Fibrotic pulmonary dust foci is an advanced pneumoconiosis lesion in rats induced by titanium dioxide nanoparticles in a 2-year inhalation study.

Abstract

Background: We have previously reported that inhalation exposure to titanium dioxide nanoparticles (TiO₂ NPs) for 13 weeks causes early pneumoconiosis lesions in the alveolar region of F344 rats. We defined these characteristic lesions as pulmonary dust foci (PDF). In this report, we re-evaluate and detail the histopathological data regarding particle-induced pneumoconiosis lesions, including progressive lesions of the early PDF lesions, that developed in F344 rats exposed TiO₂ NPs by whole body inhalation over a period of two years.

Methods: Male and female F344 rats were exposed to 0.5, 2, and 8 mg/m³ anatase type TiO₂ NPs for 6 h/day, 5 days/week for 104 weeks using a whole-body inhalation exposure system. After the final exposure, the rats were euthanized. In the present study, the collected lungs were re-evaluated macroscopically and histopathologically.

Results: Rats exposed to TiO₂ NPs developed macroscopic white lesions, primarily in the subpleural and hilar regions of the lung, which increased in size and number with exposure concentration. Histologically, two lesion types were identified: (1) Fibrotic Pulmonary Dust Foci (fPDF), characterized by collagen deposition, inflammatory infiltration, and disrupted alveolar epithelial differentiation, and (2) Dust Macules (DM), characterized by macrophage accumulation without significant fibrosis or inflammation. fPDFs, but not DMs, were observed after 13 weeks exposure to TiO₂ NPs, indicating that the DM-type pneumoconiosis lesions required a longer time to develop compared to fPDF-type pneumoconiosis lesions. Histopathological analysis revealed that the DM-type pneumoconiosis lesions that developed in rats exposed to TiO₂ NPs were similar to DM-type pneumoconiosis lesions that develop in humans.

Conclusions: Inhalation exposure to TiO₂ NPs caused the development of two types of pneumoconiosis lesions in rats with distinct pathological features, fPDFs and DMs. The histopathological similarity of the DM-type pneumoconiosis lesions that developed in rat lung in the present study with the DM-type pneumoconiosis lesions that develop in the human lung adds strong support to the conclusion that humans exposed to airborne TiO₂ NPs are at risk of developing pneumoconiosis.