Advertisement

Heavy Metal-Induced Carcinogenicity: Depleted Uranium and Heavy-Metal Tungsten Alloy

Chapter

Abstract

Continued development of novel munitions for the battlefield opens the possibility of wounds containing embedded fragments of metals or metal mixtures whose toxicological properties may not as yet be well-understood. This chapter reviews what is currently known about two recent additions to many nations’ arsenals: depleted uranium and heavy-metal tungsten alloy . The toxicological and genotoxic properties of these materials, derived from both in vitro and in vivo studies, will be discussed, as will the health effects of known human exposures. Finally, areas requiring further research will be detailed.

Keywords

Tungsten Alloy Wound Contamination Improvise Explosive Device Deplete Uranium Embed Fragment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The views expressed here are strictly those of the author and not those of the Armed Forces Radiobiology Research Institute, the Uniformed Services University, or the United States Department of Defense. Mention of any commercial reagents or devices does not constitute endorsement by the United States Government. Dr. Kalinich has been supported in part by grants from the U.S. Army Medical Research and Materiel Command (Award #: DAMD17–01-1–0821) and the U.S. Army Peer-Reviewed Medical Research Program (Award #: W81XWH-06–2-0025). The author would like to thank Dr Steven Mog, DVM for obtaining histopathological images.

References

  1. ATSDR (Agency for Toxic Substances and Disease Registry), Public Health Service, U.S. Department of Health and Human Services (1999) Toxicological profile for uraniumGoogle Scholar
  2. ATSDR (Agency for Toxic Substances and Disease Registry), Public Health Service, U.S. Department of Health and Human Services (2005) Toxicological profile for tungstenGoogle Scholar
  3. Berry JP, Zhang L, Galle P, Ansoborlo E, Henge-Napoli MH, Donnadieu-Claraz M (1997) Role of the alveolar macrophage lysosomes in metal detoxification. Microsc Res Tech 36:313–323PubMedCrossRefGoogle Scholar
  4. Bistline RW, Watters RL, Lebel JL (1972) A study of translocation dynamics of plutonium and americium from simulated puncture wounds in beagle dogs. Health Phys 22:829–831PubMedCrossRefGoogle Scholar
  5. Brand KG, Buoen LC, Johnson KH, Brand T (1975) Etiological factors, stages, and the role of the foreign body in foreign-body tumorigenesis: a review. Cancer Res 35:279–286PubMedGoogle Scholar
  6. Brand KG, Johnson KH, Buoen LC (1976) Foreign body tumorigenesis. CRC Crit Rev Toxicol 4:353–394Google Scholar
  7. Brewer L, Fairbrother A, Clark J, Amick D (2003) Acute toxicity of lead, steel, and an iron-tungsten-nickel shot to mallard ducks (Anas platyrhynchos). J Wild Dis 39:638–648Google Scholar
  8. Broughton G, Janis JE (2006) The basic science of wound healing. Plast Reconstr Surg 117 (Suppl):12S–34SPubMedCrossRefGoogle Scholar
  9. Castro CA, Benson KA, Bogo V, Daxon EG, Hogan JB, Jacocks HM, Landauer MR, McBride SA, Shehata CW (1996) Establishment of an animal model to evaluate the biological effects of intramuscularly embedded depleted uranium fragments. Armed Forces Radiobiology Research Institute. Bethesda, MD, Technical Report 96-3Google Scholar
  10. Cromwell O, Hamid Q, Corrigan CJ, Barkans J, Meng Q, Collins PD, Kay AB (1992) Expression and generation of interleukin-8, IL-6 and granulocyte-macrophage colony-stimulating factor by bronchial epithelial cells and enhancement by IL-1 beta and tumor necrosis factor. Immunology 77:330–337PubMedGoogle Scholar
  11. Dagle GE, Lebel JL, Phemister RD, Watters RL, Gomez LS (1985) Translocation kinetics of plutonium oxide from the popliteal lymph nodes of beagles. Health Phys 28:395–398CrossRefGoogle Scholar
  12. Dorsey CD, Engelhardt SM, Squibb KS, McDiarmid MA (2009) Biological monitoring for depleted uranium exposure in US veterans. Environ Health Perspect 117:953–956PubMedGoogle Scholar
  13. Dublineau I, Grison S, Grandcolas L, Baudelin C, Tessier C, Suhard D, Frelon S, Cossonnet C, Claraz M, Ritt J, Paquet P, Voisin P, Gourmelon P (2006) Absorption, accumulation and biological effects of depleted uranium in Peyer’s patches of rats. Toxicology 227:227–239PubMedCrossRefGoogle Scholar
  14. Furuya R, Kumagai H, Hishida A (1997) Acquired resistence to rechallenge injury with uranyl acetate in LLC-PK1 cells. J Lab Clin Med 129:347–355PubMedCrossRefGoogle Scholar
  15. Gazin V, Kerdine S, Grillon G, Pallardy M, Raoul H (2004) Uranium induces TNFα secretion and MAPK activation in a rat alveolar macrophage cell line. Toxicol Appl Pharmacol 194:49–59PubMedCrossRefGoogle Scholar
  16. Hahn FF (2007) Carcinogenesis of depleted uranium: studies in animals. In: Miller AC (ed) Depleted uranium: properties, uses, and health consequences. CRC Press, Boca Raton, FLGoogle Scholar
  17. Hahn FF, Guilmette RA, Hoover MD (2002) Implanted depleted uranium fragments cause soft tissue sarcomas in the muscles of rats. Environ Health Perspect 110:51–59PubMedCrossRefGoogle Scholar
  18. International Commission on Radiological Protection (1966) Deposition and retention models for internal dosimetry of the human respiratory tract. Task group on lung dynamics. Health Phys 12:173–207Google Scholar
