title: Translocation of inhaled ultrafine particles to the brain.
abstract: Ultrafine particles (UFP, particles <100 nm) are ubiquitous in ambient urban and indoor air from multiple sources and may contribute to adverse respiratory and cardiovascular effects of particulate matter (PM). Depending on their particle size, inhaled UFP are efficiently deposited in nasal, tracheobronchial, and alveolar regions due to diffusion. Our previous rat studies have shown that UFP can translocate to interstitial sites in the respiratory tract as well as to extrapulmonary organs such as liver within 4 to 24 h postexposure. There were also indications that the olfactory bulb of the brain was targeted. Our objective in this follow-up study, therefore, was to determine whether translocation of inhaled ultrafine solid particles to regions of the brain takes place, hypothesizing that UFP depositing on the olfactory mucosa of the nasal region will translocate along the olfactory nerve into the olfactory bulb. This should result in significant increases in that region on the days following the exposure as opposed to other areas of the central nervous system (CNS). We generated ultrafine elemental (13)C particles (CMD = 36 nm; GSD = 1.66) from [(13)C] graphite rods by electric spark discharge in an argon atmosphere at a concentration of 160 microg/m(3). Rats were exposed for 6 h, and lungs, cerebrum, cerebellum and olfactory bulbs were removed 1, 3, 5, and 7 days after exposure. (13)C concentrations were determined by isotope ratio mass spectroscopy and compared to background (13)C levels of sham-exposed controls (day 0). The background corrected pulmonary (13)C added as ultrafine (13)C particles on day 1 postexposure was 1.34 microg/lung. Lung (13)C concentration decreased from 1.39 microg/g (day 1) to 0.59 microg/g by 7 days postexposure. There was a significant and persistent increase in added (13)C in the olfactory bulb of 0.35 microg/g on day 1, which increased to 0.43 microg/g by day 7. Day 1 (13)C concentrations of cerebrum and cerebellum were also significantly increased but the increase was inconsistent, significant only on one additional day of the postexposure period, possibly reflecting translocation across the blood-brain barrier in certain brain regions. The increases in olfactory bulbs are consistent with earlier studies in nonhuman primates and rodents that demonstrated that intranasally instilled solid UFP translocate along axons of the olfactory nerve into the CNS. We conclude from our study that the CNS can be targeted by airborne solid ultrafine particles and that the most likely mechanism is from deposits on the olfactory mucosa of the nasopharyngeal region of the respiratory tract and subsequent translocation via the olfactory nerve. Depending on particle size, >50% of inhaled UFP can be depositing in the nasopharyngeal region during nasal breathing. Preliminary estimates from the present results show that approximately 20% of the UFP deposited on the olfactory mucosa of the rat can be translocated to the olfactory bulb. Such neuronal translocation constitutes an additional not generally recognized clearance pathway for inhaled solid UFP, whose significance for humans, however, still needs to be established. It could provide a portal of entry into the CNS for solid UFP, circumventing the tight blood-brain barrier. Whether this translocation of inhaled UFP can cause CNS effects needs to be determined in future studies.
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, New York 14642, USA. gunter_oberdorster@urmc.rochester.edu
authors.forename: G
authors.initials: G
authors.lastname: Oberdörster
authors.forename: Z
authors.initials: Z
authors.lastname: Sharp
authors.forename: V
authors.initials: V
authors.lastname: Atudorei
authors.forename: A
authors.initials: A
authors.lastname: Elder
authors.forename: R
authors.initials: R
authors.lastname: Gelein
authors.forename: W
authors.initials: W
authors.lastname: Kreyling
authors.forename: C
authors.initials: C
authors.lastname: Cox
mesh_terms: D000393:Air Pollutants / Q000493:pharmacokinetics*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002244:Carbon / Q000008:administration & dosage / Q000493:pharmacokinetics; D002531:Cerebellum / Q000378:metabolism; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000378:metabolism; D008297:Male; D009830:Olfactory Bulb / Q000378:metabolism; D010316:Particle Size; D051381:Rats; D011916:Rats, Inbred F344; D013687:Telencephalon / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000393:Air Pollutants; D002244:Carbon