Biological Response to Nano-Scale Titanium Dioxide (TiO₂): Role of Particle Dose, Shape, and Retention

Abstract

Titanium dioxide (TiO₂) is one of the most widely used nanomaterials, valued for its highly refractive, photocatalytic, and pigmenting properties. TiO₂ is also classified by the International Agency for Research on Cancer (IARC) as a possible human carcinogen. The objectives of this study were to (1) establish a lowest-observed-effect level (LOEL) for nano-scale TiO₂, (2) determine TiO₂ uptake in the lungs, and (3) estimate toxicity based on physicochemical properties and retention in the lungs. In vivo lung toxicity of nano-scale TiO₂ using varying forms of well-characterized, highly dispersed TiO₂ was assessed. Anatase/rutile P25 spheres (TiO₂-P25), pure anatase spheres (TiO₂-A), and anatase nanobelts (TiO₂-NB) were tested. To determine the effects of dose and particle characteristics, male Sprague-Dawley rats were administered TiO₂ (0, 20, 70, or 200 μg) via intratracheal instillation. Bronchoalveolar lavage fluid (BALF) and lung tissue were obtained for analysis 1 and 7 d post exposure. Despite abundant TiO₂ inclusions in all exposed animals, only TiO₂-NB displayed any significant degree of inflammation seen in BALF at the 1-d time point. This inflammation resolved by 7 d, although TiO₂ particles had not cleared from alveolar macrophages recovered from the lung. Histological examination showed TiO₂-NB produced cellular changes at d 1 that were still evident at d 7. Data indicate TiO₂-NB is the most inflammatory with a LOEL of 200 μg at 1 d post instillation.

Acknowledgments

Support for this research was provided by: University of California, Davis Atmospheric Aerosols and Health Lead Campus Program (aah.ucdavis.edu); NIEHS Nano Grand Opportunities (NanoGO) Challenge Grants (RC1 ES018232 and RC2 DE-FG02-08ER64613); and NIEHS 1U01ES020127-01, Engineered Nanomaterials: Linking Physical and Chemical Properties to Biology. Pacific Northwest National Laboratory is operated by Battelle Memorial Institute for the U.S. Department of Energy under contract DE-AC05-76RL01830. We thank Imelda Espiritu, Katherine Johnson, Amy Madl, Dipti Munshi, Leng Mut, Janice Peake, Laurel Plummer, Vish Seshachellam, Esther Shin, and Dale Uyeminami for technical assistance, and Drs. Ting Guo, Angie Louie, Otto Raabe, and Laura Van Winkle for insightful discussions during the course of this study, as well as Suzette Smiley-Jewell for article preparation. The writing of the article was the sole responsibility of the authors. It has not been published and/or submitted simultaneously for publication elsewhere.