In vivo-in vitro replicative DNA synthesis (RDS) test using perfused rat livers as an early prediction assay for nongenotoxic hepatocarcinogens: II. Assessment of judgement criteria.
To better establish in vivo-in vitro hepatocyte replicative DNA synthesis (RDS) test using male F344 rats as a screening assay for nongenotoxic (the Ames-negative) hepatocarcinogens, judgement criteria were assessed after single-gavage treatment with seven model compounds. The profiles of RDS induction by the compounds were analysed in terms of both time-course and dose-dependence. Our data reveal that a value of 2% or more for RDS incidence should be judged as positive and that of less than 1% RDS incidence as negative using maximum tolerance dose (MTD) concentrations in time-course experiments at 15, 24, 39, 48 and 63 h. In the case of an incidence value between 1 and 2%, the finding of a clear dose-dependence was considered to justify the conclusion of a positive effect for 1/4 MTD, 1/2 MTD, MTD and 2 x MTD at a fixed time. The established judgement criteria are planned for introduction in detection of nongenotoxic hepatocarcinogens (the Ames-negative carcinogens) using the RDS test.
Uno
Y
Y
Toxicology Laboratory, Mitsubishi Kasei Co., Yokohama, Japan.
Takasawa
H
H
Miyagawa
M
M
Inoue
Y
Y
Murata
T
T
Ogawa
M
M
Yoshikawa
K
K
D000818:Animals; D015197:Carcinogenicity Tests / Q000592:standards; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D010477:Perfusion; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens