doi: 10.1161/hc0402.104118
(Circulation. 2002;105:411.)
© 2002 American Heart Association, Inc.
Brief Rapid Communications |
Passage of Inhaled Particles Into the Blood Circulation in Humans
From the Laboratory of Pneumology (Lung Toxicology) (A.N., P.H.M.H., M.T., B.N.), Nuclear Medicine (B.V., H.V., L.M.), and Center for Molecular and Vascular Biology (M.F.H.), Katholieke Universiteit Leuven, Leuven, Belgium; and the MRC Toxicology Unit (D.D.), Leicester, UK.
Correspondence to Prof B. Nemery, K.U.Leuven, Laboratorium voor Pneumologie (Longtoxicologie), Herestraat 49, B-3000 Leuven, Belgium. E-mail ben.nemery{at}med.kuleuven.ac.be
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Abstract |
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Background— Pollution by particulates has been consistently associated with increased cardiovascular morbidity and mortality. However, the mechanisms responsible for these effects are not well-elucidated.
Methods and Results— To assess to what extent and how rapidly inhaled pollutant particles pass into the systemic circulation, we measured, in 5 healthy volunteers, the distribution of radioactivity after the inhalation of "Technegas," an aerosol consisting mainly of ultrafine 99mTechnetium-labeled carbon particles (<100 nm). Radioactivity was detected in blood already at 1 minute, reached a maximum between 10 and 20 minutes, and remained at this level up to 60 minutes. Thin layer chromatography of blood showed that in addition to a species corresponding to oxidized 99mTc, ie, pertechnetate, there was also a species corresponding to particle-bound 99mTc. Gamma camera images showed substantial radioactivity over the liver and other areas of the body.
Conclusions— We conclude that inhaled 99mTc-labeled ultrafine carbon particles pass rapidly into the systemic circulation, and this process could account for the well-established, but poorly understood, extrapulmonary effects of air pollution.
Key Words: air pollution • particles • translocation • blood • lung
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Introduction |
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Epidemiological studies have shown that peaks of air pollution by particulate matter with a diameter of <10 µm (PM10) are associated with increased morbidity and mortality, not only from respiratory causes but mainly from cardiovascular diseases.1–5 Recently, it has been shown that exposure to particulate air pollution for as little as 2 hours increased the occurrence of myocardial.6 The mechanisms responsible for the cardiovascular effects are not well-elucidated.7 The main current hypothesis is that the particles produce pulmonary inflammation with a systemic release of cytokines, which may influence cardiovascular endpoints.8 It has also been proposed that pollutants may cause (reflex) alterations in cardiac autonomic function thus causing changes in heart rate variability and increasing the risk of sudden cardiac death.9
An alternative hypothesis, which has not been much investigated so far, is that the smallest particles translocate from the lungs into the circulation and thus influence cardiovascular endpoints more directly. Ultrafine particles, ie, particles with diameter 
0.1 µm, represent a substantial component, in terms of particle numbers, in PM10, although they represent a relatively small fraction of the total mass.10 Ultrafine particles have also a much larger surface area, and hence, more toxic potential.11,12 Recently, we have shown, in hamster, that a substantial fraction of intratracheally instilled ultrafine particles (radiolabeled denatured albumin with diameter <100 nm) rapidly diffuses from the lungs into the systemic circulation.13 Others have recently described a systemic distribution of inhaled ultrafine silver particles in rats.14
Therefore, we wanted to verify whether this also occurs in humans inhaling ultrafine particles. No human data are available on this issue. We utilized a technique, commonly used in diagnostic nuclear medicine for measuring the distribution of ventilation,15 based on the inhalation of an aerosol of technetium-99m labeled carbon particles (Technegas).
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Methods |
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This study has been approved by our institution’s ethical committee for experimentation in human subjects.
