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

Because of its high tensile strength, chemical stability, and heat-resistance, POT is commonly used as an alternative to asbestos. POT fibers have a long needle-like shape, similar to asbestos, and are not broken down in the body. Thus, the fiber pathogenicity paradigm 2 identifies these fibers as potential carcinogens. The carcinogenicity of POT fibers was confirmed by an initial study that administered POT fibers by application of POT fibers directly to the pleural surface of Osborne-Mendel rats and a later study that administered POT fibers by intraperitoneal injection. Two recent studies infused POT fibers directly into the pleural cavity of mice and rats: one study followed the treated animals for 52 and 65 weeks and the other study followed the treated animals for 52 weeks. Although, none of the treated animals had developed mesothelioma by the time the study was terminated, all mice and rats treated with POT fibers exhibited pleural thickening. Inhalation studies that followed exposed animals for up to 2 years were mostly negative. Overall, these studies indicate that POT fibers are carcinogenic, but that a high amount of POT fibers in prolonged contact with susceptible tissue is required for induction of malignant neoplasia. They also suggest that inhalation of POT fibers is not carcinogenic in rats and that low level exposure may not be carcinogenic in humans. Thus, the physical characteristics of POT fibers suggest high carcinogenic potential, but the experimental evidence indicates low carcinogenic potential. A variety of factors could account for this discrepancy: (1) The fiber pathogenicity paradigm may not apply to POT fibers, possibly because of the chemical make-up of the fibers. (2) The relatively low sensitivity of inhalation studies using rats may be a factor in the negative results of the inhalation studies; the low sensitivity of rat inhalation studies is also noted. (3) If the fibers are not well dispersed, this will result in lower than expected levels of particles with small enough aerodynamic diameters to penetrate beyond the ciliated airways. Thus, the physical characteristics of POT fibers and the fact that they can induce malignant transformation in susceptible tissues suggest high carcinogenic potential, but inhalation studies indicate that respirable POT fibers have low carcinogenic potential in test animals. 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-nTiO2) and rutile titanium dioxide nanoparticles (r-nTiO2). We administered POT fibers and a-nTiO2 and r nTiO2 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-nTiO2 or r nTiO2. 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. Thus, the titanium dioxide composition of POT fibers does not appear to explain their lack of carcinogenicity in the lung. Therefore, we are conducting a 2-year study comparing the lung toxicity of POT fibers to r-nTiO2 and MWCNT-7, a known lung carcinogen in rats. Overall, we found that at 1 year POT fibers had a similar or greater degree of toxicity in the lung and pleural cavity compared to MWCNT-7. At 1 year in rats administered POT fibers and MWCNT-7, there were persistent inflammatory and fibrotic changes in the lung and pleura, elevated alveolar macrophage counts, elevated levels of CCL2 and CCL3 in the lung tissue, increased levels of 8-OHdG adducts in the lung tissue DNA, and increased PCNA labeling of lung alveolar cells and visceral and parietal mesothelium. Hyperplasia of the visceral mesothelium was found in 2 of 5 rats in the 0.50 mg POT group and 1 of 5 rats in the 0.50 mg MWCNT-7 group. In contrast, none of these parameters was elevated in rats administered r-nTiO2. In conclusion, there is clear evidence that POT fibers are toxic in the lung and pleura of male rats. POT fibers were biopersistent in the lung and mesothelium of rats, provoking inflammation and tissue and DNA damage. These results are in agreement with the physical characteristics of these fibers and the potential adverse health effects of thin, long, biopersistent fibers. The pulmonary and pleural toxicity of POT fibers was similar or greater than that of MWCNT-7, a known carcinogen to the rat lung