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

Mohamed Abdelgied,William T Alexander,Satoru Takahashi,David B Alexander,Hiroshi Takase,Khaled Abbas Abdou,Aya Naiki-Ito,Hiroyuki Tsuda,Mona Abdelhamid,Masaaki Iigou,Ahmed M El-Gazzar,Jun Kanno,Takamasa Numano,Yuhji Taquahashi,Akihiko Hirose

doi:10.1007/s00204-019-02410-z

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.

Highlights

Potassium octatitanate fibers (POT fibers: K 2O·8TiO2) are heat resistant and have high tensile strength and chemical stability, giving them numerous commercial uses
Application of POT fibers directly to the pleural surface of Osborne–Mendel rats and administration of POT fibers to female F344 rats by intraperitoneal injection resulted in induction of malignant tumors (Adachi et al 2001; Stanton and Layard 1978; Stanton et al 1981), demonstrating that POT fibers are carcinogenic when in contact with susceptible tissues, and in 2006 the WHO Workshop on Mechanisms of Fibre Carcinogenesis and Assessment of Chrysotile Asbestos Substitutes issued a statement that “respirable potassium octatitanate fibers are likely to pose a high hazard to humans after inhalation exposure” (WHO 2005)
This report describes the results of interim killing of a 2-year study that were performed at 1 week and 1 year after tracheal intra-pulmonary spraying (TIPS) administration of POT fibers, r-nTiO2, and MWCNT-7, a known carcinogen in the rat lung (Kasai et al 2016)

Summary

Introduction

Potassium octatitanate fibers (POT fibers: K 2O·8TiO2) are heat resistant and have high tensile strength and chemical stability, giving them numerous commercial uses. In combination with their straight, needle-like shape, these properties make POT fibers highly biopersistent in living tissues. POT fibers have been recovered from the rat lung 12 months after inhalation exposure without any erosion (Yamato et al 2002). Application of POT fibers directly to the pleural surface of Osborne–Mendel rats and administration of POT fibers to female F344 rats by intraperitoneal injection resulted in induction of malignant tumors (Adachi et al 2001; Stanton and Layard 1978; Stanton et al 1981), demonstrating that POT fibers are carcinogenic when in contact with susceptible tissues, and in 2006 the WHO Workshop on Mechanisms of Fibre Carcinogenesis and Assessment of Chrysotile Asbestos Substitutes issued a statement that “respirable potassium octatitanate fibers are likely to pose a high hazard to humans after inhalation exposure” (WHO 2005). Long-term inhalation studies have reported mostly negative results (Ikegami et al 2004; Lee et al 1981; Oyabu et al 2004; Yamato et al 2003). (See Supplementary Doc S1 for a brief overview of in vivo POT fiber studies.)

Methods

Results

Conclusion