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

Our plain-English summary of Carcinogenic effect of potassium octatitanate (POT) fibers in the lung and pleura of male Fischer 344 rats after intrapulmonary administration, by M. Abdelgied, A.M. El-Gazzar, W.T. Alexander, et al (Particle and Fibre Toxicology, 2019).

The study

• Authors: M. Abdelgied, A.M. El-Gazzar, W.T. Alexander, T. Numano, M. Iigou, A. Naiki-Ito, H. Takase, A. Hirose, Y. Taquahashi, J. Kanno, M. Abdelhamid, K.A. Abdou, S. Takahashi, D.B. Alexander, H. Tsuda
• Journal: Particle and Fibre Toxicology
• Published: 2019;16(1):34
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Potassium octatitanate fibers (K2O•8TiO2, 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-nTiO2), 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-nTiO2 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-nTiO2 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-nTiO2. 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.

In plain English

This animal experiment tested potassium octatitanate (POT) fibers, which the authors describe as an asbestos substitute. In Japan, 210 male F344 rats were split into seven groups: untreated, vehicle only, rutile titanium dioxide nanoparticles (0.25 or 0.50 mg), POT fibers (0.25 or 0.50 mg), or 0.50 mg MWCNT-7, a carbon nanotube the authors call a known lung carcinogen in rats. Materials were sprayed into the lungs through the windpipe in 8 doses over 15 days, and the rats were observed for 2 years. Malignant pleural mesothelioma developed in 3 of 17 rats given 0.25 mg POT, 1 of 16 given 0.50 mg POT and 2 of 14 given MWCNT-7. It developed in no control or titanium dioxide rats. This was not statistically significant against the study's own controls. The authors still called it biologically significant because historical records showed spontaneous mesothelioma in only 3 of 3398 rats. Overall lung tumor rates did not rise, but the authors judged the lung carcinomas in POT-treated rats very probably treatment related. The authors concluded that POT fibers are carcinogenic to the pleura of male rats.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: 2-year study in rats given test materials by spraying into the lungs through the trachea (intra-tracheal intra-pulmonary spraying, TIPS), with untreated and vehicle control groups
• Who was studied: 210 male F344/DuCrjCrlj rats housed at Nagoya City University Medical School, Japan, divided into 7 groups of 30. Five rats per group were killed at interim sacrifices at weeks 3 and 52. Rats surviving to week 73 were assessed for toxicity and carcinogenicity: 19 untreated, 19 vehicle, 20 and 19 r-nTiO2, 17 and 16 POT, and 14 MWCNT-7. The study ended at week 105.
• Exposure: Total doses of 0.25 or 0.50 mg rutile-type titanium dioxide nanoparticles (r-nTiO2), 0.25 or 0.50 mg potassium octatitanate (POT) fibers, or 0.50 mg MWCNT-7 multi-walled carbon nanotubes (positive control). A vehicle group received saline with 0.5% poloxamer-188. Doses were given as 0.5 ml once every other day over 15 days (8 doses). The POT fibers used averaged 6.06 μm long and 305 nm wide.
• Main results:
  • Malignant mesothelioma developed in 3 of 17 rats in the 0.25 mg POT group, 1 of 16 in the 0.5 mg POT group and 2 of 14 in the MWCNT-7 group. Combined, 4 of 33 POT-treated rats developed pleural mesothelioma.
  • Neither mesothelial cell hyperplasia nor mesothelioma developed in the control rats or the r-nTiO2-treated rats.
  • The increase in malignant mesothelioma in the POT and MWCNT-7 groups was not statistically significant compared with the study's control groups.
  • The authors compared the mesothelioma cases with Japan Bioassay Research Center (JBRC) historical control data, in which 3 of 3398 rats developed malignant mesothelioma spontaneously. On that basis they judged the multiple mesotheliomas in the POT and MWCNT-7 groups biologically significant.
  • Mesothelial cell hyperplasia was significantly increased compared with vehicle controls: 4 of 17 rats (0.25 mg POT), 7 of 16 (0.50 mg POT) and 10 of 14 (MWCNT-7).
  • Bronchiolo-alveolar (type II) cell hyperplasia in the lung was significantly increased in the 0.50 mg POT group (10 of 16) and the MWCNT-7 group (14 of 14).
  • Overall lung tumor incidence was not increased in the POT or MWCNT-7 groups.
  • Lung carcinomas in POT- and MWCNT-7-treated rats were accompanied by proliferative fibrous connective tissue. Carcinomas in untreated and r-nTiO2-treated rats did not contain fibrous connective tissue, and none developed in vehicle controls.
  • On the basis of tumor histology, the authors judged the lung carcinomas in the POT and MWCNT-7 groups very probably treatment related.
  • One rat in the 0.25 mg POT group developed a squamous cell carcinoma of the lung. JBRC historical control data show this tumor spontaneously in 2 of 3398 male rats.
  • Survival in the r-nTiO2 and POT groups did not differ from the vehicle control group. Survival was significantly reduced in the MWCNT-7 group.
  • At 2 years, POT fibers were found in pleural cavity lavage fluid: 570 fibers in the sample from the 0.25 mg POT rats and 650 in the sample from the 0.50 mg rats.
  • No POT or MWCNT-7 fibers were seen in the tissue sections that contained mesothelial hyperplasia or mesothelioma.
  • Rats given r-nTiO2 did not differ from controls in lung hyperplasia or tumor histology.
• The authors' conclusion: Based on the JBRC historical control data, the authors concluded that POT fibers are carcinogenic to the pleura of male rats when given to the lung through the airway by TIPS. They also stated that POT fibers are highly likely to be carcinogenic in the rat lung and that the results suggest POT fibers are a potential hazard to human health.
• Limitations the authors state:
  • The mesothelioma incidences were not statistically higher than in the study's untreated and vehicle control groups (0 of 19 each).
  • The single squamous cell carcinoma has no statistical significance on its own.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Carcinogenic, Pleura, Carcinoma, Squamous Cell Carcinoma, Mesothelial Cells, Mesothelioma, Pleural Mesothelioma, Histology.

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• Potassium octatitanate fibers induce persistent lung and pleural injury and are possibly carcinogenic in male Fischer 344 rats — M. Abdelgied, A.M. El-Gazzar, et al. (2018)
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• Inhalation toxicity study of disk-shaped potassium octatitanate particles (terracess TF) in rats following 90 days of aerosol exposure — S. Sakai, K. Inada, et al. (2010)

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