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Deposition behavior of inhaled nanostructured TiO2 in rats: fractions of particle diameter below 100 nm (nanoscale) and the slicing bias of transmission electron microscopy

Context: In experimental studies with nanomaterials where translocation to secondary organs was observed, the particle sizes were smaller than 20 nm and were mostly produced by spark generators. Engineered nanostructured materials form microsize aggregates/agglomerates. Thus, it is unclear whether primary nanoparticles or their small aggregates/agglomerates occur in non-negligible concentrations after exposure to real-world materials in the lung. Objective: We dedicated an inhalation study with nanostructured TiO2 to the following research question: Does the particle size distribution in the lung contain a relevant subdistribution of nanoparticles? Methods: Six rats were exposed to 88 mg/m3 TiO2 over 5 days with 20% (count fraction) and <0.5% (mass fraction) of nanoscaled objects. Three animals were sacrificed after cessation of exposure (5 days), others after a recovery period of 14 days. Particle sizes were determined morphometrically by transmission electron microscopy (TEM) of ultra-thin lung slices. Since the particles visible are two-dimensional surrogates of three-dimensional structures we developed a model to estimate expected numbers of particle diameters below 100 nm due to the TEM slicing bias. Observed and expected numbers were contrasted in 2 × 2 tables by odds ratios. Results: Comparisons of observed and expected numbers did not present evidence in favor of the presence of nanoparticles in the rat lungs. In simultaneously exposed satellite animals agglomerates of nanostructured TiO2 were observed in the mediastinal lymph nodes but not in secondary organs. Conclusions: For nanostructured TiO2, the deposition of nanoscaled particles in the lung seem to play a negligible role.