tests, the LLNA uses fewer animals, requires less time to perform, provides dose-response information, and eliminates the pain and distress produced by positive reactions.
Identifying strong skin sensitizers
However, past use of the LLNA has been limited to a “yes/no” determination of whether or not a substance has the potential to cause ACD in humans. The CPSC, under the Federal Hazardous Substances Act, currently requires hazard labeling of only those products that are considered to be strong skin sensitizers. Based on requests from the CPSC, ICCVAM and NICEATM evaluated the extent that the LLNA could be used to correctly predict strong versus other than strong human skin sensitizers.
ICCVAM recommended a specific potency criterion that will allow results from the LLNA to be used to categorize chemicals and products as strong skin sensitizers. However, since this criterion identified only about half of the known strong human skin sensitizers tested, the potency criterion should be used only in a screening approach. Chemicals that meet the criterion could be categorized as strong skin sensitizers but chemicals that do not meet the criterion would require additional testing or information to determine that they are not strong skin sensitizers.
NIEHS and NTP Director Linda Birnbaum, Ph.D., endorsed the ICCVAM recommendations shortly after they were issued. She noted that NIEHS scientists and the NIEHS Institutional Animal Care and Use Committee have been advised to consider the LLNA for studies evaluating ACD hazard potential, and to use the method when determined appropriate.
(Debbie McCarley is the special assistant to Rear Adm. William Stokes, D.V.M., director of NICEATM. Cathy Sprankle is a communications specialist with ILS, Inc., support contractor for NICEATM.)
Setting the stage for adoption of the LLNA by federal agencies
The ICCVAM recommendations were communicated last summer to the ICCVAM member agencies (see story). ICCVAM member agencies are Federal regulatory and research agencies that require, use, generate, or distribute toxicological and safety testing information for chemicals, products, and other substances.
Details on the ICCVAM evaluation of the use of the LLNA to categorize skin sensitizers, including a recommended protocol for the LLNA, more information on the ICCVAM recommendations, and the agency responses, can be found on the NICEATM-ICCVAM website (http://iccvam.niehs.nih.gov/methods/immunotox/LLNApotency.htm) .
The U.S. Public Health Service Policy on Humane Care and Use of Laboratory Animals (http://grants2.nih.gov/grants/olaw/references/phspol.htm) and Animal Welfare Act (http://www.aphis.usda.gov/animal_welfare/awa_info.shtml) regulations require consideration of alternative methods that may reduce, refine, or replace animal use prior to the approval of procedures involving animals, and their use when determined scientifically appropriate. Since the new testing methods reduce animal use and avoid pain and distress compared to traditional testing methods, they must now be considered and used for safety studies when appropriate.