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Overview on Current Status of Alternative Methods and Testing Approaches for Skin Irritation Testing

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Alternatives for Dermal Toxicity Testing

Abstract

In vitro test methods for skin irritation have been validated and regulatory adopted as early as 2009 in the EU and 2010 at the OECD level. Current internationally agreed approaches recommend the use of Integrated Approach for Testing and Assessment (IATA), that allow to replace or minimize to the extent possible the use of in vivo animal testing (OECD Guidance Document 203). The IATA comprises in a sequential way (1) the use of existing information, physico-chemical properties and non-testing methods, (2) a weigh-of-evidence evaluation of the existing data, and (3) if needed, the conduct of prospective testing. Although no single in vitro test method can cover across the full range of skin corrosion and irritation responses from the traditional in vivo Draize rabbit test, the currently validated and adopted in vitro methods for skin irritation and corrosion can replace the in vivo test when combined within tiered testing strategies in either a top-down or a bottom-up approach for predicting the potential skin irritation and corrosion hazard of a test chemical.

Skin irritation hazard as defined by the United Nations Globally Harmonized System for classification (UN GHS) can be predicted by the scientific valid reconstructed human epidermis (RhE) models that have been internationally adopted (OECD Test Guideline 439) including the EPISKIN™ Skin Irritation Test (SIT), the EpiDerm™ EPI-200-SIT, the SkinEthic™ RHE SIT42bis and the Labcyte EPI-MODEL 24SIT. These methods are comprised of non-transformed human-derived epidermal keratinocytes cells which have been cultured in an air-liquid interface to form a multilayered, highly differentiated model of the human epidermis. The RhE-based test methods measure the initiating events in the cascade of skin irritation, e.g. cell/tissue damage, using cell viability as readout.

Depending on the regulatory framework and the classification system in use, these test methods can be used to determine the skin irritancy of chemicals either as a stand-alone replacement test of the in vivo skin irritation testing or as a partial replacement test within a testing strategy (OECD Guidance Document 203). Test chemicals are applied topically to the RhE models and cell viability is measured by enzymatic conversion of the vital dye MTT into a blue formazan salt that is quantitatively measured after extraction from tissues. Irritant chemicals are identified by their ability to decrease cell viability below defined threshold levels (i.e. ≤50%, for UN GHS category 2 skin irritants). In regions that do not adopt the optional UN GHS Category 3 (mild irritants), such as in the EU, test chemicals that produce cell viabilities above the defined threshold level, are identified as not requiring classification (i.e. >50%).

A number of similar RhE models are being developed including the epiCS® SIT method that underwent a Performance Standards based validation followed by an independent peer-review. Furthermore novel assays based on parameters other than cell viability show promise to distinguish not only irritants from non irritants but also to determine the skin irritancy potential of chemicals including for example the discrimination of mild-irritants (Cat. 3). This is the case for example of the IRR-IS assay, which is based on the quantitative analysis of expression profiles of relevant genes.

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  1. SeCAM Services & Consultation on Alternative Methods, Magliaso, Switzerland

    Chantra Eskes

  2. Swiss Federal Office of Public Health, Bern, Switzerland

    Markus Hofmann

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    Chantra Eskes

  2. Innovitox Consulting & Services, Houten, The Netherlands

    Erwin van Vliet

  3. Department of Dermatology, University of California School of Medicine, San Francisco, California, USA

    Howard I. Maibach

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Eskes, C., Hofmann, M. (2017). Overview on Current Status of Alternative Methods and Testing Approaches for Skin Irritation Testing. In: Eskes, C., van Vliet, E., Maibach, H. (eds) Alternatives for Dermal Toxicity Testing. Springer, Cham. https://doi.org/10.1007/978-3-319-50353-0_1

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