© 2002 American Thoracic Society
Rapid translocation of nanoparticles from the lung to the bloodstream?To the Editor :In their brief communication, Nemmar and colleagues (1) report rapid clearance of instilled albumin nanoparticles from the lungs to the bloodstream of hamsters (25–30% in 5 minutes), suggesting an explanation for observed cardiovascular effects of urban, airborne particulate matter reported in epidemiological studies (2). Although this hypothesis is attractive, the results of this particular study (1) are in conflict with decades of studies on respiratory clearance of aerosolized solutes (3–6). In particular, Peterson and colleagues (3) found that aerosolized Tc99m-aggregated albumin (mol wt = 383,000 daltons; approx mol size = 20 nm) similar to the tracer used by Nemmar and colleagues (1), delivered to the lungs of sheep cleared exponentially at a rate of 0.04% per minute over an 80-minute period (less than 5% lung clearance during that time). Even the rate constant for the smallest tracer (DTPA) used in their study (3) was only 0.4% per minute with less than 10% clearance in 30 minutes. These data are inconsistent with the observations of Nemmar and colleagues (1), i.e., a rapid rate of 5–6% per minute. Huchon and colleagues (4) also studied the clearance of a variety of aerosolized, radioactive solutes from the lungs of dogs. They found that solute clearance was inversely related to molecular weight, with negligible clearance of the largest molecular weight solute, labeled transferrin (mol wt = 76,000 daltons), over a 30-minute period of observation. At the other extreme, free pertechnetate (TcO4-) (mol wt = 163 daltons) had a clearance rate of 6% per minute. Clearance rates in humans (5, 6) for aerosolized solutes that are smaller in molecular size than that employed by Nemmar and colleagues (1) are also considerably slower than that seen during the first 5 minutes of observation in their study. The above cited studies are only a few of many that are incompatible with the study by Nemmar and colleagues. The reasons for these differences are not clear, but one clear difference in protocol is that particles were instilled in their study rather than inhaled. Nevertheless, it is important that the authors fully address the discrepancies between their results and previous findings and possible reasons for those differences. Careful study of inhaled particle dosimetry is needed to lead toxicologists towards a better understanding of the biological effects of exposure to ambient particulate matter (2).
University of North Carolina at Chapel Hill Chapel Hill, North Carolina REFERENCES
From the Authors: Dr. Bennett states that our data (1) are in conflict with decades of studies on respiratory clearance of aerosolized solutes. We would contend that those who attempted to evaluate pulmonary permeability in a noninvasive way by measuring the decrease of radioactivity over the chest after inhaling a radiolabeled tracer failed to measure radioactivity in blood soon after inhaling the tracer. Our question was "Do ultrafine pollutant particles have the potential to translocate from the lungs into the blood?" Using surrogate particles (namely 99mTc-labeled nanoparticles of denatured albumin) we showed this to be the case in hamsters (1), and we have since obtained similar evidence in humans using more relevant particles, namely 99mTc-labeled carbon particles (2). Aerosolised insulin also gives a rapid therapeutic effect (3). Whole body scans after the inhalation of 99mTc-labeled tracers readily show that substantial radioactivity rapidly appears outside the lungs. This is not solely due to free 99mTc (i.e., 99mTc in the form of pertechnetate) as shown by Peterson and colleagues (4) and ourselves (1, 2). A striking fact in the studies cited by Dr. Bennett is that radioactivity was rarely measured in blood. Peterson and colleagues (4) mention in their methods section that in control sheep, only 8% of plasma 99mTc was unbound 1 hour after the administration of 99mTc-albumin, but unfortunately, the total radioactivity in plasma is not reported. However, this observation does imply that there had been passage of the tracer into the blood, although admittedly this could have occurred through lymphatic drainage. We accept that intratracheal administration may have affected the quantity of particles that passed into the blood. However, the discrepancies between reported lung clearance rates and our estimated amount of particles that passed into the blood could be explained by the fact that to measure clearance, various assumptions must be made about the starting values of radioactivity. In other words, the method may well miss a brief first phase of rapid translocation. In fact, as Figure 3 of our article shows (1), if we had assessed the passage of label on the basis of the change in radioactivity in the lungs between 5 and 60 minutes, we would also have concluded that there was hardly any translocation. However, measurements in blood showed particle-bound radioactivity within minutes of pulmonary deposition. It remains to be established why the passage then seems to slow down. However, the fact appears incontrovertible that ultrafine particles may pass rapidly from the lungs into the blood circulation, not only in hamsters (1) but also in humans who inhaled an aerosol of particles (2). We believe that this is relevant to investigate, and perhaps even to explain, at least some of the extrapulmonary effects of exposure to pollutant particles (5).
Katholieke Universiteit Leuven Leuven, Belgium REFERENCES
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