Skin sensitizers in cosmetics and beyond: potential multiple mechanisms of action and importance of T-cell assays for in vitro screening

Abstract

Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity (DTH) reaction induced by repeated contact with sensitizers. The ability of a chemical to act as a sensitizer has most frequently been tested in animals. As the use of animals for these purposes is gradually and globally being phased out, there is a need for reliable in vitro surrogate assays. Currently proposed in vitro assays are designed to test four key events of the adverse outcome pathway (AOP) involving covalent modification of self-proteins by sensitizers (haptenation) and presentation of new antigens (hapten/carrier complexes) to the immune system. There appears to be imperfect alignment of in vitro assays with clinical and/or animal data, suggesting possibly additional mechanisms of ACD development. Indeed, studies on allergies to small drugs, small chemical-induced HLA-peptide exchange for vaccination purposes and cosmetic ingredient-induced exposure of autoantigens suggest a possibility of DTH response promotion by hapten/carrier-independent mechanisms. Therefore, there is a need for additional appropriate in vitro assays, in order to achieve maximal concordance between clinical and/or animal data and in vitro assays. In this paper, we will review evidence supporting the idea of diverse mechanisms of ACD development. We will also discuss the impact of these multiple mechanisms, on the AOP and on the in vitro assays that should be used for allergen detection. We will propose alloreactivity-like reactions, aided by computer modeling and biochemical tests of compound-HLA binding, as additional tools for better prediction of DTH reactions, resulting from exposure to ingredients in cosmetic products. The combination of the proposed tests, along with the existing assays, should further enhance animal-free assessment of sensitizing potential of individual chemicals.

Keywords:

• Allergic contact dermatitis
• cosmetics
• delayed-type hypersensitivity
• dendritic cells
• fragrance
• hapten
• HLA
• human-repeated insult patch test
• local lymph node assay
• keratinocytes
• skin sensitization
• T cells

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Acknowledgements

The authors extend a note of appreciation to the anonymous reviewers selected by the Editor whose comments helped improve the clarity of the manuscript and its overall quality.

The authors thank Mike Bevan, David Ostrov and Fabio Santori for critical reading of the manuscript. The authors also wish to thank Dr. Linda Katz, for critical review of the manuscript.

Declaration of interest

The employment affiliation of the authors is as noted on the cover page. The paper was prepared during the normal course of the authors employment. The authors have no financial or other interests and have sole responsibility for the writing and content of the paper.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of commercial products, or organizations imply endorsement by the U.S. Government. This paper reflects the current thinking and experience of the authors.