Subchronic effects of dieldrin and phenobarbital on hepatic DNA synthesis in mice and rats

Dieldrin, an organochlorine pesticide, has been shown to be hepatocarcinogenic in mice but not rats. Phenobarbital, in contrast, induces hepatic tumors in both mice and rats. Previous studies have shown that acute dietary exposure of rats or mice to either dieldrin or phenobarbital produces several liver changes, including centrilobular hypertrophy, induction of hepatic cytochrome P450, and increased liver weight. The present study examined the subchronic effect of dieldrin (0.1, 1.0, 3.0, 10.0 mg dieldrin/kg diet) and phenobarbital (10, 50, 100, 500 mg phenobarbital/kg diet) on the induction of hepatic DNA synthesis and hepatocyte lethality in male B6C3F1 mice and male F344 rats. Eight-week-old animals were treated as above and evaluated for hepatic DNA synthesis after 7, 14, 21, 28, and 90 days of continual treatment to dieldrin or phenobarbital. Maximal induction of hepatic DNA synthesis in mice was seen at the 14-, 21-, and 28-day sampling times. In rats, no significant increase in hepatic DNA synthesis or hepatocyte lethality was observed at any dose of dieldrin investigated. Phenobarbital produced a significant increase in hepatic DNA synthesis in both rat and mouse liver following 7 days of treatment. The induction of DNA synthesis in rat liver was transient, with the labeling index returning to control levels by 14 days of treatment. In contrast, mice treated with phenobarbital showed a significant increase in hepatic DNA synthesis throughout the treatment. In both mice and rats, dieldrin and phenobarbital induced hepatic DNA synthesis selectively in the centrilobular region of the hepatic lobule. The lack of an increase in serum enzymes indicative of hepatic damage and the absence of liver histopathology in mice or rats fed dieldrin or phenobarbital indicate that the induction of DNA synthesis was not mediated by a cytolethal, compensatory hyperplastic response, suggesting a mitogenic mechanism. Therefore, the species-specific induction of hepatic DNA synthesis by either dieldrin or phenobarbital correlated with the previously observed species-specific induction of hepatic cancer by these two compounds.