Potassium octatitanate fibers induce persistent lung and pleural injury and are possibly carcinogenic in male Fischer 344 rats

Our plain-English summary of Potassium octatitanate fibers induce persistent lung and pleural injury and are possibly carcinogenic in male Fischer 344 rats, by M. Abdelgied, A.M. El-Gazzar, D.B. Alexander, et al (Cancer Science, 2018).

The study

• Authors: M. Abdelgied, A.M. El-Gazzar, D.B. Alexander, W.T. Alexander, T. Numano, M. Iigou, A. Naiki-Ito, H. Takase, K.A. Abdou, A. Hirose, Y. Taquahashi, J. Kanno, H. Tsuda, S. Takahashi
• Journal: Cancer Science
• Published: 2018;109(7):2164-2177
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Potassium octatitanate fibers (K2 O·8TiO2 , POT fibers) are widely used as an alternative to asbestos. We investigated the pulmonary and pleural toxicity of POT fibers with reference to 2 non-fibrous titanium dioxide nanoparticles (nTiO2 ), photoreactive anatase (a-nTiO2 ) and inert rutile (r-nTiO2 ). Ten-week-old male F344 rats were given 0.5 mL of 250 μg/mL suspensions of POT fibers, a-nTiO2 , or r-nTiO2 , 8 times (1 mg/rat) over a 15-day period by trans-tracheal intrapulmonary spraying (TIPS). Rats were killed at 6 hours and at 4 weeks after the last TIPS dose. Alveolar macrophages were significantly increased in all treatment groups at 6 hours and at 4 weeks. At week 4, a-nTiO2 and r-nTiO2 were largely cleared from the lung whereas a major fraction of POT fibers were not cleared. In the bronchoalveolar lavage, alkaline phosphatase activity was elevated in all treatment groups, and lactate dehydrogenase (LDH) activity was elevated in the a-nTiO2 and POT groups. In lung tissue, oxidative stress index and proliferating cell nuclear antigen (PCNA) index were elevated in the a-nTiO2 and POT groups, and there was a significant elevation in C-C motif chemokine ligand 2 (CCL2) mRNA and protein in the POT group. In pleural cavity lavage, total protein was elevated in all 3 treatment groups, and LDH activity was elevated in the a-nTiO2 and POT groups. Importantly, the PCNA index of the visceral mesothelium was increased in the POT group. Overall, POT fibers had greater biopersistence, induced higher expression of CCL2, and provoked a stronger tissue response than a-nTiO2 or r-nTiO2 .

© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This animal experiment from Japan tested potassium octatitanate (POT) fibers, which the authors describe as widely used as an alternative to asbestos. Male F344 rats had POT fibers or one of two non-fibrous titanium dioxide nanoparticles (anatase or rutile) sprayed into the lungs through the windpipe: eight doses over 15 days, 1 mg per rat in total. Other rats were untreated or received only the liquid used to carry the materials. Rats were examined 6 hours and 4 weeks after the last dose. The study measured short-term injury and possible early signs of cancer, not tumors. At 4 weeks, the titanium dioxide particles were largely cleared from the lungs, but a large proportion of POT fibers remained. All three materials reached the chest lymph nodes and the pleural cavity. Only POT fibers increased a marker of cell proliferation in the lining of the lung surface (visceral mesothelium), and one POT-treated rat had an area of pleural hyperplasia. The authors concluded that POT fibers may be carcinogenic in rat lung and pleura, and said they were conducting a long-term study.

