Pulmonary and pleural toxicity of potassium octatitanate fibers, rutile titanium dioxide nanoparticles, and MWCNT-7 in male Fischer 344 rats

Our plain-English summary of Pulmonary and pleural toxicity of potassium octatitanate fibers, rutile titanium dioxide nanoparticles, and MWCNT-7 in male Fischer 344 rats, by M. Abdelgied, A.M. El-Gazzar, D.B. Alexander, et al (Archives of Toxicology, 2019).

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, M. Abdelhamid, H. Tsuda, S. Takahashi
• Journal: Archives of Toxicology
• Published: 2019;93(4):909-920
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Potassium octatitanate (K2O·8TiO2, POT) fibers are used as an alternative to asbestos. Their shape and biopersistence suggest that they are possibly carcinogenic. However, inhalation studies have shown that respired POT fibers have little carcinogenic potential. We conducted a short-term study in which we administered POT fibers, and anatase and rutile titanium dioxide nanoparticles (a-nTiO2, r-nTiO2) to rats using intra-tracheal intra-pulmonary spraying (TIPS). We found that similarly to other materials, POT fibers were more toxic than non-fibrous nanoparticles of the same chemical composition, indicating that the titanium dioxide composition of POT fibers does not appear to account for their lack of carcinogenicity. The present report describes the results of the 3-week and 52-week interim killing of our current 2-year study of POT fibers, with MWCNT-7 as a positive control and r-nTiO2 as a non-fibrous titanium dioxide control. Male F344 rats were administered 0.5 ml vehicle, 62.5 µg/ml and 125 µg/ml r-nTiO2 and POT fibers, and 125 µg/ml MWCNT-7 by TIPS every other day for 2 weeks (eight doses: total doses of 0.25 and 0.50 mg/rat). At 1 year, POT and MWCNT-7 fibers induced significant increases in alveolar macrophage number, granulation tissue in the lung, bronchiolo-alveolar cell hyperplasia and thickening of the alveolar wall, and pulmonary 8-OHdG levels. The 0.5 mg POT- and the MWCNT-7-treated groups also had increased visceral and parietal pleura thickness, increased mesothelial cell PCNA labeling indices, and a few areas of visceral mesothelial cell hyperplasia. In contrast, in the r-nTiO2-treated groups, none of the measured parameters were different from the controls.

In plain English

This animal experiment reported interim results from an ongoing 2-year study in male Fischer 344 rats. It tested potassium octatitanate (POT) fibers, which the authors describe as an alternative to asbestos. Asbestos itself was not tested. Rats received POT fibers or rutile titanium dioxide nanoparticles (total 0.25 or 0.50 mg) or the carbon nanotube MWCNT-7 (0.50 mg), sprayed into the lungs in eight doses over 15 days. Five rats per group were killed at 3 and 52 weeks, and only the 1-year results were used to judge toxicity. At one year, the 0.50 mg POT and MWCNT-7 groups had more lung macrophages, more lung collagen, thicker visceral pleura and higher proliferation in mesothelial (pleural lining) cells than vehicle controls. Visceral mesothelial hyperplasia appeared in two of five rats given 0.50 mg POT and one of five given MWCNT-7. Titanium dioxide nanoparticles changed none of these measures. The authors concluded that POT fibers are toxic in rat lung and pleura, at levels similar to or greater than MWCNT-7, a known rat lung carcinogen.

