Neoplastic transformation of human osteoblast cells to the tumorigenic phenotype by heavy metal-tungsten alloy particles: induction of genotoxic effects

Heavy metal-tungsten alloys (HMTAs) are dense heavy metal composite materia ls 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 i n military munitions could result in their internalization in humans. Limit ed data exist, however, regarding the long-term health effects of internali zed HMTAs in humans. We used an immortalized, nontumorigenic, human osteobl ast-like cell line (HOS) to study the tumorigenic transforming potential of reconstituted mixtures of tungsten, nickel and cobalt (rWNiCo) and tungste n, nickel and iron (rWNiFe), We report the ability of rWNiCo and rWNiFe to transform immortalized HOS cells to the tumorigenic phenotype, These HMTA t ransformants are characterized by anchorage-independent growth, tumor forma tion 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 th e frequency in untreated cells. In comparison, an equivalent dose of crysta lline NiS resulted in a 7.7 +/- 0.73-fold increase in transformation freque ncy. The inert metal tantalum oxide did not enhance HOS transformation freq uency above untreated levels. The mechanism by which rWNiCo and rWNiFe indu ce cell transformation in vitro appears to involve, at least partially, dir ect damage to the genetic material, manifested as increased DNA breakage or chromosomal aberrations (i.e. micronuclei). This is the first report showi ng that HMTA mixtures of W, Ni and Co or Fe cause human cell transformation to the neoplastic phenotype, While additional studies are needed to determ ine if protracted HMTA exposure produces tumors in vivo, the implication fr om these in vitro results is that the risk of cancer induction from interna lized HMTAs exposure may be comparable with the risk from other biologicall y reactive and insoluble carcinogenic heavy metal compounds (e.g. nickel su bsulfide and nickel oxide).