New Approaches to Evaluating the Pulmonary Effects of Controlled Inhalation Exposures in Human Volunteers

  • P. A. Bromberg
Conference paper
Part of the ILSI Monographs book series (ILSI MONOGRAPHS)


The respiratory tract serves as a passive portal of entry for various inhaled gases (e.g., CO) and vapors (e.g., benzene, toluene, methanol) as well as a target organ for the toxicologic effects of certain reactive gases (e.g., O3) and inhaled particulate matter. I will limit my remarks to the latter class of air pollutants and discuss only effects on the respiratory system. Nevertheless, we should bear in mind the possibility that systemic as well as localized respiratory tract effects may be attributable to inhaled toxicants. My remarks will deal with some issues in experimental protocol development, with newer experimental techniques suitable for use in human subjects, and with the promise and pitfalls of in vitro toxicologic study of human cells. Most of my illustrations will come from ozone toxicology with which I have the greatest familiarity, but which I hope will be generalizable.


Chronic Obstructive Pulmonary Disease Respiratory Syncytial Virus Human Bronchial Epithelial Cell Ozone Exposure Strontium Phosphate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Avol EL, Linn WS, Shamoo DA, Valencia LM, Anzar UT, Hackney JD (1985) Respiratory effects of photochemical oxidant air pollution in exercising adolescents. Am Rev Respir Dis 132:619–622PubMedGoogle Scholar
  2. Avol EL, Linn WS, Shamoo DA, Valencia LM, Venet TG, Trim SC, Hackney JD (1987) Short-term respiratory effects of photochemical oxidant exposure in exercising children. J Air Pollut Control Assoc 37:158–162Google Scholar
  3. Bartels M (1972) Collateral Ventilation beim Menschen. Thesis, Tübingen UniversityGoogle Scholar
  4. Bascom R, Naclerio RM, Fitzgerald TK, Kagey-Sobotka A, Proud D (1990) Effect of ozone inhalation on the response to nasal challenge with antigen of allergic subjects. Am Rev Respir Dis 142:594–601PubMedCrossRefGoogle Scholar
  5. Becker S, Soukup J, Yankaskas JR (1991a) Respiratory syncytial virus infection of human primary nasal and bronchial epithelial cell cultures and bronchoalveolar macrophages. Am J Respir Cell Mol Biol (in press)Google Scholar
  6. Becker S, Madden M, Newman SL, Devlin RB, Koren HS (1991b) Modulation of human alveolar macrophage properties by ozone exposure in vitro. Toxicol Appl Pharmacol (in press)Google Scholar
  7. Ben-Jebria A, Ultman JS (1989) Fast-responding chemiluminescent ozone analyzer for respiratory applications. Rev Sci Instrum 60:3004–3011CrossRefGoogle Scholar
  8. Ben-Jebria A, Hu S-C, Ultman JS (1990) Improvements in a chemiluminescent analyzer for respiratory applications. Rev Sci Instrum 61:3435–3439CrossRefGoogle Scholar
  9. Bromberg PA, Ranga V, Stutts MJ (1991) Effects of ozone on airways epithelial permeability and ion transport. Research report 48, Health Effects Institute, Cambridge, MA, pp 1–21Google Scholar
  10. DeFries JC, Fulker DW (1985) Multiple regression analysis of twin data. Behav Genet 15:467–473PubMedCrossRefGoogle Scholar
  11. Devlin RB, Koren HS (1990) The use of two-dimensional gel electrophoresis to analyze changes in alveolar macrophage proteins in humans exposed to ozone. Am J Respir Cell Mol Biol 2:281–288PubMedGoogle Scholar
  12. Devlin RB, McDonnell WF, Mann R, Becker S, House DE, Schreinemachers D, Koren HS (1991a) Exposure of humans to ambient levels of ozone for 6.6 hours causes cellular and biochemical changes in the lung. Am J Respir Cell Mol Biol 4:72–81PubMedGoogle Scholar
  13. Devlin, RB, Noah T, McKinnon KP, Koren HS (1991b) The use of a cell line as a model system to study the interaction of environmental toxicants with human airway epithelial cells. Toxicologist 11:851Google Scholar
  14. Drechsler-Parks DM, Bedi JF, Horvath SM (1987) Pulmonary function response of older men and women to ozone exposure. Exp Gerontol 22:91–101PubMedCrossRefGoogle Scholar
