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

Abstract

Potassium octatitanate (K 2 O•8TiO 2 , 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-nTiO 2 , r-nTiO 2) 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-nTiO 2 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.

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

“…As can be seen in Additional file 1, most of the studies followed the exposed animals for 12–15 months or less, and none of these studies reported development of mesothelioma in the exposed animals. Similarly, in our study, no tumors were observed in the rats sacrificed at 1 year [12]. Only 6 studies followed the exposed animals for 2 years.…”

“…Both POT and MWCNT-7 fibers were detected in the lungs, trachea, mediastinal lymph nodes, kidney, spleen, liver, and testis (data not shown). In contrast, and unlike the 1-year sacrifice (see Additional file 4: Figure S3 in Abdelgied et al, 2019 [12]), r-nTiO2 particles were not detected in any of these organs. Alveolar macrophage numbers were increased in the POT and MWCNT-7 treated rats (Fig.…”

“…Transmission electron microscopic (TEM) images of r-nTiO 2 , POT fibers, and MWCNT-7 fibers are shown in Additional file 2: Figure S1: derived from Abdelgied et al, 2019 [12]. r-nTiO 2 forms large agglomerates composed of numerous particles while POT and MWCNT-7 fibers are mainly present as single fibers or small loose agglomerates: agglomerate is used as defined in Nichols et al 2002 [13].…”

“…POT fibers have relatively thick straight shapes and MWCNT-7 fibers are thin and more flexible. The mean length and width of individual r-nTiO 2 particles was 50.02 ± 8.24 nm and 14.35 ± 4.63 nm, respectively; the mean length and width of the POT fibers was 6.06 ± 1.53 μm and 305 ± 69 nm, respectively (Additional file 2: Figure S2; derived from Abdelgied et al, 2018 [11]); and the mean length and width of the MWCNT-7 fibers was 5.31 ± 3.81 μm and 75.65 ± 20.54 μm, respectively [11, 12]. There were no discernable changes in the size distribution of the test materials after aerosolization with the microsprayer.…”

“…Both POT and MWCNT-7 fibers, but not r-nTiO 2 , were biopersistent in the lung and pleura and were observed interacting with macrophages at 3 weeks, 1 year, and 2 years after TIPS administration of the test materials into the lung (see Abdelgied 2019 [12] and Table 2 and Fig. 2).…”