In Search of the Most Relevant Parameter for Quantifying Lung Inflammatory Response to Nanoparticle Exposure: Particle Number, Surface Area, or What?

BACKGROUND: Little is known about the mechanisms involved in lung inflammation caused by the inhalation or instillation of nanoparticles. Current research focuses on identifying the particle parameter that can serve as a proper dose metric. OBJECTIVES: The purpose of this study was to review published dose–response data on acute lung inflammation in rats and mice after instillation of titanium dioxide particles or six types of carbon nanoparticles. I explored four types of dose metrics: the number of particles, the joint length—that is, the product of particle number and mean size—and the surface area defined in two different ways. FINDINGS: With the exception of the particle size–based surface area, all other parameters worked quite well as dose metrics, with the particle number tending to work best. The apparent mystery of three equally useful dose metrics could be explained. Linear dose–response relationships were identified at sufficiently low doses, with no evidence of a dose threshold below which nanoparticle instillation ceased to cause inflammation. In appropriately reduced form, the results for three different sets of response parameters agreed quite well, indicating internal consistency of the data. The reduced data revealed particle-specific differences in surface toxicity of the carbon nanoparticles, by up to a factor of four, with diesel soot being at the low end. CONCLUSIONS: The analysis suggests that the physical characterization of nanoparticles and the methods to determine surface toxicity have to be improved significantly before the appropriate dose metric for lung inflammation can be identified safely. There is also a need for refinements in quantifying response to exposure.