Effects and Fate of Inhaled Ultrafine Particles - ACS Publications

Chapter 7

Effects and Fate of Inhaled Ultrafine Particles

Downloaded by CHINESE UNIV OF HONG KONG on March 7, 2016 | http://pubs.acs.org Publication Date: December 14, 2004 | doi: 10.1021/bk-2005-0890.ch007

Günter Oberdörster Department of Environmental Medicine, University of Rochester, 575 Elmwood Avenue, Rochester, NY 14642 ([email protected])

Concentration of inhaled particulate matter (PM) varies by orders of magnitude from ng/m to mg/m , depending on material, particle size, and proximity to sources. Particle number concentrations, expressed as particles/cm , can also span several orders of magnitude, with ultrafine particles (2 μm, impaction) and smaller ultrafine (

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46 the macrophages, whereas only -20% of ultrafine 15-20 nm and 80 nm particles could be lavaged with the macrophages. Conversely, -80% of the ultrafine particles were retained in the lavaged lung after exhaustive lavage, and -20% of the larger particles > 0.5 μηι remained in the lavaged lung. These results imply that UFP—inhaled and deposited as singlets in the alveolar space—are not efficiently phagocytized by alveolar macrophages which could be either due to an inability of macrophages to phagocytize these small particles or due to a lack of the deposited singlet UFP to generate a chemotactic signal at the site of their deposition. Studies seemingly supporting the first hypothesis, indeed, show that an optimal particle size for phagocytosis by alveolar and other macrophages is between 1-3 μιη, and that beyond these sizes phagocytosis rates become progressively slower (43-45). However, in vitro dosing of alveolar macrophages with ultrafine particles indicates that they are phagocytized by macrophages and activate these cells (23, 46; 24; 22). Since in vitro studies do not mimic realistic in vivo conditions, the second hypothesis is more likely to explain the result in Figure 4, that the macrophages do not "sense" the deposited UFP since they did not generate a chemotactic signal or only a very weak one. This suggestion is also supported by the low deposited dose per unit alveolar surface area even for those UFP (20 nm) that have the highest deposition efficiency there (Fig. lb). Still, experimental proof for this hypothesis is needed to explain the results of Figure 4 that UFP deposited by inhalation in the alveolar region are not efficiently phagocytized by alveolar macrophages. Because of the inefficiency of alveolar macrophage uptake of UFP one might expect that UFP interact instead with epithelial cells. Indeed, results from several studies show that UFP deposited in the respiratory tract readily gain access to epithelial and interstitial sites (37). We showed in studies with ultrafine PTFE fumes that shortly after a 15-min. exposure the fluorine-containing particles could be found in interstitial and submucosal sites of the conducting airways as well as in the interstitium of the periphery close to the pleura (20). Results of other studies with ultrafine and fine T i 0 particles—ranging in size from 12 nm to 250 nm—are consistent with a strongly particle size dependent translocation to epithelial and interstitial sites: 24 hours after intratracheal instillation of 500 mg into rats, more than 50% of the 12 nm sized T i 0 had translocated, whereas it was only 4% and less for 220 nm and 250 nm T i 0 (47). Of course, the smaller particle sizes of 12 and 20 nm vs. 220 and 250 nm also means that the administered particle number was more than 3 orders of magnitude higher for the ultrafines, a factor that seems to be an important determinant for particle translocation across the alveolar epithelium, as are the delivered total dose and the dose rate (48). In general, interstitial translocation of fine particles across the alveolar epithelium is more prominent in larger species (dogs, non-human primates) than in rodents (37, 49), and one may, 2

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47 therefore, assume that the high UFP translocation observed in rats are likely to occur in humans as well. Interstitial translocation constitutes another translocation pathway for those particles which are not phagocytized by alveolar macrophages, either due to their small size—which is the case for UFP—or due to an overloading of the alveolar macrophage capacity to phagocytize particles, A state of particle overload has been induced in a number of chronic rat inhalation studies with very high particle concentrations leading to increased translocation also of fine particles (50). Once in the interstitium, translocation to regional lymph nodes either as free particles or after phagocytosis by interstitial macrophages can occur. Some particles after accumulation in lymph nodes will also translocate further into post-nodal lymph and entering the blood circulation. This mechanism was demonstrated for fibrous particles in dogs: Intrabronchially instilled amosite fibers were found in post-nodal lymph samples of the right thoracic duct collected in the neck area before entering the venous circulation (51). There was an obvious size limitation in that only the shorter and thinner fibers (< 500 nm diameter) appeared in the post-nodal lymph. This lympho-hematogeneous pathway appears to exist also in non-human primates where it was shown that fine crystalline silica particles translocated to the livers of exposed monkeys following chronic exposure to high concentrations (52. 53). Thus, the clearance pathway from local lymph nodes to the blood circulation is not restricted to UFP but occurs also for larger particles, although rates are likely different. The initial step, however, involving transcytosis across the alveolar epithelium into the pulmonary interstitium, seems to occur with larger particles only in high lung load situations when the phagocytic capacity of alveolar macrophages is overwhelmed and the particles are present in the alveoli as free particles for an extended period of time. Once the particles have reached pulmonary interstitial sites, uptake into the blood circulation in addition to lymphatic pathways can occur, a pathway that again is dependent on particle size, favoring ultrafine particles. Several recent studies in rodents and humans indicate that rapid translocation of inhaled UFP into the blood circulation occurs. Nemmar et al. (14) reported findings in humans that inhalation of ""Relabelled ultrafine carbon particles (Technegas®) resulted in the rapid appearance of the label in the blood circulation shortly after exposure and also in the liver. They suggested that this at least partly indicated translocation of inhaled UFP into the blood circulation. In contrast, other studies in humans with ""Relabeled carbon particles (33 nm) by Brown et al. (23) did not confirm such uptake into the liver, and the authors cautioned that the findings by Nemmar et al. (14) were likely due to soluble pertechnetate rather than labeled UFP. Our inhalation studies in rats have shown that ultrafine elemental C particles (CMD -30 nm) had accumulated to a large degree in the liver of rats by 24 , 3


48 hours after exposure, indicating efficient translocation into the blood circulation (54). Suggested pathways into the blood could be across the alveolar epithelium as well as across intestinal epithelium from particles swallowed into the GI tract. On the other hand, using a method of intratracheal inhalation of ultrafine Ir particles in rats, Kreyling et al. (37) found only minimal translocation (

Effects and Fate of Inhaled Ultrafine Particles - ACS Publications

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