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View document: Recommended Performance Standards: Murine Local Lymph Node Assay
[PDF]
Please Note: A correction has been made to the document
regarding the details for one of the the
performance standards reference substances. This correction affects the content
of Appendices E and F. If you have a hard copy of this document (NIH Publication No. 09-7357),
please be aware of these revisions.
View correction to Performance Standards document (August 2010) [PDF]
Overview and Recommendations
The LLNA was the first alternative test method evaluated and recommended by
ICCVAM. Based on the recommendations of ICCVAM and an independent scientific peer review panel, the
LLNA has been accepted by U.S. and international regulatory authorities
as a stand-alone test method for assessing the potential
of a substance to induce allergic contact dermatitis in humans.
ICCVAM currently routinely develops performance standards for test methods. Before
a new test method is accepted for regulatory testing applications, validation studies are
conducted to assess its reliability (i.e., the extent of intra- and inter-laboratory reproducibility),
and its relevance (i.e., the ability of the test method to correctly predict or measure the biological
effect of interest, which is partly dependent on the accuracy of the test method). Performance
standards communicate the basis by which new test methods have been determined to have sufficient accuracy and reliability for
a specific testing purpose. These performance standards can then be used to evaluate the accuracy and
reliability of other proposed test methods that are considered functionally and mechanistically similar
to the accepted test method.
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When ICCVAM evaluated the LLNA in 1999, the concept of performance standards had not been
developed. ICCVAM subsequently defined performance standards and
described a process for their development (ICCVAM 2003). In 2007, the U.S. Consumer Product Safety Commission (CPSC) asked ICCVAM
and NICEATM to evaluate the scientific validity of nonradioactive versions of the LLNA that could
be used in place of the traditional LLNA, which measures the incorporation of radioactivity
in the draining auricular lymph nodes. ICCVAM decided at that time to develop
performance standards that could be used to more rapidly and efficiently determine the validity of
these and other modified versions of the LLNA.
The European Centre for the Validation of Alternative Methods (ECVAM) also independently drafted
LLNA performance standards in 2007, and the Japanese Center for the Validation of Alternative
Methods (JaCVAM) initiated two validation studies of modified LLNA test methods using a list of
proposed reference substances to evaluate their validity. With obvious international interest in
developing LLNA performance standards, ICCVAM, JaCVAM, and ECVAM agreed to work together to develop
internationally-harmonized LLNA performance standards.
ICCVAM developed recommended performance standards for the LLNA and published them in 2009. These
performance standards reflect extensive discussions that took place between ICCVAM, ECVAM, and
JaCVAM during 2007 and 2008, and represent a set of internationally-harmonized standards for the
conduct of the LLNA. The recommendations on the use of these performance standards 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-recommended LLNA performance standards.
View publications and presentations on ICCVAM evaluations of the murine local
lymph node assay for identification and classification of sensitizers
Federal Register Notices
View Federal Register notice announcing availability of agency responses to ICCVAM recommendations
(75 FR 25866, May 10, 2010) [PDF]
View Federal Register notice announcing availability of ICCVAM-recommended performance standards
(74 FR 50212, September 30, 2009) [PDF]
View Federal Register notice announcing availability of initial draft of performance standards
(72 FR 52130, September 12, 2007) [PDF]
View public comments submitted in response to FR notice
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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