Embedded Weapons-Grade Tungsten Alloy Shrapnel Rapidly Induces Metastatic High-Grade Rhabdomyosarcomas in F344 Rats

Journal article by John F. Kalinich, Christy A. Emond, Thomas K. Dalton, Steven R. Mog, Gary D. Coleman, Jessica E. Kordell, Alexandra C. Miller, David E. Mcclain; Environmental Health Perspectives, Vol. 113, 2005

Journal Article Excerpt

by John F. Kalinich , Christy A. Emond , Thomas K. Dalton , Steven R. Mog , Gary D. Coleman , Jessica E. Kordell , Alexandra C. Miller , David E. McClain Continuing concern regarding the potential health and environmental effects of depleted uranium and lead has resulted in many countries adding tungsten alloy (WA)-based munitions to their battlefield arsenals as replacements for these metals. Because the alloys used in many munitions are relatively recent additions to the list of militarily relevant metals, very little is known about the health effects of these metals after internalization as embedded shrapnel. Previous work in this laboratory developed a rodent model system that mimicked shrapnel loads seen in wounded personnel from the 1991 Persian Gulf War. In the present study, we used that system and male F344 rats, implanted intramuscularly with pellets (1 mm x 2 mm cylinders) of weapons-grade WA, to simulate shrapnel wounds. Rats were implanted with 4 (low dose) or 20 pellets (high dose) of WA. Tantalum (20 pellets) and nickel (20 pellets) served as negative and positive controls, respectively. The high-dose WA-implanted rats (n = 46) developed extremely aggressive tumors surrounding the pellets within 4-5 months after implantation. The low-dose WA-implanted rats (n = 46) and nickel-implanted rats (n = 36) also developed tumors surrounding the pellets but at a slower rate. Rats implanted with tantalum (n = 46), an inert control metal, did not develop tumors. Tumor yield was 100% in both the low- and high-dose WA groups. The tumors, characterized as high-grade pleomorphic rhabdomyosarcomas by histopathology and immunohistochemical examination, rapidly metastasized to the lung and necessitated euthanasia of the animal. Significant hematologic changes, indicative of polycythemia, were also observed in the high-dose WA-implanted rats. These changes were apparent as early as 1 month postimplantation in the high-dose WA rats, well before any overt signs of tumor development. These results point out the need for further studies investigating the health effects of tungsten and tungsten-based alloys. Key words: cobalt, embedded fragment, nickel, rat, rhabdomyosarcoma, tungsten, tungsten alloy. doi:10.1289/ehp.7791 available via http://dac.doi.org/ [Online 15 February 2005] Tungsten has been used for many years in a variety of applications. Combining the hard, brittle tungsten metal with various other metals, including nickel and cobalt, produces tungsten alloys (WAs) with specific characteristics, some of which are of interest to the military. Recently, WAs have replaced lead in some small-caliber ammunition (the "green bullet") [Oak Ridge National Laboratory (ORNL) 1998] and depleted uranium (DU) in kinetic-energy penetrators (ORNL 1996). Based on a small number of studies, prevailing theory is that elemental tungsten or insoluble tungsten compounds have only limited toxicity (Leggett 1997). For example, tungsten coils implanted into the subclavian artery of rabbits rapidly degrade, leading to elevated serum tungsten levels as early as 15 min after implantation. However, after 4 months, no signs of local or systemic toxicity were observed (Peuster et al. 2003). Studies on health effects of Ni and Co are more numerous. Intramuscular injections (28 mg) of soluble metallic Ni or Co result in formation of rhabdomyosarcomas at the injection site. With Ni, 100% of injected rats develop a tumor within 41 weeks (Heath and Daniel 1964), whereas administration of Co results in tumor formation in 40% of the rats with a latency period of 71 weeks (Heath 1954, 1956). However, intramuscular implantation of rods or pellets composed of various Ni or Co alloys used in orthopedic prosthetics results in no excessive tumor formation (Gaechter et al. 1977; Sunderman 1989). A variety of other Ni compounds, including nickel subsulfide, nickel oxide, and nickel monosulfide, have been tested for carcinogenic potential via intramuscular administration (Gilman 1962; Sunderman and Maenza 1976; Sunderman et al. 1977). Tumors (rhabdomyosarcoma and fibrosarcoma) were found in many cases at the injection site, with tumor yield dependent on solubility and concentration of the administered compound. It has been postulated that the yield of localized tumors is inversely related to the rate of solubilization of the Ni-containing compound (Kasprzak et al. 1983). This hypothesis does not appear to hold for Co compounds (Lison et al. 2001). Metal alloys present additional problems when investigating health effects. The various metals comprising the alloy, as well as the method of production, can all factor into the overall health effect observed upon exposure. Investigations on hard-metal disease have shown that either tungsten carbide or Co alone has limited toxicity on lung tissue (Lasfargues et al. 1992). However, when ...

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