Deposited dose rate and dissolution of nanoparticles in the respiratory tract impact the acute inflammatory response

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Environmental Medicine, 2014.The increasing use of nanoparticles (NPs) has led to concerns about the potential for human exposures and associated health outcomes. Although there are several likely routes of exposure to NPs, we focus on the respiratory tract (RT) and subsequent effects in the lungs. Since there is a lack of real world exposure data for NPs, no RT exposure limits have been imposed by regulatory agencies. Due to the overwhelming number of NPs being produced, it is not possible to interrogate all of them for hazard assessment purposes. Therefore, there is a need for exposure models that reflect real world exposures and that are adequately predictive of hazard for NPs that share the same physicochemical properties. Toxicological responses to NPs have been explored, typically using high dose rate (bolus) delivery and high doses; however, little is known about the roles of dose rate and dissolution rate in determining response outcomes. We hypothesize that the NP deposited dose rate and dissolution rate are key determinants of the acute inflammatory responses in the RT when the deposited dose is held constant. We exposed F-344 male rats to poorly soluble titanium dioxide (TiO2), partially soluble copper-doped TiO2, or partially soluble copper oxide NPs by high dose rate intratracheal instillation or low dose rate whole body inhalation. We observed more robust inflammation, hallmarked by neutrophil influx and neutrophil chemoattractant proteins, following high dose rate instillation of poorly soluble TiO2 NPs compared to low dose rate inhalation. Therefore, high dose rate delivery of the poorly soluble TiO2 NPs overestimates NP hazard. Using partially soluble Cu containing NPs, we demonstrated that both the deposited dose rate and dissolution rate impact inflammation. Our studies provide a better understanding of the roles of deposited dose rate and dissolution rate in acute inflammation, the respective mechanisms of response, and the importance of careful exposure method selection to help establish safety regulations regarding the production and disposal of NPs