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Toxicologic Pathology
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Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report

Carina Ittrich

Central Unit Biostatistics German Cancer research Center (DKFZ), P.O. Box 101949, D-69009 Heidelberg, Germany

Erhard Deml

Department Technical Security GSF-National Research Center for Environment and Health, Ingolstädter Landstr.1, D-85764 Neuherberg, Germany

Doris Oesterle

Institute of Toxicology, GSF-National Research Center for Environment and Health, Ingolstädter Landstr.1, D-85764 Neuherberg, Germany

Karin Küttler

Product Safety-Regulations, Toxicology and Ecology, BASF AG, D-67056 Ludwigshafen/Rhein, Germany

Werner Mellert

Product Safety-Regulations, Toxicology and Ecology, BASF AG, D-67056 Ludwigshafen/Rhein, Germany

Susanne Brendler-Schwaab

Toxicology-Rodent Studies and Genetic Toxicology, Bayer AG, D-42096 Wuppertal, Germany

Harald Enzmann

Toxicology-Rodent Studies and Genetic Toxicology, Bayer AG, D-42096 Wuppertal, Germany

Ludwig Schladt

Toxicology-Rodent Studies and Genetic Toxicology, Bayer AG, D-42096 Wuppertal, Germany

Peter Bannasch

Department of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), P.O. Box 101949, D-69009 Heidelberg, Germany

Thomas Haertel

Department of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), P.O. Box 101949, D-69009 Heidelberg, Germany

Oliver Mönnikes

Department of Toxicology, Institute of Pharmacology and Toxicology, University of Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany

Michael Schwarz

Department of Toxicology, Institute of Pharmacology and Toxicology, University of Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany

Annette Kopp-Schneider

Central Unit Biostatistics German Cancer research Center (DKFZ), P.O. Box 101949, D-69009 Heidelberg, Germany, kopp{at}dkfz.de

A rat liver foci bioassay (RLFB) based on an initiation-promotion protocol employing preneoplastic foci of altered hepatocytes (FAH) as an endpoint, was prevalidated in 5 different laboratories. FAH were identified by immunohistochemical demonstration of glutathione-S-transferase (placental form, GSTP) and by staining with hematoxilin/eosin (H&E), and their area fraction was quantified morphometrically. The four model hepatocarcinogens N-nitrosomorpholine, 2-acetylaminofluoren, phenobarbital, and clofibrate were selected according to characteristic differences in their presumed mode of action, and tested in a total of 1,600 male and female rats at 2 different dose levels. The chemicals were found to differ characteristically in their potency and dose-response relationship to induce FAH when given alone or when administered following initiation with diethylnitrosamine. The interlaboratory variation was small for results obtained with the GSTP-stain and somewhat larger with respect to H&E. The assessment of the carcinogenic potential of the four chemicals by the different laboratories was in the same range and the nature of their dose-response relationships did not differ essentially between laboratories. Our results suggest that this RLFB is a sensitive bioassay, providing potentially valuable information for risk assessment including the classification of carcinogenic chemicals according to their mode of action.

Key Words: Hepatocarcinogenesis • foci of altered hepatocytes • rat liver foci bioassay • prevalidation study • phenobarbital • clofibrate • N-nitrosomorpholine • 2-acetylaminofluorene.

Toxicologic Pathology, Vol. 31, No. 1, 60-79 (2003)
DOI: 10.1080/01926230390173888
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