Evaluating the response of animals to a toxic or therapeutic agent requires the knowledge of the dose of the agent in the respiratory tract. Dose is the amount retained in the lungs. It is the difference between the amount deposited and the amount cleared. Many factors influence the amount of and the site of deposition in the respiratory tract. For particles, the characteristics of the aerosol, most importantly size, the physiology of the animal, most importantly breathing pattern, and the geometry of the respiratory tract all play a role in determining local dose. These factors and their relative importance in determining regional deposition are discussed. Finally, ways in which dose can be measured in the respiratory tract are explored. These range from simple estimates of total dose using whole lung digests to the precise localization of dose in well-defined lung compartments using morphometry or in cellular or subcellular compartments using electron energy loss spectroscopy. The techniques utilized by an investigator depend on the amount of resolution desired. Their use and implementation in inhalation studies are the key to fully understanding the response of an animal to an inhaled toxic or therapeutic agent.
AlbertRE, LippmannM, PetersonHTJr, BergerJ, SanbornK, and BohningD (1973). Bronchial deposition and clearance of aerosols.Arch. Intern. Med.131: 115–127.
2.
BaileyMR, KreylingWG, AndreS, BatchelorA, CollierCG, DrosselmeyerE, FerronGA, FosterP, HaiderB, HodgsonA, MasseR, MetivierH, MorganA, MüllerHL, PatrickG, PearmanI, RamsdenPickerings D., StirlingC, and TalbotRJ (1989). An interspecies comparison of the lung clearance of inhaled monodisperse cobalt oxide particles-part 1: Objectives and summary of results.J. Aerosol Sci.20: 169–188.
3.
BlanchardJD and WillekeK (1984). Total deposition of ultrafine sodium chloride particles in human lungs.J. Appl. Physiol.57: 1850–1856.
4.
BrainJD, KnudsonDE, SorokinSP, and DavisMA (1976). Pulmonary distribution of particles given by intratracheal instillation or by aerosol inhalation.Environ. Res.11: 13–33.
5.
BrainJD and ValbergPA (1979). Deposition of aerosol in the respiratory tract.Am. Rev. Respir. Dis.120: 1325–1373.
6.
BrainJD, BloomSD, ValbergPA, and GehrP (1984). Correlation between the behavior of magnetic iron oxide particles in the lungs of rabbits and phagocytosis.Exp. Lung Res.6: 115–131.
7.
BrainJD (1988). Species differences in inhalation toxicology: Variations in exposure-dose relationships and macrophage function. In: Inhalation Toxicology, DungworthD, KimmerleG, LewkowskiJ, McClellanR, and StoberW (eds). Springer Verlag, New York, pp. 11–23.
8.
BrainJD (1988). Lung macrophages—How many kinds are there? What do they do?Am. Rev. Respir. Dis.137: 507–509.
9.
BrainJD, BlanchardJD, and SweeneyTD (1989). Deposition and fate of inhaled pharmacologic aerosols. In: Provocative Challenge Procedures: Background and Methodology, SpectorSL (ed). Futura Pub. Co., Mt. Kisco, New York, pp. 1–36.
10.
BrainJD and SweeneyTD (1989). Effects of ventilatory patterns and pre-existing disease on deposition of inhaled particles in animals. In: Extrapolation of Dosimetric Relationships for Inhaled Particles and Gases, CrapoJD, SmolkoED, MillerFJ, GrahamJA, and HayesAW (eds). Academic Press, Inc., New York, pp. 167–186.
11.
BriantJK and CohenBS (1989). Flow distribution through human and canine airways during inhalation and exhalation.J. Appl. Physiol.67: 1649–1654.
12.
BrodyAR, HillLH, AdkinsB, and O'ConnorRW (1981). Chrysotile asbestos inhalation in rats: Deposition pattern and reaction of alveolar epithelium and pulmonary macrophages.Am. Rev. Respir. Dis.123: 670–679.
13.
ChristensenTG, KorthyAL, SniderGL, and HayesJA (1977). Irreversible bronchial goblet cell metaplasia in hamsters with elastase-induced panacinar emphysema.J. Clin. Invest.59: 397–404.
14.
