THE OBJECTIVE OF THIS PHASE I PROPOSAL IS TO CONDUCT PILOT STUDIES TOWARD DEVELOPMENT OF A RAPID, RELIABLE AND SENSITIVE IN VIVO ASSAY FOR SCREENING POTENTIAL HEPATOCARCINOGENS.

THE OBJECTIVE OF THIS PHASE I PROPOSAL IS TO CONDUCT PILOT STUDIES TOWARD DEVELOPMENT OF A RAPID, RELIABLE AND SENSITIVE IN VIVO ASSAY FOR SCREENING POTENTIAL HEPATOCARCINOGENS. THE RESEARCH EFFORT IS DESIGNED TO PROVIDE PRELIMINARY INFORMATION ON THE FEASIBILITY OF USING THE CHOLINE DEFICIENT RAT, A MODEL FOR LIVER TUMOR PROMOTION, FOR THIS PURPOSE. TO ACCOMPLISH THIS GOAL, MALE WEANLING RATS WILL BE MAINTAINED ON HIGH FAT SEMI-SYNTHETIC DIETS THAT VARY IN CHOLINE CONTENT. RATS WILL THEN BE SUBJECTED TO EITHER ACUTE OR SUBACUTE INTRAGASTRIC DOSING REGIMENS WITH VEHICLE, A POTENT NEPATOCARCINOGEN (AFB1) OR PHENOBARBITAL, A NONCARCINOGENIC STIMULATOR OF HEPATOCELLULAR HYPERTROPHY AND HYPERPLASIA. SELECTED HISTOPATHOLOLOGIC, HISTOCHEMICAL, IMMUNOCYTOCHEMICAL AND BLOOD SERUM PARAMETERS POTENTIALLY USEFUL IN DETECTING OR PREDICTING NEOPLASTIC CHANGE WILL BE EVALUATED OVER TIME. RESULTS WILL BE ANALYZED FOR EVIDENCE OF DIETARY AND DOSING REGIMEN EFFECTS ON TYPE, INCIDENCE, RATE OF DEVELOPMENT AND PERSISTENCE OF LIVER LESIONS. DATA INTERPRETATION WILL ALLOW DETERMINATION OF WHETHER THE CHOLINE DEFICIENT RAT MODEL SHOWS PROMISE AS A RAPID CARCINOGEN BIOASSAY SYSTEM. PHASE II RESEARCH WILL BE DIRECTED TOWARD DETERMINATION OF THE SENSITIVITY AND SPECIFICITY OF THE ASSAY AND TOWARD FURTHER DEVELOPMENT FOR COMMERCIAL EXPLOITATION. SUCCESSFUL COMPLETION OF THIS PROJECT WILL ALLOW DEVELOPMENT OF A COMMERCIALLY IMPORTANT BIOASSAY SYSTEM FOR USE IN CONTRACT TOXICOLOGY COMPANIES AND IN INDUSTRIES THAT PRODUCE COMPOUNDS REQUIRING ASSESSMENT FOR CARCINOGENICITY. THIS RESEARCH AREA IS OF INTEREST TO NCI, NIEHS AND FDA.