Translocation of inhaled ultrafine manganese oxide particles to the central nervous system

An important step in assessing the toxicology of particles is to determine their fate after inhalation. Of particular interest to us are airborne ultrafine particles (UFPs; < 100 nm), which are abundant in ambient urban air and are of the same size as engineered nanoparticles. Translocation to extrapulmonary sites after respiratory tract deposition represents an important mechanism for these particles to cause direct effects in secondary target organs (Oberdorster et al. 2005). The extent to which this process occurs depends on several factors including particle solubility, particle or aggregate size, the site of deposition, and the integrity of the epithelial lining. UFPs deposit efficiently in all regions of the respiratory tract, depending on their size; specifically, as particle size decreases toward the smallest UFPs, nasopharyngeal deposition increases (International Committee on Radiological Protection 1994). Studies in rats have shown translocation of soluble manganese compounds from the nose along olfactory neuronal pathways to the olfactory bulb (Dorman et al. 2004; Henriksson and Tjalve 2000; Tjalve et al. 1996; Tjalve and Henriksson 1999) after inhalation or intranasal instillation exposures. Likewise, the few studies that have examined the fate of UFPs deposited on the nasal mucosa identified translocation along the neuronal olfactory route as a pathway to the olfactory bulb of the central nervous system (CNS). These include early studies in non-human primates, which demonstrated the translocation of solid nanosized particles (30 nm poliovirus; 50 nm silver-coated gold colloids) along the axons of olfactory nerves into the olfactory bulb (Bodian and Howe 1941a, 1941b; DeLorenzo 1970). We have also shown that inhaled elemental carbon particles (13C; 35 nm, count median diameter) accumulate in rat olfactory bulb after whole-body inhalation (Oberdorster et al. 2004). Regarding penetration into deeper brain regions, Tjalve et al. (1995) demonstrated that soluble ionic Mn instilled into the olfactory chamber of pike has the ability to pass synaptic junctions and migrate from the olfactory tract to more distal regions, including the hypothalamus. Dorman et al. (2004) found Mn in the striatum and cerebellum of rats after subchronic inhalation exposure to a soluble Mn salt (sulfate); however, this was attributed to uptake from the blood. Thus, contributions to brain Mn levels from the blood need to be considered and may also be an issue for inhaled solid UFPs. The effects of translocated particles in the brain are also important to determine. For example, preliminary information has emerged from populations of welders that some of them may develop parkinsonism 17 years earlier than the general population (Racette et al. 2001). Welding produces high amounts of fumes containing Mn UFPs (Zimmer et al. 2002). Several recent epidemiologic studies describe occupational exposure ranges of approximately 0.01–5 mg/m3 Mn in fumes from various welding processes and materials (Korczynski 2000; Li et al. 2004; Sinczuk-Walczak et al. 2001). Conflicting data emerge from animal studies, however, regarding effects of inhaled Mn compounds in the brain. Henriksson and Tjalve (2000) reported changes in glial fibrillary acidic protein (GFAP) and S-100b, markers of astrocyte activation, in several brain regions from rats exposed intranasally to Mn chloride. However, Dorman et al. (2004) did not find any evidence of changes in GFAP levels in the brain after exposure to Mn sulfate or phosphate. Potential contributing factors to the lack of concurrence in results include differences in the solubilities of the Mn salts used, the doses, and the contribution of olfactory epithelial damage. In the present study, we sought to address the hypothesis that a major translocation route for inhaled poorly soluble Mn oxide UFPs from deposits in the nose is to the olfactory bulb in the CNS. We characterized the size, oxidation state, and in vitro solubility of gas-phase–generated Mn oxide particles and also compared the translocation kinetics to the olfactory bulb of Mn oxide and MnCl2 that were applied to the nasal epithelium of rats via instillation. We then measured the accumulation of Mn in lung, liver, and olfactory bulb after repeated inhalation exposures with both nares patent or with one naris occluded. We show that Mn oxide UFPs are translocated to and retained in the olfactory bulb (ipsilateral to the patent naris only) and present evidence of exposure-induced effects in that region of the brain. These studies demonstrate the importance of UFPs size and of solubility in olfactory translocation processes.