ColemanRE, MercerRR, JaszczakRJ, GreerKL, and CrapoJD (1989). Regional dosimetry of inhaled particles using SPECT. In: Extrapolation of Dosimetric Relationships for Inhaled Particles and Gases, CrapoJD, SmolkoED, MillerFJ, GrahamJA, and HayesAW (eds). Academic Press, Inc., New York, pp. 201–210.
15.
Cruz-OriveLM and WeibelER (1981). Sampling designs for stereology.J. Microsc.122: 235–257.
16.
CuddihyRG (1976). Respiratory tract retention of inhaled particles in experimental animals.Inhalation Toxicology Research Institute Annual Report 1975–76 LF-56.Lovelace Foundation, Albuquerque, New Mexico, pp. 137–142.
17.
EschJL, SpektorDM, and LippmannM (1988). Effect of lung airway branching pattern and gas composition on particle deposition. II. Experimental studies in human and canine lungs.Exp. Lung Res.14: 321–348.
18.
FederspielWJ, and FredbergJJ (1988). Axial dis-persion in respiratory bronchioles and alveolar ducts.J. Appl. Physiol.64: 2614–2621.
19.
FelicettiSA, WolffRK, and MuggenburgBA (1981). Comparison of tracheal mucous transport in rats, guinea pigs, rabbits, and dogs.J. Appl. Physiol.51: 1612–1617.
20.
FerronGA and GebhartJ (1988). Estimation of the lung deposition of aerosol particles produced with medical nebulizers.J. Aerosol Sci.19: 1083–1086.
21.
FerronGA, OberdörsterG, and HennebergR (1989). Estimation of the deposition of aerosolized drugs in the human respiratory tract due to hygroscopic growth.J. Aerosol Med.2: 271–284.
22.
GeiserM., ImhofV, GehrP, and Cruz-OriveLM (1988). Histological and stereological analysis of particle deposition in the conductive airways of hamster lungs.J. Aerosol Med.1: 197.
23.
GodleskiJJ, StearnsRC, KatlerM, and HastingsCL (1990). Detection of elements by electron spectro-scopic imaging and analysis of electron energy loss spectra in alveolar macrophages prepared by slam-freeze molecular distillation processing.EMSA Proc.48: 776–777.
24.
GodleskiJJ and KreylingWG (1990). Localization of cobalt in the matrix of airway cartilage.Am. Rev. Respir. Dis.141: A525.
25.
GodleskiJJ, HastingsCL, KatlerM, and SweeneyTD (1991). Preservation of the relationship of airway mucus and epithelium by slam freezing. In: Proceedings of the 49th Annual Meeting of the Electron Microscopy Society of America, BaileyGW (ed). San Francisco Press, San Francisco, pp. 72–73.
26.
GoldbergIS and LourençoRV (1973). Deposition of aerosols in pulmonary disease.Arch. Intern. Med.131:88–91.
27.
HarbisonML and BrainJD (1983). Effects of exercise on particle deposition in Syrian golden hamsters.Am. Rev. Respir. Dis.128: 904–908.
28.
HesseltineRK, WolffRK, HansonRL, McClellanRO, and MauderlyJL (1985). Comparison of lung burdens of inhaled particles of rats exposed during the day or night.J. Toxicol. Environ. Health16: 323–329.
29.
HeyderJ., GebhartJ, StahlhofenW, and StuckB (1982). Biological variability of particle deposition in the human respiratory tract during controlled and spontaneous mouth-breathing.Ann. Occup. Hyg.26: 137–147.
30.
HeyderJ. (1982). Particle transport onto human airway surfaces.Eur. J. Respir. Dis.63: 29–50.
31.
HeyderJ., GebhartJ, RudolfG, SchillerCF, and StahlhofenW (1986). Deposition of particles in the human rspiratory tract in the size range 0. 005–15 μm.J. Aerosol Sci.17: 811–825.
32.
HindsWC (1982). Aerosol Technology.John Wiley & Sons, New York.
33.
HorsfieldK and CummingG (1968). Morphology of the bronchial tree in man.J. Appl. Physiol.24: 373–383.
34.
HorsfieldK and CummingG (1976). Morphology of the bronchial tree in the dog.Respir. Physiol.26: 173–182.
35.
