Prevalidation of a rat liver foci bioassay (RLFB) based on results from 1600 rats: a study report.
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.
Ittrich
Carina
C
Central Unit Biostatistics, German Cancer Research Center (DKFZ), P.O. Box 101949, D-69009 Heidelberg, Germany.
Deml
Erhard
E
Oesterle
Doris
D
Küttler
Karin
K
Mellert
Werner
W
Brendler-Schwaab
Susanne
S
Enzmann
Harald
H
Schladt
Ludwig
L
Bannasch
Peter
P
Haertel
Thomas
T
Mönnikes
Oliver
O
Schwarz
Michael
M
Kopp-Schneider
Annette
A
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests / Q000379:methods; D002273:Carcinogens / Q000633:toxicity*; D002994:Clofibrate / Q000633:toxicity; D003043:Cocarcinogenesis; D004052:Diethylnitrosamine / Q000633:toxicity; D005260:Female; D022781:Hepatocytes / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009602:Nitrosamines / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000633:toxicity; D011230:Precancerous Conditions / Q000139:chemically induced*; D051381:Rats; D017208:Rats, Wistar
D002273:Carcinogens; D009602:Nitrosamines; D004052:Diethylnitrosamine; C002741:N-nitrosomorpholine; D015073:2-Acetylaminofluorene; D002994:Clofibrate; D010634:Phenobarbital