An integrative test strategy for cancer hazard identification

Abstract

Assessment of genotoxic and carcinogenic potential is considered one of the basic requirements when evaluating possible human health risks associated with exposure to chemicals. Test strategies currently in place focus primarily on identifying genotoxic potential due to the strong association between the accumulation of genetic damage and cancer. Using genotoxicity assays to predict carcinogenic potential has the significant drawback that risks from non-genotoxic carcinogens remain largely undetected unless carcinogenicity studies are performed. Furthermore, test systems already developed to reduce animal use are not easily accepted and implemented by either industries or regulators. This manuscript reviews the test methods for cancer hazard identification that have been adopted by the regulatory authorities, and discusses the most promising alternative methods that have been developed to date. Based on these findings, a generally applicable tiered test strategy is proposed that can be considered capable of detecting both genotoxic as well as non-genotoxic carcinogens and will improve understanding of the underlying mode of action. Finally, strengths and weaknesses of this new integrative test strategy for cancer hazard identification are presented.

Keywords:

• Carcinogenicity
• chromosome aberration
• DNA damage
• genotoxic carcinogens
• genotoxicity
• mutagenicity
• non-genotoxic carcinogens
• regulatory implementation
• risk assessment

Acknowledgements

The authors wish to thank David Kirkland and Stefan Pfuhler for their thorough reviews and valuable comments. They also thank Eric Gremmer for providing a graphic design of the integrative strategy. The authors also gratefully acknowledge the extensive comments of six reviewers selected by the Editor and anonymous to the authors. These comments were valuable in revising the manuscript.

Declaration of interest

The authors’ employment affiliations are as shown on the cover page. Mirjam Luijten, Evelyn D. Olthof, Betty C. Hakkert, Emiel Rorije and Jan van Benthem are affiliated to the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. RIVM is a government agency under the Dutch Ministry of Health, Welfare and Sports, which has fully sponsored the present piece of work. Jan-Willem van der Laan is affiliated to the Medicines Evaluation Board, Utrecht, the Netherlands. Ruud A. Woutersen is affiliated to the Netherlands Organization for Applied Scientific Research (TNO), Zeist, the Netherlands. The design of the appraisal, the conduct of the appraisal and the conclusions drawn in the paper are the exclusive work product of the authors and may not necessarily be those of their employers.