HounamRF and MorganA (1977). Particle deposition. In: Lung Biology in Health and Disease, Vol. 5. Respiratory Defense Mechanisms, Part 1, BrainJD, ProctorDF, and ReidLM (eds). Marcel Dekker, Inc., New York, pp. 125–156.
36.
IlowiteJS, SmaldoneGC, PerryRJ, BennettWD, and FosterWM (1989). Relationship between tracheobronchial particle clearance rates and sites of initial deposition in man.Arch. Environ. Health44: 267–273.
37.
JakabGL and HemenwayDR (1989). Restraint of animals required for nose-only inhalation toxicologic studies suppresses pulmonary antibacterial defenses.Inhal. Toxicol.1: 289–300.
38.
KarlinskyJB and SniderGL (1978). Animal models of emphysema.Am. Rev. Respir. Dis.117: 1109–1133.
39.
KimCS, BrownLK, LewarsGG, and SacknerMA (1983). Deposition of aerosol particles and flow resistance in mathematical and experimental airway modelsJ. Appl. Physiol.55: 154–163.
40.
LangenbackE., BergofskyEH, HalpernJG, and FosterWM (1990). Determining deposition sites of inhaled lung particles and their effect on clearance.J. Appl. Physiol.68: 1427–1434.
41.
LinnerJG, LiveseySA, HarrisonDS, and SteinerAL (1986). A new technique for removal of amorphous phase tissue water without ice crystal damage: A preparative technique to ultrastructural analysis and immunoelectron microscopy.J. Histochem. Cytochem.34: 1123–1135.
42.
LinnerJG and LiveseySA (1988). Low temperature molecular distillation drying of cryofixed biological samples. In: Low Temperature Biotechnology: Emerging Applications and Engineering Contributions. BED-Vol. 10/HTD-Vol. 98, McGrathJJ and DillerKR (eds). Am. Soc. Mech. Eng., New York.
43.
LippmannM (1977). Regional deposition of particles in the human respiratory tract. In: Reactions to Environmental Agents, Sec. 9 of Handbook of Physiology, LeeDHK (ed). Am. Physiol. Soc., Bethesda, Maryland, pp. 213–232.
44.
LippmannM., YeatesDB, and AlbertRE (1980). Deposition, retention, and clearance of inhaled particles.Br. J. Indust. Med.37: 337–362.
45.
LippmannM and SchlesingerRB (1984). Interspecies comparisons of particle deposition and mucociliary clearance in tracheobronchial airways.J. Toxicol. Environ. Health13: 441–469.
46.
LippmannM., and EschJL (1988). Effect of lung airway branching pattern and gas composition on particle deposition. I. Background and literature review.Exp. Lung Res.14: 311–320.
47.
LoganGR, SchnittSJ, and DvorakAM (1987). Rapid microwave fixation of human tissues for light microscopic immunoperoxidase identification of diagnostically useful antigens.Lab. Invest.57: 585–591.
48.
LogusJW, TrajamM, HooperHR, LentleBC, and MannSFP (1984). Single photon emission tomography of lungs imaged with Tc-labeled aerosol.J. Can. Assoc. Radiol.35: 133–138.
49.
LumH and MitznerW (1987). A species comparison of alveolar size and surface forces.J. Appl. Physiol.62: 1865–1871.
50.
MauderlyJ (1986). Respiration of F344 rats in nose-only inhalation exposure tubes.J. Appl. Toxicol.6: 25–30.
51.
McMahonTA, BrainJD, and LeMottS (1977). Species differences in aerosol deposition. In: Inhaled Particles IV, WaltonWH (ed). Pergamon Press, Oxford, pp. 23–33.
52.
MelandriCV, TarroniG, ProdiV, DeZaiacomoT, FormignaniM, and LombardiCC (1983). Deposition of charged particles in the human airways.J. Aerosol Sci.14: 657–669.
53.
MercerRR and CrapoJD (1989). Anatomical mod-eling of microdosimetry of inhaled particles and gases in the lung. In: Extrapolation of Dosimetric Relationships for Inhaled Particles and Gases, CrapoJD. SmolkoED, MillerFJ, GrahamJA, andHayesAW (eds). Academic Press, New York, pp. 69–78.
54.
