Academic journal article Environmental Health Perspectives

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

Academic journal article Environmental Health Perspectives

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

Article excerpt

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.

KEY WORDS: joint length, lung inflammation, particle mass, particle number, saturation effects, specific surface area, ultrafine carbon particles. Environ Health Perspect 114:187-194 (2006). doi:10.1289/ehp.9254 available via [Online 3 October 2006]


Possible adverse health effects due to the inhalation of airborne particulate matter (PM) are a topic of ongoing scientific and public concern (Lippmann et al. 2003). Recently, attention has focused on the effect of particles with sizes < 100 nm, referred to as ultrafine particles (Brown et al. 2000) or nanoparticles (Nel et al. 2006; Oberdorster et al. 2005). Interest in ultrafine particles is due to the fact that, on the basis of the toxicity of the various chemical compounds contained in ambient PM, the epidemiologically identified associations between adverse health effects and PM are not plausible (Green et al. 2002; Valberg 2004). Hence, one needs to explore the idea that the mere physical presence of insoluble nanoparticles deposited deep in the lung may cause adverse effects, including the possibility that these small particles may enter into the blood circulation and are subsequently translocated to sensitive body organs such as the liver, the heart, or even the brain (Oberdorster et al. 2005).

The toxic potential of insoluble nanoparticles is commonly explored in laboratory studies involving rats or mice. A frequently studied response parameter is lung inflammation. In vivo studies have aimed at determining the (physical) parameter that can serve as a relevant measure of the applied dose. The knowledge derived from such studies may pave the way to identifying mechanistic pathways of lung inflammation. Previous work has shown that, for the same dose in terms of mass, response increases with decreasing particle size. To explain these observations, investigators have considered the surface area as the proper dose metric (Donaldson et al. 2000; Duffin et al. 2002; Oberdorster 1996, 2000; Oberdorster et al. 2005; Stoeger et al. 2006). One of the problems in such studies is that nanoparticles made from different materials exhibit large differences in inflammogenic potential. The surface toxicity was found to be low for carbon, titanium dioxide, and latex but very high for quartz, cobalt, and nickel (Duffin et al. …

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