Depleted uranium (DU) is a dense heavy metal used primarily in military applications. Although the health effects of occupational uranium exposure are well known, limited data exist regarding the long-term health effects of internalized DU in humans. We established an in vitro cellular model to study DU exposure. Microdosimetric assessment, determined using a Monte Carlo computer simulation based on measured intracellular and extracellular uranium levels, showed that few (0.0014%) cell nuclei were hit by alpha particles. We report the ability of DU-uranyl chloride to transform immortalized human osteoblastic cells (HOS) to the tumorigenic phenotype. DU-uranyl chloride-transformants are characterized by 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. DU-uranyl chloride treatment resulted in a 9.6 (+/- 2.8)-fold increase in transformation frequency compared to untreated cells. In comparison, nickel sulfate resulted in a 7.1 (+/- 2.1)-fold increase in transformation frequency. This is the first report showing that a DU compound caused human cell transformation to the neoplastic phenotype. Although additional studies are needed to determine if protracted DU exposure produces tumors in vivo, the implication from these in vitro results is that the risk of cancer induction from internalized DU exposure may be comparable to other biologically reactive and carcinogenic heavy-metal compounds (e.g., nickel).ImagesFigure 1Figure 2Figure 3

Depleted uranium (DU) is a dense heavy metal used primarily in military applications. Although the health effects of occupational uranium exposure are well known, limited data enxst rding the long-term health effects of internaized DU in humans. We established an in viuro cellular model to study DU exposure. Microdosimetric assessment, determined using a Monte Carlo computer simulation based on measured intracelular and etacelular u m levels, showed that few (0.0014%) cell nuldei were hit by alph partidles. We report the ability of DU-uranyl chloride to tansform immortalized human osteoblastic cells (HOS) to the tumoriWnic phenotype. DU-uranyl chloride-transformants are characterized by anchorage-independent growth, tumor formation in nude mice, expression of high levels of the k-ras oncogene, reduced production of the Rb tumorsuppressor protein, and elevated levels of sister chromatid nges per cell. DU-uranyl

High doses of radiation induce septicaemia, from bacterial translocation, and death in animals. Mice were exposed to either comparable lethal (LD90/30) or sublethal (LD0/30) doses of mixed-field [n/(n + y) = 0.67] or pure 60Co gamma-photon radiation. The relative biological effectiveness of these comparable doses of radiation was 1.82, determined by probit analysis. Mice given a lethal dose of mixed-field radiation developed a significant (p < 0.01), 10(9)-fold increase in Gram-negative facultative bacteria in their ilea over values in control mice. In contrast, mice given a lethal dose of gamma-photon radiation developed a significant (p < 0.01) increase in only Gram-positive bacteria in their ilea, while the number of Gram-negative bacteria remained near values in control mice. Data correlated with bacteria that were isolated and identified from the livers of mice that were given comparable lethal doses (LD99/30) of mixed-field or gamma-photon radiation. In sublethally irradiated mice, fluctuation in the total number of bacteria was detected in their ilea during the first week following irradiation, after which the number approximated the value in control mice. This difference in the predominant facultative bacteria in ilea resulting from different qualities of radiation has important implications for the treatment of septicaemic-irradiated hosts.

Using an agarose gel electrophoresis assay, single-strand breaks (ssb) induced by fission neutrons and 60Co gamma-rays in aerobic aqueous solutions of pBR322 plasmid DNA were studied. The energy-deposition events of the two radiations were characterized using a Rossi-type proportional counter to measure lineal-energy spectra. For neutrons, the dose-weighted lineal-energy mean, yD, is 63 keV micron-1--about 30 times that for gamma-rays. With increasing yD, hydroxyl radicals produced within spurs or tracks are less likely to survive due to recombination effects, resulting in decreased ssb yields. In TE buffer solution, the ssb yield induced by gamma-rays is 3.2 +/- 0.66 times that induced by neutrons at the same dose. Since the direct radiation effect is small under these conditions, we can estimate that the previously unknown G for hydroxyl radical production by fission neutrons is 0.088 mumol J-1. For glycerol concentrations that give the solution a hydroxyl radical scavenging capacity similar to that of cellular environments, the ssb yield induced by gamma-rays is about 2.0 +/- 0.24 times that induced by neutrons. Analysis shows that this trend with added scavenger is caused primarily by hydroxyl radical yields.

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