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Dosimetry can change mechanistic models:

Dosimetry can change mechanistic models:. The challenge of scrutinizing the source before gathering and analyzing the data. Owen R. Moss, Ph.D. PGD 2 -N-methyl-2-picolinyl ester. Particulate Matter Health Effects. Dosimetry of pulmonary hypersensitivity Macrophage uptake of nanoparticles

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Dosimetry can change mechanistic models:

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  1. Dosimetry can change mechanistic models: The challenge of scrutinizing the source before gathering and analyzing the data Owen R. Moss, Ph.D. (RASS: Moss presentation.)

  2. PGD2-N-methyl-2-picolinyl ester Particulate Matter Health Effects • Dosimetry of pulmonary hypersensitivity • Macrophage uptake of nanoparticles • Biomarkers of long-term response (RASS: Moss presentation.)

  3. Nanoparticle Toxicology • Warheit (2005) • “Toxicity depends on surface characteristics, • particularly surface area and free radical generation by interaction of particles with cells” (RASS: Moss presentation.)

  4. When nanoparticles get in the way: Impact of projected area on in vivo and in vitro macrophage function. Moss, O. R. and Wong, V. A. (2006) Inhalation Toxicology (in review January 2006) (RASS: Moss presentation.)

  5. Frontiers in the “application” of nanoparticle dosimetry • Application in experimental design to determine mechanisms of action of inhaled nanoparticles. • Two examples: • In vivo example from the toxicology literature. • In vitro example from confocal microscopy. (RASS: Moss presentation.)

  6. Oberdorster et al. 1994 • Oberderster et al. (1994) Correlation between Particle Size, in Vivo Particle Persistence, and Lung Injury,Environmental Health Perspectives Vol. (102), Supplement 5, 1-11 • … “A correlation between particle surface area and [impairment of macrophage function] was observed.” • Was that chemical interaction or physical obstruction? • Was that particle surface area or particle projected surface? (RASS: Moss presentation.)

  7. . A story of 4 spheres • 12,400 nm diameter macrophage • 3,000 nm diameter PSL particles • 250 nm diameter TiO2 particles • 20 nm diameter TiO2 particles (RASS: Moss presentation.)

  8. 20 nm TiO2 1,600,000 . Coverage 250 nm TiO2 10,000 (RASS: Moss presentation.)

  9. Experimental Design (12 week TiO2 exposure; 29 week clearance) 20 nm diameter TiO2 particles* EXPOSURE** CLEARANCE EXPOSURE** CLEARANCE 1000 to 1 300 to 1 1E+6 to 1 4E+5 to 1 PSL t(1/2) PSL t(1/2) PSL t(1/2) PSL t(1/2) PSL t(1/2) PSL t(1/2) Oberdorster 1994 250 nm diameter TiO2 particles* * Mass deposition of 250 nm and 20 nm diameter particles the same. ** Target no-overload: Alveolar space TiO2 particle volume < 6% of macrophage volume. (RASS: Moss presentation.)

  10. 250 nm TiO2 20 nm TiO2 Macrophage toxicity and “surface area” (PSL clearance half-time for controls = 66 d) (RASS: Moss presentation.)

  11. 250 nm TiO2 20 nm TiO2 Impact of masking on macrophage mediated clearance. (PSL clearance half-time for controls = 66 d) (RASS: Moss presentation.)

  12. 250 nm TiO2 20 nm TiO2 Impact of masking on macrophage mediated clearance. (PSL clearance half-time for controls = 66 d) (RASS: Moss presentation.)

  13. In vitro tests • 2x1013 fluorescent 26 nm diameter PSL beads per ml • 0.2 ml injected • 300,000 cells • 1.3x107 fluorescent particles per cell • time-lapse photography on confocal scope • resolution: 300x increase in concentration. (RASS: Moss presentation.)

  14. Confocal images (RASS: Moss presentation.)

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  21. 240 seconds (RASS: Moss presentation.)

  22. 300 seconds (RASS: Moss presentation.)

  23. Number of Beads per Cell (RASS: Moss presentation.)

  24. 1 1 1 1 2 2 2 2 4 4 4 4 3 3 3 3 5 5 5 5 6 6 6 6 7 7 7 7 8 8 9 9 8 8 9 9 Cell 4 - Nanometer particle uptake 26 nm PSL Minutes - (RASS: Moss presentation.)

  25. Dose metrics • Impairment of macrophage function can be directly related to the potential for TiO2 particles to mask the surface of the macrophage. • Nanoparticle deposition modeling is needed in resolving chemical and physical impact on cell and organ function. (RASS: Moss presentation.)

