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Alexandra C. Miller,¹ William F. Blakely,¹ David Livengood,¹ Tim Whittaker,¹ Jiaquan Xu,¹ John W. Ejnik,¹ Matthew M. Hamilton,¹ Eric Parlette,¹ Theodore St. John,² Henry M. Gerstenberg,² and Hannah Hsu³

¹Applied Cellular Radiobiology Department and ²Radiation Sciences Department, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889-5603 USA
³Molecular Pharmacology Branch, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA

Abstract

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) . Key words: alpha radiation, depleted uranium, osteoblast, transformation. Environ Health Perspect 106:465-471 (1998) . [Online 6 July 1998]

http://ehpnet1.niehs.nih.gov/docs/1998/106p465-471miller/ abstract.html

Address correspondence to A.C. Miller, Applied Cellular Radiobiology Department, Armed Forces Radiobiology Research Institute, 8901 Wisconsin Avenue, Bethesda, MD 20889-5603 USA.

The contributions of Eric Daxon, David McClain, John Kalanich, C. Robert Woodruff, Ramesh Bhatt, Gerald Vavrina, Christopher Pitcher, and Betty Ann Torres are greatly appreciated and were invaluable to the success of this project.

This research was supported in part by the Armed Forces Radiobiology Research Institute under work unit numbers AFRRI-98-3 and AFRRI-98-4. The views presented are those of the authors and do not reflect the official views of the Department of Defense or the U.S. government.

Received 7 November 1997 ; accepted 11 March 1998.