  19. Kalinich JF, McClain DE (2001) Staining of intracellular deposits of uranium in cultured murine macrophages Biotech Histochem 76:247–252Google Scholar
  20. Kalinich JF, Ramakrishnan N, Villa V, McClain DE (2002) Depleted uranium-uranyl chloride induces apoptosis in mouse J774 macrophages. Toxicology 179:105–114PubMedCrossRefGoogle Scholar
  21. Kalinich JF, Emond CA, Dalton TK, Mog SR, Coleman GD, Kordell JE, Miller AC, McClain DE (2005) Embedded weapons-grade tungsten alloy shrapnel rapidly induces metastatic high-grade rhabdomyosarcomas in F344 rats. Environ Health Perspect 113:729–734PubMedCrossRefGoogle Scholar
  22. Kalinich JF, Vergara VB, Emond CA (2008) Urinary and serum metal levels as indicators of embedded tungsten alloy fragments. Mil Med 173:754–758PubMedGoogle Scholar
  23. Kelly ME, Fitzgerald SD, Aulerich RJ, Balander RJ, Powell DC, Stickle RL, Stevens W, Cray C, Tempelman RJ, Bursian SJ (1998) Acute effects of lead, steel, tungsten-iron, and tungsten-polymer shot administered to game-farm mallards J Wild Dis 34:673–687Google Scholar
  24. Kraabel BJ, Miller MW, Getzy DM, Ringelman JK (1996) Effects of embedded tungsten-bismuth-tin shot and steel shot on mallards (Anas platyrhynchos). J Wild Dis 32:1–8Google Scholar
  25. Leggett RW (1997) A model of the distribution and retention of tungsten in the human body. Sci Total Environ 206:147–165PubMedGoogle Scholar
  26. Leggett RW, Pellmar TC (2003) The biokinetics of uranium migrating from embedded DU fragments. J Environ Radioact 64:205–225PubMedCrossRefGoogle Scholar
  27. Li J, Chen J, Kirsner R (2007) Pathophysiology of acute wound healing. Clin Dermatol 25:9–18PubMedCrossRefGoogle Scholar
  28. Lin H-Y, Bumgardner JD (2004) Changes in the surface oxide composition of Co-Cr-Mo implant alloy by macrophage cells and their released reactive chemical species. Biomaterials 25:1233–1238Google Scholar
  29. Lin RH, Wu LJ, Lee CH, Lin-Shiau SY (1993) Cytogenetic toxicity of uranyl nitrate in Chinese hamster ovary cells. Mut Res 319:197–203CrossRefGoogle Scholar
  30. Lison D, Buchet JP, Hoet P (1997) Toxicity of tungsten. Lancet 349:58–59PubMedCrossRefGoogle Scholar
  31. Lizon C, Fritsch P (1999) Chemical toxicity of some actinides and lanthanides toward alveolar macrophages: an in vitro study. Int J Radiat Biol 75:1459–1471PubMedCrossRefGoogle Scholar
  32. Lloyd RD, Atherton DR, Mays CW, McFarland SS, Williams JL (1974) The early excretion, retention and distribution of injected curium citrate in beagles. Health Phys 27:61–67PubMedCrossRefGoogle Scholar
  33. Marquet P, Francois B, Vignon P, Lachatre G (1996) A soldier who had seizures after drinking quarter of a litre of wine. Lancet 348:1070PubMedCrossRefGoogle Scholar
  34. Marquet P, Francois B, Lotfi H, Turcant A, Debord J, Nedelec G, Lachatre G (1997) Tungsten determination in biological fluids, hair and nails by plama emission spectrometry in a case of severe acute toxication in man. J Forensic Sci 42:527–530PubMedGoogle Scholar
  35. McClain DE, Miller AC (2007) Depleted uranium biological effects: introduction and early in vitro and in vivo studies. In: Miller AC (ed) Depleted uranium: properties, uses, and health consequences. CRC Press, Boca RatonGoogle Scholar
  36. McDiarmid MA, Keogh JP, Hooper FJ, McPhaul K, Squibb K, Kane R, DiPino R, Kabat M, Kaup B, Anderson L, Hoover D, Brown L, Hamilton M, Jacobson-Kram D, Burrows B, Walsh M (2000) Health effects of depleted uranium on exposed Gulf War veterans. Environ Res 82:168–180PubMedCrossRefGoogle Scholar
  37. McDiarmid MA, Squibb K, Engelhardt S, Oliver M, Gucer P, Wilson PD, Kane R, Kabat M, Kaup B, Anderson L, Hoover D, Brown L, Jacobson-Kram D (2001) Surveillance of depleted uranium exposed Gulf War veterans: health effects observed in an enlarged “friendly fire” cohort. J Occup Environ Med 43:991–1000PubMedGoogle Scholar
