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

Abstract

Potassium octatitanate fibers (K2O·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 (nTiO 2), photoreactive anatase (a‐nTiO 2) and inert rutile (r‐nTiO 2). Ten‐week‐old male F344 rats were given 0.5 mL of 250 μg/mL suspensions of POT fibers, a‐nTiO 2, or r‐nTiO 2, 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‐nTiO 2 and r‐nTiO 2 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‐nTiO 2 and POT groups. In lung tissue, oxidative stress index and proliferating cell nuclear antigen (PCNA) index were elevated in the a‐nTiO 2 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‐nTiO 2 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‐nTiO 2 or r‐nTiO 2.

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

“…To investigate the possibility that this apparent discrepancy was due to the titanium dioxide composition of POT fibers, we conducted a short-term experiment to compare the toxicity of POT fibers with two titanium dioxide nanoparticles, anatase titanium dioxide nanoparticles (a-nTiO 2 ) and rutile titanium dioxide nanoparticles (r-nTiO 2 ). We administered POT fibers and a-nTiO 2 and r-nTiO 2 to the lungs of rats using intra-tracheal intra-pulmonary spraying (TIPS) and found that POT fibers had greater biopersistence and induced a greater degree of toxicity in the lung than a-nTiO 2 or r-nTiO 2 (Abdelgied et al 2018). These results are in agreement with the findings of studies with other materials that fiber-shaped materials are more toxic to the lungs than spherical-shaped nanoparticles of the same chemical composition (Braakhuis et al 2014).…”

Effects of administering different vehicles via single intratracheal instillation on responses in the lung and pleural cavity of Crl:CD(SD) rats

“…Overall, the result obtained from the 0.5% KP188-treated group indicates that intratracheal instillation of this vehicle caused tissue damage and subsequent inflammation, but that this effect may be transitory. This conclusion is supported by another study where KP188 (also known as Poloxamer 188 which is used as an alterna-tive to Pluronic F-68: MDL number MFCD00082049) was used as the vehicle, and 4 weeks after the final intratracheal instillation of 0.5 ml of 0.5% KP188 in saline (a total of 8 intratracheal instillation procedures), the vehicle administered group did not differ from the untreated group in any of the parameters examined 20 . Importantly, neither LDH, ALP, albumin, nor total protein was elevated in the BALF of pure water, saline; PBS, Tween 20 or BSA-treated groups, thereby suggesting that intratracheal instillation of these vehicles caused little tissue damage in the lung.…”

“…A further study is therefore required to elucidate the recovery process of the damage. However, it has been reported that the toxic effects of KP188 were transient 20 .…”

“…The choice of vehicle depends on both the toxicity of the vehicle and the solubility/dispersibility of the test agent in the vehicle. For example, polyoxyethylene-polyoxypropylene copolymers such as Pluronic F-68 (discontinued) and KP188 have been used for dispersal of hydrophobic carbon nanotubes and potassium octatitanate fibers 10,[20][21][22] . KP188 is used as the vehicle; however, it is water-soluble and not bio-persistent in the lung.…”

Predictive hazard markers for the ranking of pulmonary toxicity of nanomaterials

“…Fujita et al also reported that CCL2 and CCL7 were upregulated in the lungs of rats injected intratracheally with in ammogenetic SWCNT [27,33]. Abdelgied et al found that CCL2 expression was increased in rat lungs following intratracheal instillation of potassium octatitanate bers (POT bers), which are suggested to have carcinogenic potential [34]. On the other hand, it has also been reported that CCL2 and CCL7 expression was transient in rat lungs following intratracheal instillation of C60 fullerenes with low toxicity [30].…”