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The rat bone marrow micronucleus test: Statistical considerations on historical negative control data.
Igl, Bernd-Wolfgang; Bitsch, Annette; Bringezu, Frank; Chang, Steffi; Dammann, Martina; Frötschl, Roland; Harm, Volker; Kellner, Rupert; Krzykalla, Volker; Lott, Jasmin; Nern, Marlies; Pfuhler, Stefan; Queisser, Nina; Schulz, Markus; Sutter, Andreas; Vaas, Lea; Vonk, Richardus; Zellner, Dietmar; Ziemann, Christina.
Afiliación
  • Igl BW; Bayer AG, Research and Clinical Sciences Statistics, Müllerstr. 178, 13353, Berlin, Germany.
  • Bitsch A; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Nikolai-Fuchs-Str. 1, 30625, Hannover, Germany.
  • Bringezu F; Merck KGaA, Biopharma and Non-Clinical Safety, Frankfurter Str. 250, 64293 Darmstadt, Germany.
  • Chang S; Envigo CRS GmbH, In den Leppsteinswiesen 19, 64380 Rossdorf, Germany.
  • Dammann M; BASF SE, RB/TC - Z470, Carl-Bosch-Str. 38, 67056 Ludwigshafen am Rhein, Germany.
  • Frötschl R; Federal Institute for Drugs and Medical Devices (BfArM), Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Germany.
  • Harm V; Bayer AG, Research and Clinical Sciences Statistics, Müllerstr. 178, 13353, Berlin, Germany.
  • Kellner R; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Nikolai-Fuchs-Str. 1, 30625, Hannover, Germany.
  • Krzykalla V; Boehringer Ingelheim Pharma GmbH & Co. KG, Biostatistics and Data Sciences Europe, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.
  • Lott J; Boehringer Ingelheim Pharma GmbH & Co. KG, Development NCE NDS, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.
  • Nern M; Bayer AG, Research & Development, Pharmaceuticals, Genetic Toxicology Wuppertal, Aprather Weg 18a, 42096, Wuppertal, Germany.
  • Pfuhler S; Procter & Gamble, 8700 Mason-Montgomery Rd., Cincinnati, 45040, Ohio, USA.
  • Queisser N; Bayer AG, Research & Development, Pharmaceuticals, Genetic Toxicology, 13342, Berlin, Germany.
  • Schulz M; Envigo CRS GmbH, In den Leppsteinswiesen 19, 64380 Rossdorf, Germany.
  • Sutter A; Bayer AG, Research & Development, Pharmaceuticals, Genetic Toxicology, 13342, Berlin, Germany.
  • Vaas L; Bayer AG, Research and Clinical Sciences Statistics, Müllerstr. 178, 13353, Berlin, Germany.
  • Vonk R; Bayer AG, Medical Writing and Statistics Oncology, Müllerstr. 178, 13353, Berlin, Germany.
  • Zellner D; Boehringer Ingelheim Pharma GmbH & Co. KG, Biostatistics and Data Sciences Europe, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.
  • Ziemann C; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Nikolai-Fuchs-Str. 1, 30625, Hannover, Germany. Electronic address: christina.ziemann@item.fraunhofer.de.
Regul Toxicol Pharmacol ; 102: 13-22, 2019 Mar.
Article en En | MEDLINE | ID: mdl-30572081
Recent updates of the OECD Guidelines for the Testing of Chemicals (Section 4: Health Effects) on genotoxicity testing emphasize the use of appropriate statistical methods for data analysis and proficiency proof. Updates also concern the mammalian erythrocyte micronucleus test (OECD 474), as the currently most often performed regulatory in vivo test. As the updated guideline gives high importance to adequate statistical assessment of historical negative control data to estimate validity of experiments and judge results, the present study evaluated statistical methodologies for handling of historical negative control data sets, and comes forward with respective proposals and reference data. Therefore, the working group "Statistics" within the German-speaking "Gesellschaft für Umwelt-Mutationsforschung e.V." (GUM) compiled a data set of 891 negative control rats from valid OECD 474-studies of four laboratories. Based on these data, Analysis-of-Variance (ANOVA) identified "laboratory" and "strain", but not "gender" as relevant stratification parameters, and argued for approximately normally distributed micronucleus frequencies in polychromatic erythrocytes per animal. This assumption provided the basis for further specifying one-sided parametric tolerance intervals for determination of corresponding upper historical negative control limits. Finally, the stability of such limits was investigated as a function of the number of experiments performed, using a simulation-based statistical strategy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pruebas de Micronúcleos / Grupos Control Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Regul Toxicol Pharmacol Año: 2019 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pruebas de Micronúcleos / Grupos Control Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Regul Toxicol Pharmacol Año: 2019 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Países Bajos