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Overview and Recommendations
ICCVAM has developed recommendations for current uses and limitations of the reduced murine local
lymph node assay (rLLNA) as a modification to the multidose murine local lymph node assay (LLNA)
to reduce the use of animals in allergic contact dermatitis hazard testing. ICCVAM concludes that the performance of
the rLLNA, when conducted in accordance with the updated ICCVAM-recommended LLNA test method
protocol, is sufficient to distinguish between skin sensitizers and nonsensitizers in cases that do
not require dose-response information or if the test substance is expected to have no
allergic contact dermatitis hazard potential. ICCVAM also concludes that the rLLNA will reduce animal use
by 40% for each test compared to the multidose LLNA. Therefore, ICCVAM recommends that the rLLNA
test method be used routinely to determine the allergic contact dermatitis potential of chemicals
and products before conducting the multidose LLNA.
The ICCVAM recommendations for current uses and limitations of the rLLNA, as well as
recommendations for standardized protocols and future studies, can be found
in the report, ICCVAM Test Method Evaluation Report: The Reduced Murine Local Lymph Node Assay: An
Alternative
Test Method Using Fewer Animals to Assess the Allergic Contact Dermatitis Potential of Chemicals and Products.
The ICCVAM recommendations on the use of the rLLNA were communicated
to Federal agencies in letters from Dr. Linda Birnbaum, Director, NIEHS. These letters are available below,
along with the responses from each of the 15 ICCVAM agencies that indicate their concurrence with the ICCVAM recommendations on the rLLNA.
View Test Method Evaluation Report
View Federal Register notice announcing availability of the ICCVAM Test Method Evaluation Report
(74 FR 50212, September 30, 2009) [PDF]
Background
The LLNA is an alternative test method for assessing the potential for a substance to cause
allergic contact dermatitis in humans. The LLNA requires fewer animals and less
time than traditional guinea pig tests such as the guinea pig maximization test and the Buehler
test. Compared to guinea pig tests, the LLNA also provides dose-response information and
can substantially reduce or avoid animal pain and
distress.
The rLLNA, also referred to as the “cut-down” or “limit dose” LLNA, was one of several
modified versions of the LLNA nominated by the U.S. Consumer Product Safety Commission in 2007 for
evaluation by ICCVAM and NICEATM. The rLLNA can reduce the number of animals used
for allergic contact dermatitis hazard testing by 40% compared to the multidose LLNA.
The ICCVAM interagency Immunotoxicity Working Group, working with NICEATM, prepared a draft background review
document (BRD) and draft test method recommendations for use of the rLLNA. These documents were
provided to an independent international scientific peer review panel (“Panel”) and the
public for consideration
and comment. In finalizing their test method recommendations, ICCVAM considered the conclusions and
recommendations of the Panel and ICCVAM’s
Scientific Advisory Committee on Alternative Toxicological
Methods, as well as comments from the public.
ICCVAM concluded that the scientific validity of the rLLNA has been adequately evaluated.
They also concluded that the performance of the rLLNA,
when conducted in accordance with the ICCVAM-recommended
rLLNA test method protocol, is sufficient to distinguish between skin sensitizers and
nonsensitizers. ICCVAM recommends that the rLLNA test method be used
routinely before conducting the multidose LLNA
in cases that do not require dose-response information or if the
test substance is expected to have no allergic contact dermatitis hazard potential.
Negative substances can be classified as nonsensitizers,
and positive substances can be classified as sensitizers. In cases that require
dose-response information, positive substances must be tested in the
multidose LLNA. Therefore, if dose-response information is required for a substance
that, after consideration of all available information, is also suspected of having the
potential to produce allergic contact dermatitis,
it should be evaluated initially using the multidose LLNA.
View rLLNA Background Review Document (Appendix D of the Test Method Evaluation Report - 147 pages)
[PDF]
View publications and presentations on NICEATM-ICCVAM evaluations of the murine local
lymph node assay for identification and classification of sensitizers
National and International Acceptance of the Reduced LLNA
View Federal Register notice announcing availability of agency responses to ICCVAM recommendations
(75 FR 25866, May 10, 2010) [PDF]
In April 2011, the U.S. Environmental Protection Agency announced that it was adopting the rLLNA,
noting that the rLLNA allows a 40% reduction in animal use compared to the multidose LLNA.
