Lee K P, Henry N W, Trochimowicz H J, Reinhardt C F
Environ Res. 1986 Oct;41(1):144-67. doi: 10.1016/s0013-9351(86)80177-3.
Rats were exposed to TiO2 by the inhalation route at concentrations of 0, 10, 50, or 250 mg/m3 for 6 hr/day, 5 days/week for 2 years. Lung weights of rats at 10 mg/m3 were within normal limits after 2 years exposure. Lung weights increased significantly after 6 months at 50 mg/m3 and after 3 months at 250 mg/m3. After 2 years exposure, TiO2 retention in dried lung was 3.1% (26.5 mg per lung) at 10 mg/m3, 16.9% (124 mg per lung) at 50 mg/m3, and 28% (665 mg per lung) at 250 mg/m3. Lung clearance mechanisms appeared to be overloaded at 250 mg/m3. Dust particles were retained in the lung in a dose-related fashion, but there was no significant difference in lung clearance rate between 10 and 50 mg/m3. Lung response at 10 mg/m3 satisfied the biological criteria for a "nuisance dust," while adverse effects resulting from gradually accumulated particles (8.1%, 67.7 mg per lung) were found after 1 year of exposure to 50 mg/m3. An early pulmonary response indicating an overloaded lung clearance mechanism was manifested by massive accumulation of dust-laden macrophages (dust cells), foamy dust cells, free particles, or cellular debris derived from disintegrated foamy dust cells in the alveoli adjacent to the alveolar ducts. Alveolar proteinosis also appeared to be an important marker of an overloaded lung clearance mechanism and was observed at 50 and 250 mg/m3 after 1 year of exposure. Cholesterol granulomas were developed with degenerative foamy dust cells at 50 and 250 mg/m3 after 1 year of exposure. After 2 years exposure at 250 mg/m3, bronchioalveolar adenomas occurred in the alveoli showing type II pneumocyte hyperplasia, while cystic keratinizing squamous carcinomas were developed from squamous metaplasia of alveoli showing bronchiolarization in the alveolar duct region. Since the lung tumors were a unique type of experimentally induced tumors under exaggerated exposure conditions and have not usually been seen in man or animals, their relevance to man is questionable.
将大鼠通过吸入途径暴露于浓度为0、10、50或250毫克/立方米的二氧化钛环境中，每天6小时，每周5天，持续2年。暴露2年后，10毫克/立方米组大鼠的肺重量在正常范围内。50毫克/立方米组在暴露6个月后肺重量显著增加，250毫克/立方米组在暴露3个月后肺重量显著增加。暴露2年后，10毫克/立方米组干燥肺中二氧化钛的潴留量为3.1%（每肺26.5毫克），50毫克/立方米组为16.9%（每肺124毫克），250毫克/立方米组为28%（每肺665毫克）。250毫克/立方米组的肺清除机制似乎已超负荷。粉尘颗粒以剂量相关的方式滞留在肺中，但10毫克/立方米组和50毫克/立方米组之间的肺清除率无显著差异。10毫克/立方米组的肺反应符合“ nuisance dust”（无害粉尘）的生物学标准，而暴露于50毫克/立方米1年后，由于颗粒逐渐积累（8.1%，每肺67.7毫克）产生了不良反应。肺清除机制超负荷的早期肺部反应表现为在肺泡管附近的肺泡中，充满粉尘的巨噬细胞（尘细胞）、泡沫状尘细胞、游离颗粒或来自解体的泡沫状尘细胞的细胞碎片大量积聚。肺泡蛋白沉积症似乎也是肺清除机制超负荷的一个重要标志，在暴露1年后，50毫克/立方米组和250毫克/立方米组均观察到该现象。暴露1年后，50毫克/立方米组和250毫克/立方米组出现了由退行性泡沫状尘细胞形成的胆固醇肉芽肿。暴露于250毫克/立方米2年后，肺泡中出现了显示II型肺泡上皮细胞增生的细支气管肺泡腺瘤，而在肺泡管区域显示细支气管化生的肺泡鳞状化生则发展为囊性角化性鳞状癌。由于这些肺肿瘤是在过度暴露条件下实验诱导产生的一种独特类型的肿瘤，在人类或动物中通常未见，因此它们与人类的相关性值得怀疑。
