Liver Tumor Induction

The significance of the development of nodular liver lesions in rodents following the administration of test agents raises several questions which could be placed in one of two general categories: diagnostic and interpretational. From a diagnostic point of view, the proper classification of liver tumors into a benign and malignant category has to be based on the direct correlation between the morphology and the biologic behavior of the lesions. Therefore, extreme care should be taken to separate the malignant tumors from the benign and the benign neoplasia from the hyperplasia. The substitution of the term "neoplastic nodule" for hyperplastic nodule in rats is misleading. Most of these nodules, when induced under special experimental conditions, may regress or remodel and thus they are not neoplastic in nature. Chronic carcinogenicity bioassays should include "stop" type of treatment leaving enough of the observational time to establish the fate of induced nodular lesions. The induction of histochemically changed foci can serve only as an indication of potential hepatocarcinogenicity and should not be equated with the induction of bona fide cancer. The biologic interpretation of nodular liver lesions, especially in mice, needs further scrutiny because these lesions have a tendency to develop spontaneously with high incidence in some strains. This characteristic then raises the question as to the mechanism by which various agents augment and/or accelerate the development of such tumors. Is this action primarily promoting or initiating in nature or does it represent the induction of tumors de novo? The answer to this dilemma may have a decisive bearing on carcinogenic risk assessment and the type of regulatory action, since the promoting agents possess a threshold effect and the promoted changes may regress following withdrawal of treatment. The interpretation of hepatocarcinogenesis is further complicated by the fact that several factors, such as sex hormonal environment, increased mitotic activity following an excessive loss of parenchymal cells, degree of caloric intake, enzymatic complement, and animals' age at the time of the exposure to a test agent, may influence the outcome of liver tumor development by modulating "initiation" and/or "promotion" of carcinogenesis. Broad fluctuation in the historic incidence of liver tumors further compounds the complexity of the proper bioassay interpretation. The specifically designed experiments may have the objective to explore predominantly the initiating or promoting effects of the agent. Such protocols should be used whenever necessary to differentiate between these two mechanisms of action. In the Caucasians, the "spontaneous" development of the primary hepatocellular tumors is rare. The majority of these tumors are malignant and rapidly fatal. According to some human pathologists, the benign variety of liver tumors is rare and it does not represent necessarily a premalignant stage in tumor development. Carcinoma of the liver may occur in infancy, especially in males before the age of 2 years. This suggests a genetic causation or carcinogenic exposure in utero. One of the geographic factors which significantly enhances the incidence of hepatocellular carcinoma in humans is exposure to aflatoxin B₁ which is apparently potentiated by concurrent liver cirrhosis. Because many more agents have been found to be hepatocarcinogenic in mice and rats than in men, a question arises as to the direct relevance of rodent studies to humans. A balanced assessment of the carcinogenicity of the agent could only be reached in considering both the pharmacokinetics and the development of malignant neoplasia in other organs. In the case of positive carcinogenicity assessment, the outcome of the mutagenicity bioassays can suggest genic (genotoxic) or paragenic (epigenetic) mode of action in mammalian systems.