MorganWKC, ClagueHW, and VinitskiS (1983). On paradigms, paradoxes, and particles.Lung161: 195–206.
MorrowPE (1988). Possible mechanisms to explain dust overloading of the lungs.Fund. Appl. Toxicol.10: 369–384.
57.
OberdörsterG (1988). Lung clearance of inhaled insoluble and soluble particles.J. Aerosol Med.1: 289–330.
58.
PaivaM (1973). Gas transport in the human lung.J. Appl. Physiol.35: 401–410.
59.
PatraAL (1986). Comparative anatomy of mammalian respiratory tracts: The nasopharyngeal region and the tracheobronchial region.J. Tox. Environ. Health17: 163–174.
60.
PattleRE (1961). The retention of gases and particles in the human nose. In: Inhaled Particles and Vapors, DaviesCN (ed). Pergamon Press, New York, pp. 302–309.
61.
PhalenRF, YehHC, SchumGM, and RaabeOG (1978). Application of an idealized model to morphometry of the mammalian tracheobronchial tree.Anat. Rec.190: 167–176.
62.
PhalenRF, OldhamJM, BeaucageCB, CrockerTT, and MortensenJD (1985). Postnatal enlargement of human tracheobronchial airways and implications for particle deposition.Anat. Rec.212: 368–380.
63.
PhippsPR, GondaI, BaileyDL, BorhamP, BautovichG, and AndersonSD (1989). Comparisons of planar and tomographic gamma scintigraphy to measure the penetration index of inhaled aerosols.Am. Rev. Respir. Dis.139: 1516–1523.
64.
PinkertonKE, PlopperCG, MercerRR, RoggliVL, PatraAL, BrodyAR, and CrapoJD (1986). Airway branching patterns influence asbestos fiber location and the extent of tissue injury in the pulmonary parenchyma.Lab. Invest.55: 688–695.
65.
ProctorDF (1973). The upper respiratory tract and the ambient air.Clin. Notes Respir. Dis.12: 2–10.
66.
RaabeOG, BennickJE, LightME, HobbCH, ThomasRL, and TilleryMI (1973). An improved apparatus for acute inhalation exposure of rodents to radioactive aerosol.Toxicol. Appl. Pharmacol.26: 264–273.
67.
RaabeOG, YehHC, NewtonGJ, PhalenRF, and VelasquezDJ (1977). Deposition of inhaled monodisperse aerosols in small rodents. In: Inhaled Particles IV, Part 1, WaltonWH (ed). Pergamon Press, New York, pp. 3–21.
68.
RaabeOG (1982). Deposition and clearance of inhaled aerosols. In: Mechanisms in Respiratory Toxicology, Vol. 1, WitschiH and NettesheimP (eds). CRC Press, Boca Raton, Florida, pp. 27–75.
69.
ScheidP and PiiperJ (1980). Intrapulmonary gas mixing and stratification. In: Pulmonary Gas Exchange, Vol. 1, WestJB (ed). Academic Press, New York, pp. 87–130.
70.
SchlesingerRB and McFaddenLA (1981). Comparative morphometry of the upper bronchial tree of six mammalian species.Anat. Rec.199: 99–108.
71.
SchlesingerRB (1985). Comparative deposition of inhaled aerosols in experimental animals and humans: A review.J. Toxicol. Environ. Health15: 197–214.
72.
SchlesingerRB (1985). Clearance from the respiratory tract.Fund. Appl. Toxicol.5: 435–450.
73.
SchreiderJP and RaabeO (1981). Anatomy of the nasal-pharyngeal airway of experimental animals.Anat. Rec.200: 195–205.
74.
SchusterDP (1989). Positron emission tomography: Theory and its application to the study of lung disease.Am. Rev. Respir. Dis.139: 818–840.
75.
SmaldoneGC, PerryRJ, BennettWD, MessinaMS, ZwangJ, and IlowiteJ (1988). Interpretation of “24 hour lung retention” in studies of mucociliary clearance.J. Aerosol Med.1: 11–20.
76.
SnipesMB, BoeckerBB, and McClellanRO (1983). Retention of monodisperse or polydisperse aluminosilicate particles inhaled by dogs, rats, and mice.Toxicol. Appl. Pharmacol.69: 345–362.
