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 Research Topics    |    Major Focus Areas    |    Reports
Research Topics
Health and Human Services Department of Defense Veterans Affairs Health and Human Services Gulf War Information Department of Defense Gulf War Information Veterans Affairs Gulf War Information Home Home Advanced Search Glossary FAQs Site Map Contact Us
 Research Topics    |    Major Focus Areas
Research Topics
ACCIDENTS & INJURIES
BONE, JOINT & MUSCLE
BRAIN & NERVOUS
CANCER
CARDIOVASCULAR
CHEMICAL WARFARE
DIGESTIVE HEALTH
ENVIRONMENTAL & OCCUPATIONAL HEALTH
FAMILY HEALTH
GENERAL HEALTH & PHYSICAL SYMPTOMS
GENETIC STUDIES
HEALTH RESEARCH OF ALLIED FORCES
IMMUNE/BLOOD SYSTEM
INFECTIONS
LUNG & RESPIRATORY
MENTAL HEALTH
MILITARY WORKING DOGS
MORTALITY/DEATH
REPRODUCTIVE HEALTH/OUTCOMES
SLEEP DISORDER
Treatment
VACCINES & PROTECTIVE MEDICATIONS
Cancer
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 and determine the mechanism of action of embedded fragments of DU and a proposed surrogate metal, heavy metal tungsten alloy (HMTA) using both cell culture and animal studies.
Status/Results to Date: Previous studies at AFFRI indicate that exposure to DU or HMTA causes changes in cells, both in vivo and in vitro, suggesting that DU has carcinogenic potential. DU induces a 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 were 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. Urine from DU-implanted animals was mutagenic; a consequence of the presence of excreted DU. Exposure of cultured human bone cells to DU or 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. DU and HMTA were also shown to be genotoxic and mutagenic in model system studies.
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
Focus Category:Cancer
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 a rat model and to investigate potential mechanisms of action. The animal study will provide data from two general treatment groups that include a carcinogenicity/rat longevity study. A parallel study to analyze tissues obtained at various time points to investigate cellular changes associated with the metal exposures will also be conducted. Cell culture studies will be used to examine additional mechanisms and the role radiation plays in DU-induced effects.
Methodology: Rats will be implanted with pellets of DU, HMTA, the known metal carcinogen nickel (positive controls), the suspected carcinogen lead, and the biologically inert metal tantalum (negative control). Longevity studies will be carried out under guidelines suggested by the National Toxicology Program. Tissue analyses after necropsy will be used to determine the cause of death and the nature of any abnormal tissues observed. Subgroups of animals will be similarly implanted but euthanized at various times after tissue implantation to correlate tissue metal content with long-term biological effect analysis. Mutagenicity, cytogenicity, and genomic instability will be assessed. Experiments using an in vitro cell model were designed to determine the role alpha particle radiation plays in DU effects and examine other mechanisms of neoplastic transformation.
Most Recent Publications:

McClain DE, Benson KA, Dalton TK, Ejnik JW, Emond C, Hodge S, Kalinich JF, Landauer MR, Miller AC, Pellmar T, Stewart M, Villa V, Xu J. Biological effects of embedded depleted uranium (DU): summary of armed forces radiobiology research institute research. Sci Total Environ, 274(1-3):115-8, Jul 2001. Abstract

Miller AC, Stewart M, Brooks K, Shi L, Page N. Depleted uranium-catalyzed oxidative DNA damage: absence of significant alpha particle decay. J Inorg Biochem, 91(1):246-52. Jul 2002. Abstract

Miller AC, Brooks K, Stewart M, Anderson B, Shi L, McClain DE, Page N. Genomic instability in human osteoblast cells after exposure to depleted uranium: delayed lethality and micronuclei formation. J Environ Radioact, 64(2-3):247-59. 2003. Abstract

McClain DE, Benson KA, Dalton TK, Ejnik JW, Emond C, Hodge S, Kalinich JF, Landauer MR, Livengood D, Miller AC, Pellmar T, Stewart M, Villa V, Xu J. Health effects of embedded depleted uranium. Military Medicine, 167(2 Suppl):117-9, Feb 2002. Abstract

Miller AC, Mog S, McKinney L, Lei L, Allen J, Xu J, Page N. Neoplastic transformation of human osteoblast cells to the tumorigenic phenotype by heavy metal-tungsten alloy particles: induction of genotoxic effects. Carcinogenesis, 22(1):115-25, Jan 2001. Abstract

Miller AC, Xu J, Stewart M, Brooks K, Hodge S, Shi L, Page N, McClain DE. Observation of radiation-specific damage in human cells exposed to depleted uranium: dicentric frequency and neoplastic transformation as endpoints. Radiat Prot Dosimetry, 99(1-4):275-8. 2002. Abstract

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, Stewart M, Prasanna P, Page N. Potential late health effects of depleted uranium and tungsten used in armor-piercing munitions: comparison of neoplastic transformation and genotoxicity with the known carcinogen nickel. Military Medicine, 167(2 Suppl):120-2, Feb 2002. 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, phenyl acetate: chemoprevention by targeting the p21RAS protein pathway. 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 Perspectives, 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