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International regulatory needs for development of an IATA for non-genotoxic carcinogenic chemical substances

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Miriam N. Jacobs 1, Annamaria Colacci 2, Kimmo Louekari 3, Mirjam Luijten 4, Betty C. Hakkert 5, Martin Paparella 6 and Paule Vasseur 7
1 Department of Toxicology, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Oxfordshire, UK
2 Center for Environmental Toxicology and Risk Assessment, Environmental Protection and Health Prevention Agency, Emilia Romagna Region, Italy
3 European Chemicals Agency, Helsinki, Finland
4 Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
5 Bureau REACH, Department for Industrial Chemicals, Centre for Safety of Substances and Products (VSP), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
6 Chemicals & Biocides, Environment Agency Austria, Vienna, Austria; 7CNRS UMR 7360, University of Lorraine, Metz, France


Although regulatory requirements for carcinogenicity testing of chemicals vary according to product sector and regulatory jurisdiction, the standard approach starts with a battery of genotoxicity tests. If any of the in vivo genotoxicity tests are positive, a lifetime rodent cancer bioassay may be requested, which allows the detection of non-genotoxic carcinogens (NGTxC). However, under most chemical regulations the cancer bioassay is rarely requested, specific requests to obtain information on non-genotoxic mechanisms of carcinogenicity are few, and there are no OECD approved screening methods. When the in vitro genotoxicity battery is negative, usually no further carcinogenicity testing is requested. Consequently NGTxC might remain unidentified and therefore the risks they may pose to human health will not be managed. In contrast to genotoxic carcinogens NGTxC act through a large variety of specific mechanisms, and a panel of tests covering multiple biological traits will be needed.

The development of an integrated approach to testing and assessment (IATA) of NGTxC could assist regulatory decision makers. We examine what NGTxC are and discuss chemical regulatory requirements and limitations. With a strong drive to reduce animal testing and costs in mind, it is essential that proper and robust alternatives for animal testing methods (3Rs) for addressing non-genotoxic modes of action are developed and used. Therefore relevant in vitro mechanisms and assays are described and tentatively organized in levels of information, indicating both a possible structure of the future IATA for NGTxC and associated OECD Test Guideline development priorities.


Keywords: non-genotoxic carcinogens, integrated approaches to testing and assessment of chemicals


ALTEX 33(4), 2016: 359-392

doi: 10.14573/altex.1601201

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