EXAMINATION OF MUTAGENICITY, GENOTOXICITY , AND COGENOTOXICITY OF NITRO MUSKS IN THE ENVIRONMENT

In the present study a new in vivo/in vitro animal model was used to s tudy the ability and potency of musk ketone and musk xylene to induce liver specific oxigenases (in vivo) which are necessary of toxify diff erent premutagens, pregenotoxicants and/or precarcinogens to the ultim ate DNA damaging agents. Therefore, rats were pretreated with 10, 20 a nd 40 mg/d nitro musk (NMV) for 5 days by intraperitoneal (i.p.) injec tion. Then the postmitochondrial fractions of the hepatocytes (S9(M)) were used to examine the metabolic potency for toxification of the pre genotoxicants benzo[a]pyrene (B[a]P) and 2-aminoanthracene (2-AA) usin g the SOS chromotest(in vitro). Furthermore, musk xylene, musk ketone, musk ambrette, musk moskene and musk tibetene were examined for their mutagenicity in the Salmonella/microsome assay using S. typhimurium T A97, TA98, TA100 and TA102 and for their genotoxicity in the SOS chrom otest using Escherichia coli PQ37 (sfiA::lacZ) in the presence and abs ence of an exogenous metabolizing system (S9 of PCB induced rats = S9( A)). Both musk ketone and musk xylene were identified ais inducers of toxifying enzymes (oxigenases) in rat liver. Using the in vivo/in vitr o model these isoenzyme inductions led to a metabolisation (toxificati on) of the pregenotoxicants benzo[a]pyrene (B[a]P) and/or 2-aminoanthr acene (2-AA) (cogenotoxicity). Using S9(M) fractions of rats which wer e i.p.-pretreated with 5 x 40 mg musk ketone the induction factor in t he SOS chromotest was IFmax = 4,0 by using 1 nmole B[a]P and IFmax > 4 ,0 by using 20 nmole 2-AA. Thus, musk ketone seems to be a Cytochrome P450 1A1 and 1A2 isoenzyme inducer in mammals. On the other hand the S 9(M) fractions of musk xylene pretreated rats showed only a toxificati on of 2-AA (IFmax = 3,0). Therefore, a synergistic effect of enzyme in ducers, i.e. musk xylene and musk ketone, and pregenotoxicants, i.e. B [a]P and 2-AA, regarding DNS damaging effects was identified. Musk amb rette showed high mutagenicity in S. typhimurium TA100 (500 His(-)-rev ertants per mu mole, + S9(A)). Unexpectedly, these DNA damaging effect s were not caused by bacterial nitroreductases but by rat S9(A) metabo lisation (1). SOS inducing DNA damages in E. coli PQ37 were not produc ed (IFmax < 1.5). On the basis of the results presented and under cons ideration of the concentrations of NMV, other cogenotoxicants and preg enotoxicants such as B[a]P and 2-AA in environmental samples and human tissues, a genotoxic risk fur humans has to be assumed.