title: Correlation of In Vivo Versus In Vitro Benchmark Doses (BMDs) Derived From Micronucleus Test Data: A Proof of Concept Study.
abstract: In this study, we explored the applicability of using in vitro micronucleus (MN) data from human lymphoblastoid TK6 cells to derive in vivo genotoxicity potency information. Nineteen chemicals covering a broad spectrum of genotoxic modes of action were tested in an in vitro MN test using TK6 cells using the same study protocol. Several of these chemicals were considered to need metabolic activation, and these were administered in the presence of S9. The Benchmark dose (BMD) approach was applied using the dose-response modeling program PROAST to estimate the genotoxic potency from the in vitro data. The resulting in vitro BMDs were compared with previously derived BMDs from in vivo MN and carcinogenicity studies. A proportional correlation was observed between the BMDs from the in vitro MN and the BMDs from the in vivo MN assays. Further, a clear correlation was found between the BMDs from in vitro MN and the associated BMDs for malignant tumors. Although these results are based on only 19 compounds, they show that genotoxicity potencies estimated from in vitro tests may result in useful information regarding in vivo genotoxic potency, as well as expected cancer potency. Extension of the number of compounds and further investigation of metabolic activation (S9) and of other toxicokinetic factors would be needed to validate our initial conclusions. However, this initial work suggests that this approach could be used for in vitro to in vivo extrapolations which would support the reduction of animals used in research (3Rs: replacement, reduction, and refinement).
authors.affiliation: *National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands;
authors.forename: Lya G
authors.initials: LG
authors.lastname: Soeteman-Hernández
authors.affiliation: AstraZeneca, R&D Alderley Park, Macclesfield, Cheshire SK10 4TF, United Kingdom; and mick.fellows@astrazeneca.com.
authors.forename: Mick D
authors.initials: MD
authors.lastname: Fellows
authors.affiliation: Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP Wales, United Kingdom.
authors.forename: George E
authors.initials: GE
authors.lastname: Johnson
authors.affiliation: *National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands;
authors.forename: Wout
authors.initials: W
authors.lastname: Slob
mesh_terms: D000826:Animal Testing Alternatives / Q000592:standards*; D000818:Animals; D019985:Benchmarking / Q000592:standards*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000473:pathology; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D015162:Micronucleus Tests / Q000592:standards*; D008954:Models, Biological; D015203:Reproducibility of Results; D018570:Risk Assessment
keywords: TK6 cells, benchmark dose approach; genotoxic potency; in vitro micronucleus