  15. Gerrity TR, Weaver RA, Berntsen J, House DE, O’Neil JJ (1988) Extrathoracic and intrathoracic removal of ozone in tidal-breathing humans. J Appl Physiol 65:393–400PubMedGoogle Scholar
  16. Gerrity TR, Bennett WD, Keefe M, DeWitt P, Chapman W (1991) The response of tracheobronchial clearance of inhaled particles to acute ozone exposure in healthy humans. Am Rev Respir Dis 143:A91Google Scholar
  17. Gliner JA, Horvath SM, Folinsbee LJ (1983) Pre-exposure to low ozone concentrations does not diminish the pulmonary function response on exposure to higher ozone concentration. Am Rev Respir Dis 127:51–55PubMedGoogle Scholar
  18. Hazucha MJ, Bates DV, Bromberg PA (1989) Mechanism of action of ozone on the human lung. J Appl Physiol 67:1535–1541PubMedGoogle Scholar
  19. Hazucha MJ, Pape G, Madden M, Koren H, Kehrl H, Bromberg P (1991) Effects of cyclooxygenase inhibition on ozone-induced respiratory inflammation and lung function changes. Am Rev Respir Dis 143:A701Google Scholar
  20. Heyder J, Blanchard JD, Feldman HA, Brain JD (1988) Convective mixing in human respiratory tract: estimates with aerosol boli. J Appl Physiol 64:1273–1278Google Scholar
  21. Higgins ITT, D’Arcy JB, Gibbons DI, Avol EL, Gross KB (1990) Effect of exposures to ambient ozone on ventilatory lung function in children. Am Rev Respir Dis 141:1136–1146PubMedGoogle Scholar
  22. Horstman D, Roger LJ, Kehrl H, Hazucha MJ (1986) Airway sensitivity of asthmatics to sulfur dioxide. Toxicol Ind Health 2:289–298PubMedGoogle Scholar
  23. Horstman DH, Folinsbee LJ, Ives PJ, Abdul-Salaam S, McDonnell WF (1990) Ozone concentration and pulmonary response relationships for 6.6-hour exposures with five hours of moderate exercise. Am Rev Respir Dis 142:1158–1163PubMedGoogle Scholar
  24. Hu S-C, Ben-Jebria A, Ultman JS (1992) Longitudinal distribution of ozone absorption in the lung: quiet respiration in healthy subjects. J Appl Physiol 73:1655–1661PubMedGoogle Scholar
  25. Ke Y, Reddel RR, Gerwin BI, Miyashita M, McMenamin M, Lechner JF, Harris CC (1988) Human bronchial epithelial cells with integrated SV40 virus T antigen genes retain the ability to undergo squamous differentiation. Differentiation 38:60–66PubMedCrossRefGoogle Scholar
  26. Keefe MJ, Bennett WD, DeWitt P, Seal E, Strong AA, Gerrity TR (1991) The effect of ozone exposure on the dispersion of inhaled aerosol boluses in healthy human subjeçts. Am Rev Respir Dis 144:23–30PubMedCrossRefGoogle Scholar
  27. Kehrl HR, Hazucha MJ, Solic JJ, Bromberg PA (1985) Responses of subjects with chronic obstructive pulmonary disease after exposure to 0.3 ppm ozone. Am Rev Respir Dis 131:719–724PubMedGoogle Scholar
  28. Kehrl HR, Vincent LM, Kowalsky RJ, Horstman DH, O’Neil JJ, McCartney WH, Bromberg PA (1987) Ozone exposure increases respiratory epithelial permeability in man. Am Rev Respir Dis 135:1124–1128PubMedGoogle Scholar
  29. Koenig JQ, Covert DS, Smith MS, Van Belle G, Pierson WE (1988) The pulmonary effects of 03 and NO2 alone and combined in healthy and asthmatic adolescent subjects. Toxicol Ind Health 4:521–532PubMedGoogle Scholar
  30. Koren HS, Devlin RB, Graham DE, Mann R, McGee MP, Horstman DH, Kozumbo WJ, Becker S, House DE, McDonnell WF, Bromberg PA (1989) Ozone-induced inflammation in the lower airways of human subjects. Am Rev Respir Dis 139:407–415PubMedCrossRefGoogle Scholar
  31. Koren HS, Devlin RB, Becker S, Perez R, McDonnell WF (1991) Time-dependent changes of markers associated with inflammation in the lungs of humans exposed to ozone. Toxicol Pathol 19:406–411PubMedGoogle Scholar
  32. McCawley M, Lippmann M (1988) Development of an aerosol dispersion test to detect early changes in lung function. Am Ind Hyg Assoc J 49:357–366PubMedCrossRefGoogle Scholar
  33. McDonnell WF, Horstman DH, Hazucha MJ, Seal E Jr, Haak ED, Salaam SA, House DE (1983) Pulmonary effects of ozone exposure during exercise: dose- response characteristics. J Appl Physiol 54:1345–1352PubMedGoogle Scholar
