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Overview and Recommendations
The murine local lymph node assay (LLNA) is a stand-alone test method for assessing the hazard
potential of a test substance to induce allergic contact dermatitis (ACD). ICCVAM evaluated the use
of the LLNA for potency categorization of chemicals causing ACD in humans. ICCVAM concluded that the
LLNA can be used to categorize substances as strong sensitizers (Globally Harmonized System of
Classification and Labelling of Chemicals Subcategory 1A). However, substances that are not
identified as strong sensitizers using the LLNA require additional information to categorize
them as other than strong sensitizers (Globally Harmonized System of
Classification and Labelling of Chemicals Subcategory 1B). Strong sensitizers are those
substances considered to have a significant potential for causing hypersensitivity.
Background
For over 10 years, the LLNA has been accepted worldwide as a valid alternative to traditionally
accepted guinea pig test methods for assessing ACD hazard potential for most testing situations.
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.
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In January 2007, the U.S. Consumer Product Safety Commission (CPSC) requested that NICEATM and
ICCVAM assess the validation status of the LLNA as a stand-alone test method to classify potentially
skin-sensitizing chemicals according to potency. The CPSC, under the Federal Hazardous Substances
Act, currently only requires products that are considered to be strong skin sensitizers to carry
hazard labeling warning of ACD hazard potential. Results from tests that could be used to identify
potential strong human skin sensitizers would be helpful for the purposes of hazard identification
for CPSC and other agencies with an interest in identifying strong skin sensitizers.
Accordingly, NICEATM and ICCVAM evaluated the extent that LLNA results could be used to correctly
predict “strong” versus “other than strong” human skin sensitizers. The ICCVAM interagency
Immunotoxicity Working Group (IWG), working with NICEATM, prepared a draft background review
document (BRD) and draft recommendations for use of the LLNA for potency categorization of chemicals
that cause ACD in humans.
The draft BRD and draft ICCVAM recommendations were reviewed in a public meeting of an
international independent scientific peer review panel in March 2008. The peer review panel agreed
with ICCVAM that the LLNA can be used as part of a weight-of-evidence evaluation for categorizing
skin sensitizers based on potency, although it should not be used as a stand-alone test method for
this purpose. The peer review panel also recommended that NICEATM perform additional analyses using alternative
approaches that might provide more appropriate thresholds for the human reference data for
evaluating the use of the LLNA for potency categorization of human skin sensitizers.
The final ICCVAM recommendations stating that the LLNA can be used to categorize substances as
strong sensitizers are included in the ICCVAM Test Method Evaluation Report: Usefulness and
Limitations of the Murine Local Lymph Node Assay for Potency Categorization of Chemicals Causing
Allergic Contact Dermatitis in Humans. The test method evaluation report also includes an updated
ICCVAM-recommended protocol for the LLNA and recommendations for future studies to further evaluate
the usefulness and limitations of the LLNA for potency determinations. The final BRD, including the
data and analyses on which the recommendations are based, is included as an appendix to the test
method evaluation report.
View publications and presentations on NICEATM-ICCVAM evaluations of the murine local
lymph node assay for identification and classification of sensitizers
Federal Register Notices
Report and Recommendations on the Usefulness and Limitations of the
Murine Local Lymph Node Assay for Potency Categorization of Chemicals
Causing Allergic Contact Dermatitis in Humans
(76 FR 18639, July 28, 2011) [PDF]
Peer Review Panel Report on the Validation Status of New Versions and Applications
of the Murine Local Lymph Node Assay (LLNA): A Test Method for Assessing the Allergic Contact Dermatitis Potential of Chemicals and Products: Notice of Availability and Request for Public Comments
(73 FR 29136, May 20, 2008) [PDF]
Announcement of an Independent Scientific Peer Review Panel Meeting on the Murine Local Lymph Node Assay; Availability of Draft Background Review Documents; Request for Comments
(73 FR 1360, January 8, 2008) [PDF]
View public comments received in response to notice
Transmittal of Recommendations to Federal Agencies
- Agency for Toxic Substances and Disease Registry (ATSDR)
- Letter from Dr. Birnbaum to Thomas R. Frieden, M.D., M.P.H., Director, Centers for Disease
Control, and Administrator, ATSDR
[PDF]
- Response from Christopher J. Portier, Ph.D., Director, National Center for Environmental Health and ATSDR
(received January 5, 2012) [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 February 7, 2012) [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 January 6, 2012) [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 January 6, 2012) [PDF]
- National Cancer Institute (NCI)
- Letter from Dr. Birnbaum to Harold Varmus, M.D., Director, NCI [PDF]
- Response from Dr. Varmus (received July 15, 2011) [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 December 12, 2011) [PDF]
- National Institute of Environmental Health Sciences (NIEHS)
- Letter from Linda Birnbaum, Ph.D., DABT, ATS, Director, NIEHS, to the ICCVAM Committee (August 5, 2011)
[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 November 8, 2011) [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 December 15, 2011) [PDF]
- Occupational Safety and Health Administration (OSHA)
- Letter from Dr. Birnbaum to David Michaels, Ph.D., M.P.H., Assistant Secretary of Labor for Occupational Safety and Health,
OSHA [PDF]
- Response from Dr. Michaels
(received December 13, 2011) [PDF]
- U.S. Department of Agriculture
- Letter from Dr. Birnbaum to Tom Vilsack, Secretary of Agriculture [PDF]
- Response from Jose Diez, Associate Deputy Administrator, Animal and Plant Health Inspection Service (received July 18, 2011) [PDF]
- U.S. Department of Defense
- Letter from Dr. Birnbaum to Leon E. Panetta, Secretary of Defense [PDF]
- Response from Patrick Mason, Ph.D., SES, Director, Human Performance, Training, and BioSystems (received December 16, 2011) [PDF]
- U.S. Department of Energy
- Letter from Dr. Birnbaum to Steven Chu, Secretary of Energy [PDF]
- Response from Dr. Michael Kuperberg, Office of Biological and Environmental Research (received October 31, 2011) [PDF]
- U.S. Department of the Interior
- Letter from Dr. Birnbaum to Ken Salazar, Secretary of the Interior [PDF]
- Response from David Russ, Regional Executive, Northeast Area, U.S. Geological Survey (received January 10, 2012) [PDF]
- U.S. Department of Transportation
- Letter from Dr. Birnbaum to Ray LaHood, Secretary of Transportation [PDF]
- Response from Cynthia Quarterman, Pipeline and Hazardous Materials Safety Administration (received December 20, 2011) [PDF]
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