  38. McDiarmid MA, Engelhardt S, Oliver M, Gucer P, Wilson PD, Kane R, Kabat M, Kaup B, Anderson L, Hoover D, Brown L, Handwerger B, Albertini R, Jacobson-Kram D, Thorne CD, Squibb KS (2004) Health effects of depleted uranium on exposed Gulf War veterans: a ten-year follow-up. J Toxicol Environ Health—Part A—Curr Issues 67:277–296CrossRefGoogle Scholar
  39. McDiarmid MA, Engelhardt SM, Oliver M, Gucer P, Wilson PD, Kane R, Kabat M, Kaup B, Anderson L, Hoover D, Brown L, Albertini RJ, Gudi R, Jacobson-Kram D, Thorne CD, Squibb KS (2006) Biological monitoring and surveillance results of Gulf War I veterans exposed to depleted uranium. Int Arch Occup Environ Health 79:11–21PubMedCrossRefGoogle Scholar
  40. McDiarmid MA, Engelhardt SM, Oliver M, Gucer P, Wilson PD, Kane R, Cernich A, Kaup B, Anderson L, Hoover D, Brown L, Albertini R, Gudi R, Jacobson-Kram D, Squibb KS (2007a) Health surveillance of Gulf War I veterans exposed to depleted uranium: updating the cohort. Health Phys 93:60–73CrossRefGoogle Scholar
  41. McDiarmid MA, Squibb K, Engelhardt S, Gucer P, Oliver M (2007b) Surveillance of Gulf War I veterans exposed to depleted uranium: 15 years of follow-up. Euro J Oncol 12:235–242Google Scholar
  42. McDiarmid MA, Engelhardt SM, Dorsey CD, Oliver M, Gucer P, Wilson PD, Kane R, Cernich A, Kaup B, Anderson L, Hoover D, Brown L, Albertini R, Gudi R, Squibb KS (2009) Surveillance results of depleted uranium-exposed Gulf War I veterans: sixteen years of follow-up. J Toxicol Environ Health—Part A—Curr Issues 72:14–29CrossRefGoogle Scholar
  43. Miller AC, Blakely WF, Livengood D, Whittaker T, Xu J, Ejnik JW, Hamilton MM, Parlette E, St John T, Gerstenberg HM, Hsu H (1998) Transformation of human osteoblast cells to the tumorigenic phenotype by depleted uranium-uranyl chloride. Environ Health Perspect 106:465–471PubMedCrossRefGoogle Scholar
  44. Miller AC, Xu J, Stewart M, Emond E, Hodge S, Matthews C, Kalinich J, McClain DE (2000) 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. In: Centeno JA, Collery PH, Vernet G, Finkelman RB, Gibb H, Etienne JC (eds) Metals in biology and medicine, vol 6. John Libbey Eurotext, ParisGoogle Scholar
  45. Miller AC, Mog S, McKinney L-A, Luo L, Allen J, Xu J, Page N (2001) Neoplastic transformation of human osteoblast cells to the tumorigenic phenotype by heavy metal-tungsten alloy particles: induction of genotoxic effects. Carcinogenesis 22:115–125PubMedCrossRefGoogle Scholar
  46. Miller AC, Stewart M, Brooks K, Shi L, Page N (2002a) Depleted uranium-catalyzed oxidative DNA damage: absence of significant alpha particle decay. J Inorg Biochem 91:246–252CrossRefGoogle Scholar
  47. Miller AC, Xu J, Stewart M, Brooks K, Hodge S, Shi L, Page N, McClain D (2002b) Observation of radiation-specific damage in human cells exposed to depleted uranium: dicentric frequency and neoplastic transformation as endpoints. Radiat Protec Dosim 99:275–278CrossRefGoogle Scholar
  48. Miller AC, Xu J, Stewart M, Prasanna PGS, Page N (2002c) 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. Mil Med 167(Suppl 1):120–122Google Scholar
  49. Miller AC, Brooks K, Stewart M, Anderson B, Shi L, McClain D, Page N (2003) Genomic instability in human osteoblast cells after exposure to depleted uranium: delayed lethality and micronuclei formation. J Environ Radioact 64:247–259PubMedCrossRefGoogle Scholar
  50. Miller AC, Brooks K, Smith J, Page N (2004) Effect of the militarily-relevant heavy metals, depleted uranium and heavy metal tungsten-alloy on gene expression in human liver carcinoma cells (HepG2). Mol Cell Biochem 255:247–256PubMedCrossRefGoogle Scholar
  51. Mirto H, Henge-Napoli MH, Gibert R, Ansoborlo E, Fournier M, Cambar J (1999) Intracellular behavior of uranium (VI) on renal epithelial cell in culture (LLC-PK1): influence of uranium speciation. Toxicol Lett 104:249–256PubMedCrossRefGoogle Scholar