Technegas consists on an aerosol suspension of 99mTc-labeled, ultrafine carbon particles produced in an atmosphere of high-purity argon. It was considered that 100% of the inhaled particles in Technegas were labeled with 99mTc and that the aerosol did not contain pertechnetate (TcO4-).16 The size of the individualized particles was of the order of 5 to 10 nm, as we confirmed by electron microscopy of particles collected with a thermophoretic precipitator. However, particle aggregates were also seen. Inhalation of these particles enabled static and dynamic images in multiple projections to be acquired.17
We studied 5 healthy, male nonsmoking volunteers (24 to 47 years, mean age 32.8 years). They inhaled, according to a standard procedure,18 approximately 100 MBq of Technegas in 3 to 5 breaths via a mouthpiece. Immediately after the Technegas inhalation, body images were acquired as follows: static acquisition (1 to 3 minutes) of lungs and thyroid followed by dynamic acquisition (5 to 45 minutes) of the abdomen, including liver, stomach, and bladder, and then successive images of the whole body (50 to 60 minutes). Blood samples were collected (via a venous catheter) at 1, 5, 10, 20, 30, 45, and 60 minutes after Technegas inhalation, and their radioactivity was measured in a gamma counter. At each time point, thin layer chromatography (TLC) was done on a droplet of blood using silica impregnated glass fiber ITLC-SG strips (Gelman Sciences) with NaCl 0.9% as the mobile phase. The chromatograms were cut into 1-cm lengths and their radioactivity measured with a gamma counter (1480W12ARD, Wallac) with a correction for background radiation. TLC was also done on a urine sample at 60 minutes.
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Results |
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Figure 1a illustrates the time course of the radioactivity in blood expressed as counts per minute (CPM) per gram of blood. The radioactivity was detected in blood already after 1 minute, reached a maximum between 10 and 20 minutes, and remained at this level up to 60 minutes. At all time points, TLC of blood (Figure 1b) showed a peak of radioactivity at the application point and another peak that moved with the solvent front. In urine, there was mainly the latter peak. For comparison, we also present the results of TLC after the direct addition of Technegas particles (collected on a filter, at the mouth) or 99mTc-pertechnetate (TcO4-) to blood, showing that the bound radioactivity stays at the origin while the free pertechnetate moves with the solvent front. We also show a TLC of blood at 1 and 60 minutes after the instillation of 200 µL of free 99mTc-pertechnetate (3.7 MBq) in hamsters (n=3), showing a single peak of radioactivity at the solvent front.
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The radioactivity recorded over the liver and bladder was expressed as a percentage of the initial lung radioactivity. In liver, the radioactivity remained stable at around 8%, while in the bladder it increased with time (Figure 2).
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Discussion |
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This study was designed to investigate a plausible mechanistic explanation for the consistent but puzzling epidemiological observations that particulate air pollution is associated with cardiovascular effects.3–6 Our working hypothesis, which is different but not opposed to more traditional ones,8,9 is that ultrafine particles may pass into the circulation and thus exert direct effects on the heart and vessels.
The type of aerosol used in our study is probably relevant urban air pollutant aerosols. Particles with diameters ranging from 0.02 µm to more than 100 µm are measurable in the air of cities.11,19 Ultrafine particles (smaller than 100 nm) are often emitted from combustion and other high-temperature processes in the form of fractal-like aggregates composed of solid nanoparticles. The primary particle size of atmospheric aggregates ranges from 6 to 100 nm. This broad polydispersity has been related to the fact that atmospheric aggregates come from a variety of sources with different primary particle sizes.20 In addition, Shi et al21 found that the primary particles in diesel aggregates range from 10 to 40 nm. The size of the individualized particles used in our study (5 to 10 nm), as well as the aggregates that were also seen by electron microscopy is therefore relevant to atmospheric ultrafine particles.
Technegas is different from Pertechnegas, which is also used in nuclear medicine (for measuring lung permeability).22 Pertechnegas is produced in an atmosphere of argon and oxygen, thus allowing the technetium to become oxidized to the hydrosoluble pertechnetate (TcO4-), the kinetics of which have been studied.23 In contrast, Technegas is generated in a pure argon atmosphere, and therefore, the aerosol only consists of 99mTc-labeled particles without any appreciable TcO4-. We verified this to be the case by TLC of the material collected on a filter at the mouth. However, after deposition of 99mTc-labeled particles in the body, some TcO4- is produced. Thus, a species behaving as TcO4- was found by TLC in blood and in urine (Figure 1b), as well as in saliva (not shown), and the intense radioactivity detected over the thyroid, salivary glands, and stomach (Figure 2) is essentially due to the well-known accumulation of TcO4- in these organs.24 In the stomach, besides TcO4- from saliva and gastric secretion, some radioactivity also came from swallowed particles that had deposited in the mouth or been cleared from the trachea via the mucociliary escalator.
