The in vivo-in vitro replicative DNA synthesis (RDS) test with hepatocytes prepared from male B6C3F1 mice as an early prediction assay for putative nongenotoxic (Ames-negative) mouse hepatocarcinogens.
To assess the efficacy of the in vivo-in vitro hepatocyte replicative DNA synthesis (RDS) test as a short-term assay, 41 putative nongenotoxic (Ames-negative) mouse hepatocarcinogens, as well as 31 noncarcinogens, were examined using male 8-week-old B6C3F1 mice and an in vitro [methyl-3]thymidine-incorporation technique. Animals were exposed to the maximum tolerated dose (MTD) and 1/2 MTD of each chemical by gavage and after 24, 39 or 48 h, hepatocytes were prepared with a collagenase-perfusion technique. Assessment of the distribution of spontaneous RDS in a total of 337 control mice gave an average incidence of 0.15 +/- 0.08% within the range of 0 to 0.39% (mean +/- 3 x SE) with a 99.7% probability. Values of 0.4% or more for RDS incidences induced by test samples were therefore judged as indicating a positive response in our RDS test. Under the experimental conditions applied, 32 of 41 putative nongenotoxic hepatocarcinogens gave clear positive responses (positive sensitivity: 78%), and of 31 noncarcinogens 25 samples gave negative responses (negative specificity: 81%), thus giving an overall concordance for the RDS test with long-term findings of 79%.
Miyagawa
M
M
Yokohama Laboratory, Mitsubishi Chemical Safety Institute Ltd., Yokohama, Japan.
Takasawa
H
H
Sugiyama
A
A
Inoue
Y
Y
Murata
T
T
Uno
Y
Y
Yoshikawa
K
K
D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D002460:Cell Line; D003433:Crosses, Genetic; D004261:DNA Replication / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009152:Mutagenicity Tests; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D002273:Carcinogens