Chronic mesothelial reaction and toxicity of potassium octatitanate fibers in the pleural cavity in mice and F344 rats

Our plain-English summary of Chronic mesothelial reaction and toxicity of potassium octatitanate fibers in the pleural cavity in mice and F344 rats, by M. Yokohira, Y. Nakano-Narusawa, K. Yamakawa, et al (Cancer Science, 2016).

The study

• Authors: M. Yokohira, Y. Nakano-Narusawa, K. Yamakawa, N. Hashimoto, S. Yoshida, S. Kanie, K. Imaida
• Journal: Cancer Science
• Published: 2016;107(7):1047-54
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Fiber-shaped particles of potassium octatitanate (tradename TISMO; chemical formula K2 O·6TiO2 ), which are morphologically similar to asbestos particles, were shown to induce severe proliferative reactions in the pleural mesothelium in a previous experiment carried out over 21 weeks. The present study aims to determine whether these fibers induce malignant mesotheliomas in rodents, and to examine chronic toxicity induced. Additionally, we investigated the specific differences observable between the biological responses to the direct infusion of the fibers alone into the pleural cavity and those induced by the co-administration of the fibers with a known carcinogen. To detect the induction of malignant pleural mesotheliomas, two experiments were undertaken. In Experiment 1, four strains of mice, A/J, C3H, ICR, and C57BL, were examined for 52 weeks after experimental treatment with TISMO. In Experiment 2, the F344 rats were treated with TISMO alone, the lung carcinogen N-bis (2-hydroxypropyl) nitrosamine (DHPN) alone, both TISMO and DHPN, or left untreated and were then examined for 52 weeks. In this experiment, malignant lesion induction was expected in the co-administration group. TISMO fibers were observed in the alveoli, indicating penetration through the visceral pleura in mice and rats. The histopathological detection of TISMO fibers in the liver and kidneys of mice and rats indicated migration of the fibers out of the pleural cavity. Atypical mesothelial cells with severe pleural proliferation were observed, but malignant mesotheliomas were not detected. Among the rats, there were no observed malignant alterations in the mesothelium induced by DHPN-TISMO co-administration.

© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This animal experiment from Kagawa University, Japan, tested potassium octatitanate fibers (tradename TISMO), which the authors describe as similar in shape to asbestos. Asbestos itself was not tested. In Experiment 1, female mice of four strains (A/J, ICR, C3H, C57BL) had 3 mg of fibers placed by surgery into the left chest (pleural) cavity, alongside sham-operated comparison mice. It ended at day 415 because of falling numbers of surviving mice. In Experiment 2, 46 male F344 rats received 30 mg of fibers, the lung carcinogen DHPN, both, or neither, and were followed for 52 weeks. All fiber-treated mice and rats developed pleural thickening with chronic inflammation, and atypical mesothelial cells were seen, but no malignant mesothelioma was found. Fibers reached the lungs' air sacs and also the liver and kidneys. Lung tumors in DHPN-treated rats were bronchioloalveolar adenomas or adenocarcinomas, and adding fibers made no significant difference to how often they occurred. The authors said a longer study would have been desirable, and that clumping of the fibers might explain why no mesothelioma appeared.

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 (two experiments: one comparing four mouse strains, one in rats with and without a known carcinogen)
• Who was studied: Experiment 1: 144 female mice of four strains (A/J, ICR, C3H, C57BL), in four fiber-treated groups of 30 and four sham-operated groups of 6. Experiment 2: 46 male F344 rats in four groups of 15, 15, 11 and 5. Studied at Kagawa University, Japan. Study dates not given.
• Exposure: Potassium octatitanate (TISMO) fibers, length under 50 micrometers and width under 2 micrometers, infused by thoracotomy into the left pleural cavity: 3 mg in 0.2 mL saline per mouse, and 30 mg in 2 mL saline per rat. In Experiment 2, some rats also received 0.1% DHPN, a lung carcinogen, in drinking water for 2 weeks.
• Main results:
  • Of the fiber-treated mice, 28 died just after treatment (9 in A/J group 1, 2 in ICR group 2, 4 in C3H group 3, 13 in C57BL group 4). The authors presumed these deaths resulted from surgery and/or anesthesia.
  • Pleural thickening and infolding of the pleura into the lungs were seen in all fiber-treated mice of all four strains (11/11, 22/22, 7/7 and 9/9).
  • Responses differed by mouse strain: ICR mice showed milder thickening and more inflammatory cell infiltration, and A/J mice showed severe atypia of pleural cells.
  • In rats given fibers (with or without DHPN), pleural thickening and atypical cells were observed: pleural thickening in 10/10 rats given both and 11/11 rats given fibers alone.
  • Atypical mesothelial cells with severe pleural proliferation were seen, but no malignant mesothelioma was detected in the mice or the rats.
  • Fibers were found in the alveoli (air sacs) of the lungs in mice and rats, which the authors took as a sign that the fibers passed through the visceral pleura.
  • In mice, fibers were also found in the liver and kidneys, with inflammation around fibers in the liver but no inflammation in the kidney. In rats, fibers were found in the kidneys and livers of all fiber-treated rats, with no inflammatory reaction.
  • The lung nodules seen by eye in DHPN-treated rats were confirmed as bronchioloalveolar adenomas or adenocarcinomas. The difference in how often they occurred between rats given DHPN plus fibers and rats given DHPN alone was not statistically significant.
  • Invasive lung lesions in rats given both DHPN and fibers were positive for napsin A and negative for calretinin, and were diagnosed as bronchioloalveolar adenocarcinoma rather than mesothelioma.
  • Lung tumors (adenoma or adenocarcinoma) were found in 10/10 rats given DHPN plus fibers and 11/11 rats given DHPN alone. Bronchioloalveolar adenocarcinoma was found in 8/10 and 10/11 of these groups. No lung tumors occurred in rats given fibers alone (0/11) or in untreated rats (0/5).
• The authors' conclusion: The authors concluded that infusing TISMO fibers into the chest cavity did not cause malignant mesothelioma in several strains of mice or in rats, but did produce severe chronic inflammation and proliferation of pleural mesothelial cells. They added that the fibers may spread from the pleural cavity to the liver and kidneys.
• Limitations the authors state:
  • The mouse experiment ended at day 415 because of rising deaths, and the authors said a longer period would have been desirable for malignant lesions to develop.
  • The fibers clumped together in the pleural cavity, with fewer single fibers than aggregates, which the authors suggested might explain why no mesothelioma developed.
  • Mouse lungs could not be weighed because of severe adhesions.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Cavity, Mesothelium, Malignant Mesothelioma, Pleural Mesothelioma, Alveoli, Visceral Pleura, Mesothelial Cells.

Related studies

• Strain differences in pleural mesothelial cell reactions induced by potassium octatitanate fibers (TISMO) infused directly into the thoracic cavity — M. Yokohira, Y. Nakano, et al. (2013)
• Pulmonary and pleural toxicity of potassium octatitanate fibers, rutile titanium dioxide nanoparticles, and MWCNT-7 in male Fischer 344 rats — M. Abdelgied, A.M. El-Gazzar, et al. (2019)
• 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)
• 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)
• Potassium octatitanate fibers (TISMO) induce pleural mesothelial cell reactions with iron accumulation in female A/J mice — M. Yokohira, N. Hashimoto, et al. (2010)
• Carcinogenic effect of potassium octatitanate (POT) fibers in the lung and pleura of male Fischer 344 rats after intrapulmonary administration — M. Abdelgied, A.M. El-Gazzar, et al. (2019)

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