There is evidence indicating that humans may develop influenza-like symptoms after inhalation of fumes resulting from pyrolysis of polymers (e.g., Teflon), and from freshly produced fumes containing various oxides of metals. Exceptionally even more severe health effects have been reported. It seems that an essential factor in the generation of fume-fever is the ultrafine size of the inhaled particles. To test the hypothesis that ultrafine particles differ in their effect on the lung from larger particles, we compared effects on rats exposed to two types of anatase-titanium dioxide (TiO2) particles: TiO2-D with primary particle diameter of 20 nm, or TiO2-F with primary particle diameter of 250 nm. TiO2 is generally considered a substance with very low chemical toxicity. The rats were exposed by single intrapulmonary instillation, or by repeated inhalation exposures (12 weeks). The resulting health effects and their recovery indicate that the rats exposed to the ultrafine sample of TiO2 showed a dramatically higher toxicity and slower recovery compared to the group exposed to the larger particles. It seems that ultrafine particles compared to larger particles penetrate the interstitium of the lung to a much larger extent, that their clearance from the lung is prolonged, and that the ultrafine particles provoke an extensive acute inflammatory response. Our results suggest that medical and technical countermeasures should be developed against the effects of particles, to be used in case of an accidental thermodegradation event, or a failure of on-board experiments in which ultrafine particles may be generated and released into the air of the spacecraft.