National Toxicology Program

National Toxicology Program
http://ntp.niehs.nih.gov/go/40500

ICCVAM Evaluations of Non-Animal Skin Sensitization Test Methods and Testing Strategies


ICCVAM and NICEATM scientists are developing computational models that use chemical property information and non-animal test data to predict testing outcomes for the murine local lymph node assay (LLNA), the standard animal test to identify potential skin sensitizers. The models use test data from the direct peptide reactivity assay, the KeratinoSens assay, and the human cell line activation test. These non-animal test methods were recommended by the European Union Reference Laboratory for Alternatives to Animal Testing for use in integrated testing strategies to identify potential skin sensitizers. The computational models also use read-across predictions of skin sensitization potential derived from in vivo data for analogs using QSAR Toolbox, a software package developed by the Organisation for Economic Co-operation and Development.

Details of the models were presented in a poster at the 2015 Annual Meeting of the Society of Toxicology and are the subject of a manuscript in preparation for publication in the peer-reviewed literature. To follow up on this work, ICCVAM and NICEATM scientists are developing computational models using the same non-animal data to predict human skin sensitization outcomes.

These activities follow ICCVAM’s plan to advance the state of the science for alternative skin sensitization test methods and testing strategies. ICCVAM’s plan took into consideration input from international collaborators and from responses to a November 2013 Federal Register notice.

Federal Register notice: Request for Information on Alternative Skin Sensitization Test Methods and Testing Strategies and for Comment on ICCVAM's Proposed Activities (78 FR 68076, November 13, 2013)
View notice as webpage

View comments received in response to notice

NICEATM LLNA Database

On behalf of ICCVAM, NICEATM conducted a number of analyses to evaluate the usefulness of the LLNA to identify potential skin sensitizers. Data from these analyses are available to interested stakeholders as a reference for developing and evaluating alternative methods that replace, reduce, or refine the use of animals for identification of potential skin sensitizers.

NICEATM LLNA database

Database users please note:

  • The Excel spreadsheet contains three pages: (1) data, (2) references, and (3) abbreviations.
  • The database includes data published through 2010.
  • These data have been extracted from published and unpublished data sources with permission. Users of this database should consult the original data source for questions regarding data quality and/or authenticity.

Background on Skin Sensitization Test Methods

Allergic contact dermatitis (ACD) is a skin reaction characterized by localized redness, swelling, blistering, or itching after direct contact with a skin allergen. Pesticides and other marketed chemicals, including cosmetic ingredients, are routinely tested for their potential to cause ACD so that products can be appropriately labeled for safe use and handling.

Substances with the potential to cause ACD are known as skin sensitizers, and skin sensitization is the process by which a sensitizer induces ACD. For substances that initiate the process through covalent binding to skin proteins, the key biological events have been fairly well characterized. These events form the basis for an “adverse outcome pathway” (AOP) for skin sensitization. An AOP is a conceptual model that links exposure to a substance to a toxic effect by identifying the sequence of biochemical events required to produce the toxic effect. The AOP for skin sensitization provides a framework for the development of toxicity tests that can assess chemical effects on each biological event in the pathway and thereby provide evidence on the skin sensitization potential of a substance.

Current ICCVAM Activities

The potential for a substance to bind skin proteins can be assessed by evaluating its physical and chemical properties and by testing the substance using assays such as the electrophilic allergen screening assay (EASA) and the direct peptide reactivity assay. The developer of the EASA submitted a nomination in 2012 requesting that NICEATM and ICCVAM evaluate this method as a screening assay for identification of potential sensitizers. ICCVAM is considering the nomination in the context of ongoing international evaluations of testing approaches intended to replace the use of animals in skin sensitization testing. These include studies being conducted by the European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) and by Cosmetics Europe. NICEATM and ICCVAM provided expertise and advice to the management group conducting the EURL ECVAM study, and will comment on Cosmetics Europe's ongoing evaluations of alternative test methods and testing strategies for the identification of skin sensitizers.

Information about the EASA Nomination

NTP is located at the National Institute of Environmental Health Sciences, part of the National Institutes of Health.