However, 3 lines of evidence indicate that the radioactivity that we measured in blood consists, at least partly, of particle-bound radioactivity, ie, radioactivity associated with carbon particles having passed the air-blood barrier, rather than free radioactivity. Firstly, TLC of all blood samples showed, in addition to radioactivity having moved with the solvent front and corresponding to oxidized 99mTc, ie, pertechnetate (TcO4-), a substantial proportion of radioactivity that stayed at the application point and corresponded to particle-bound 99mTc. Such a profile was similar to that obtained after spiking blood with 99mTc-carbon particles collected from the Technegas generator. In contrast, there was only one peak at the solvent front after adding 99mTc-pertechnetate to blood or in blood collected after the intratracheal administration of 99mTc-pertechnetate to hamsters. This excludes the possibility that the noneluting radioactivity was due to free technetium having become bound to plasma proteins. Secondly, the TLC of urine showed only one peak at the solvent front, and this is in agreement with an elimination of free 99mTc-pertechnetate via the urine.24 Finally, the presence of radioactivity in the liver is compatible with an accumulation of particles by Kupffer cells, as is known to occur with colloidal particles.25,26 Because of the rapidity of the accumulation of radioactivity in liver, we think it is unlikely that the liver radioactivity came from the stomach. Admittedly, the above reasoning only provides indirect arguments that radioactivity outside the lungs corresponded to particles, and we would have liked to have more direct evidence. However, we were unable to detect the carbon particles in ultrathin sections of blood by electron microscopy, most probably because of their low electron density. Nevertheless, despite this limitation, we are confident that our findings provide plausible evidence for particle translocation from the lung into the blood and then its distribution to the organs. This conclusion is supported by recent studies in animals.13,14 The exact mechanism for this translocation remains to be established, but its rapidity makes it unlikely that phagocytosis by macrophages and/or endocytosis by epithelial and endothelial cells are (solely) responsible for particle-translocation to the blood. There are experimental data suggesting the existence of (functional) pores in the alveolar-blood barrier,27 and this is supported by the fact that "pneumoproteins" may be found in the blood.28
We conclude that inhaled ultrafine 99mTc-carbon particles, which are very similar to (the ultrafine fraction of) actual pollutant particles, diffuse rapidly into the systemic circulation, and this should be considered relevant for the cardiovascular morbidity and mortality related to ambient particle pollution.
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Acknowledgments |
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This work was supported by the funds of K.U.Leuven (F/00/058). We are very grateful to K. Stessel (Nuclear Medicine, K.U.Leuven) for his excellent technical assistance.
Received November 14, 2001; revision received December 11, 2001; accepted December 19, 2001.
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P. Borm, F. C. Klaessig, T. D. Landry, B. Moudgil, J. Pauluhn, K. Thomas, R. Trottier, and S. Wood Research Strategies for Safety Evaluation of Nanomaterials, Part V: Role of Dissolution in Biological Fate and Effects of Nanoscale Particles Toxicol. Sci., March 1, 2006; 90(1): 23 - 32. [Abstract] [Full Text] [PDF]
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N. L. Mills, N. Amin, S. D. Robinson, A. Anand, J. Davies, D. Patel, J. M. de la Fuente, F. R. Cassee, N. A. Boon, W. MacNee, et al. Do Inhaled Carbon Nanoparticles Translocate Directly into the Circulation in Humans? Am. J. Respir. Crit. Care Med., February 15, 2006; 173(4): 426 - 431. [Abstract] [Full Text] [PDF]
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 A. Nel, T. Xia, L. Madler, and N. Li Toxic Potential of Materials at the Nanolevel Science, February 3, 2006; 311(5761): 622 - 627. [Abstract] [Full Text] [PDF]
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 H C Routledge, S Manney, R M Harrison, J G Ayres, and J N Townend Effect of inhaled sulphur dioxide and carbon particles on heart rate variability and markers of inflammation and coagulation in human subjects Heart, February 1, 2006; 92(2): 220 - 227. [Abstract] [Full Text] [PDF]
