Yamano Shotaro, Umeda Yumi
National Institute of Occupational Safety and Health, Japan Organization of Occupational Health and Safety, 2-26-1 Muraoka-Higashi, Fujisawa, Kanagawa, 251-8555, Japan.
Part Fibre Toxicol. 2025 Apr 18;22(1):7. doi: 10.1186/s12989-025-00623-y.
We have previously reported that inhalation exposure to titanium dioxide nanoparticles (TiO 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 TiO NPs by whole body inhalation over a period of two years.
Male and female F344 rats were exposed to 0.5, 2, and 8 mg/m anatase type TiO 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.
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.
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.
我们之前报道过，对F344大鼠进行为期13周的二氧化钛纳米颗粒（TiO NPs）吸入暴露会在其肺泡区域引发早期尘肺病病变。我们将这些特征性病变定义为肺尘埃灶（PDF）。在本报告中，我们重新评估并详细阐述了有关颗粒诱导的尘肺病病变的组织病理学数据，包括在通过全身吸入暴露于TiO NPs两年的F344大鼠中出现的早期PDF病变的进展性病变。
使用全身吸入暴露系统，将雄性和雌性F344大鼠暴露于0.5、2和8mg/m锐钛矿型TiO NPs中，每天暴露6小时，每周暴露5天，持续104周。最后一次暴露后，对大鼠实施安乐死。在本研究中，对收集的肺部进行了宏观和组织病理学的重新评估。
暴露于TiO₂ NPs的大鼠出现了肉眼可见的白色病变，主要位于肺的胸膜下和肺门区域，其大小和数量随暴露浓度增加。组织学上，鉴定出两种病变类型：（1）纤维化肺尘埃灶（fPDF），其特征为胶原沉积、炎症浸润和肺泡上皮分化破坏；（2）尘斑（DM），其特征为巨噬细胞聚集，无明显纤维化或炎症。在暴露于TiO₂ NPs 13周后观察到fPDF，但未观察到DM，这表明与fPDF型尘肺病病变相比，DM型尘肺病病变的发展需要更长时间。组织病理学分析显示，暴露于TiO₂ NPs的大鼠中出现的DM型尘肺病病变与人类中出现的DM型尘肺病病变相似。
吸入TiO₂ NPs导致大鼠出现两种具有不同病理特征的尘肺病病变类型，即fPDF和DM。本研究中大鼠肺中出现的DM型尘肺病病变与人类肺中出现的DM型尘肺病病变在组织病理学上的相似性，有力支持了暴露于空气中TiO₂ NPs的人类有患尘肺病风险这一结论。
