PIM-1 TRANSGENIC MICE TO DETECT ENVIRONMENTAL TOXINS

A MAJOR CHALLENGE TO FEDERAL AND STATE REGULATORY AGENCIES IS THE PERFORMANCE OF HAZARD AND RISK ASSESSMENTS ON CHEMICALS AREADY IN THE ENVIRONMENT AND ON NEW CHEMICALS WHOSE RELEASE IS PROPOSED. THE DEFENITIVE EXPERIMENTAL MEANS FOR DETERMINING A MATERIAL'S CARCINOGENIC POTENTIAL REMAINS THE RODENT LIFETIME BIOASSAY. THE LONG "IN-LIFE" PHASE (TWO YEARS) FOR THIS STUDY REMAINS ITS MAJOR LIMITATION AND IS ALSO ONE OF THE MAJOR FACTORS CONTRIBUTING TO ITS HIGH COST. ANTHER IS THE PROBLEM OF NEEDING TO USE LARGE NUMBERS OF ANIMALS IN ORDER TO DETECT RELATIVELY WEAK CARCINOGENS. THE STUDIES REPRESENT THE FIRST PHASE IN THE VALIDATION OF A TRANGENIC MOUSE CARCINOGEN BIOASSAY WHICH COULD SHORTEN THE IN-LIFE TESTING PHASE BY APPROXIMATELY 75%. TRANSGENIC MICE EXPRESS THE PIM-1 ONCOGENE (EU-PIM-1) IN LYMPHOID TISSUES ARE MILDLY PREDISPOSED TOWARD THE DEVELOPMENT OF T CELL LYMPHOMAS. EU-PIM-1 MICE TREATED WITH THE MODEL MUTAGEN/CARCINOGEN ETHYLNITROSOUREA ARE APPROXIMATELY 25-FOLD MORE SENSITIVE TO THE DEVELOPMENT OF LYMPHOMAS THAN ARE CONTROL MICE (17). IN THE STUDIES, A MODEL CHEMICAL P-CRESIDINE, CURRENTLY BEING EVALUATED USING OTHER TRANSGENIC MOUSE MODELS WILL BE TESTED FOR CARCINOGENIC ACTIVITY IN EU-PIM-1 MICE AND NONTRANSGENIC CONTROLS. P-CRESIDINE IS A GENOTOXIC CARCINOGEN WHICH HAS BEEN SHOWN TO INDUCE TUMORS IN BOTH RATS AND MICE. TRANSGENIC AND CONTROL MICE WILL BE TREATED WITH P-CRESIDINE FOR 150 DAYS BY DOSED FEED. TUMOR TYPES, TUMOR FREQUENCIES AND LATENCY PERIODS WILL BE COMPARED AT THE END OF THE STUDY.