Evaluation of carcinogenic potential of two nitro-musk derivatives, musk xylene and musk tibetene in a host-mediated in vivo/in vitro assay system

We have developed a host-mediated assay system for detection of the transforming activity of chemical carcinogens on peritoneal macrophages. Directly, as well as indirectly acting carcinogenic substances, administered intraperitoneally to NMRI mice, could be examined in this way. Resident macrophages were recovered by peritoneal lavage from treated and untreated mice and cultured in soft agar. After 5-6 days the normal and transformed cells could be distinguished. Statistical analysis comparing cells from musk xylene- or musk tibetene-treated Animals with those from control mice proved that the test is positive. Musk xylene and musk tibetene revealed a cell-transforming potential that showed a dose-dependent response in our host-mediated assay system. We have succeeded in establishing permanent cell lines from mice treated with musk xylene, or musk tibetene. The oncogenicity of these cell lines was tested in athymic nu/nu mice. Animals injected subcutaneously with these cells (1 x 10(6) cells at each side of the neck) developed tumors at the injection sites within 3 weeks of treatment. The experimental data reported here lead to the conclusion that musk xylene, as well as musk tibetene, have carcinogenic activity. In contrast to the negative results for mutagenicity and genotoxicity, a non-genotoxic mechanism for the carcinogenicity of musk xylene and musk tibetene must be considered.