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: report of interim kills (3 weeks and 52 weeks) from an ongoing 2-year study. Test materials were given by intra-tracheal intra-pulmonary spraying (TIPS).
• Who was studied: 210 male F344 (Fischer 344) rats bought at nine weeks of age, housed at Nagoya City University, Japan. They were divided into seven groups of 30: untreated, vehicle, two doses of rutile titanium dioxide nanoparticles, two doses of POT fibers, and MWCNT-7. Five rats from each group were killed at 3 weeks and five at 52 weeks.
• Exposure: Potassium octatitanate (POT) fibers and rutile titanium dioxide nanoparticles (r-nTiO2), each at total doses of 0.25 mg and 0.50 mg per rat, and MWCNT-7 (multi-walled carbon nanotubes, the positive control) at 0.50 mg per rat. Each was sprayed into the lungs every other day over 15 days (eight doses). The vehicle was saline with 0.5% poloxamer-188. No asbestos was administered.
• Main results:
  • At week 52, alveolar macrophage counts were significantly higher than in vehicle controls in the 0.50 mg POT group (2.96 ± 0.59 × 10^3 per cm2) and the MWCNT-7 group (2.82 ± 0.43 × 10^3 per cm2). The vehicle group had 1.51 ± 0.20 × 10^3 per cm2.
  • Pulmonary collagen (%) at 1 year was significantly higher than in vehicle controls (10.35 ± 0.99) in three groups: 0.25 mg POT (14.77 ± 5.06), 0.50 mg POT (17.72 ± 2.53) and MWCNT-7 (19.06 ± 1.13).
  • Granulation tissue lesions (three lung sections per rat) averaged 5.20 ± 2.28 in the 0.50 mg POT group. This was significantly lower than the 56.40 ± 12.20 in the MWCNT-7 group.
  • Hyperplasia of the visceral mesothelium was found in two of five rats in the 0.50 mg POT group and one of five rats in the 0.50 mg MWCNT-7 group.
  • Visceral pleural thickness at 1 year was significantly greater than in vehicle controls (19.98 ± 5.67) in three groups: 0.25 mg POT (38.47 ± 10.88), 0.50 mg POT (38.45 ± 5.46) and MWCNT-7 (32.93 ± 5.90). Units are not stated in the table.
  • The proliferation marker (PCNA labeling index, %) in visceral mesothelium was significantly increased in the 0.50 mg POT group (13.80 ± 2.95) and the MWCNT-7 group (20.08 ± 6.26), compared with vehicle (3.92 ± 1.85). In parietal mesothelium it was also significantly increased: 6.36 ± 1.64 for 0.50 mg POT and 7.72 ± 2.90 for MWCNT-7, compared with 0.96 ± 0.44 for vehicle. The difference between POT and MWCNT-7 was not significant.
  • The PCNA labeling index of lung alveolar epithelium was significantly increased in the 0.25 mg POT, 0.50 mg POT and MWCNT-7 groups.
  • Pulmonary 8-OHdG (a marker of DNA damage) was significantly increased in the 0.50 mg POT group: 79.11 ± 10.60 pg/mg DNA, compared with 38.88 ± 5.34 for vehicle. In the MWCNT-7 group it was elevated (101.85 ± 32.11), but this was not statistically significant.
  • Total protein in pleural lavage fluid was elevated in the 0.50 mg POT group: 856.30 ± 126.96, compared with 259.02 ± 76.97 for vehicle. It was also significantly higher than in the MWCNT-7 group (287.51 ± 63.87).
  • In the pleural cavity lavage cell pellet, several POT fibers and only a very few, mostly long, MWCNT-7 fibers were detected. No r-nTiO2 particles were detected there.
  • In rats given rutile titanium dioxide nanoparticles, none of the measured lung or pleural parameters was elevated.
• The authors' conclusion: The authors concluded that there is clear evidence that POT fibers are toxic in the lung and pleura of male rats. They found the fibers biopersistent, provoking inflammation and tissue and DNA damage. They judged the pulmonary and pleural toxicity of POT fibers to be similar to or greater than that of MWCNT-7, a known carcinogen to the rat lung.
• Limitations the authors state:
  • At 1 week after the final dose, macrophage counts were higher in the vehicle control group than in untreated rats. For this reason, only the 1-year data were used to assess toxicity.

Topics

Medical terms in this study, explained in our Lexicon: biopersistence, Carcinogenic, Alveolar Macrophage, 8-OHdG, Parietal Pleura, Mesothelial Cells.

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)
• 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)
• 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)
• 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)
• Safety evaluation of titanium dioxide nanoparticles by their absorption and elimination profiles — K. Sugibayashi, H. Todo, et al. (2008)
• 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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