Cell transforming and oncogenic activity of 2,3,7,8--tetrachloro--and 2,3,7,8 tetrabromodibenzo-p-dioxin.

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 normal and transformed cells could be distinguished. Statistical analysis comparing cells from 2, 3, 7, 8-tetrachlorodibenzo-dioxin (TCDD)-treated animals with those from control mice proved that the test is positive at least on a significance level of 5%, using the t-test. TCDD revealed a cell-transforming potential that showed a dose-dependent response in this host-mediated assay. The co-carcinogenic activity of TCDD was established in experiments with diphenylhydantoin. Low doses of diphenylhydantoin which did not exhibit any transforming potential in our system gained a high oncogenic potential by the simultaneous administration of low doses of TCDD, which also had no transforming activity. We have compared the cell transforming potential of TCDD with its bromo analog TBrDD. The cell transforming potential of TCDD is 7 times that of TBrDD. We have succeeded in establishing a permanent cell lined from mice treated with TBrDD. The oncogenicity of this cell line was tested in athymic nu/nu mice. Animals treated subcutaneously with these cells (1 x 10(6) cells) developed tumors at the injection site. Using monospecific antibodies to tumor necrosis factor alpha (TNF-alpha), we have found that TCDD stimulates the secretion of TNF-alpha. The experimental data reported here lead to the conclusion that TCDD has a carcinogenic as well as a co-carcinogenic activity and has the property to induce TNF-alpha.