title: Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? I. Reports of individual databases presented at an EURL ECVAM Workshop.
abstract: Positive results in the Ames test correlate well with carcinogenic potential in rodents. This correlation is not perfect because mutations are only one of many stages in tumour development. Also, situations can be envisaged where the mutagenic response may be specific to the bacteria or the test protocol, e.g., bacterial-specific metabolism, exceeding a detoxification threshold, or the induction of oxidative damage to which bacteria may be more sensitive than mammalian cells in vitro or tissues in vivo. Since most chemicals are also tested for genotoxicity in mammalian cells, the pattern of mammalian cell results may help identify whether Ames-positive results predict carcinogenic or in vivo mutagenic activity. A workshop was therefore organised and sponsored by the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) to investigate this further. Participants presented results from other genotoxicity tests with Ames-positive compounds. Data came from published, regulatory agency, and industry sources. The question was posed whether negative results in mammalian cell tests were associated with absence of carcinogenic or in vivo genotoxic activity despite a positive Ames test. In the limited time available, the presented data were combined and an initial analysis suggested that the association of negative in vitro mammalian cell test results with lack of in vivo genotoxic or carcinogenic activity could have some significance. Possible reasons why a positive Ames test may not be associated with in vivo activity and what additional investigations/tests might contribute to a more robust evaluation were discussed. Because a considerable overlap was identified among the different databases presented, it was recommended that a consolidated database be built, with overlapping chemicals removed, so that a more robust analysis of the predictive capacity for potential carcinogenic and in vivo genotoxic activity could be derived from the patterns of mammalian cell test results obtained for Ames-positive compounds.
authors.affiliation: Kirkland Consulting, PO Box 79, Tadcaster LS24 0AS, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Kirkland
authors.affiliation: Errol Zeiger Consulting, 800 Indian Springs Rd., Chapel Hill, NC 27514, USA.
authors.forename: Errol
authors.initials: E
authors.lastname: Zeiger
authors.affiliation: European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), Systems Toxicology Unit; Institute for Health and Consumer Protection (IHCP), European Commission - Joint Research Centre, TP 126, Via E. Fermi 2749, I-21027 Ispra, Va, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Madia
authors.affiliation: Surgery and Cancer, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Gooderham
authors.affiliation: BfArM, Genetic Toxicology, Kurt-George-Kiesinger Allee 3, D-53175 Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kasper
authors.affiliation: GlaxoSmithKline R&D, Park Road, Ware, Herts SG12 0DP, England, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Lynch
authors.affiliation: Division of Safety Information on Drug, Food and Chemicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Morita
authors.affiliation: L'Oreal 1, Avenue Eugéne Schueller, 93601 Aulnay-sous-Bois, France.
authors.forename: Gladys
authors.initials: G
authors.lastname: Ouedraogo
authors.affiliation: European Food Safety Authority (EFSA), Via Carlo Magno, a-43126 Parma, Italy.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Parra Morte
authors.affiliation: Procter & Gamble Co., Miami Valley Innovation Center, 11810 East Miami River Road, Cincinnati, OH 45239 8707, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfuhler
authors.affiliation: Department of Toxicology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: Vera
authors.initials: V
authors.lastname: Rogiers
authors.affiliation: BASF, Wöhlerstraße 15, 67063 Ludwigshafen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schulz
authors.affiliation: Sanofi, 13 Quai Jules Guesde, BP 14, 94403 Vitry-sur-Seine Cedex, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Thybaud
authors.affiliation: National Institute of Public Health and the Environment, Antonie van Leeuwenhoeklaan 9, PO Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: van Benthem
authors.affiliation: Gentoxicon BVBA, Boskant 101, B-2350 Vosselaar, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vanparys
authors.affiliation: European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), Systems Toxicology Unit; Institute for Health and Consumer Protection (IHCP), European Commission - Joint Research Centre, TP 126, Via E. Fermi 2749, I-21027 Ispra, Va, Italy.
authors.forename: Andrew
authors.initials: A
authors.lastname: Worth
authors.affiliation: European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), Systems Toxicology Unit; Institute for Health and Consumer Protection (IHCP), European Commission - Joint Research Centre, TP 126, Via E. Fermi 2749, I-21027 Ispra, Va, Italy. Electronic address: raffaella.corvi@ec.europa.eu.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Corvi
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D016208:Databases, Factual; D005060:Europe; D006801:Humans; D066298:In Vitro Techniques; D009153:Mutagens / Q000633:toxicity*; D012377:Rodentia; D018675:Toxicity Tests / Q000379:methods / Q000639:trends*
chemical_list: D002273:Carcinogens; D009153:Mutagens
keywords: Carcinogenicity; Database; Genotoxicity in vitro; Genotoxicity in vivo; Mammalian cell tests; Positive Ames tests