Ultrafine particles: mechanisms of lung injury

Many ultrafine particles comprised classically of low-toxicity, low-solubility materials such as carbon black and titanium dioxide have been found to have greater toxicity than larger, respirable particles made of the same material. The basis of the increased toxicity of the ultrafine form is not well understood and a programme of research has been carried out in Edinburgh on the toxicology of ultra-fines aimed at understanding the mechanism. We used fine and ultrafine carbon black, TiO2 and latex and showed that there was an approximately 10-fold increase in inflammation with the same mass of ultrafine compared with fine particles. Using latex particles in three sizes-64, 202 and 535 nm-revealed that the smallest particles (64 nm) were profoundly inflammogenic but that the 202 and 535 nm particles had much less activity, suggesting that the cut-off for ultrafine toxicity lies somewhere between 64 and 202 nm. Increased oxidative activity of the ultrafine particle surface was shown using the fluorescent molecule dichlorofluorescein confirming that oxidative stress is a likely process by which the ultrafines have their effects. However, studies with transition-metal chelators and soluble extracts showed that the oxidative stress of ultrafine carbon black is not necessarily due to transition metals. Changes in intracellular Ca2+ levels in macrophage-like cells after ultrafine particle exposure suggested one way by which ultrafines might have their pro-inflammogenic effects.