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J. S. Tsuji, A. D. Maynard, P. C. Howard, J. T. James, C.-w. Lam, D. B. Warheit, and A. B. Santamaria Research Strategies for Safety Evaluation of Nanomaterials, Part IV: Risk Assessment of Nanoparticles Toxicol. Sci., January 1, 2006; 89(1): 42 - 50. [Abstract] [Full Text] [PDF]
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F. Forastiere, M. Stafoggia, S. Picciotto, T. Bellander, D. D'Ippoliti, T. Lanki, S. von Klot, F. Nyberg, P. Paatero, A. Peters, et al. A Case-Crossover Analysis of Out-of-Hospital Coronary Deaths and Air Pollution in Rome, Italy Am. J. Respir. Crit. Care Med., December 15, 2005; 172(12): 1549 - 1555. [Abstract] [Full Text] [PDF]
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H. M. Kipen and D. L. Laskin Smaller is not always better: nanotechnology yields nanotoxicology Am J Physiol Lung Cell Mol Physiol, November 1, 2005; 289(5): L696 - L697. [Full Text] [PDF]
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R-S Koskela, P Mutanen, J-A Sorsa, and M Klockars Respiratory disease and cardiovascular morbidity Occup. Environ. Med., September 1, 2005; 62(9): 650 - 655. [Abstract] [Full Text] [PDF]
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D. H. R. F. Rivero, S. R. C. Soares, G. Lorenzi-Filho, M. Saiki, J. J. Godleski, L. Antonangelo, M. Dolhnikoff, and P. H. N. Saldiva Acute Cardiopulmonary Alterations Induced by Fine Particulate Matter of Sao Paulo, Brazil Toxicol. Sci., June 1, 2005; 85(2): 898 - 905. [Abstract] [Full Text] [PDF]
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W. S. Beckett, D. F. Chalupa, A. Pauly-Brown, D. M. Speers, J. C. Stewart, M. W. Frampton, M. J. Utell, L.-S. Huang, C. Cox, W. Zareba, et al. Comparing Inhaled Ultrafine versus Fine Zinc Oxide Particles in Healthy Adults: A Human Inhalation Study Am. J. Respir. Crit. Care Med., May 15, 2005; 171(10): 1129 - 1135. [Abstract] [Full Text] [PDF]
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A. Nemmar, B. Nemery, P. H. M. Hoet, N. Van Rooijen, and M. F. Hoylaerts Silica Particles Enhance Peripheral Thrombosis: Key Role of Lung Macrophage-Neutrophil Cross-Talk Am. J. Respir. Crit. Care Med., April 15, 2005; 171(8): 872 - 879. [Abstract] [Full Text] [PDF]
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P S Gilmour, E R Morrison, M A Vickers, I Ford, C A Ludlam, M Greaves, K Donaldson, and W MacNee The procoagulant potential of environmental particles (PM10) Occup. Environ. Med., March 1, 2005; 62(3): 164 - 171. [Abstract] [Full Text] [PDF]
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R. Maheswaran, R. P. Haining, P. Brindley, J. Law, T. Pearson, P. R. Fryers, S. Wise, and M. J. Campbell Outdoor Air Pollution and Stroke in Sheffield, United Kingdom: A Small-Area Level Geographical Study Stroke, February 1, 2005; 36(2): 239 - 243. [Abstract] [Full Text] [PDF]
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 T. MORENO, W. GIBBONS, T. JONES, and R. RICHARDS Geochemical and size variations in inhalable UK airborne particles: the limitations of mass measurements Journal of the Geological Society, December 1, 2004; 161(6): 899 - 902. [Abstract] [Full Text] [PDF]
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 J.E. Sharman, J.R. Cockcroft, and J.S. Coombes Cardiovascular implications of exposure to traffic air pollution during exercise QJM, October 1, 2004; 97(10): 637 - 643. [Abstract] [Full Text] [PDF]
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 A. Nemmar, P. H.M. Hoet, J. Vermylen, B. Nemery, and M. F. Hoylaerts Pharmacological Stabilization of Mast Cells Abrogates Late Thrombotic Events Induced by Diesel Exhaust Particles in Hamsters Circulation, September 21, 2004; 110(12): 1670 - 1677. [Abstract] [Full Text] [PDF]
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 N. Li, J. Alam, M. I. Venkatesan, A. Eiguren-Fernandez, D. Schmitz, E. Di Stefano, N. Slaughter, E. Killeen, X. Wang, A. Huang, et al. Nrf2 Is a Key Transcription Factor That Regulates Antioxidant Defense in Macrophages and Epithelial Cells: Protecting against the Proinflammatory and Oxidizing Effects of Diesel Exhaust Chemicals J. Immunol., September 1, 2004; 173(5): 3467 - 3481. [Abstract] [Full Text] [PDF]
