Carcinogenic and Genotoxic Effects

Filippova and colleagues (1978) studied the carcinogenic effects of intratracheal injection with 90 percent enriched 235U as tetravalent uranium (0.57–18.7 mg U/kg body weight) or hexavalent uranium (0.55–5.32 mg U/kg body weight) in the rat. A variety of cancers developed in both groups of uranium-injected rats (osteosarcoma, carcinoma of the lungs and kidneys, reticulolymphosarcoma of the lung, and leukemia) at a rate that was statistically significantly different from controls (24 percent with tetravalent uranium, 24 percent with pentavalent uranium, and 12 percent in controls). Cross and colleagues (1981a) measured the effects of inhalation exposure on tumor development in golden Syrian hamsters. Animals inhaled uranium ore dust at a concentration of 19 mg U/m3 for 16 months. The authors reported no apparent increase in the number of tumors in several tissues (liver, kidney, spleen, trachea, lungs, and heart) compared to unexposed animals.

In a chronic inhalation study, Leach and colleagues (1973) reported that uranium dioxide exposure (5 mg U/m3) led to pulmonary lymphatic neoplasm development and atypical epithelial proliferation in 30–46 percent of exposed beagle dogs. Although the rate of tumor development was 50–100 times higher than the expected spontaneous incidence in this species, the authors cautioned against extrapolating these findings to humans, given the infrequent occurrence of these types of lymphatic neoplasms in humans. Long-term feeding studies found no evidence of cancer in several animal species that were exposed to high levels of uranium (Maynard and Hodge, 1949; ATSDR, 1999b). The committee did not locate studies on the tumorigenic effects of uranium following dermal exposure.

A recent report is the first to suggest that, at least in vitro, DU can cause human cell transformation to a neoplastic phenotype, an effect that is comparable to other biologically reactive and carcinogenic heavy-metal compounds, such as nickel (Miller et al., 1998a). DU uranyl chloride-transformed cells displayed anchorage-independent growth, tumor formation in nude mice, expression of high levels of the k-ras oncogene, reduced production of the Rb tumor-suppressor protein, and elevated levels of sister chromatid exchanges per cell; all are associated with carcinogenic processes.

To assess the potential mutagenic effects of long-term exposure to internalized depleted uranium, Sprague-Dawley rats received 20 pellets of either tantalum or DU in various combinations (low DU: 4 DU and 16 tantalum pellets; medium DU: 10 DU and 10 tantalum pellets; high DU: 16 DU and 4 tantalum pellets) (Miller et al., 1998b). The rats excreted significant concentrations of uranium in urine throughout the 18 months of the study (224 ± 32 μg U/L urine in the low-dose rats and 1010 ± 87 μg U/L urine in the high-dose rats at 12 months). Investigators assessed the mutagenic potential of uranium at 0 days, 6 months, 12 months, and 18 months after implantation. Urine from animals implanted with DU pellets at each of the assessed time points enhanced mutagenic activity in Salmonella typhimurium strain TA98 and the Ames II mixed strains (TA7001–7006). Urine samples from animals implanted with tantalum alone



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