  34. McDonnell WF, Horstman DH, Salaam SA, House DE (1985a) Reproducibility of individual responses to ozone exposure. Am Rev Respir Dis 131:36–40PubMedGoogle Scholar
  35. McDonnell WF, Chapman RS, Leigh MW, Strope GL, Collier AM (1985b) Respiratory response of vigorously exercising children to 0.12 ppm ozone exposure. Am Rev Respir Dis 132:875–879PubMedGoogle Scholar
  36. McDonnell WF, Kehrl HR, Abdul-Salaam S, Ives PJ, Folinsbee LJ, Devlin RB, O’Neil JJ, Horstman DH (1991) Respiratory responses of humans exposed to low levels of ozone for 6.6 hours. Arch Environ Health 46:145–150PubMedCrossRefGoogle Scholar
  37. McDonnell WF, Muller KE, Bromberg PA, Shy CM (1993) Predictors of individual differences in acute response to ozone exposure. Am Rev Respir Dis 147: xxx-xxx (in press)Google Scholar
  38. Menkes HA, Traystman RJ (1977) Collateral ventilation. Am Rev Respir Dis 116:287–309PubMedGoogle Scholar
  39. Molfino NA, Wright SC, Katz I, Tarlo S, Silverman F, McClean PA, Szalai JP, Raizenne M, Slutsky AS, Zamel N (1991) Effect of low concentrations of ozone on inhaled allergen responses in asthmatic subjects. Lancet 338:199–203PubMedCrossRefGoogle Scholar
  40. Pryor WA, Das B, Church DF (1991) The ozonation of unsaturated fatty acids: aldehydes and hydrogen peroxide as products and possible mediators of ozone toxicity. Chem Res Toxicol 4:341–348PubMedCrossRefGoogle Scholar
  41. Reddel RR, Ke Y, Gerwin BI, McMenamin MG, Lechner JF, Su RT, Brash DE, Park J-B, Rhim JS, Harris CC (1988) Transformation of human bronchial epithelial cells by infection with SV40 or adenovirus-12 SV40 hybrid virus, or transfection via strontium phosphate coprecipitation with a plasmid containing SV40 early region genes. Cancer Res 48:1904–1909PubMedGoogle Scholar
  42. Rennard SI, Basset G, Lecossier D, O’Donnell K, Martin P, Crystal RG (1986) Estimation of volume of epithelial lining fluid recovered by lavage using urea as a marker of dilution. J Appl Physiol 60:532–538PubMedGoogle Scholar
  43. Rennard SI, Ghafouri M, Thompson AB, Linder J, Vaughan W, Jones K, Ertl RF, Christensen K, Prince A, Stahl MG, Robbins RA (1990) Fractional processing of sequential bronchoalveolar lavage to separate bronchial and alveolar samples. Am Rev Respir Dis 141:208–217PubMedGoogle Scholar
  44. Rombout P, Lioy PJ, Goldstein BD (1986) Rationale for an eight-hour ozone standard. J Air Pollut Control Assoc 36:913–917Google Scholar
  45. Samet JM, Noah T, McKinnon K, Devlin RB, Friedman M (1991) Effect of ozone on platelet activating factor (PAF) synthesis in human bronchial epithelial cells. FASEB J 5:A484Google Scholar
  46. Schelegle ES, Adams WC, Siefkin AD (1987) Indomethacin pretreatment reduces ozone-induced pulmonary function decrements in human subjects. Am Rev Respir Dis 136:1350–1354PubMedCrossRefGoogle Scholar
  47. Schelegle ES, Siefkin AD, McDonald RJ (1991) Time course of ozone-induced neutrophilia in normal humans. Am Rev Respir Dis 143:1353–1358PubMedGoogle Scholar
  48. Seltzer J, Bigby BG, Stulbarg M, Holtzman MJ, Nadel JA, Ueki IF, Leikauf GD, Goetzl EJ, Boushey HA (1986) Ozone-induced change in bronchial reactivity to methacholine and airway inflammation in humans. J Appl Physiol 60:1321–1326PubMedGoogle Scholar
  49. Spektor DM, Lippmann M, Lioy PJ, Thurston GD, Citak K, James DJ, Bock N, Speizer FE, Hayes C (1988) Effects of ambient ozone on respiratory function in active, normal children. Am Rev Respir Dis 137:313–320PubMedGoogle Scholar
  50. Webster PM, Lorimer EG, Paul SF, Woolf CR, Zamel N (1979) Pulmonary function in identical twins: comparison of non-smokers and smokers. Am Rev Respir Dis 119:223–228PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • P. A. Bromberg
    • 1
  1. 1.Center for Environmental Medicine and Lung BiologyUniversity of North CarolinaChapel HillUSA

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