Observations on altered hepatocellular foci in National Toxicology Program two-year carcinogenicity studies in rats

Retrospective characterization of morphological and stereological features of altered hepatocellular foci (AHF) in hematoxylin & eosin (H&E)-stained sections was performed on 6 conventional 2-yr carcinogenicity studies conducted in Fischer 344 (F344) rats by the National Toxicology Program (NTP). In 3 of these studies where there was clear evidence of hepatocarcinogenicity [1-amino-2,4-dibromoanthraquinone (ADBAQ), C.I. Acid Red 114, methyl carbamate], there was greater morphological variability in AHF than in the studies of chemicals that were not hepatocarcinogenic [4-hydroxyacetanilide, epinephrine, dimethoxane]. In addition to having the expected types of AHF, rats treated with ADBAQ, C.I. Acid Red 114, and methyl carbamate had atypical basophilic AHF. In addition, atypical eosinophilic AHF were present in rats treated with ADBAQ. Both types of atypical AHF showed a morphological spectrum and sequential changes suggesting they could develop into hepatocellular neoplasms. For the 3 liver tumor positive studies, there were dose and time-dependent increases in stereological parameters for the atypical as well as commonly occurring clear, vacuolated, and mixed cell AHF. Consistent stereological changes were not found for commonly occurring basophilic and eosinophilic AHF. Aside from some decreases in stereological measurements in some rats treated with 4-hydroxyacetanilide and epinephrine, there were no significant quantitative changes in AHF in the three liver tumor negative studies. These results show that hepatocarcinogens may induce unique types of AHF in conventional 2-yr carcinogenicity/toxicity studies in rats and may cause quantitative increases in commonly occurring clear, vacuolated, and mixed cell AHF. Such qualitative and quantitative changes are potentially useful predictors of hepatic neoplasia.