  52. Mitchell RR, Fitzgerald SD, Aulerich RJ, Balander RJ, Powell DC, Tempelman RJ, Cray C, Stevens W, Bursian SJ (2001a) Hematological effects and metal residue concentrations following chronic dosing with tungsten-iron and tungsten-polymer shot in adult game-farm mallards. J Wild Dis 37:459–467Google Scholar
  53. Mitchell RR, Fitzgerald SD, Aulerich RJ, Balander RJ, Powell DC, Tempelman RJ, Stevens W, Bursian SJ (2001b) Reproductive effects and duckling survivability following chronic dosing with tungsten-iron and tungsten-polymer shot in adult game-farm mallards. J Wild Dis 37:468–474Google Scholar
  54. Mitchell RR, Fitzgerald SD, Aulerich RJ, Balander RJ, Powell DC, Tempelman RJ, Stickle RL, Stevens W, Bursian SJ (2001c) Health effects following chronic dosing with tungsten-iron and tungsten-polymer shot in adult game-farm mallards. J Wild Dis 37:451–458Google Scholar
  55. Monleau M, De Meo M, Paquet F, Chazel V, Dumenil G, Donnadieu-Clarz M (2006) Genotoxic and inflammatory effects of depleted uranium particles inhaled by rats. Toxicol Sci 89:287–295PubMedCrossRefGoogle Scholar
  56. Morrow PE, Gibb FR, Gazioglu KM (1967) A study of particulate clearance from the human lungs. Am Rev Respirat Dis 96:1209–1221Google Scholar
  57. Osawa R, Abe R, Inokuma D, Yokota K, Ito H, Nabeshima M, Shimizu H (2006) Chain saw blade granuloma: reaction to a deeply embedded metal fragment. Arch Dermatol 142:1079–1080PubMedGoogle Scholar
  58. Pellmar TC, Fuciarelli AF, Ejnik JW, Hamilton M, Hogan J, Strocko S, Emond C, Mottaz HM, Landauer MR (1999) Distribution of uranium in rats implanted with depleted uranium pellets. Toxicol Sci 49:29–39PubMedCrossRefGoogle Scholar
  59. Peuster M, Fink C, von Schnakenburg C (2003) Biocompatibility of corroding tungsten coils: in vitro assessment of degradation kinetics and cytotoxicity on human cells. Biomaterials 24:4057–4061PubMedCrossRefGoogle Scholar
  60. Prat O, Berenguer F, Malard V, Tavan E, Sage N, Steinmetz G, Quemeneur E (2005) Transcriptomic and proteomic responses of human renal HEK293 cells to uranium toxicity. Proteomics 5:297–306PubMedCrossRefGoogle Scholar
  61. Saruwatari H, Kamiwada R, Matsushita S, Hashiguchi T, Kawai K, Kanekura T (2009) Tungsten granuloma attributable to a piece of lawn-mower blade. Clin Exp Dermatol 34:e268–e269PubMedCrossRefGoogle Scholar
  62. Schins RP, Borm PJ (1999) Mechanisms and mediators in coal dust induced toxicity: a review. Ann Occup Hygiene 43:7–33Google Scholar
  63. Sica A, Allavena P, Mantovani A (2008) Cancer related inflammation: the macrophage connection. Cancer Lett 264:204–215CrossRefGoogle Scholar
  64. Tasat DR, De Ray BM (1987) Cytotoxic effect of uranium dioxide on rat alveolar macrophages. Environ Res 112:1628–1635Google Scholar
  65. Thomsen P, Gretzer C (2001) Macrophage interactions with modified material surfaces. Curr Opin Solid State Mater Sci 5:163–176CrossRefGoogle Scholar
  66. Tsirogianni AK, Moutsopoulos NM, Moutsopoulos HM (2006) Wound healing: immunological aspects. Injury 375:S5–S12CrossRefGoogle Scholar
  67. van der Voet GB, Todorov TI, Centeno JA, Jonas W, Ives J, Mullick FG (2007) Metals and health: a clinical toxicological perspective on tungsten and review of the literature. Mil Med 172:1002–1005PubMedGoogle Scholar
  68. Wan B, Fleming JT, Schultz TW, Sayler GS (2006) In vitro immune toxicity of depleted uranium: effects on murine macrophages, CD+ T cells, and gene expression profiles. Environ Health Perspect 114:85–91PubMedCrossRefGoogle Scholar
  69. Yokel RA, Lasley SM, Dorman DC (2006) The speciation of metals in mammals influences their toxicokinetics and toxicodynamics and therefore human health risk assessment. J Toxicol Environ Health Part B 9:63–85CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Armed Forces Radiobiology Research InstituteBethesdaUSA

Personalised recommendations