PHENOBARBITAL MECHANISTIC DATA AND RISK ASSESSMENT - ENZYME-INDUCTION, ENHANCED CELL-PROLIFERATION, AND TUMOR PROMOTION

Chronic exposure to high doses of phenobarbital (PB) causes hepatocell ular adenomas in both mice and rats and hepatocellular carcinomas in s ome strains of mice, Long term PB therapy has not been found to cause human tumors, PB is not DNA reactive, and most genotoxicity tests have yielded negative results, PB has been extensively studied as an epige netic, rodent liver tumor promoter, At exposures causing rodent liver tumors, PB has measurable effects on hepatocytes: PB inhibits cell-to- cell communication; PB induces enzymes, including P450 cytochromes; PB stimulates proliferation and inhibits apoptosis of hepatocytes in neo plastic foci, Threshold exposures for some of these endpoints coincide with the threshold exposure for tumorigenesis.