Project Summary

Title: Carcinogenic Potential of Depleted Uranium and Tungsten Alloys
Synopsis: This study in animals is designed to determine whether or not embedded fragments of depleted uranium (DU) cause changes in cells suggestive of cancer.
Overall Project Objective: This project seeks to assess the degree of carcinogenic potential of embedded fragments of DU and a proposed surrogate metal, heavy metal tungsten alloy (HMTA), and determine their mechanisms of action.
Status/Results to Date: Previous studies at AFRRI indicate that exposure to DU causes changes in cells both in vivo and in vitro that suggest DU has carcinogenic potential. There is a DU dose- and time-dependent increase in the expression of specific oncogenes in kidney, muscle, and liver of rats implanted with pellets of DU. No oncogene increases are observed in rodents implanted with the non-toxic metal tantalum. Significant increases in both micronuclei and sister chromatid exchanges indicators of genotoxic damage, were measured in lymphocytes obtained from DU-implanted rats 18 months after implantation, but not in tantalum-implanted rats. Injection of sodium tungstate into Fischer rats produced significant increases in both micronuclei and SCE. Exposure of cultured human bone cells to DU compounds and HMTA resulted in a transformation of those cells to a type with biochemical and growth characteristics typical of tumor cells. The magnitude of transformation observed with DU and HMTA was similar to that observed with the known heavy metal carcinogen, nickel. These cells, once transformed, produced tumors when injected into immune deficient mice. Urine from DU-implanted animals was mutagenic; a consequence of the presence of excreted DU. The activities of DU and HMTA in a single-gene mutation assay (HGPRT loci) were examined in CHO cells. DU was mutagenic at the HGPRT locus at a non-toxic concentration, while HMTA was only slightly mutagenic.
Project: DoD-122
Agency: Department Of Defense
Location: Armed Forces Radiobiology Research Institute (AFRRI)
P.I. Name: Alexandra C Miller, Ph. D.
Research Type: Mechanistic
Research Focus: Depleted Uranium
Status: Ongoing
Study Start Date:  
Estimated Completion Date: December 31,2004
Specific Aims: This project seeks to determine whether exposure to embedded fragments of DU and HMTA cause cancer in the Fisher 344 rat and investigates potential mechanisms of action. The study obtains data from two general treatment groups. One investigates whether metal fragment implantation affects rat longevity and their cause of death. The other, parallel study performs tissue analysis at various points during the study to investigate cellular changes associated with the metal exposures.
Methodology: Rats are implanted with pellets of DU, HMTA, the known metal carcinogen nickel (positive control), the suspected carcinogen lead, and the biologically inert metal tantalum (negative control). Longevity studies are carried out under guidelines suggested by the National Toxicology Program. Tissue analyses after necropsy determine the cause of death and the nature of any abnormal tissues observed. Subgroups of animals are similarly implanted but euthanized at various times after tissue implantation to correlate tissue metal content with long-term biological effect analysis. Experiments using an in vitro cell model are designed to determine the role alpha particle radiation plays in DU effects.
Most Recent Publications:

Miller AC, Whittaker T, Hogan J, McBride S, Benson KA. Oncogenes as Biomarkers for Low Dose Radiation-induced Health effects. Can Detect and Prevent, 20(5); 235-236, 1996. Article

Miller AC, Xu J, Stewart M, Edmond C, Hodge S, Matthews M, Kalinich JF, McClain DE. Potential Health Effects of the Heavy Metals, Depleted Uranium and Tungsten, Used in Armor-Piercing Munitions: Comparison of Neoplastic Transformation, Mutagenicity, Genomic Instability, and Oncogenesis. Metal Ions, 6:09-211, 2000. Article

Miller AC, Xu J, Prasanna P, Page N. Potential Late Health Effects of the Heavy Metals, Depleted Uranium sand Tungsten, used in Armor Piercing Munitions: Comparison of Neoplastic Transformation and Genotoxicity Using the Known Carcinogen Nickel. Military Medicine, 167(2 Suppl):120-2, FEB 2000. Abstract

Miller AC, Xu J, Whittaker T, Stewart M, McClain DE. Suppression of Depleted Uranium Induced Neoplastic Transformation of Human Cells by the Phenyl Fatty Acid Phenylacetate. Radiation Research, 155(1 PT 2):163-170, Jan 2001. Abstract

Miller AC, Blakely WF, Livengood D, Whittaker T, Xu J, Ejnik JW, Hamilton MM, Parlette E, St John S, Gerstenberg HM, Hsu H. Transformation of human osteoblast cells to the tumorigenic phenotype by depleted uranium-uranyl chloride. Environmental Health Prospective, 106(8):465-71, Aug 1998. Abstract

Miller AC, Fuciarelli AF, Jackson WE, Ejnik EJ, Emond C, Strocko S, Hogan J, Page N, Pellmar T. Urinary and Serum Mutagenicity Studies with Rats Implanted with Depleted Uranium or Tantalum Pellets. Mutagenesis, 13(6):643-8, Nov 1998. Abstract