Date of Graduation

2008

Document Type

Dissertation/Thesis

Abstract

The purpose of this study was to test this hypothesis examining the in vivo effects of ultrafine and fine particles on certain parameters of pulmonary damage and inflammation in the rat model. To do this each treatment group received a dosage based on mass particles. This dosage was then expressed as surface area of the particles (instead of mass) to determine if surface area rather than mass is the more appropriate metric of dose for pulmonary toxicity studies. To assess inflammation, BAL was conducted harvested and PMNs were counted as an indicator of pulmonary inflammation. LDH activity was also measured to assess cellular cytotoxicity.Results showed that on an equal mass basis the ultrafine particles produce greater inflammation and cytotoxicity than the fine sized particles. However, when dose of particles is normalized to equal surface area administered, at most doses the fine sized particles caused greater inflammation and cytotoxicity than the ultrafine particles; therefore, conflicting with the hypothesis. Due to these conflicting results, experiments were conducted to determine the best method to disperse nanosized particles.Ultrafine and fine carbon black and titanium dioxide were suspended in PBS, rat BALF, and PBS containing DPPC. To assess and compare how these various suspension media dispersed the nanoparticles, images were taken using light microscopy, SEM, and TEM. The results of this study show that PBS is not a satisfactory medium to prepare nanoparticle suspensions. However, BALF was an excellent media in which to suspend nanoparticles. The use of PBS containing DPPC, in concentrations found in BALF, did not result in satisfactory particle dispersion. Our previous studies found that nanoparticle agglomeration in PBS results in inaccurate dose delivery, which leads to misinterpretation of the toxicity of the particulate being assessed. We found that acellular BALF is effective in dispersing nanoparticles without masking the biological surface activity of the test particle. After establishing an accurate protocol for dispersing nanosized particles, assessment of the inflammatory and cytotoxic potential of ultrafine and fine carbon black and titanium dioxide (TiO2) was conducted. Rats were exposed by intratracheal instillation to varying doses of ultrafine and fine carbon black or TiO2. At 1, 7, or 42 days post-exposure, inflammatory and cytotoxic potential of each particle type was compared on both an equal mass dosage (mg/rat) as well as an equal surface area dosage (cm2 of particles per cm2 of alveolar epithelium). The findings of the study show that on an equal mass basis the ultrafine particles caused significantly more inflammation and were significantly more cytotoxic than the fine sized particles. However, when doses were equalized based on surface area of particles given, the ultrafine particles were only slightly more inflammogenic and cytotoxic when compared to the fine sized particles. In conclusion, this study suggests that surface area of particles may be a more appropriate dose metric for pulmonary toxicity studies than mass of particles.

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