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  1. Uptake and Disposition of Gases and Vapors in the Respiratory Tract Paul M. Schlosser U.S. Environmental Protection Agency National Center for Environmental Assessment schlosser.paul@epa.gov, 919-541-4130 This presentation only describes my professional opinion and does not necessarily reflect EPA policy.

  2. Why do we care about uptake & disposition of gases in the respiratory tract (RT)? • Portal of entry for rest of body • Toxicity to RT tissues Paul M. Schlosser - UNC TOXC 207 Lecture

  3. Dosimetry: Quantitative Biology & Physiology • Most of this lecture will focus on qualitative aspects of biology and gas properties that determine uptake. • But dosimetry is ultimately quantitative! • Some algebra will be shown and part of the exam question will involve algebra and/or calculations. Paul M. Schlosser - UNC TOXC 207 Lecture

  4. Dibasic esters: olfactory mucosa (sustentacular cells) Ozone: conducting airways Formaldehyde: transitional & respiratory mucosa of nasal passages Butadiene: lung tumors Different Gases  Different Targets … Why? (Diagram courtesy of Dr. Jack R. Harkema, Professor of Comparative Physiology, Michigan State University.) Paul M. Schlosser - UNC TOXC 207 Lecture

  5. What properties of gases & vapors might effect their uptake & deposition? • Partition coefficient (“solubility”) • Reactivity Paul M. Schlosser - UNC TOXC 207 Lecture

  6. Partition Coefficients (PCs) • A PC is the affinity of gas for a “tissue” (mucus, tissue, blood) compared to air • Equilibrium constant • Solubility = total amount of a substance that can be dissolved in a medium, not relative affinity • PC values are generally the same for a given chemical across animal species • Air:respiratory tissue PC for benzene in a rat  the PC in a human Paul M. Schlosser - UNC TOXC 207 Lecture

  7. Measuring PCs • With no removal, the concentration in air and a tissue in contact will approach equilibrium • By measuring the loss of chemical from air over a tissue in a closed vial, the PC can be calculated Paul M. Schlosser - UNC TOXC 207 Lecture

  8. Measuring PCs (cont.) • PBA = [Blood]/[Air] • PTA = [Tissue]/[Air] • PTB = PTA /PBA GC Air Tissue homogenate or blood Paul M. Schlosser - UNC TOXC 207 Lecture

  9. Calculating PBA • If T moles of a gas are added to an equilibration vile with 70 ml gas volume and 30 ml blood volume, and after equilibration the concentration in the headspace (gas) is CG (M), what is PBA? • Amount in gas phase = AG = CG·0.07 l • Amount in blood = T - AG • Conc. in blood = CB = (T - AG)/0.03 l • PBA = CB/CG = (T - AG)/(CG·0.03 l) = (T - CG·0.07 l)/(CG·0.03 l) Paul M. Schlosser - UNC TOXC 207 Lecture

  10. Some Partition Coefficients Paul M. Schlosser - UNC TOXC 207 Lecture

  11. Uptake: Respiratory Exchange of Gases and Vapors Qair, Cair Qair, Calv inhaled air Lung air Calv alveolar air arterial blood venous blood Lung blood Cart Qc, Cven Qc, Cart Gas Exchange Region Qi = flow rate (volume/time) Ci = concentration in fluid “i” Mass balance: amount removed from air = amount taken up by blood Qair•(Cair – Calv) = Qc•(Cart – Cven) Alveolar air and arterial blood are presumed to be at equilibrium, defined by the partition coefficient, PB: Calv = Cart/PB Cart = (Qair•Cair + Qc•Cven)/(Qair/PB + Qc) Paul M. Schlosser - UNC TOXC 207 Lecture

  12. Blood:Air = 25 Blood:Air = 5 Blood:Air = 1 Dependence of Gas Uptake on the Blood:Air PC 60 48 36 24 12 0 Why do the concentration curves rise faster in the first 1-2 hr of exposure than later in the exposure? Exposure Concentration in blood (mg gas/ml blood) 0 2 4 6 8 10 12 Hours Paul M. Schlosser - UNC TOXC 207 Lecture

