IN VITRO MODELS FOR EVALUATION

THE LONG-TERM OBJECTIVE IS TO ESTABLISH AND VALIDATE IN VITRO SYSTEMS FOR DETECTING AND STUDYING PEROXISOMAL PROLIFERATORS (PP), AND TO ASSESS THE HAZARD OF THESE CHEMICALS TO HUMAN HEALTH. THE SPECIFIC AIMS OF PHASE I ARE TO ESTABLISH AND EVALUATE THE RELIABILITY OF IN VITRO SYSTEMS INCLUDING (1) RAT PRIMARY HEPATOCYTE CULTURE, (2) RAT LIVER SLICE CULTURE, AND (3) HUMAN HEPATOCYTE AND/OR SLICE CULTURE. THESE IN VITRO SYSTEMS WILL BE EVALUATED USING CHEMICALS KNOWN TO INDUCE PP AND OTHER CHEMICALS WHICH DO NOT INDUCE PP, AND SPECIFIC INDICATORS OF THE PP RESPONSE WILL BE MEASURED. THESE INDICATORS INCLUDE (1) ALTERED RATIONS OF INTRACELLULAR BETA-OXIDATION:CATALASE ACTIVITY, (2) INCREASED DNA SYNTHESIS, AND (3) ALTERED CELL MORPHOLOGY. THE RESULTS OF THESE STUDIES SHOULD PROVIDE INFORMATION ABOUT THE RELIABILITY, ACCURACY, AND SENSITIVITY OF THESE SYSTEMS FOR DETECTING AND STUDYING MECHANISMS OF PP. IN PHASE II, A WIDE VARIETY OF PP-INDUCING CHEMICALS WILL BE STUDIED IN BOTH RODENT AND HUMAN IN VITRO SYSTEMS TO BETTER DEFINE THE HAZARD OF THESE CHEMICALS TO HUMAN HEALTH.