Inhaled Particle Dosimetry: Session Commentary

The Third Colloquium on Particulate Matter and Human Health addressed the roles that inhaled particle dosimetry plays in understanding the potential health risks of human populations exposed to particulate air pollution. Nineteen papers, including posters, were presented that addressed particle deposition and clearance in both humans and laboratory animals. The effects of age, gender, and illness were addressed, as well as ultra fine particles and correlations between particle deposits and tissue pathology. The papers and related discussions also illuminated some important gaps in knowledge, such as the accuracy of dosimetry predictions for individuals; the underrepresentation of susceptible populations; the movement of deposited particles to nonlung tissues and organs; and the accuracy of extrapolations across species. Although current dosimetric information is useful for understanding the effects of particulate air pollution, several unsolved problems remain.

It is we ll und erstood in toxicol ogy that "the dose makes the poison" (Paracelsus, 16th century), and inh aled particles are no excep tio n. The session question addressed by 16 posters, 3 platform papers, and a general discussion at the Third Colloquium on Parti cul ate M atter (PM) and Human Health (Durham, NC, June 6-8, 1999) was: Wh at improvements in dosimetry and extrapol ation mod elin g wi ll prov ide for better evaluation of hum an health effec ts and risk assessmen t? Plenary speaker Joachim Heyder emp hasized the power of aerosol dosimetry w hen applied to indi vidu als, as oppose d to gro ups. Heyder obse rved that in aerosol inhalation studies w ith dogs, those animals that responded were those w ith the greatest doses. Heyder reco mme nded a focus o n " individual dosimetry," beca use indi vidu al respo nses are most often the crux of toxico log ical pro blems. Plenary speaker Frederick Mill er chose to focus o n thr ee fund amental uncertainti es relatin g to PM dosimetry. First, the parti cle property (or prope rties) most closely tied to po tential adverse health o utco mes has (have) not been identi fied: Candid ates include particle number, surface area, volume and mass. Second, region al doses within the respiratory tract are still poorl y und erstood. Third, the important adverse effec ts o f inhaled parti cles have not been well elucidated. From the ob servation s of these speakers it is clear that dosimetry has much to offe r, and that it faces substantial challenges in relation to the question 'addressed by the sessio n.

R. F. PHALEN
Aside from the major advances over the past 50 years in und erstanding the phenom ena of inhaled parti cle depo sition and clearance, some recent achieveme nts were presented at the co llo quium. (Autho rs of papers are given in parentheses.) Three papers add ressed airways disease. Tw o mod elin g papers indi cated that airflow-obstructe d lun gs can be expec ted to have increased parti cle deposition as we ll as increased heterogeneit y of deposits w ithin the respirator y tract (T. B. M arton en, R. A. Segal, and C. S. Kim; and L S. Brown , D. Crawford-Brown, and W. D. Bennett ). Experim ent s w ith inh aled radiolabeled S-um mass median aerodynamic diameter particl es in patient s with obstructiv e airways disease indi cated that in co mparison to healthy co ntrols, the patient s, in fact, exhibited increased deposition, and that po orl y ventilated region s had Ultrafin e (U F, diameter 0.1 IJm and less) parti cles w ere studied in inh alation expe riments with both rats and hum ans. In rats, inh aled ult rafine radio acti ve Ag parti cles indi cated that silver was dissolved in blood , but that focal accumulatio ns (of grains in autoradiog rams) w ere seen in lun g and liver (G. L. In hum an studies, U F part icles o f 0.0 4 IJm di ameter had greater depositio n efficiencies in females (n = 11) than in males (n = 11), but larger UF parti cles (0.08 and 0.10 IJm diameter) had similar gender-related depo sition; U F parti cles of 0.06 IJm di ameter had marginally greater deposition in females (P. A. Jaques and C. S. Kim). Do ses per unit airway surface area was greatest in large airways for UF (and fine and coarse) parti cles in bo th men and wo me n; women tended to have greater depos itio n efficie ncies of UF (and coa rse) par-ticles than did men (c. S. Kim, S. C. Hu, P. laques, j. Di ng, and P. DeWitt; S. C. Hu and C. S. Kim).
Body size wi ll affect bo th airway size and specif ic ventilatio n (volume of air breathed per unit of body mass); thu s, age-related effects on particle do simetry can be expecte d. Studies of 2-J.lm-diameter particle depo sition in subjec ts aged 7 to 35 yr found that children had a higher rate of particle deposition norm alized to lung surface area than did adults and adolescents. The investigators attr ibuted the difference to increased specif ic ventilation in relation to lung size, instead of differences in age or bo dy height (W. D. Bennett and K. L. Zeman). In a modelin g study co mparing the depo sition of t-urn aerodynamic diameter particl es in a 22-mo old versus an adult, the infant had a predicted 38% relative increase in deposition (c. l-Mu sante and T. B.