  13. Concept: Driving Force • The rate of movement of a substance from one medium to another is proportional to the extent of disequilibrium between them • Likewise, if the concentration differs between one location and another within a medium, there will be diffusion from the higher to lower concentration location, with rate proportional to the difference Paul M. Schlosser - UNC TOXC 207 Lecture

  14. PC Air Air Time More time CB/CA 0 Blood 0 Time Driving Force (cont.) • The lack of equilibrium, or difference in concentration from equilibrium, can be thought of as a driving force for transport As system approaches equilibrium, the rate of “uptake” into blood decreases. Paul M. Schlosser - UNC TOXC 207 Lecture

  15. Gas Property: Reactivity • Reactivity: the tendency of a gas to react with constituents of mucus and/or tissue • Removes the gas • Forms products • Can be quantified by first-order reaction rate-constant, k (at low concentrations) • Highly reactive gases are removed quickly • Keeps concentration of the gas in lining low • Keeps driving force for uptake high • Reactive gases are taken up more rapidly than non-reactive, all else being equal Paul M. Schlosser - UNC TOXC 207 Lecture

  16. Uptake of Reactive vs. Inert Gas Lumen Mucus Epithelium Blood-perfused tissue Air flow in Non-intuitive: more reactive gases are taken up faster but have lower concentrations in tissue! Gas concentration Inert gas Reactive gas Distance Paul M. Schlosser - UNC TOXC 207 Lecture

  17. RT Dosimetry Distribution Reactive/high-PC gas Inert/low-PC gas (Diagram courtesy of Dr. Jack R. Harkema, Professor of Comparative Physiology, Michigan State University.) Paul M. Schlosser - UNC TOXC 207 Lecture

  18. Dibasic esters: olfactory mucosa (sustentacular cells) Ozone: conducting airways Formaldehyde: transitional & respiratory mucosa of nasal passages Butadiene: lung tumors Gas Properties  Distribution (Diagram courtesy of Dr. Jack R. Harkema, Professor of Comparative Physiology, Michigan State University.) Paul M. Schlosser - UNC TOXC 207 Lecture

  19. What properties of the respiratory tract might effect uptake & deposition? • Anatomy • Shape/geometry • Surface area • Thickness (mucus, tissue) • Removal of compound • Blood perfusion • Metabolism Paul M. Schlosser - UNC TOXC 207 Lecture

  20. Effect of Anatomy • Processes of uptake • Convection (Airflow, Blood Perfusion) • Diffusion • Concepts • Driving Force • Resistance • Role of surface area Paul M. Schlosser - UNC TOXC 207 Lecture

  21. Convection • Convection occurs when molecules of a dilute material (gas or vapor) are carried by the flow of a ‘bulk’ fluid (air or blood) • When air containing a toxic gas is inhaled, convection carries the gas down into the respiratory tract • Airway geometry effects the direction & velocity of airflow • This in turn has a significant effect on the site of deposition of some gases Paul M. Schlosser - UNC TOXC 207 Lecture

  22. Anatomy - Rat Cross-Section • Histological section of F344 • rat nose. Major airways or • meatuses: • DM - dorsal medial • MM - middle medial • SVM - superior ventral medial • IVM - inferior ventral medial • DL - dorsal lateral • ML - middle lateral • VL - ventral lateral From Morgan et al., Toxicol Appl Pharmacol, 110:223-240, 1991. Paul M. Schlosser - UNC TOXC 207 Lecture

  23. Anatomy - Rat vs. Monkey Rat (Nostrils) (Not to scale!) Monkey From Morgan et al., Toxicol Appl Pharmacol, 110:223-240, 1991. Paul M. Schlosser - UNC TOXC 207 Lecture

