INITIATION-PROMOTION BIOASSAY IN MOUSE LIVER

SHORT-TERM/LIMITED BIOASSAYS FOR THE DETECTION OF CHEMICAL CARCINOGENS, TUMOR INITIATORS, AND TUMOR PROMOTERS HAVE BEEN RECOGNIZED AS IMPORTANT COMPONENTS TO THE DETERMINATIONOF THE CARCINOGENIC HAZARD OF ENVIRONMENTAL CHEMICALS AND COMPLEX MIXTURES. THESE BIOASSAYS ARE USEFUL TO DETERMINE (1) WHEATER A SUBSTANCE IS CARCINOGENIC, (2) DOSE-RESPONSE RELATIONSHIPS, AND (3) MECHANISM, I.E., TUMOR INITIATOR AND/OR PROMOTER. MANY OF THE CHEMICALS THAT HAVE BEEN POSITIVE IN THE LONG-TERM CARCINOGENESIS BIOASSAY WERE ACTIVE IN MOUSE LIVER. THE PROPOSED OBJECTIVES OF THIS PROJECT ARE TO DETERMINE WHETHER THE 15-DAY-OLD MOUSE LIVER INITIATION-PROMOTION BIOASSAY CAN BE USED TO DISTINGUISH CARCINOGENS FROM NONCARCINOGENS AND THEN TO DEVELOP THE BIOASSAY SO THAT IT CAN BE USED TO DETERMINE THEIE MECHANISM OF ACTION. C3H AND B6C3F1 MALE MICE WILL BE USED BECAUSE (1) STUDIES DETERMINED THEM TO BE SENSITIVE STRAINS AND SEX, (2) THE B6C3F1 MOUSE IS USED IN THE NTP LONG-TERM BIOASSAY, AND (3) OPPOSING EFFECTS OF PHENOBARBITOL ON DIETHYLNITROSAMINE (DENA)-INITIATED HEPATOCARCINOGENESIS HAVE BEEN FOUND (PROMOTION IN B6C3F1 AND INHIBITION IN C3H). IN PHASE I, THE RELATIVE SENSITIVITY OF THE TWO STRAINS OF MICE TO DIFFERENT CHEMICAL CLASSES AND THE EFFECT OF PHENOBARBITOL WILL BE DETERMINED. THE PROTOCOL WILL CONSIST OF (1) ADMINISTERING THE TEST SUBSTANCE TO MALE MICEON DAY 15 OF AGE, (2) STARTING AT WEANING AND CONTINUING UNTIL SACRIFICE, ADMINISTERING 500 PPM SODIUM PHENOBARBITOL IN THE DRINKING WATER, (3) SACRIFICING THE MICE AT 180 DAYS OF AGE, AND (4) EVALUATING THE LIVER FOR NEOPLASTIC LESIONS. ONCE THE PROTOCOL FOR THE 15-DAY-OLD MOUSE INITIATION-PROMOTION BIOASSAY HAS BEEN DEVELOPED, PHASE II WILL EVALUATE THE ABILITY OF THE ASSAY TO DETERMINE DOSE-RESPONSE AND STRUCTURE-ACTIVITY RELATIONSHIPS, AND TO DISTINGUISH TUMOR INITIATORS AND PROMOTERS.