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: Short-term animal experiment comparing POT fibers with two non-fibrous titanium dioxide nanoparticles, plus untreated and vehicle control groups
• Who was studied: 96 male F344 rats, 10 weeks old at the start of dosing, housed at Nagoya City University Medical School, Japan. They were divided into 6 groups of 16: untreated, saline vehicle, saline plus 0.5% Pluronic F-68 vehicle, anatase nTiO2, rutile nTiO2, and POT fibers. Eight rats per group were killed at 6 hours and eight at 4 weeks after the last dose.
• Exposure: Potassium octatitanate (POT) fibers, mean length 6.06 plus or minus 1.53 micrometers and mean width 305 plus or minus 69 nm, compared with photoreactive anatase titanium dioxide nanoparticles (mean diameter 6.02 nm) and inert rutile titanium dioxide nanoparticles. Each was given as 0.5 mL of a 250 micrograms per mL suspension by trans-tracheal intrapulmonary spraying, every other day for 15 days: 8 doses, 1 mg per rat in total.
• Main results:
  • At both 6 hours and 4 weeks, alveolar macrophages were significantly increased in all 3 treatment groups.
  • At 4 weeks, the anatase and rutile titanium dioxide particles were largely cleared from the lung, but a large proportion of POT fibers was still present.
  • Electron microscopy showed POT fibers penetrating alveolar macrophages, which the authors described as frustrated phagocytosis.
  • Scattered granulomas were seen in the lungs of anatase- and POT-treated rats, with slight fibrotic changes of the alveolar wall in areas of granulomatous inflammation.
  • All 3 test materials were found in the mediastinal lymph nodes and in pleural cavity lavage cell pellets.
  • At 4 weeks, the PCNA labeling index (a marker of cell proliferation) of lung alveolar cells was significantly increased in the anatase group (28.0 plus or minus 12.0) and the POT group (41.7 plus or minus 3.1). Their vehicle controls were 8.9 plus or minus 6.2 and 10.7 plus or minus 0.4 (P less than .001).
  • The PCNA labeling index of visceral mesothelial cells was significantly increased only in the POT group: 5.9 plus or minus 1.9, compared with 0.96 plus or minus 0.02 in its vehicle control (P less than .001).
  • One POT-treated rat had an area of hyperplasia in the visceral pleura.
  • At 4 weeks, CCL2 and CCL4 RNA expression, but not CCL3, was significantly increased in POT-treated lungs, and CCL4 was increased in the rutile group. CCL2 protein in lung tissue was significantly higher in the POT group (31.92 plus or minus 8.28) than in vehicle controls (17.38 plus or minus 1.79) (P less than .001).
  • At 4 weeks, total oxidant status and the oxidative stress index in lung tissue were slightly but significantly raised in the anatase group and more markedly raised in the POT group. Total antioxidant capacity did not differ in any treatment group.
  • In bronchoalveolar lavage fluid at 4 weeks, LDH activity was significantly higher in the anatase group (2132.88 plus or minus 781.94) and the POT group (2243.05 plus or minus 515.44) than in their vehicle controls (927.94 and 794.06). ALP activity was significantly higher in all 3 treatment groups.
  • In pleural cavity lavage fluid at 4 weeks, LDH activity was significantly higher in the anatase group (1815.12) and the POT group (1876.58) than in their vehicle controls (1076.35 and 918.20). Total protein was significantly increased in all 3 treatment groups.
• The authors' conclusion: The authors concluded that POT fibers were more biopersistent, caused more lung and pleural injury, and produced stronger early indicators of possible carcinogenicity than either titanium dioxide nanoparticle. They suggested that POT fibers may be carcinogenic in the lung and pleura of rats, and said they were conducting a long-term study.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenic, Alveolar Macrophage, Bronchoalveolar Lavage (BAL), Lactate Dehydrogenase (LDH), Oxidative Stress, Pleural Cavity, Mesothelium, biopersistence.

Related studies

• 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)
• 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)
• Expression of heme oxygenase-1 in the lungs of rats exposed to potassium octatitanate whiskers — Y. Obata, Y. Morimoto, et al. (2011)
• Chronic mesothelial reaction and toxicity of potassium octatitanate fibers in the pleural cavity in mice and F344 rats — M. Yokohira, Y. Nakano-Narusawa, et al. (2016)
• 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)
• The effect of lung burden on biopersistence and pulmonary effects in rats exposed to potassium octatitanate whiskers by inhalation — T. Oyabu, H. Yamato, et al. (2004)

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