Hepatotoxicity of chronic high dose administration of acetaminophen to mice. A critical review and implications for hazard assessment.

To evaluate the degree of toxicity to the liver of chronic administration of acetaminophen, the slides from two independent previously reported experiments using different strains of mouse were reviewed and compared. One experiment was performed using B6C3F1 mice of both sexes which were fed 0.3, 0.6 or 1.25% acetaminophen in the diet for 41 weeks. The other was conducted with NIH general purpose mice of both sexes which were fed 1.1% acetaminophen in the diet for 48 weeks. In both experiments, at the levels of 1.1 or 1.25%, the drug produced severe liver injury characterized by centrilobular necrosis which was comparable in both males and females at the end of the experiments. The findings show that ingestion of dietary levels of greater than 1% leads to chronic hepatotoxicity to mice. The import of these findings in interpretation of carcinogenicity studies of acetaminophen is discussed.