HAMSTER OVARY CELL CHROMOSOMAL ABERRATION ASSAY FOR EXAMINING INDIRECT MECHANISMS OF MUTAGENS

IN VITRO CYTOGENETIC TESTS TO EVALUATE THE GENETIC HAZARDS OF CHEMICALS ARE INCREASING IN IMPORTANCE FOR PREDICTING IN VIVO EFFECTS. IN PARTICULAR, STUDIES HAVE DEMONSTRATED (1) THE RELEVANCE OF CHROMOSOMAL MUTATION TO INHERITANCE IN GERMCELLS; (2) THAT SPECIFIC CHROMOSOMAL DEFECTS ARE ASSOCIATED WITH MOST NEOPLASIAS; AND (3) THAT CHROMOSOMAL REARRANGEMENTMAY PLAY A ROLE IN ONCOGENE ACTIVATION. HOWEVER, THE CURRENTLY USED NTP CHINESE HAMSTER OVARY (CHO) CHROMOSOMAL ABERRATION (CA) ASSAY LACKS SENSITIVITY AND, THUS, PRESENT CHO-CA RESULTS ARE OF LITTLE USE FOR EXAMINING THE MECH- ANISMS OF CLASTOGENESIS, MUTAGENESIS, NEOPLASIA, AND THEIR INTERRELATIONSHIPS. PHASE I RESEARCH WILL DEVELOP A NEW FRAGILE SITE CHO-CA ASSAY WHICH WILL INCLUDE: (1) PRE- TREATMENT OF CHO CELLS TO INDUCE SYNCHRONY AND ENHANCE CLASTOGENESIS AND TO MORE CLOSELY MIMIC IN CHO CELLS HUMAN SUBPOPULATIONS AT RISK FOR CHEMICALLY INDUCED NEOPLASIA; (2)USE OF A MORE INFORMATIVE PRETEST TO DETERMINE EFFECTIVE CONCENTRATIONS AND TO SELECT FIXATION TIMES BASED ON CHEMICALLY INDUCED CELL DELAY; AND (3) USE OF AUTOMATED SYSTEMS TO REDUCE CYTOGENETICIST TIME REQUIRED FOR EVALUA- TING THE RESULTS OF THE CA ASSAY. PHASE II RESEARCH WILL EVALUATE THE EFFECTS OF HIGH TOXICITY, HIGH SALT CONCENTRA- TIONS, OSMOLARITY, AND PH ON THE INDUCTION OF FRAGILE SITE- SPECIFIC CAS. AN EVALUATION OF THIS SYSTEM USING CODED COMPOUNDS WILL ALSO BE PERFORMED IN PHASE II.