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Senlin Lu,^1,2 Rodger Duffin,¹ Craig Poland,¹ Paul Daly,¹ Fiona Murphy,¹ Ellen Drost,¹ William MacNee,¹ Vicki Stone,³ and Ken Donaldson¹

¹University of Edinburgh, Edinburgh, UK; ²School of Environmental and Chemical Engineering, Shanghai University, Shanghai, China; ³Napier University, Edinburgh, UK

Abstract
Background: There has been concern regarding risks from inhalation exposure to nanoparticles (NPs) . The large number of particles requiring testing means that alternative approaches to animal testing are needed.

Objectives: We set out to determine whether short-term in vitro assays that assess intrinsic oxidative stress potential and membrane-damaging potency of a panel of metal oxide NPs can be used to predict their inflammogenic potency.

Methods: For a panel of metal oxide NPs, we investigated intrinsic free radical generation, oxidative activity in an extracellular environment, cytotoxicity to lung epithelial cells, hemolysis, and inflammation potency in rat lungs. All exposures were carried out at equal surface area doses.

Results: Only nickel oxide (NiO) and alumina 2 caused significant lung inflammation when instilled into rat lungs at equal surface area, suggesting that these two had extra surface reactivity. We observed significant free radical generation with 4 of 13 metal oxides, only one of which was inflammogenic. Only 3 of 13 were significantly hemolytic, two of which were inflammogenic.

Conclusions: Potency in generating free radicals in vitro did not predict inflammation, whereas alumina 2 had no free radical activity but was inflammogenic. The hemolysis assay was correct in predicting the proinflammatory potential of 12 of 13 of the particles examined. Using a battery of simple in vitro tests, it is possible to predict the inflammogenicity of metal oxide NPs, although some false-positive results are likely. More research using a larger panel is needed to confirm the efficacy and generality of this approach for metal oxide NPs.

Key words: electron paramagnetic resonance, EPR, inflammation, lungs, nanoparticles, oxidative stress, ROS. Environ Health Perspect 117:241–247 (2009) . doi:10.1289/ehp.11811 available via http://dx.doi.org/ [Online 17 September 2008]

Address correspondence to K. Donaldson, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ UK. Telephone: 0-131-242-6580. Fax: 0-131-242-6582. E-mail ken.donaldson@ed.ac.uk

We thank J. Ayres and K. Sternad for assistance.

We acknowledge support from the Colt Foundation, the Chinese Scholarship Council, the National Natural Science Foundation of China (40675080, 10775094) , and China Ministry of Science and Technology 973 Project (2006CB705604) .

K.D. and V.S. have consulted with industry on the toxicology of nanoparticles. The other authors declare they have no competing financial interests.

Received 17 June 2008 ; accepted 16 September 2008.