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A 3D-Perspective on in vitro genotoxicity testing

KERSTIN REISINGER*, THOMAS FÖRSTER, SIMONE HOFFMANN-DÖRR, DIRK PETERSOHN
*Corresponding author
Henkel AG & Co. KGaA, Düsseldorf, Germany

Abstract

The classical in vitro genotoxicity test battery is known to be sensitive for indicating genotoxicity. However, a high rate of ’misleading’ positives is reported when three tests are combined as requested by several legislations (e.g. REACh).  Despite the recent optimization of standard in vitro tests, two gaps could merely be addressed with assays based on monolayer cell cultures, i.e., the route of exposure and a relevant xenobiotic metabolism to transform chemicals into reactive metabolites. For many products skin is the first site-of-contact. Therefore, human reconstructed skin, such as Phenion® Full-Thickness Skin Models, have been combined with classical toxicological parameters to develop new in vitro genotoxicity assays.

We here report on the 3D Skin Comet assay, which has been developed and validated in a joint research project. In parallel, it has been used for toxicological safety assessments of three hair dye ingredients of which one will be delineated. These case studies exemplify the use of the assay as a follow up on unfavorable results from classical testing (i.e. Ames test results) of dermally applied compounds.


INTRODUCTION 

Toxicological safety assessment evolves, fostered by amendments to European legislations (1, 2), which support the use of in vitro methods. In parallel, a far-reaching report was released by the US National Research Council which proposes new ways of safety assessment based on advances made in molecular biology, biotechnology, etc. (3). In response, worldwide initiatives are addressing the demand for new predictive in vitro methods which intend to be more directly related to human exposure. One example in the field of genotoxicity, i.e., the investigation of possible DNA damage, will be delineated in the following.

In the safety assessment of chemicals, genotoxicity is a major endpoint which co-decides whether a chemical is further considered for product development. The Investigation of the genotoxic hazard starts with in vitro testing across sector industries. However, respective assays are characterized by a reduced predictivity (4). Despite their optimization (see revised OECD Testing Guidelines, e.g. 5), these classical ass ...




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