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August 2011

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Committee recommends alternative method for product safety testing

August 2011

from left to right, Dagmar JírovÁ, M.D., Ph.D., William Stokes, D.V.M., and Nathalie Alépée, Ph.D.

The current ICCVAM recommendations were finalized after considering comments from an international independent peer review panel. Here, NICEATM Director William Stokes, D.V.M., center, appears with two members of the panel at their meeting at CPSC headquarters. Pictured with Stokes are Dagmar JírovÁ, M.D., Ph.D., left, toxicologist at the National Institute of Public Health, Czech Republic, and Nathalie Alépée, Ph.D., right, research manager at L'Oréal Research and Development in France. (Photo courtesy of NICEATM)

In July, recommendations from the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) were transmitted to federal agencies for using alternative method safety testing results to identify substances that have a high potential for causing allergic contact dermatitis (ACD) in humans.

NIEHS/NTP Director Linda Birnbaum, Ph.D., forwarded the ICCVAM recommendations on behalf of the Secretary of Health and Human Services. ICCVAM, an interagency committee of the U.S. federal government, is administered by the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), a center within the NTP at NIEHS. NICEATM provided scientific support to the ICCVAM interagency working group that developed the recommendations (see text box).

Murine local lymph node assay

According to the U.S. Bureau of Labor Statistics, occupational skin diseases are the most common type of occupational illness. Many of these cases arise from exposure to skin-sensitizing substances, which can lead to the development of ACD. ACD is a delayed hypersensitivity reaction caused by an immune response after repeated exposures to a skin-sensitizing substance. People with ACD typically experience redness, itching, swelling, or blistering of the skin after re-exposure to the sensitizing substance. Studies have shown that ACD has a significant adverse impact on quality of life in affected individuals.

The recent ICCVAM recommendations are for use of the murine local lymph node assay, or LLNA, to categorize the potency of chemicals that cause ACD in humans. ICCVAM concluded that the LLNA can be used to categorize some substances as strong skin sensitizers. Strong skin sensitizers are those substances considered to have a high potential for causing ACD in humans.

The LLNA uses fewer animals than other commonly used test methods for ACD hazard determination that use guinea pigs. The LLNA also eliminates the discomfort that can be experienced by animals when the guinea pig test methods are used. Other advantages of the LLNA are that it can be performed more rapidly and it provides dose-response information.

For more than 10 years, the LLNA has been accepted worldwide as a valid alternative to guinea pig methods for identifying chemicals with the potential to cause ACD. However, the 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. Availability of a test method that could be used to identify substances as strong human skin sensitizers would be helpful to regulatory agencies such as the U.S. Consumer Product Safety Commission (CPSC).

Categorizing potentially hazardous substances

The Globally Harmonized System of Classification and Labeling of Chemicals, or GHS, is a hazard classification system developed by the United Nations for use by governments to inform workers and consumers of potential hazards. The ICCVAM evaluation assessed the extent to which a GHS criterion based on LLNA results can correctly categorize substances as strong sensitizers, Subcategory 1A, and determined that the GHS criterion correctly identifies about half of known human strong skin sensitizers. ICCVAM concluded that additional information would need to be considered to confirm whether substances that do not meet this criterion are or are not strong sensitizers

The ICCVAM test method evaluation report, which contains the complete ICCVAM recommendations, is available on the NICEATM-ICCVAM website( The current recommendations complete a series of evaluations that NICEATM and ICCVAM have been conducting on the LLNA. Other ICCVAM recommendations to Federal agencies on new versions and applications of the LLNA can also be found on the NICEATM-ICCVAM website(

collage of pictures
This collage of pictures representing the use of the murine LLNA for potency categorization of chemicals causing allergic contact dermatitis in humans includes, clockwise from top left, scintillation vials used to measure the quantity of radioactive tracer chemical incorporated into dividing lymph node cells; flasks and bottles containing liquids representing chemicals; a human clinical patch test for skin allergy; a graph of data used in the evaluation of the murine LLNA for potency categorization; and a lab technician resuspending cells in a plastic tube. (Photo courtesy of NICEATM)

ICCVAM interagency Immunotoxicity Working Group

The ICCVAM interagency Immunotoxicity Working Group (IWG) developed the recommendations with support from NICEATM. The IWG is co-chaired by Abigail Jacobs, Ph.D., of the U.S. Food and Drug Administration (FDA) and Joanna Matheson, Ph.D., of the CPSC. It includes scientists from the CPSC, Environmental Protection Agency, FDA, NIEHS, and the National Institute for Occupational Safety and Health. NIEHS scientists Dori Germolec, Ph.D., William Stokes, D.V.M., and Warren Casey, Ph.D., contributed to the ICCVAM recommendations. Stokes is director of NICEATM and executive director of ICCVAM.

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