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

Potassium octatitanate fibers (K(2)O·8TiO(2), 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).