View the April 2011 EPA policy document
[PDF]
The rLLNA was included as an option in the revised OECD Test Guideline 429 for the LLNA that was adopted in July 2010.
Read the revised OECD Test Guideline 429 [PDF]
Transmittal of Recommendations to Federal Agencies
- National Institutes of Environmental Health Sciences (NIEHS)
- Letter from Linda Birnbaum, Ph.D., DABT, ATS, Director, NIEHS, to the ICCVAM Committee (March 17, 2010)
[PDF]
- Agency for Toxic Substances and Disease Registry (ATSDR)
- Letter from Dr. Birnbaum to Thomas R. Frieden, M.D., M.P.H., Administrator, ATSDR
[PDF]
- Response from Thomas R. Frieden, M.D., M.P.H., Director, Centers for Disease
Control, and Administrator, ATSDR (received March 4, 2010) [PDF]
- Consumer Product Safety Commission (CPSC)
- Letter from Dr. Birnbaum to Inez Moore Tenenbaum, Chairman, CPSC [PDF]
- Response from Todd Stevenson, Office of the Secretary (received March 19, 2010) [PDF]
- Environmental Protection Agency (EPA)
- Letter from Dr. Birnbaum to Lisa P. Jackson, Administrator, EPA [PDF]
- Response from John Fowle, Ph.D., DABT, Office of Pesticide Programs (received March 18, 2010) [PDF]
- Food and Drug Administration (FDA)
- Letter from Dr. Birnbaum to Margaret Hamburg, M.D., Commissioner [PDF]
- Response from Jesse L. Goodman, M.D., M.P.H. , Chief Scientist and Deputy Commissioner (Acting) for
Science and Public Health (received March 23, 2010) [PDF]
- National Cancer Institute (NCI)
- Letter from Dr. Birnbaum to John E. Niederhuber, M.D., Director, NCI [PDF]
- Response from Dr. Niederhuber (received October 9, 2009) [PDF]
- National Institutes of Health (NIH)
- Letter from Dr. Birnbaum to Francis S. Collins, M.D., Ph.D., Director, NIH [PDF]
- Response from Dr. Collins (received February 19, 2010) [PDF]
- National Institute for Occupational Safety and Health (NIOSH)
- Letter from Dr. Birnbaum to John Howard, M.D., Director, NIOSH [PDF]
- Response from Dr. Howard (received March 5, 2010) [PDF]
- National Library of Medicine (NLM)
- Letter from Dr. Birnbaum to Donald A.B. Lindberg, M.D., Director, NLM [PDF]
- Response from Dr. Lindberg (received March 22, 2010) [PDF]
- Occupational Safety and Health Administration (OSHA)
- Letter from Dr. Birnbaum to Jordan Barab, Deputy Assistant Secretary of Labor and Acting Assistant Secretary,
OSHA [PDF]
- Response from David Michaels, Ph.D., M.P.H., Office of the Assistant Secretary for Occupational Safety and Health (received March 19, 2010) [PDF]
- U.S. Department of Agriculture
- Letter from Dr. Birnbaum to Tom Vilsack, Secretary of Agriculture [PDF]
- Response from Cindy Smith, Administrator, Animal and Plant Health Inspection Service (received October 16, 2009) [PDF]
- U.S. Department of Defense
- Letter from Dr. Birnbaum to Robert M. Gates, Ph.D., Secretary of Defense [PDF]
- Response from Dr. Robert Foster, Director, BioSystems (received January 4, 2010) [PDF]
- U.S. Department of Energy
- Letter from Dr. Birnbaum to Steven Chu, Secretary of Energy [PDF]
- Response from Dr. Anna Palmisano, Associate Director of Science for Biological and Environmental Research (received February 2, 2010) [PDF]
- U.S. Department of the Interior
- Letter from Dr. Birnbaum to Ken Salazar, Secretary of the Interior [PDF]
- Response from William Werkhiser, Regional Director, Eastern Region, U.S. Geological Survey (received March 25, 2010) [PDF]
- U.S. Department of Transportation
- Letter from Dr. Birnbaum to Ray LaHood, Secretary of Transportation [PDF]
- Response from Magdy El-Sibaie, Associate Administrator for Hazardous Materials Safety (received March 19, 2010) [PDF]
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