IN-VITRO MUTAGENICITY AND GENOTOXICITY STUDY OF A NUMBER OF SHORT-CHAIN CHLORINATED HYDROCARBONS USING THE MICRONUCLEUS TEST AND THE ALKALINE SINGLE-CELL GEL-ELECTROPHORESIS TECHNIQUE (COMET ASSAY) IN HUMAN-LYMPHOCYTES - A STRUCTURE-ACTIVITY RELATIONSHIP (QSAR) ANALYSIS OF THE GENOTOXIC AND CYTOTOXIC POTENTIAL

Using the micronucleus (MN) test and the alkaline single cell gel elec trophoresis (Comet) assay, potential mutagenicity (MN formation), geno toxicty (DNA breakage capacity) and cytotoxicity (cell proliferation r eduction) of five chlorinated hydrocarbons (carbon tetrachloride, hexa chloroethane, 1,2-dichloroethane, 1-chlorohexane and 2,3-dichlorobutan e) have been evaluated in isolated human lymphocytes. With the MN test a low but statistically significant mutagenic activity was detected f or all tested substances (except 2,3-dichlorobutane),vith one out of t he two donors and in the presence or absence of an exogenous metabolic activation system (S9 mix), However, at the concentration ranges test ed none of the positive compounds induced a clear dose-dependent mutag enic effect, The Comet assay detected a strong DNA damaging effect for 1-chlorohexane, 2,3-dichlorobutane and 1,2-dichloroethane, but not fo r carbon tetrachloride and hexachloroethane. The influence of metaboli sm on the genotoxic activity of the chemicals was more clear in the Co met assay than in the MN test, The experimental genotoxicity and cytot oxicity data obtained in this study, together with data on five more r elated chemicals previously investigated, and their physico-chemical d escriptors or electronic parameters have been used for QSAR analysis, The QSAR analysis highlighted that the toxicity of the tested compound s was influenced by different parameters, like lipophilicity (logP), e lectron donor ability (charge) and longest carbon-chlorine (LBC-Cl) bo nd length, In addition, steric parameters, Like molar refractivity (MR ) and LBC-Cl, and electronic parameters, like E-LUMO (energy of the lo west unoccupied molecular orbital, indicating electrophlicity), were p redominant factors discriminating genotoxins from non-genotoxins in th e presence but not in the absence of S9 mis, Although a limited number of compounds have been examined and cytotoxicity and genotoxicity wer e identified in two different bioassay tests, the data set was obtaine d by the same experimentor, strengthening the reliability of the QSAR.