  24. Monkey Anatomy - Effect on Airflow Rat From Morgan et al., Toxicol Appl Pharmacol, 110:223-240, 1991. Paul M. Schlosser - UNC TOXC 207 Lecture

  25. Anatomy  Site-SpecificityFormaldehyde-induced lesion distribution in the monkey From Monticello et al., Am J Pathol, 134:515-527, 1991. Paul M. Schlosser - UNC TOXC 207 Lecture

  26. Comparative Anatomy - URT Human Dog Monkey Rabbit Rat Exposed mucosal surface of nasal lateral wall: HP, hard palate; n, naris; NP, nasopharynx; et, ethmoid turbinate; nt, nasoturbinate; mx maxiloturbinate; it, inferior turbinate; st, superior turbinate. From Harkema, Toxicol Pathol, 19:321-336, 1991. Paul M. Schlosser - UNC TOXC 207 Lecture

  27. Process: Diffusion • When the concentration of a substance varies within a medium (e.g., air) between one location and another, random molecular motion results in a net movement of the substance from regions of higher concentration to regions of lower concentration. Paul M. Schlosser - UNC TOXC 207 Lecture

  28. Air-phase diffusion from bulk air to mucosa surface. Distance from surface Region of very slow air flow & little convection: gas must diffuse across. } depth = da Speed of airflow Chemical reactions may occur in mucosa. dm cm Dissolution cas Diffusion in mucus and tissue cms Diffusion (cont.) Air Convection: flow of “bulk” air carrying gas or vapor. ca Mucosa (ca > cas & cms > cm) Paul M. Schlosser - UNC TOXC 207 Lecture

  29. Concept: Resistance • Concentration differences create a driving force for diffusion • But movement is not instantaneous • Resistance is the limitation to transport due to the intervening medium (air, mucus, tissue) Paul M. Schlosser - UNC TOXC 207 Lecture

  30. Slower diffusion Slowest diffusion Air Tissue Distance Distance 0 D 0 D Longer distance Denser medium Case 3 Case 2 Diffusion ResistanceDependence on Distance and Density C c Air Fast diffusion Concentration Distance 0 d Case 1 Molecular weight also effects diffusion rate (larger = slower), but the variation between most gases & vapors in not as great as the effect of other factors, such as partition coefficients. Paul M. Schlosser - UNC TOXC 207 Lecture

  31. Surface Area“Opportunity for Uptake” • Concentration differences, solubility, reactivity, and diffusion length and medium create the “driving force” for and “resistance” to uptake. • Given all these factors, the rate of uptake in a given region is proportional to the surface area of epithelium exposed to the airway lumen. • The alveolar region has a large surface area because oxygen has a low PC and is not reactive, so the driving force is low, and hence a large area is needed. Paul M. Schlosser - UNC TOXC 207 Lecture

  32. What properties of the respiratory tract might effect uptake & deposition? • Anatomy • Shape/geometry • Surface area • Thickness (mucus, tissue) • Removal of compound • Blood perfusion • Metabolism Paul M. Schlosser - UNC TOXC 207 Lecture

  33. Blood Perfusion • Varies regionally • Effected by irritation/stimulation • Only important for less reactive gases • Must last long enough to reach the blood! Paul M. Schlosser - UNC TOXC 207 Lecture

  34. Respiratory Olfactory Transitional Squamous epithelium ADH - aldehyde dehydrogenase; NBE - naphthyl butyrate esterase; FDH - formaldehyde dehydrogenase; P450 - cytochrome P450; EH - epoxide hydrolase; GST - glutathione S-transferase. From Morgan, pp. 41-57, in Miller (ed.), Nasal Toxicity and Dosimetry of Inhaled Xenobiotics: Implications for Human Health, Taylor & Frances, 1991. Metabolism • Removal process for less reactive gases • Increases driving force for uptake • Activates compounds to toxic products Paul M. Schlosser - UNC TOXC 207 Lecture

