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

Abstract

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 × 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.

In vitro profiling of epigenetic modifications underlying heavy metal toxicity of tungsten-alloy and its components

“…Extensive use of heavy metals including tungsten-alloys and its constituent metals can cause harmful health effects (Kalinich, et al, 2005;Lagarde and Leroy, 2002). The employment of tungsten-alloys in military ammunition has produced a new route of long-term metal exposures as embedded shrapnels, which can be difficult to remove because of their location and/or small size (van der Voet et al, 2007).…”

“…Tungsten is known to alter phosphatedependent biochemical pathways in a cell-type-dependent manner that may negatively affect downstream cellular functions (Johnson et al, 2010). A rat model with intramuscular implanted tungsten-alloy pellets has shown a carcinogenic potential for tungsten-alloy in the muscle and lungs (Kalinich et al, 2005). Tungsten-alloys also instigated neoplastic transformation of human osteoblast cells indicating its genotoxic potential (Miller et al, 2001).…”

“…The cytotoxicity and carcinogenicity of heavy metals have been well recognized (for reviews see: Beyersmann and Hartwig, 2008;Denkhaus and Salnikow, 2002;Kalinich, et al, 2005;Leonard and Lauwerys, 1990;Valko et al, 2005). However, the involved mechanisms and molecular targets have not been fully elucidated because of their complex mode of action and variable degree of impact.…”

High-resolution measurement and mapping of tungstate in waters, soils and sediments using the low-disturbance DGT sampling technique

“…Tungsten (W) is a metal toxin with suspected carcinogenic properties [1][2][3][4]. As a dense lithophilic element noted for its hardness, superior electrical conductivity, high melting point and corrosion-resistance, W has a wide range of uses in daily household items (such as lamp filaments), building and construction tools (i.e.…”

“…However, it's not just the manufacturing processes that are a cause of concern, leachates from E-waste repositories and recycling sites can also contain considerable amounts of W [12]. Measures to phase out lead in ammunition, has seen W being used as its replacement [13], resulting in a relatively new and poorly characterized exposure source/pathway [1,4,9].…”