77.
SweeneyTD, BrainJD, TrykaAF, and GodleskiJJ (1983). Retention of inhaled particles in hamsters with pulmonary fibrosis.Am. Rev. Respir. Dis.128: 138–143.
78.
SweeneyTD, BrainJD, LeavittSA, and GodleskiJJ (1987). Emphysema alters the deposition pattern of inhaled particles in hamsters.Am. J. Pathol.128: 19–28.
79.
SweeneyTD, BlanchardJD, ZeltnerTB, CarterJE, and BrainJD (1990). Delivery of aerosolized drugs to the lungs with a metered-dose inhaler: Quantitative analysis of regional deposition.J. Aerosol Sci.21: 350–354.
80.
SweeneyTD (1990). Exposing animals to aerosols: Considerations that influence regional lung deposition.J. Aerosol Med.3: 169–186.
81.
SweeneyTD, BlanchardJD, CarterJE, VadasE, and BrainJD (1990). Changing drug concentration in a metered-dose inhaler: Does it alter the site of particle deposition in excised dog lungs?Am. Rev. Respir. Dis.141: A522.
82.
SweeneyTD, LeithDE, and BrainJD (1991). Re-straining hamsters alters their breathing pattern.J. Appl. Physiol.70: 1271–1276.
83.
SwiftDL, CarpinJC, and MitznerW (1982). Pulmonary penetration and deposition of aerosols in different gases: Fluid flow effects.Ann. Occup. Hyg.26: 109–117.
84.
TaplinGV, TaskinDP, ChopraSK, AnselmiOE, ElamD, CalvareseB, CoulsonA, DetelsR, and RokawSN (1977). Early detection of chronic obstructive pulmonary disease using radionuclide lung-imaging procedure.Chest71: 567–575.
85.
TenneySM and RemmersJE (1963). Comparative quantitative morphology of the mammalian lung.Nature197: 54–56.
86.
TrykaAF, SkornikWA, GodleskiJJ, and BrainJD (1982). Potentiation of bleomycin-induced lung injury by exposure to 70% oxygen: Morphologic assessment.Am. Rev. Respir. Dis.126: 1074–1079.
87.
TrykaAF, GodleskiJJ, SkornikWA, and BrainJD (1983). Progressive pulmonary fibrosis in hamsters.Exp. Lung Res.5: 155–171.
88.
ValbergPA, BrainJD, SneddonSL, and LeMottSR (1982). Breathing patterns influence aerosol deposition sites in excised dog lungs.J. Appl. Physiol.53: 824–837.
89.
ValbergPA, WolffRK, and MauderlyJL (1985). Redistribution of retained particles.Am. Rev. Respir. Dis.131: 273–280.
90.
ValbergPA and BlanchardJD (In Press). Pulmonary macrophage origin, endocytic function, and fate. In: The Normal Lung, Comparative Pulmonary Biology, Sect. IV: Defense Capability of the Respiratory Tract, SchlesingerRB (ed). CRC Press.
91.
WarheitDB and HartskyMA (1990). Species comparisons of proximal alveolar deposition patterns of inhaled particulates.Exp. Lung Res.16: 83–99.
92.
WarnerAE and BrainJD (1990). The cell biology and pathogenic role of pulmonary intravascular macrophages.Am. J. Physiol.: Lung Cell. Mol. Physiol. 2:1–12.
93.
WeibelER, TaylorCR, GehrP, HoppelerH, MathieuO, and MaloiyMO (1981). Design of the mammalian respiratory system. IX. Functional and structural limits for oxygen flow.Respir. Physiol.44: 151–164.
94.
WillekeK (ed) (1980). Generation of Aerosols and Facilities for Exposure Experiments.Ann Arbor Sci., Ann Arbor.
95.
WolffRK, TillquistH, MuggenbergBA, HarkemaJR, and MauderlyJL (1989). Deposition and clearance of radiolabeled particles from small ciliated airways.J. Aerosol Med.3: 261–270.
96.
ZeltnerTB, SweeneyTD, SkornikWA, FeldmanHA, and BrainJD (1991). Retention and clearance of 0.9 μm particles inhaled by hamsters during rest or exercise.J. Appl. Physiol.70: 1137–1145.
