Morphological and Stereological Characterization of Hepatic Foci of Cellular Alteration in Control Fischer 344 Rats

Abstract

Quantitative evaluation of altered hepatocellular foci (AHF), followed by stereological analysis was performed on standard hematoxylin and eosin-stained liver sections from control Fischer 344 (F344) rats of both sexes from seven 2-yr carcinogenicity studies conducted by the National Toxicology Program (NTP). Liver samples were collected at 6, 9, 12, 15, 18, and/or 24 months on study. 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, mixed cell foci. Approximately 50% of the animals had foci at 6 months, and the incidence reached nearly 100% at 15 months in both sexes. The number, size and volume fraction of AHF increased with age in both sexes; these changes were most evident for basophilic and clear cell foci. The number of basophilic foci was significantly greater in females than in males while clear cell foci were more numerous in males. This sex difference was observed at each time point. Mean number of all types of AHF 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 foci do not progress to neoplasia in control F344 rats used in 2-yr studies.