Comparative toxicity study of three surface-modified titanium dioxide nanoparticles following subacute inhalation

This study aimed to compare the toxic effects of three different titanium dioxide nanoparticles encoded in the European nanomaterial repository as NM-103 (rutile, hydrophobic), NM-104 (rutile, hydrophilic), and NM-105 (anatase/rutile, hydrophilic), suggesting different toxic potentials after uptake in the lungs. Wistar rats were exposed by nose-only inhalation to aerosol concentrations of 3, 12 and 48 mg/m³ for 4 weeks. This dosing scheme should induce non, partial and complete lung overload. The 4-week inhalation period was followed by 3-, 45- and 94-day exposure-free periods. Investigations according to the OECD 412 guideline were performed. Additional examinations, such as transmission electron microscopy and image analysis of tissue slides and cytospots, were performed to reveal possible differences among the three particle types.

Bronchoalveolar lavage fluid from the groups exposed to low concentrations of NM-103 or NM-104 presented slight inflammation. In the mid- and high-exposure groups, this was also present for the NM-105 group, however, weaker than those of NM-103 and NM-104. Histologically, all three groups presented similar distributions of particles in the respiratory tract. Although marginal differences in the degree of some changes exist, no obvious differences in the degree or characteristics of the induced lesions were observable. In general, compared with the higher exposure groups, all the middle exposure groups presented a greater accumulation and aggregation of macrophages at the terminal bronchi. Using transmission electron microscopy, particles were detected mainly in intraalveolar macrophages, followed by type 1 pneumocytes in the low- and mid-concentration groups and intraalveolar free particles in the high-concentration groups. Compared with the other groups, the NM-103 group presented greater numbers of free particles in the alveoli and fewer in the macrophages. With image analysis, the movement of particles to the bronchus-associated lymphoid tissue and lymph nodes could be detected comparably for the three different particle types.

The no observed adverse effect concentration was 3 mg/m³ for all three different TiO₂ particles. Despite minimal differences, a ranking mainly based on granulocyte influx into the lung was NM-104 > NM-103 > NM-105.