ABSTRACT
The National Toxicology Program (NTP) developed the chronic 2-year bioassay as a mechanism for predicting the carcinogenic potential of chemicals in humans. The cost and duration of these studies has limited their use to small numbers of selected chemicals. Many different short-term methods aimed at increasing predictive accuracy and the number of chemicals evaluated have been developed in attempts to successfully correlate their results with evidence of carcinogenicity (or lack of carcinogenicity) are assessed. Using NTP studies, the effectiveness of correlating prechronic liver lesions with liver cancer encompassing multiple studies using mice (83 compounds) and rats (87 compounds). These lesions include hepatocellular necrosis, hepatocellular hypertrophy, hepatocellular cytomegaly, bile duct hyperplasia, and hepatocellular degeneration, along with increased liver weight. Our results indicate that pooling 3 of these prechronic data points (hepatocellular necrosis, hepatocellular hypertrophy, and hepatocellular cytomegaly) can be very predictive of carcinogenicity in the 2-year study (p < 0.05). The inclusion of increased liver weight as an endpoint in the pool of data points increases the number of rodent liver carcinogens that are successfully predicted (p < 0.05), but also results in the prediction of increased numbers of noncarcinogenic chemicals as carcinogens. The use of multiple prechronic study endpoints provides supplementary information that enhances the predictivity of identifying chemicals with carcinogenic potential.
Subject(s)
Biological Assay , Carcinogens/toxicity , Liver Neoplasms/veterinary , Rodent Diseases/pathology , Toxicity Tests, Acute , Administration, Oral , Animals , Carcinogenicity Tests/veterinary , Carcinogens/administration & dosage , Carcinogens/metabolism , Female , Liver Neoplasms/chemically induced , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred Strains , Necrosis/chemically induced , Organ Size/drug effects , Predictive Value of Tests , Rats , Rats, Inbred F344 , Retrospective Studies , Toxicity Tests, Acute/veterinary , United States , United States Dept. of Health and Human ServicesABSTRACT
The morphology of the parathyroids in rats with hypergastrinemia, induced by antral exclusion, was compared with that of glands from untreated rats and animals from which the main source of gastrin- 17 was excluded (antral resection). Fourteen weeks after induction of hypergastrinemia the volume of the parathyroids was significantly increased owing to hyperplasia of the parenchymal cells. Removal of the antral gastrin-producing capacity of the same duration was not accompanied by any significant changes in the parathyroids. These findings suggest that hypergastrinemia could be a stimulus for the development of hyperplasia of the parathyroids, and that it may be an etiological factor in the production of hyperparathyroidism.