M arton en).
A mul tipl e-path (airway) particl e depo sition mod el for rats and hum ans was used to indi cate significant differences in particle deposition among the lob es for both species; the mod el also indi cated that UF particl e deposition was high, but co nfined to relatively few acini (R. Subramaniam, J. I. Freijer, B. Asgharian, F. J. Miller, F. R. Cassee, L. van Bree, and P. J. A. Rombout). The co mp utatio nal mod el was used succe ssfully in predictin g the deposition of inhaled cadmium chlor ide particles of various sizes in experimentally-exposed rats. The rats lungs were also evaluated toxicolo gically, and prelimin ary results failed to show a particle size effec t on biochemical changes as determin ed by analysis of bronchoalveo lar lavage samples (F. R. Cassee, A. J. F. Boere, L. van Bree, P. H. B. Fok kens and J. I. Freijer). Clearance of insoluble radio active sulfur co lloi d particl es deposited directly into the bronchi (via bronchoscope and breathho ld) of anesthetized dogs (n = 5) was studied. Sublo bar segments differed in initial clearance rates of the particles, but clearance appeared to be complete in all of the studied region s by 24h (W. M . Foster, K. M acri, S. M cCulloch, T. M yers, and A. N. Freed). Finally, airflow patterns in a transparent repli ca of the hum an nasal cavity we re examined using a particle laser veloci metry techniqu e: The co mplex geometry produced very complex flow patterns havin g region s of flow separatio n, reverse flows, and stagnation (J. T. Kelly, L. M. Hopkins, A. S. W exler, and A. K. Prasad).
The papers just described clearly do not rep resent all of the research activity in particle dosimetry, but they illu strate the types of studies that are bein g co nducted in response to the question s surrounding parti culate air pollution; th ese papers should be co nsidered to be only samples of current relevant research. On the oth er hand, each of the papers made on e or more useful co ntributions to the und erstandin g of inhaled particl e do simetry.

UNCERTAINTIES
The paper' s just describ ed, along w ith similar research in the literature, no t only represent recent advances in und erstandin g th e dosimet ry of inhaled particles, but they also show that gaps in knowledge tend to overw helm wh at is known. A co mplete analysis of do simetry-related unc ertainties is not feasible, so a sampling will have to suffice. For the purposes of und erstandin g parti cul ate air pollution, uncert ainti es exist with respect to the following issues: • Particl e deposition and clearance requires mu ch mor e study in diseased/ abnormal humans and laborator y animals. The di seases and condition s of int erest are numerou s and include asthma, upper and lower respirator y tract infections, sleep apnea, em physema, fibro sis, respirator y tract cance r, ede ma, and con genit al abnormalities of the airw ays. The currently usedlaboratory animal models of di seased humans repr esent a special challenge for do simetry as such models are not only varied, but th ey are often produced by unu sual and extreme treatm ent s. Species differences in structure and fun ction further co mplicate co mparative do simetry co nside ratio ns. • Particl e clearance and translocation to sites beyond the airway surfaces requires more emphasis. Wh ere and why insolubl e particl es accumulate and how di seases/abnormaliti es influence thos e pro cesses is a large area for investigation. Thi s is an especia lly crucial topic for ultrafin e particles, as they may have significant access to sube pithelial tissues in th e respiratory tract, and th ey may translocate int act to or gans such as th e heart, blood vasculatur e, brain, kidn ey, and liver. Accumul ation of insolubl e particles in suc h lo cation s may have adverse co nsequences that are relevant to particulate air pollution. Conversely, knowled ge of whi ch accumul ations are beni gn is also important. • Althou gh some do sim etry information is available related to difference s in body size and gende r, thi s knowl ed ge is incompl ete, especially in relation to particl e clearance, acc um ulatio n, and potenti al transport to nonlung tissues. This issue is comp ounded by possible differences in the effects of di sease co nditions in the very youn g and the very old co mpared to typi cal adults. The extent to whi ch non anatomical gende r differenc es (such as hormonal and immunological) influ ence do simetr y is important for study. • Correlatin g particl e dosimetr y and toxicolo gic respon ses is an area that has ju st begun to be inv estigated. The relevant characteristics of particles, such as number, surface, volum e, and mass that produce adverse response s, is a part of this issue, as is the significance of prior exposures (which may produ ce tol erance or sensitizatio n). • Species differen ces in do simetry and their implications for und erstanding hum an risks require more study. Clearly, a large fraction of our knowledge of the effect s of parti cul ate air pollution mu st com e from laboratory animal studies. Both co nfident extrapolations and und erstandin g mechanisms of actio n require additional do simetry research. • How w ell dosimetry models work for individu als is largely unknown. There is a need to valid ate all aspec ts o f do simetry, including region al deposition and clearance ph enomena, for indi vidual peopl e and laboratory animals. Techniqu es for suc h studies are available, but they have yet to be ade quately explo ited.
• Realistic air pollution, which includes complex particles and particle/gas mixtures , requires study. The real world is more complex than what has been examined in dosimetry investigations. Real aerosols include particles that are hygroscopic, contain organic and inorganic components, and have properties that may significantly modify breathing patterns and airway structure. Real-world activities involve unusual breathing patterns as well as costressors (thermal and emotional, for example) that may alter the dosimetry and effects of inhaled particles.
As expected, the uncertainties related to dosimetry are substantial, and clearly not all can be investigated thoroughly. Therefore, judgment, careful planning, and increased interactions across relevant disciplines will all be essential if dosimetry research is to make important contributions in the near term . The time for such contributions is at hand, because there is currently an appreciation for the importance of dosimetry in providing for a better evaluation of the human health effects of particulate air pollution.