The aim of this work was to compare lung clearance and retention kinetics as well as biological effects of two poorly soluble, low toxicity nanoparticles (nano-PSLT) after 1, 4, 13 and 52 weeks of inhalation exposure. The two tested nano-PSLT may represent a range of biological responses within the group. Cerium dioxide (CeO2; NM-212) and barium sulfate (BaSO4) nanoparticles were tested for toxic effects and organ burden after inhalation exposure. Female Wistar rats inhaled nano-CeO2 or - BaSO4 by whole-body exposure, 6 hours per day, 5 days per week for a total of two years. Interim results after 13 and 52 weeks of exposure including bronchoalveolar lavage fluid (BALF) analysis and determination of lung- and lymph node burdens are presented in this dissertation work. The tested aerosol concentrations were 0.1, 0.3, 1 and 3 mg/m³ CeO2 and 50 mg/m³ BaSO4. The aerosol concentrations were selected based on the results of short-term inhalation studies with 1 and 4 weeks of exposure to 0.5, 5 and 25 mg/m³ CeO2 and 50 mg/m³ BaSO4. Lung, lymph node and liver burdens (by inductively coupled plasma optical emission spectrometry), histopathology of lung and extrapulmonary organs and examination of BALF and blood were assessed after short-term exposure and post-exposure periods up to 129 days.In the short-term studies, inhaled nano-BaSO4 showed an unusually fast short-term clearance. This may be explained by higher in vivo dissolution compared to our cell-free in vitro solubility studies since the observed fast lung clearance and high systemic bioavailability of inhaled BaSO4 cannot be achieved by any known physiological process unless there may be a specific rapid translocation of nano-BaSO4. It is of utmost interest which mechanisms are involved; this needs to be addressed in future investigations. In the long-term study, lung burdens increased strongly with longer exposure period indicating a change in clearance from short-term to long-term exposure. Long-term exposure to high aerosol concentrations of nano-BaSO4 led to high lung burdens and, eventually, pulmonary inflammation based on increased BALF parameters. There were no indications of barium-ion toxicity and the effects are regarded as being particle effects in the lung. Nano-BaSO4 seems to exhibit peculiar characteristics concerning kinetics and effects compared to nano-PSLT. Nano-BaSO4 could be regarded as not being a classical PSLT, but rather soluble in vivo albeit indicated to be insoluble by its chemical properties. The remarkably low toxicity of inhaled nano-BaSO4 could only partly be assigned to its fast lung clearance, but may also be the result of its low inherent toxicity. Nano-CeO2, on the other hand, was biopersistent. Low lung burdens were cleared at physiological rates whereas higher burdens induced retarded clearance and toxicity already after short-term exposure. Comparing the observed effects in our studies with the literature data, CeO2 seems to possess a higher toxicity than TiO2 (Ma-Hock et al. 2009; Eydner et al. 2012). It may represent the higher toxicity and high biopersistence end of the group of PSLT.Comparing the two tested nanoparticles, aerosol concentrations of 3 mg/m³ CeO2 and 50 mg/m³ BaSO4 resulted in similar lung burdens after 13 weeks of exposure, but the effects (based on BALF parameters) were different; this probably depends on the properties of the deposited material, the dose-rate and the toxicity of the released ions. Different (nano-)particles will span a continuous range of solubilities in the lung without a distinct threshold dividing poorly soluble from soluble (nano-)particles. Likewise, most particle may not exhibit mere particle effects or mere released-ion effects. The local no observed adverse effect concentrations in the lung (NOAEC) of CeO2 - based on BALF in female rats after 13 and 52 weeks of exposure - are 0.3 and 0.1 mg/m³, respectively. The local NOAEC of BaSO4 in the lung - based on BALF in female rats after 13 and 52 weeks of exposure is below 50 mg/m³. Inhalation exposure to CeO2 and BaSO4 elicited no or only minimal systemic effects after short-term and long-term exposure. The two nanoparticles examined in this body of work differed in their particle kinetics and effects in the lung already after one week and up to 52 weeks of exposure. Whether the lung burdens and effects observed within the first 52 weeks of exposure will lead to lung tumour formation will be revealed by histopathology after 2 years of exposure in the current long-term inhalation study.
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