Pulmonary Instillation Studies with Nanoscale TiO2 Rods and Dots in Rats: Toxicity Is not Dependent upon Particle Size and Surface Area

TLDR

Nanoparticles are generally more toxic than larger particles of the same chemistry at equal mass concentrations in rat lung studies. This study compared acute lung toxicity of pigment‑grade TiO₂, nanoscale TiO₂ rods, and nanoscale TiO₂ dots to quartz in rats. Rats received 1 or 5 mg/kg intratracheal instillations of each particle type in PBS, and lung responses were evaluated by BAL biomarkers, cell proliferation assays, and histopathology at multiple time points up to 3 months. Nanoscale TiO₂ rods and dots caused only transient inflammation and cell injury at 24 h, similar to larger TiO₂ particles, whereas quartz induced dose‑dependent inflammation, foamy macrophages, and early fibrosis; thus, nanoscale TiO₂ particles were not more cytotoxic or inflammogenic than larger particles, contradicting the hypothesis that surface area drives pulmonary toxicity.

Abstract

Pulmonary toxicology studies in rats demonstrate that nanoparticles administered to the lung are more toxic than larger, fine-sized particles of similar chemistry at identical mass concentrations. The aim of this study was to evaluate the acute lung toxicity in rats of intratracheally instilled pigment-grade TiO2 particles (rutile-type particle size = ∼300 nm) versus nanoscale TiO2 rods (anatase = 200 nm × 35 nm) or nanoscale TiO2 dots (anatase = ∼10 nm) compared with a positive control particle type, quartz. Groups of rats were instilled with doses of 1 or 5 mg/kg of the various particle types in phosphate-buffered saline (PBS). Subsequently, the lungs of PBS- and particle-exposed rats were assessed using bronchoalveolar lavage fluid biomarkers, cell proliferation methods, and by the histopathological evaluation of lung tissue at 24 h, 1 week, 1 month, and 3 months postinstillation exposure. Exposures to nanoscale TiO2 rods or nanoscale TiO2 dots produced transient inflammatory and cell injury effects at 24 h postexposure (pe) and were not different from the pulmonary effects of larger sized TiO2 particle exposures. In contrast, pulmonary exposures to quartz particles in rats produced a dose-dependent lung inflammatory response characterized by neutrophils and foamy lipid-containing alveolar macrophage accumulation as well as evidence of early lung tissue thickening consistent with the development of pulmonary fibrosis. The results described herein provide the first example of nanoscale particle types which are not more cytotoxic or inflammogenic to the lung compared to larger sized particles of similar composition. Furthermore, these findings run counter to the postulation that surface area is a major factor associated with the pulmonary toxicity of nanoscale particle types.