title: Neoplastic transformation of human osteoblast cells to the tumorigenic phenotype by heavy metal-tungsten alloy particles: induction of genotoxic effects.
abstract: Heavy metal-tungsten alloys (HMTAs) are dense heavy metal composite materials used primarily in military applications. HMTAs are composed of a mixture of tungsten (91-93%), nickel (3-5%) and either cobalt (2-4%) or iron (2-4%) particles. Like the heavy metal depleted uranium (DU), the use of HMTAs in military munitions could result in their internalization in humans. Limited data exist, however, regarding the long-term health effects of internalized HMTAs in humans. We used an immortalized, non-tumorigenic, human osteoblast-like cell line (HOS) to study the tumorigenic transforming potential of reconstituted mixtures of tungsten, nickel and cobalt (rWNiCo) and tungsten, nickel and iron (rWNiFe). We report the ability of rWNiCo and rWNiFe to transform immortalized HOS cells to the tumorigenic phenotype. These HMTA transformants are characterized by anchorage-independent growth, tumor formation in nude mice and high level expression of the K-ras oncogene. Cellular exposure to rWNiCo and rWNiFe resulted in 8.90 +/- 0.93- and 9.50 +/- 0.91-fold increases in transformation frequency, respectively, compared with the frequency in untreated cells. In comparison, an equivalent dose of crystalline NiS resulted in a 7.7 +/- 0.73-fold increase in transformation frequency. The inert metal tantalum oxide did not enhance HOS transformation frequency above untreated levels. The mechanism by which rWNiCo and rWNiFe induce cell transformation in vitro appears to involve, at least partially, direct damage to the genetic material, manifested as increased DNA breakage or chromosomal aberrations (i.e. micronuclei). This is the first report showing that HMTA mixtures of W, Ni and Co or Fe cause human cell transformation to the neoplastic phenotype. While additional studies are needed to determine if protracted HMTA exposure produces tumors in vivo, the implication from these in vitro results is that the risk of cancer induction from internalized HMTAs exposure may be comparable with the risk from other biologically reactive and insoluble carcinogenic heavy metal compounds (e.g. nickel subsulfide and nickel oxide).
authors.affiliation: Applied Cellular Radiobiology Department, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889-5603, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Miller
authors.forename: S
authors.initials: S
authors.lastname: Mog
authors.forename: L
authors.initials: L
authors.lastname: McKinney
authors.forename: L
authors.initials: L
authors.lastname: Luo
authors.forename: J
authors.initials: J
authors.lastname: Allen
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: N
authors.initials: N
authors.lastname: Page
mesh_terms: D000497:Alloys / Q000633:toxicity*; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D011905:Genes, ras / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019216:Metals, Heavy / Q000633:toxicity*; D051379:Mice; D008819:Mice, Nude; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D012516:Osteosarcoma; D010641:Phenotype; D011208:Powders; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014414:Tungsten / Q000633:toxicity*
chemical_list: D000497:Alloys; D019216:Metals, Heavy; D011208:Powders; D004247:DNA; D014414:Tungsten