Carcinogenic effect of potassium octatitanate (POT) fibers in the lung and pleura of male Fischer 344 rats after intrapulmonary administration
Carcinogenic effect of potassium octatitanate (POT) fibers in the lung and pleura of male Fischer 344 rats after intrapulmonary administration
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DOI：
10.1186/s12989-019-0316-2
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发表时间：
2019-09-02
影响因子：
10
通讯作者：
Tsuda, Hiroyuki
中科院分区：
文献类型：
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作者：
Abdelgied, Mohamed;El-Gazzar, Ahmed M.;Tsuda, Hiroyuki
八钛酸钾纤维（K2 O中心点8 TiO（2），POT纤维）用作石棉替代物。它们的物理特性表明，可吸入POT纤维在肺和胸膜中可能是致癌的。然而，先前的2年吸入研究报告，呼吸的POT纤维几乎没有或没有致癌潜力。在本研究中，10周龄的雄性F344大鼠未接受治疗或通过气管内肺内喷雾（TIPS）给予载体、0.25或0.5 mg金红石型纳米TiO 2（r-nTiO（2））、0.25或0.5 mg POT纤维或0.5 mg MWCNT-7，然后观察2年。结果r-nTiO（2）组与对照组相比无显著性差异。在用0.50 mg POT和0.50 mg MWCNT-7处理的组中，细支气管肺泡细胞增生的发生率显著增加。然而，在POT或MWCNT-7处理组中，肺肿瘤的总体发病率均未增加。值得注意的是，在POT和MWCNT-7处理的大鼠中发展的癌伴随有增生的纤维结缔组织，而在未处理的大鼠和r-nTiO（2）处理的大鼠中发展的癌则没有（在载体对照大鼠中没有发展癌）。此外，在用0.25 mg POT治疗的大鼠中发展的癌是鳞状细胞癌，一种在约1/1700只大鼠中自发发展的肿瘤。在0.25 mg POT、0.5 mg POT和MWCNT-7给药组中，间皮瘤细胞增生的发生率分别为4/17、7/16和10/14，恶性间皮瘤的发生率分别为3/17、1/16和2/14。在对照组大鼠和r-nTiO（2）处理组大鼠中，既没有间皮瘤细胞增生，也没有间皮瘤。由于大鼠中自发发生的恶性间皮瘤的发生率极低，约为1/1000只动物（日本生物测定研究中心[JBRC]历史对照数据），因此POT和MWCNT-7给药组中多发性恶性间皮瘤的发生具有生物学意义。结论给予POT纤维和MWCNT-7的雄性F344大鼠中胸膜间皮瘤的发生率显著高于JBRC历史对照数据，表明使用TIPS通过气道给予POT纤维和MWCNT-7纤维的组中胸膜间皮瘤的发生率具有生物学意义。POT处理大鼠中II型上皮细胞增生的发生率和癌的组织学也表明可吸入POT纤维在雄性F344大鼠的肺中极有可能致癌。
Background Potassium octatitanate fibers (K2O center dot 8TiO(2), POT fibers) are used as an asbestos substitute. Their physical characteristics suggest that respirable POT fibers are likely to be carcinogenic in the lung and pleura. However, previous 2-year inhalation studies reported that respired POT fibers had little or no carcinogenic potential. In the present study ten-week old male F344 rats were left untreated or were administered vehicle, 0.25 or 0.5 mg rutile-type nano TiO2 (r-nTiO(2)), 0.25 or 0.5 mg POT fibers, or 0.5 mg MWCNT-7 by intra-tracheal intra-pulmonary spraying (TIPS), and then observed for 2 years. Results There were no differences between the r-nTiO(2) and control groups. The incidence of bronchiolo-alveolar cell hyperplasia was significantly increased in the groups treated with 0.50 mg POT and 0.50 mg MWCNT-7. The overall incidence of lung tumors, however, was not increased in either the POT or MWCNT-7 treated groups. Notably, the carcinomas that developed in the POT and MWCNT-7 treated rats were accompanied by proliferative fibrous connective tissue while the carcinomas that developed in the untreated rats and the r-nTiO(2) treated rats were not (carcinomas did not develop in the vehicle control rats). In addition, the carcinoma that developed in the rat treated with 0.25 mg POT was a squamous cell carcinoma, a tumor that develops spontaneously in about 1 per 1700 rats. The incidence of mesothelial cell hyperplasia was 4/17, 7/16, and 10/14 and the incidence of malignant mesothelioma was 3/17, 1/16, and 2/14 in the 0.25 mg POT, 0.5 mg POT, and MWCNT-7 treated groups, respectively. Neither mesothelial cell hyperplasia nor mesothelioma developed in control rats or the rats treated with r-nTiO(2). Since the incidence of spontaneously occurring malignant mesothelioma in rats is extremely low, approximately 1 per 1000 animals (Japan Bioassay Research Center [JBRC] historical control data), the development of multiple malignant mesotheliomas in the POT and MWCNT-7 treated groups was biologically significant. Conclusion The incidence of pleural mesotheliomas in male F344 rats administered POT fibers and MWCNT-7 was significantly higher than the JBRC historical control data, indicating that the incidence of pleural mesothelioma in the groups administered POT fibers and MWCNT-7 fibers via the airway using TIPS was biologically significant. The incidence of type II epithelial cell hyperplasia and the histology of the carcinomas that developed in the POT treated rats also indicates that respirable POT fibers are highly likely to be carcinogenic in the lungs of male F344 rats.