FOCI OF CELLULAR ALTERATION IN THE RAT LIVER: A REVIEW

Abstract

In order to help clarify the biological and predicitive significance of phenotypically altered bepatocellular foci (AHF) for liver neoplasia. qualitative and quantitative evaluations of AHF followed by stereological analysis were performed on standard hematoxylin and eosin-stained liver sections from control and treated Fischer 344 (F344) rats of both sexes. The rats were used in conventional 2-year carcinogenicity studies of 7 chemical agents: 1-amino-2, 4-dibromoanthraquinone (ADBAQ), C.I. Acid Red 114, methyl carbamate, 4-hydroxyacetanilide, epinephrine hydrochloride, dimethoxane, and talc. The first three chemicals were clearly hepatocarcinogenic while the latter four were not. Liver samples were collected at 6, 9, 12, 15, 18, and/or 24 months on study. 1. Control rats: Although AHF had a broad spectrum of morphological features, they could be classified into the following 5 types using previously published criteria: basophilic, eosinophilic, clear, vacuolated, and mixed cell AHF. Approximately 50% of the animals had AHF at 6 months, and the incidence reached nearly 100% at 15 months in both sexes. Stereological analysis revealed that the number, size and volume fraction of AHF increased with age in both sexes and the changes were most evident for basophilic and clear cell AHF. The number of basophilic AHF was significantly greater in females than in males while clear cell AHF were more numerous in males. This sex difference was observed at each time point. Mean number of AHF including all types in males and females at 24 months was 547 and 460 per cubic centimeter of liver, respectively. Despite the high incidence of AHF in control rats, the incidence of hepatocellular neoplasms is low. The implication is that most AHF do not progress to neoplasia in control F344 rats. 2. Rats treated with hepatocarcinogens: The morphological variability of AHF was much greater than in the controls and unique types of basophilic and/or eosinophilic AHF were found in addition to the common (typical in control rats) types of AHF. The unique AHF showed a morphological spectrum and sequential changes suggesting they could develop into hepatocellular neoplasms. There were dose and time-dependent increases in stereological parameters of number, size, and volume fraction for the unique AHF as well as commonly occurring clear, vacuolated, and mixed cell AHF. Consistent stereological changes were not found for commonly occurring basophilic and eosinophilic AHF. These results indicate that hepatocarcinogens may induce unique types of AHF and also cause quantitative increases in some types of commonly occurring AHF such as clear, vacuolated and mixed cell types. 3. Rats treated with non-hepatocarcinogens: The morphological variability of AHF was the same as that in the controls. There were no increases in stereological measurements of AHF although some quantitative changes in the number of AHF were noted.