10th International Aerosol Conference September 2 - September 7, 2018 America's Center Convention Complex St. Louis, Missouri, USA
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Surface Area Is the Biologically Most Relevant Dose Metric for Particle-Induced Inflammation in the Lung
OTMAR SCHMID, Kristina B. Knudsen, Sarah Søs Poulsen, Yaobo Ding, Rambabu Atluri, Kirsten Kling, Anne T Saber, Nicklas R. Jacobsen, Keld A. Jensen, Håkan Wallin, Tobias Stoeger, Ulla Vogel, Helmholtz Zentrum Munchen, Comprehensive Pneumology Center
Abstract Number: 1568 Working Group: Aerosols and Health - Connecting the Dots
Abstract As part of the SmartNanoTox project (Horizon 2020, EU-funded ) a large body of data on short-term (1d) and intermediate-term (28d) pulmonary inflammation was assessed in rodents after pulmonary application of low-solubility particles. Due to the complexity of inhalation studies with animals there is a much larger body of data on particle induced toxicity employing the technically much simpler route of intratracheal instillation (IT), where of a small volume of a particle suspension is injected directly via the trachea into the lungs. Here rodent studies (mice, rats) were included which determined the pulmonary inflammatory response via neutrophil influx into the lungs and applied at least three different particle doses with a single IT application.
Hundreds of data points published in more than 20 studies from numerous laboratories were included in this overview study comprising ca. 50 different types of (nano-)particles varying with respect to material (six types of soot, graphene, polystyrene, various metal oxides), crystallinity (crystalline, amorphous), shape (spherical, fiber-/tube-like), size (diameter: 9 – 1500 nm, fiber-like: diameter x length 10 – 60 nm x 0.7 – 10 µm) and mass-specific BET surface area (5 – 1000 m2/g).
After scaling to lung-delivered dose (applied dose per mass of the lung) there was excellent agreement between data from different animal models (mice and rats) and from different laboratories. This lends credibility to conclusions drawn from the combined data sets. Surface area, measured according to the BET method, was identified as the biologically most relevant dose metric explaining about 80% of the observed variability in acute (1d) pulmonary inflammation (R2~0.8). For comparison, mass and close-packed volume (R2~0.5), joint length (R2~0.4), and number of primary particles (R2~0.2) had a much lower predictive power for particle-induced inflammation.
Moreover, surface area was the only dose metric which allowed clustering of all of these ca. 50 different materials into different classes of toxicity independent of their primary and agglomerate size. At 1d, materials without intrinsic toxicity having EC50 values of ca. 175 cm2/g lung (dose at which 50% of the maximum possible neutrophil influx was observed) could be clearly distinguished from materials with moderate to high intrinsic toxicity such as some transition metal oxides (here: Co, Ni, Zn, Fe; EC50=15 cm2/g lung) and crystalline quartz (EC50 < 5 cm2/g lung)). It is interesting to note that all types of soot particles, which were investigated here, belonged to the low toxicity class in spite of their very different organic loadings. Moreover, a large number of multi-walled carbon nanotubes (MWCNTs) belonged to the low-toxicity class, but some types of MWCNTs showed enhanced inflammatory response. Prolonged inflammation (here up to 28d) also scaled best with surface area as dose metric and the degree of prolonged inflammation was well predicted by the acute response profile (1d).
This analysis suggests that mainly surface-related modes of action are driving particle-induced pulmonary inflammation. Moreover, lung-deposited surface area (in addition to mass and possibly number) should be measured for the assessment of aerosol-related health effects.