  26. The Toxicology of Numbers • The Avalanche Scenario implies that • snowflakes are toxic because avalanches are lethal • The toxicology of nanoparticles includes: • the impact of individual nanoparticles • the impact of the composite (RASS: Moss presentation.)

  27. Dosimetry Counts:Molecular hypersensitivity may not drive pulmonary hyperresponsiveness Moss, O. R.(1) and Oldham, M. J.(2) (2006) J. Aerosol Med (in second review February 2006) (1) CIIT Centers for Health Research; (2) University of California, Irvine (RASS: Moss presentation.)

  28. Reanalysis of Previous Research • DeLorme, M.P. and O.R. Moss. 2002. Pulmonary function assessment by whole-body plethysmography in restrained versus unrestrained mice. J. Pharmacol. Toxicol. Meth. 47:1–10. • Oldham, M.J. and R.F. Phalen, 2002. Dosimetry implications of upper tracheobronchial airway anatomy in two mouse varieties. Anat. Rec. 268:59–65. • Oldham, M.J., R.F. Phalen, G.M. Schum, and D.S. Daniels. 1994. Predicted nasal and tracheobronchial particle deposition efficiencies for the mouse. Ann. Occup. Hyg. 38 (Supp. 1):135–141. (RASS: Moss presentation.)

  29. Airway response • Bronchoconstrictive agonist • Murine model Most Responsive Least Responsive AJ > BALB/c > CD-1 > B6C3F1 (RASS: Moss presentation.)

  30. Airway Response Measurement • Change in airway resistance • Based on pulmonary function values • Change in enhanced pause (Penh) reflects change in resistance • DeLorme and Moss (2002) J Pharm Tox. Methods 47:1-10. (RASS: Moss presentation.)

  31. Methacholine Solution (mg/ml) C1 C2 … Cn Airway Response Generator Chamber (RASS: Moss presentation.)

  32. Whole Body Plethysmograph (RASS: Moss presentation.)

  33. PEP END of breath START of breath Ti Te Tr time 36% of area PIP inhalation exhalation Enhanced Pause • Penh = ( Te/Tr – 1)( PEP/PIP ) (RASS: Moss presentation.)

  34. PC200R = 19.6 mg/ml PC200R (BALB/c) BALB/c (RASS: Moss presentation.)

  35. Methacholine for 200% increase in resistance 12x (RASS: Moss presentation.)

  36. Airway Diameters Oldham and Phalen, 2002, Anatomical Record 268:59-65 (RASS: Moss presentation.)

  37. Particle deposition at PC200R (RASS: Moss presentation.)

  38. Methacholine Solution Concentrations (mg/ml) 0 2.5 10 20 40 80 160 320 5 Different aerosols (RASS: Moss presentation.)

  39. Size Distribution at PC200R (RASS: Moss presentation.)

  40. P”D”200R 3.6x (RASS: Moss presentation.)

  41. 3.6x difference in hypersensitivity • Airway resistance from nasal tissue • response time • Close enough • possible but dosimetry seems incomplete • Molecular biology component • genomic component may be morphometry (RASS: Moss presentation.)

  42. Change in Circumference d0 dF DEP p dF d0 ( – ) = - K p d0 L0 Smooth Muscle Constriction (RASS: Moss presentation.)

  43. Change in Circumference d0 dF DEP p dF d0 ( – ) = - K p d0 L0 Smooth Muscle Constriction (RASS: Moss presentation.)

  44. Change in Resistance 4 1 1 RF = R0 DEP K 1 - p2 (d0)2 L0 ∆ in Resistance to Flow (RASS: Moss presentation.)

  45. Equal Resistance Change RaF RbF = If Ra0 Rb0 DEPa DEPb then = (da0)2 (db0)2 La0 Lb0 Comparing equal resistance ∆ (RASS: Moss presentation.)

  46. Representative airway generation • By Volume • By Sensitivity (RASS: Moss presentation.)

  47. Airway Volumes (RASS: Moss presentation.)

  48. Airway Generation Sensitivity Sensitivity as a multiple of the sensitivity of generation 1, the trachea. (RASS: Moss presentation.)

  49. Airway Generation Sensitivity Sensitivity as a multiple of the sensitivity of generation 1, the trachea. (RASS: Moss presentation.)

  50. Airway Generation Sensitivity Sensitivity as a multiple of the sensitivity of generation 1, the trachea. (RASS: Moss presentation.)

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