Mutagenesis Advance Access originally published online on March 16, 2007
Mutagenesis 2007 22(3):161-175; doi:10.1093/mutage/gem006
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© The Author 2007. Published by Oxford University Press. All rights reserved.
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In vitro approaches to develop weight of evidence (WoE) and mode of action (MoA) discussions with positive in vitro genotoxicity results
Covance Laboratories Limited, Otley Road, Harrogate HG3 1PY, UK 1The Procter & Gamble Company, Miami Valley Laboratories, PO Box 538707, Cincinnati, OH 45253-8707, USA 2Henkel KGaA, Henkelstrasse 67, D-40191 Düsseldorf, Germany 3Unilever, Safety & Environment Assurance Centre, Sharnbrook MK44 1LQ, UK 4Kao Professional Salon Services (KPSS) GmbH, Pfungstaedter Strasse 92-100, D-64297 Darmstadt, Germany 5L'Oréal, Avenue Eugène Schuller, F-93600 Aulnay sous Bois Cedex, France 6Procter & Gamble, Rte de Chesalles 26, CH-1723 Marly, Switzerland
A recent analysis by Kirkland et al. [Kirkland, D., Aardema, M., Henderson, L. and Müller, L. (2005) Evaluation of the ability of a battery of 3 in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity, specificity and relative predictivity. Mutat. Res. 584, 1–256] demonstrated an extremely high false positive rate for in vitro genotoxicity tests when compared with carcinogenicity in rodents. In many industries, decisions have to be made on the safety of new substances, and health risk to humans, without rodent carcinogenicity data being available. In such cases, the usual way to determine whether a positive in vitro genotoxicity result is relevant (i.e. indicates a hazard) for humans is to develop weight of evidence (WoE) or mode of action (MoA) arguments. These are based partly on further in vitro investigations, but usually rely heavily on tests for genotoxicity in one or more in vivo assays. However, for certain product types in the European Union, the use of animals for genotoxicity testing (as well as for other endpoints) will be prohibited within the next few years. Many different examples have been described that indicate DNA damage and genotoxic responses in vitro can arise through non-relevant in vitro events that are a result of the test systems and conditions used. The majority of these non-relevant in vitro events can be grouped under a category of ‘overload of normal physiology’ that would not be expected to occur in exposed humans. However, obtaining evidence in support of such MoAs is not easy, particularly for those industries prohibited from carrying out in vivo testing. It will become necessary to focus on in vitro studies to provide evidence of non-DNA, threshold or in vitro-specific processes and to discuss the potential for such genotoxic effects to occur in exposed humans. Toward this end, we surveyed the published literature for in vitro approaches that may be followed to determine whether a genotoxic effect observed in vitro will occur in humans. Unfortunately, many of the approaches we found are based on only a few published examples and validated approaches with consensus recommendations often do not exist. This analysis highlights the urgent need for developing consensus approaches that do not rely on animal studies for dealing with in vitro genotoxins.
* To whom correspondence should be addressed. Tel: +44 1423 848401; Fax: +44 1423 848983; Email: david.kirkland{at}covance.com
Received on October 16, 2006; revised on January 3, 2007; accepted on January 22, 2007.
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