  35. Dibasic esters: olfactory mucosa (sustentacular cells) Ozone: conducting airways Formaldehyde: transitional & respiratory mucosa of nasal passages Butadiene: lung tumors Gas Properties  Distribution (Diagram courtesy of Dr. Jack R. Harkema, Professor of Comparative Physiology, Michigan State University.) Paul M. Schlosser - UNC TOXC 207 Lecture

  36. Cell-Specific Toxicity(Olfactory Mucosa) Sustentacular cells Carboxylesterase Dibasic esters Bowman’s gland Cytochrome P450 Chloroform Dichlorobenil From Morgan, pp. 41-57, in Miller (ed.), Nasal Toxicity and Dosimetry of Inhaled Xenobiotics: Implications for Human Health, Taylor & Frances, 1991. Paul M. Schlosser - UNC TOXC 207 Lecture

  37. Classifying Gases Hydrophobic, Reactive Hydrophilic, Reactive Reactivity Hydrophobic, Non-reactive Hydrophilic, Non-reactive Blood:Air PC Hydrophobic Hydrophilic Paul M. Schlosser - UNC TOXC 207 Lecture

  38. Formaldehyde-induced tumor sites in rat URT. From Morgan et al., Toxicol. Appl. Pharmacol., 82:264-271, 1986. Hydrophilic - Reactive • Absorbed almost completely in the URT (nose) • Smaller amount in trachea & upper airways • Oral breathing in humans delivers more to LRT • Anatomy-airflow interaction • Example: formaldehyde • Induces squamous-cell carcinomas in rat nose Paul M. Schlosser - UNC TOXC 207 Lecture

  39. Hydrophilic - Non-Reactive • More distal absorption (including URT) • Systemic distribution becomes important • Examples: ethanol, dibasic esters • May be activated by metabolism • Feature: “wash in-wash out” effect Paul M. Schlosser - UNC TOXC 207 Lecture

  40. Airway lumen Mucosa “Wash In-Wash Out” Effect Airway lumen Mucosa [Vapor] Distance from center of airway • Vapor absorbed by mucosa during inhalation • Remains in mucosa because it’s non-reactive • Air depleted in vapor in lower airways • Vapor desorbs into depleted air on exhalation • Net uptake is less than during inhalation alone (Figure from Medinsky and Bond, Toxicology, 160:165-172, 2001.) Paul M. Schlosser - UNC TOXC 207 Lecture

  41. Relative Absorption vs. PC(Non-Reactive Gases) (From Gerde and Dahl, Toxicol Appl Pharmacol, 109:276-288, 1991.) Paul M. Schlosser - UNC TOXC 207 Lecture

  42. Ozone uptake in the lung From Miller et al., Environ. Res., 17:84-101, 1978. Hydrophobic - Reactive • More distal airway distribution than hydrophilic-reactive • Systemic distribution unlikely (except reaction products) • Toxicity at sites of delivery • Example: ozone Paul M. Schlosser - UNC TOXC 207 Lecture

  43. Hydrophobic - Non-Reactive • Absorbed throughout URT • Most absorbed in alveolar space (surface area) • Systemic circulation • Uptake dependent on metabolism • Tissue sensitivity  site specificity • Example: butadiene Paul M. Schlosser - UNC TOXC 207 Lecture

  44. Butadiene Closed-System Uptake Butadiene Gas sampling Oxygen Paul M. Schlosser - UNC TOXC 207 Lecture

  45. Butadiene Closed-System Uptake Continued disappearance (uptake) due to hepatic metabolism. From Medinsky et al., Carcinogenesis, 15:1329-1340, 1994. Paul M. Schlosser - UNC TOXC 207 Lecture

  46. Classifying Gases - Summary Ozone, Conducting airway damage (high) Reactivity (low) Formaldehyde, Nasal tumors Dibasic esters, Sustentacular cell toxicity Butadiene, Lung tumors Blood:Air PC Hydrophobic Hydrophilic Paul M. Schlosser - UNC TOXC 207 Lecture