title: 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.
authors.affiliation: a Centre for Health Protection, National Institute for Public Health and the Environment (RIVM) , Bilthoven , the Netherlands ;
authors.forename: Mirjam
authors.initials: M
authors.lastname: Luijten
authors.affiliation: a Centre for Health Protection, National Institute for Public Health and the Environment (RIVM) , Bilthoven , the Netherlands ;
authors.forename: Evelyn D
authors.initials: ED
authors.lastname: Olthof
authors.affiliation: b Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM) , Bilthoven , the Netherlands ;
authors.forename: Betty C
authors.initials: BC
authors.lastname: Hakkert
authors.affiliation: b Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM) , Bilthoven , the Netherlands ;
authors.forename: Emiel
authors.initials: E
authors.lastname: Rorije
authors.affiliation: c Medicines Evaluation Board , Utrecht , the Netherlands ;
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: van der Laan
authors.affiliation: d Netherlands Organization for Applied Scientific Research (TNO) , Zeist , the Netherlands.
authors.forename: Ruud A
authors.initials: RA
authors.lastname: Woutersen
authors.affiliation: a Centre for Health Protection, National Institute for Public Health and the Environment (RIVM) , Bilthoven , the Netherlands ;
authors.forename: Jan
authors.initials: J
authors.lastname: van Benthem
mesh_terms: D000818:Animals; D001681:Biological Assay; D015197:Carcinogenicity Tests / Q000379:methods* / Q000592:standards; D002273:Carcinogens / Q000633:toxicity; D004249:DNA Damage; D006801:Humans; D009152:Mutagenicity Tests / Q000379:methods / Q000592:standards; D009153:Mutagens / Q000633:toxicity; D009369:Neoplasms; D018570:Risk Assessment / Q000379:methods
chemical_list: D002273:Carcinogens; D009153:Mutagens
keywords: Carcinogenicity; DNA damage; chromosome aberration; genotoxic carcinogens; genotoxicity; mutagenicity; non-genotoxic carcinogens; regulatory implementation; risk assessment