Ultrafine or fine titanium dioxide (TiO(2)) particles are widely used in the production of white pigments, for sunscreens, and in cleanup techniques. However, currently knowledge is deficient concerning cellular responses to these particles. The study evaluated and compared the biological activity of ultrafine and fine TiO(2) particles in RAW 264.7 macrophages according to an oxidative stress paradigm. In vitro exposure of macrophages to ultrafine or fine TiO(2) in the range of 0.5-200 microg/ml did not significantly alter cell viability. However, ultrafine TiO(2) enhanced intracellular generation of reactive oxygen species (ROS) to a greater extent than fine TiO(2) at each exposure concentration. Ultrafine TiO(2) induced ERK1/2 activation in a concentration-dependent manner, while the fine TiO(2)-induced changes were minimal. Phosphorylation of ERK1/2 occurred following 10 min exposure to higher concentrations of ultrafine TiO(2) (> or = 25 microg/ml). Similarly, ultrafine TiO(2) exposure significantly enhanced tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2 secretion in a concentration-dependent manner, and its potency was higher than fine TiO(2). These findings suggest that when exposure concentration is based upon equivalent mass, ultrafine TiO(2) exerts greater biological activity as measured by ROS generation, ERK 1/2 activation, and proinflammatory mediator secretion in RAW 264.7 macrophages than fine TiO(2).