Non-animal sensitization testing: State-of-the-art

Abstract

Predictive tests to identify the sensitizing properties of chemicals are carried out using animals. In the European Union timelines for phasing out many standard animal tests were established for cosmetics. Following this policy, the new European Chemicals Legislation (REACH) favors alternative methods, if validated and appropriate. In this review the authors aim to provide a state-of-the art overview of alternative methods (in silico, in chemico, and in vitro) to identify contact and respiratory sensitizing capacity and in some occasions give a measure of potency. The past few years have seen major advances in QSAR (quantitative structure-activity relationship) models where especially mechanism-based models have great potential, peptide reactivity assays where multiple parameters can be measured simultaneously, providing a more complete reactivity profile, and cell-based assays. Several cell-based assays are in development, not only using different cell types, but also several specifically developed assays such as three-dimenionally (3D)-reconstituted skin models, an antioxidant response reporter assay, determination of signaling pathways, and gene profiling. Some of these assays show relatively high sensitivity and specificity for a large number of sensitizers and should enter validation (or are indeed entering this process). Integrating multiple assays in a decision tree or integrated testing system is a next step, but has yet to be developed. Adequate risk assessment, however, is likely to require significantly more time and efforts.

Keywords::

• 3D-reconstructed epidermal model
• Alternative testing
• gene expression profiling
• integrated testing
• oxidative stress response
• peptide reactivity
• sensitization
• QSAR
• signaling pathway

Acknowledgements

The authors gratefully acknowledge the critical review of early drafts of the manuscript by Drs. J. Ezendam, J. Pennings, and E. Rorije.

Declaration of interest

The Dutch Ministry of Health, Welfare, and Sports, and the Netherlands Genomics Initiative/Netherlands Toxicogenomics Centre provided financial support for preparation of the review. The review was conducted by the authors during the normal course of their employment as shown on the first page. The authors alone are responsible for the contents and writing of the review. The conclusions drawn and the recommendations made are those of the authors and are not necessarily the views of their employer or the Dutch Ministry of Health, Welfare and Sport.