Experimental research into the pathogenesis of cobalt/hard metal lung disease

Abstract

In recent years clinical, epidemiological and experimental evidence has accumulated indicating that cobalt metal particles, when inhaled in association with other agents such as metallic carbides (hard metals) or diamond dust, may produce an interstitial lung disease termed "hard metal disease" or "cobalt lung". This article summarizes the progress accomplished in our two laboratories to understand the pathogenesis of this disease. Gaps and weaknesses in our current knowledge have also been highlighted in order to suggest potential avenues for further research. Whilst animal models have proved useful for the demonstration of the toxic synergy between cobalt and carbides (e.g. tungsten carbide), most animal models have remained descriptive and have not provided information on the mechanism for this synergy. In particular, the bizarre multinucleated giant cells which are an important hallmark of the human disease, have not been reproduced consistently in experimental animals. Since cobalt is a known sensitizer, there may also be a need to develop experimental models to test the possible involvement of immunological mechanisms in the pathogenesis of the interstitial disease. In vitro systems including macrophage cell cultures and physico-chemical tests have been useful to investigate the mechanism underlying the toxic synergy.The recent finding that, in vitro, cobalt and metallic carbides interact with oxygen to produce toxic activated oxygen species opens a new avenue of research and may offer an alternative interpretation of the fact that only a limited proportion of exposed workers develop interstitial disease. Besides the possible involvement of immunological mechanisms, it may be speculated that individuals with a lower antioxidant defence are more susceptible to the toxic effect of activated oxygen species produced by cobalt-containing dusts from hard metal.

Characteristics of Dusts Encountered during the Production of Cemented Tungsten Carbides

“…If Co particles in the presence of WC particles cause HMD via generation of ROS [4][5][6] , then our characterization of airborne particles may help to explain the inconsistent findings of epidemiological studies, e.g., between Meyer-Bisch et al 1) and Sprince et al 2) ; only Sprince et al 2) showed a higher risk in the later stages of the CTC manufacturing process. We observed that airborne particles potentially available for inhalation in spray drying and all subsequent work areas were a mixture of elemental tungsten and elemental Co particles and/or multi-constituent W/Co particles (ostensibly WC/Co particles, but the relative carbon contribution of the collection substrate and metal carbides is unknown).…”

“…It is interesting to speculate on the potential implications of our results, which suggest more intimate contact between Co and WC in post-screened particles relative to pre-spray dried particles, for generation of ROS and risk of HMD. It has been reported that the Co constituent of pre-sintered WC/Co powder is oxidized in vitro, releasing electrons that are transferred to the surface of WC where atmospheric oxygen is reduced, resulting in generation of ROS [4][5][6] . In pre-sintered powder, metallic Co and WC may be held in contact by weak electrostatic bonds or by van der Waals forces.…”

Characterization of exposures among cemented tungsten carbide workers. Part I: Size-fractionated exposures to airborne cobalt and tungsten particles

“…Using powder concentrations of 22.5 mg/ml (which is high relative to observed mass concentrations in Table 1) and an electron spin resonance technique, Lison et al ( , 1996 proposed the following precise mechanism for HMD: when both cobalt metal (which is thermodynamically able to reduce ambient oxygen) particles and tungsten carbide (a good electron conductor) particles are associated, electrons provided by the cobalt metal are easily transferred to the surface of the carbide particles, where reduction of oxygen can occur at an increased rate, resulting in the generation of free radicals. Analogous results have been reported for genotoxicity studies (Anard et al, 1997;Van Goethem et al, 1997;Lison et al, 2001;De Boeck et al, 2003a, b;Mateuca et al, 2005): cobalt associated with tungsten carbide particles (mechanical mixture or pre-sintered hard metal powder) produce more free radicals and DNA strand breaks than pure cobalt or tungsten carbide powder alone.…”

“…Using in vitro and in vivo models, researchers investigating the mechanistic basis of HMD (Lasfargues et al, 1992;Lison and Lauwerys, 1990, 1994, 1995Lison et al, , 1996Zanetti and Fubini, 1997;Keane et al, 2002;Mutti and Corradi, 2006;Moriyama et al, 2007) observed that a mechanical mixture of pure cobalt and tungsten carbide powders prepared in the laboratory and pre-sintered hard metal powder (mixture of cobalt, tungsten, and carbon) were more toxic than pure tungsten carbide or pure cobalt powder alone; the increased toxicity of the powder mixtures was attributed to the generation of free radicals via a localized reaction, that is, on a particle surface or between particle surfaces in contact, and not from the reaction of a solubilized component at the solid surface. Using powder concentrations of 22.5 mg/ml (which is high relative to observed mass concentrations in Table 1) and an electron spin resonance technique, Lison et al ( , 1996 proposed the following precise mechanism for HMD: when both cobalt metal (which is thermodynamically able to reduce ambient oxygen) particles and tungsten carbide (a good electron conductor) particles are associated, electrons provided by the cobalt metal are easily transferred to the surface of the carbide particles, where reduction of oxygen can occur at an increased rate, resulting in the generation of free radicals.…”

“…Workplace studies have identified cases of occupational asthma among CTC workers exposed to both cobalt and tungsten (Davison et al, 1983;Sprince et al 1988;Meyer-Bisch et al, 1989;Shirakawa et al, 1989;Kusaka et al, 1996) and diamond polishers exposed to cobalt alone (Gheysens et al, 1985). Cases of HMD have been reported among workers in all phases of CTC production (Bech et al, 1962;Coates and Watson, 1971;Sjo¨gren et al, 1980;Davison et al, 1983;Sprince et al, 1984Sprince et al, , 1988Meyer-Bisch et al, 1989;Cugell et al, 1990;Figueroa et al, 1992;Fischbein et al, 1992), which may be due to exposures to tungsten carbide particles in association with cobalt particles (Lasfargues et al, 1992(Lasfargues et al, , 1995Lison and Lauwerys, 1990, 1994, 1995Lison et al, , 1996. In humans, excess lung cancer has been observed among hard metal workers exposed to CTC dusts (Lasfargues et al, 1994;Moulin et al, 1998;Wild et al, 2000;Lison et al, 2001), but not among cobalt production workers exposed to cobalt alone (Moulin et al, 1993).…”