Repeat-assessment of 1,4-dioxane in a rat-hepatocyte replicative DNA synthesis (RDS) test: Evidence for stimulus of hepatocyte proliferation

1,4-Dioxane is a nongenotoxic hepatocarcinogen but in our previous replicat ive DNA synthesis (RDS) studies with the [H-3]thymidine (TdR)-technique, it failed to increase hepatocyte RDS values when given by gavage to male F344 rats as a single 2000 mg/kg body weight dose. However, in a current series of trials with TdR, it showed equivocal responses 24 or 48 hr following tr eatment with 2000 mg/kg in time-course experiments, and positive responses 24 hr following 1000, 1500 and 2000 mg/kg in dose-response experiments. An increased RDS incidence was also observed at the dose of 2000 mg/kg with da ta for 5-bromo-2'-deoxyuridine (BrdU)-incorporation. These present findings thus support the hypothesis that a capacity to induce cell proliferation m ay play a key role in 1,4-dioxane hepatocarcinogenesis.