Implementation of a dermal sensitization threshold (DST) concept for risk assessment: structure-based DST and in vitro data-based DST

Abstract

Skin sensitization resulting in allergic contact dermatitis represents an important toxicological endpoint as part of safety assessments. When available substance-specific sensitization data are inadequate, the dermal sensitization threshold (DST) concept has been proposed to set a skin exposure threshold to provide no appreciable risk of skin sensitization. Structure-based DSTs, which include non-reactive, reactive, and high potency category (HPC) DSTs, can be applied to substances with an identified chemical structures. An in vitro data-based “mixture DST” can be applied to mixtures based on data from in vitro test methods, such as KeratinoSens™ and the human Cell Line Activation Test. The purpose of this review article is to discuss the practical use of DSTs for conducting sound sensitization risk assessments to assure the safety of consumer products. To this end, several improvements are discussed in this review. For application of structure-based DSTs, an overall structural classification workflow was developed to exclude the possibility that “HPC but non-reactive” chemicals are misclassified as “non-reactive”, because such chemicals should be classified as HPC chemicals considering that HPC rules have been based on the chemical structure of high potency sensitizers. Besides that, an extended application of the mixture DST principle to mixtures that either is cytotoxic or evaluated as positive was proposed. On a final note, we also developed workflows that integrate structure-based and in vitro-based mixture DST. The proposed workflows enable the application of the appropriate DST, which serves as a point of departure in the quantitative sensitization risk assessment.

Keywords:

• Skin sensitization
• dermal sensitization threshold (DST)
• reactive DST
• high potency category DST
• mixture DST

Acknowledgements

The authors wish to thank past and present members of their laboratories for helpful discussions and comments. Additionally, the authors gratefully acknowledge the comments provided by the editor and four anonymous peer-reviewers selected by the editor. These comments were quite helpful for revising the manuscript.

Declaration of interest

Taku Nishijo, Masaaki Miyazawa, and Hitoshi Sakaguchi are employees of Kao Corporation. Anne Marie Api and Mihwa Na are employees of the Research Institute for Fragrance Materials. G. Frank Gerberick receives support from Kao Corporation and Research Institute for Fragrance Materials as a consultant. The authors declare no conflict of interest other than employment or receiving support.

Supplemental material

Supplemental material for this article is available online here.