Carcinogenic effect of potassium octatitanate (POT) fibers in the lung and pleura of male Fischer 344 rats after intrapulmonary administration

Abstract

Background Potassium octatitanate fibers (K 2 O•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 TiO 2 (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. Electronic supplementary material The online version of this article (10.1186/s12989-019-0316-2) contains supplementary material, which is availab...

Lung toxicity of a vapor-grown carbon fiber in comparison with a multi-walled carbon nanotube in F344 rats

“…Significant increases in absolute and relative lung weights were observed in both the male and female vehicle-treated groups compared to the untreated group. KP188, which is known to cause weak toxic effects in the lungs, has been used in several intratracheal instillation studies for dispersing test materials 15 , 16 , 20 , 21 , 22 , 23 , 24 . The increase in the absolute and relative lung weights of the rats in the vehicle-treated groups was accompanied by a slight toxic effect due to repeated intratracheal instillation of the vehicle solution, KP188, as shown previously 16 .…”

Two-year intermittent exposure of a multiwalled carbon nanotube by intratracheal instillation induces lung tumors and pleural mesotheliomas in F344 rats

“…In contrast, in previous 2-year intratracheal instillation studies, the lung carcinogenicity of MWNT-7 was not higher than controls. For instance, when a total of 1.5 mg of MWNT-7 was instilled in rats, no lung tumors were reported, possibly due to the early death of the rats due to mesothelioma [ 21 ], In another 2-year study, in which MWNT-7 was used as reference material, instillation of 0.5 mg of MWNT-7 did result in 43% of the rats developing lung tumors at 2 years, however, the tumor incidence was not significantly increased compared with the control, possibly due to an abnormally high incidence of tumors in the untreated control group coupled with low animal numbers [ 28 ]. Therefore, the present study is the first to show overt lung carcinogenicity of MWNT-7 when administered by intratracheal instillation.…”

Spontaneous Primary Pleural Mesothelioma in Fischer 344 (F344) and Other Rat Strains: A Retrospective Review

“…27 Many reports of experimentally induced pleural mesotheliomas in rats either do not histologically subtype the neoplasms; consist of very low numbers of cases; and/or vary in whether epithelioid or sarcomatoid subtypes had the higher incidences. [9][10][11][12][13][14][15]17,18,21,40 These methodological disparities preclude plausible comparison of subtype incidences in the present series versus incidences in previous reports of induced pleural mesotheliomas.…”

“…27,37,54 Mesothelial hyperplasia, which is considered by many authors to have the potential to progress to mesothelioma, can precede or be concurrent with peritoneal/pleural mesotheliomas in rats. 9,12,15,20,50,55 The light microscopic diagnostic criteria for hyperplasia include focal or papillary proliferation of mesothelial cells with little or no connective tissue stroma or extension/ invasion into adjacent tissues. 27,37 Because mesothelial cells can contain hyaluronan (hyaluronic acid), stains suggestive of hyaluronan, like hyaluronidase-sensitive Alcian blue, and colloid-iron stains have been used in humans and occasionally in rats to help distinguish mesothelial proliferations from other types of neoplasms.…”

“…3,5,6,8 In rats, intrathoracic pleural/pericardial mesotheliomas have been experimentally induced by exposure (usually via intrapleural, inhalation, or intratracheal instillation routes) to asbestos, erionite, and other naturally occurring and synthetic minerals; radionuclides; and carbon nanotubes. [9][10][11][12][13][14][15][16][17][18][19][20][21][22] Induction of pleural mesotheliomas in rats by orthotopic implantation of syngeneic rat mesothelioma cells (II-45 cells) is a welldescribed animal model for human pleural mesothelioma. 23,24 On the other hand, spontaneous mesotheliomas in any intrathoracic or extrathoracic site are uncommon in rats.…”