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R. D. Brook, B. Franklin, W. Cascio, Y. Hong, G. Howard, M. Lipsett, R. Luepker, M. Mittleman, J. Samet, S. C. Smith Jr, et al. Air Pollution and Cardiovascular Disease: A Statement for Healthcare Professionals From the Expert Panel on Population and Prevention Science of the American Heart Association Circulation, June 1, 2004; 109(21): 2655 - 2671. [Abstract] [Full Text] [PDF]
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 D. Liao, Y. Duan, E. A. Whitsel, Z.-j. Zheng, G. Heiss, V. M. Chinchilli, and H.-M. Lin Association of Higher Levels of Ambient Criteria Pollutants with Impaired Cardiac Autonomic Control: A Population-based Study Am. J. Epidemiol., April 15, 2004; 159(8): 768 - 777. [Abstract] [Full Text] [PDF]
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A. Khandoga, A. Stampfl, S. Takenaka, H. Schulz, R. Radykewicz, W. Kreyling, and F. Krombach Ultrafine Particles Exert Prothrombotic but Not Inflammatory Effects on the Hepatic Microcirculation in Healthy Mice In Vivo Circulation, March 16, 2004; 109(10): 1320 - 1325. [Abstract] [Full Text] [PDF]
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A. Bhatnagar Cardiovascular pathophysiology of environmental pollutants Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H479 - H485. [Full Text] [PDF]
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R. L. Johnson Jr Relative Effects of Air Pollution on Lungs and Heart Circulation, January 6, 2004; 109(1): 5 - 7. [Full Text] [PDF]
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H C Routledge, J G Ayres, and J N Townend Why cardiologists should be interested in air pollution Heart, December 1, 2003; 89(12): 1383 - 1388. [Abstract] [Full Text] [PDF]
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A. Nemmar, B. Nemery, P. H. M. Hoet, J. Vermylen, and M. F. Hoylaerts Pulmonary Inflammation and Thrombogenicity Caused by Diesel Particles in Hamsters: Role of Histamine Am. J. Respir. Crit. Care Med., December 1, 2003; 168(11): 1366 - 1372. [Abstract] [Full Text] [PDF]
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L. Calderon-Garciduenas, R. R. Maronpot, R. Torres-Jardon, C. Henriquez-Roldan, R. Schoonhoven, H. Acuna-Ayala, A. Villarreal-Calderon, J. Nakamura, R. Fernando, W. Reed, et al. DNA Damage in Nasal and Brain Tissues of Canines Exposed to Air Pollutants Is Associated with Evidence of Chronic Brain Inflammation and Neurodegeneration Toxicol Pathol, August 1, 2003; 31(5): 524 - 538. [Abstract] [PDF]
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A. Nemmar, P. H.M. Hoet, D. Dinsdale, J. Vermylen, M. F. Hoylaerts, and B. Nemery Diesel Exhaust Particles in Lung Acutely Enhance Experimental Peripheral Thrombosis Circulation, March 4, 2003; 107(8): 1202 - 1208. [Abstract] [Full Text] [PDF]
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 B.E. Lee, E.H. Ha, H.S. Park, Y.J. Kim, Y.C. Hong, H. Kim, and J.T. Lee Exposure to air pollution during different gestational phases contributes to risks of low birth weight Hum. Reprod., March 1, 2003; 18(3): 638 - 643. [Abstract] [Full Text] [PDF]
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W. M. Burch, A. Nemmar, P.H.M. Hoet, M. Thomeer, B. Nemery, B. Vanquickenborne, H. Vanbilloen, L. Mortelmans, M.F. Hoylaerts, A. Verbruggen, et al. Passage of Inhaled Particles Into the Blood Circulation in Humans * Response Circulation, November 12, 2002; 106 (20): e141 - e142. [Full Text] [PDF]
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J. S. Brown, K. L. Zeman, and W. D. Bennett Ultrafine Particle Deposition and Clearance in the Healthy and Obstructed Lung Am. J. Respir. Crit. Care Med., November 1, 2002; 166(9): 1240 - 1247. [Abstract] [Full Text] [PDF]
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A. Nemmar, M. F. Hoylaerts, P. H. M. Hoet, D. Dinsdale, T. Smith, H. Xu, J. Vermylen, and B. Nemery Ultrafine Particles Affect Experimental Thrombosis in an In Vivo Hamster Model Am. J. Respir. Crit. Care Med., October 1, 2002; 166(7): 998 - 1004. [Abstract] [Full Text]
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R. L. Verrier, M. A. Mittleman, and P. H. Stone Air Pollution: An Insidious and Pervasive Component of Cardiac Risk Circulation, August 20, 2002; 106(8): 890 - 892. [Full Text] [PDF]
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W. D. Bennett, A. Nemmar, H. Vanbilloen, M. F. Hoylaerts, P. H. M. Hoet, A. Verbruggen, and B. Nemery Rapid translocation of nanoparticles from the lung to the bloodstream? Am. J. Respir. Crit. Care Med., June 15, 2002; 165(12): 1671 - 1672. [Full Text] [PDF]
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