FURTHER EVIDENCE OF THE TUMOR-SUPPRESSIVE EFFECTS OF CADMIUM IN THE B6C3F1 MOUSE-LIVER AND LUNG - LATE-STAGE VULNERABILITY OF TUMORS TO CADMIUM AND THE ROLE OF METALLOTHIONEIN

Previously, we studied the ability of cadmium to initiate or promote t umors in B6C3F1 mice and, contrary to expectation, found that cadmium inhibited development of N-nitrosodiethylamine (NDEA)-initiated and so dium barbital-promoted liver tumors. In this study, the time course of cadmium inhibition of NDEA-initiated tumor formation was studied. A s ingle dose of NDEA (90 mg/kg i.p.) was given at 5 weeks of age (time 0 ) followed by cadmium (1 000 ppm) in drinking water from 2 to 48, 4 to 48, 8 to 48, 16 to 48 and 32 to 48 weeks. The study ended at 48 weeks . NDEA-induced elevations in liver tumor incidence (22 tumor-bearing m ice/25 total) over control (5/25) were prevented by cadmium regardless of the period of administration (NDEA + cadmium: 2-48 weeks, 2/25; 4- 48 weeks, 1/25; 8-48 weeks, 1/25; 16-48 weeks, 2/25; 32-48 weeks, 6/24 ). Cadmium alone (2-48 weeks) eliminated (0/25) spontaneously occurrin g liver tumors (5/25). NDEA-induced lung tumor incidence (25/25) and m ultiplicity (7.28 tumors/lung) were also reduced by cadmium (maximal d ecreases 28% and 80%, respectively). Some evidence of a specific defic iency of metallothionein in tumor cells was seen immunohistologically in NDEA-induced hepatic lesions and pulmonary lesions. These results i ndicate that cadmium prevents or reduces tumor formation in the B6C3F1 mouse liver and lung regardless of the exposure interval and apparent ly by cell-specific cytotoxicity. Auxiliary studies indicated that in mice bearing multiple liver foci resulting from NDEA treatment there w as a marked reduction in basal metallothionein levels and in response to zinc induction. The possibility exists that cadmium has a specific toxicity toward previously initiated cells within mouse liver and lung . The mechanisms involved in cadmium-induced tumor suppression deserve further study.