ELABORATION AND COMPARATIVE EVALUATION OF TEST SYSTEMS FOR THE ASSESSMENT OF GENETIC EFFECTS OF ENVIRONMENTAL CHEMICALS AND OF THE PRODUCTS OF THEIR METABOLIC TRANSFORMATION.

THE PROJECT IS SUBDIVIDED IN TWO PARTS:

1) THE RESULTS FOR SHORT TERM MUTAGENICITY TESTS DO NOT ALWAYS CORRELATE WELL WITH THE CARCINOGENIC POTENTIAL, AS DEMONSTRATED FOR A SERIES OF POLYCYCLIC AROMATIC HYDROCARBONS WHERE STRONG CARCINOGENS WERE SHOWN TO BE WEAK MUTAGENS AND VICE VERSA.
THE POOR PREDICTIVITY OF THESE TESTS IS MAINLY RELATED TO THE ACTIVATION SYSTEMS USED. IN THIS PROJECT, THE CAPACITY OF ANIMALS AND IN VITRO PREPARATIONS SUCH AS ISOLATED HEPATOCYTES, LIVER MICROSOMES AND NUCLEAR MEMBRANES, TO ACTIVATE POTENTIALLY HARMFUL COMPOUNDS TO CHEMICALLY REACTIVE INTERMEDIATES WHICH MAY CAUSE MUTAGENIC DAMAGE TO MICROORGANISMS OR CELLS WILL BE STUDIED IN QUANTITATIVE TERMS. THE DEGREE OF MUTAGENICITY WILL BE CORRELATED TO THE EXTENT OF COVALENT BINDING TO SELECTED PROTEINS AND DNA OF BOTH "ACTIVATING SYSTEM" AND "TARGET".

2) THIS PART OF THE PROJECT WILL FOCUS ON THE CAPACITY OF NUCLEAR MEMBRANE TO ACTIVATE FOREIGN COMPOUNDS TO TOXIC INTERMEDIATES WHICH MAY CAUSE MUTAGENIC DAMAGE TO MICROORGANISMS OR CELLS. THE STUDY WILL USE A SELECTED NUMBER OF TEST COMPOUNDS KNOWN TO BE MUTAGENIC WHEN INCUBATED WITH LIVER MICROSOMES. THE METABOLISM OF THESE COMPOUNDS WILL BE STUDIED FIRST IN NUCLEI IN ORDER TO FIND SIMILARITIES WITH OR DIFFERENCES TO THE MICROSOMAL METABOLISM. TO THIS END, THE RESPECTIVE TOXIFYING AND DETOXIFYING PATHWAYS FOR EACH COMPOUND IN THE TWO SUBCELLULAR FRACTIONS WILL BE ASSESSED IN ORDER TO CORRELATE MUTAGENIC EFFECTS WITH METABOLISM, AND TO DEVELOP A RATIONAL BASIS FOR PREDICTING THE EXTENT TO WHICH THE NUCLEAR METABOLISM PARTICIPATES IN THE ONSET OF TOXIC EFFECTS CAUSED BY CHEMICALS.