Chapter 4. Dosimetry 

4.1. Introduction 

Particle dosimetry refers to the characterization of deposition, translocation, clearance, and 

retention of particles and their constituents within the respiratory tract and extrapulmonary tissues. 

This chapter summarizes basic concepts presented in dosimetry chapters of the 1996 and 2004 PM 

AQCDs (U.S. EPA, 1996, 079380; U.S. EPA, 2004, 056905), and updates the state of the science 

based upon new literature appearing since publication of these PM AQCDS. Although the basic 

understanding of the mechanisms governing deposition and clearance of inhaled particles has not 

changed, there is significant additional information on the role of certain biological determinants 

such as gender, age and lung disease on deposition and clearance. Additionally, new studies have 

further characterized the retention and translocation of ultrafine particles (UFPs; also commonly 

referred to as nanoparticles) following deposition in the respiratory tract. 

The dose from inhaled particles deposited and retained in the respiratory tract is governed by a 

number of factors. These include exposure concentration and duration, activity and ventilatory 

parameters, and particle properties (e.g., particle size, hygroscopicity, and solubility in airway fluids 

and cellular components). The basic characteristics of particles as they relate to deposition and 

retention, as well as anatomical and physiological factors influencing particle deposition and 

retention, were discussed in depth in Chapter 10 of 1996 PM AQCD and updated in Chapter 6 of the 

2004 PM AQCD. Species differences between humans and rats in particle exposures, deposition 

patterns, and pulmonary retention were also reviewed in Brown et al. (2005, 089308). The current 

review of PM dosimetry focuses mainly on issues that may affect the susceptibility of an individual 

to adverse effects as well as issues that affect our ability to extrapolate findings between studies 

(e.g., in vitro to in vivo) and between species. Other than a brief overview in this introductory 

section, the disposition (i.e., deposition, absorption, distribution, metabolism, and elimination) of 

fibers and unique nano-objects (viz., dots, hollow spheres, rods, fibers, tubes) is not reviewed herein. 

Substantial exposures to fibers and unique nano-objects generally occur in the occupational settings 

rather than the ambient environment. 

The deposition by interception of micro-sized fibers was briefly discussed in the 1996 and 

2004 PM AQCD, but fiber retention in the respiratory tract was not addressed. Airborne fibers 

(length/diameter ratio ≥ 3), can exceed 150 μm in length and appear to be relatively stable in air. 

This is because their aerodynamic size is determined predominantly by their diameter, not their 

length. Fibers longer than 10 μm can deposit by interception and when aligned with the direction of 

airflow may penetrate deep into the respiratory tract. Once deposited, macrophage mediated 

clearance is the primary mechanism of removing micro-sized particles from the pulmonary region. 

The length of fibers can, however, affect their phagocytosis and clearance. For example, fibers of 

>17 μm in length are too long to be fully engulfed by rat alveolar macrophages and can protrude 

from macrophages (i.e., macrophage frustration) (Zeidler-Erdely et al., 2006, 190967). Further 

discussion of the fiber disposition in the respiratory tract is beyond the scope of this chapter. 

The term “ultrafine particle” has traditionally been used by the aerosol research and 

occupational and environmental health communities to describe airborne particles or other laboratory 

generated aerosols used in toxicological studies that are <100 nm in size (based on physical size, 

diffusivity, or electrical mobility). Generally consistent with the definition of an UFP, the 

International Organization for Standardization (ISO) recently defined a nanoparticle as an object 

with all 3 external dimensions in the nanoscale, i.e., from approximately 1 and 100 nm (ISO, 2008, 

190066). The ISO also defined a nano-object as a material with one or more external dimensions in 

 

 Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and 

Environmental Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of 

developing science assessments such as the Integrated Science Assessments (ISA) and the Integrated Risk Information System (IRIS). 

December 2009 4-1 
the nanoscale. The terms, nanoparticle and UFP, have been used rather synonymously in the recent 

literature. However, the terms nanoparticle and nano-object are more commonly associated with 

engineered materials that are created for consumer products and industrial applications. With the 

current interest in nanotechnologies, many nano-objects have been created by manipulating materials 

at the atomic or molecular scale for the purpose of forming new materials, structures, and devices 

that exploit the unique physical and chemical properties associated with their nanoscale. 

Toxicological studies are becoming available that evaluate in vivo translocation and heath effects 

unique of nano-objects (viz., dots, hollow spheres, rods, tubes). The in vivo disposition of these 

unique nano-objects is not, however, necessarily relevant to the behavior of UF aerosols in the urban 

environment that are created by combustion sources and photochemical formation of secondary 

organic aerosols. Therefore, the disposition of unique nano-objects (viz., dots, hollow spheres, rods, 

fibers, tubes) is not considered in this chapter. 

4.1.1. Size Characterization of Inhaled Particles 

Particle size is a major determinant of the fraction of inhaled particles depositing in and 

cleared from various regions of the respiratory tract. The distribution of particle sizes in an aerosol is 

typically described by the lognormal distribution (i.e., the situation in which the logarithms of 

particle diameter are distributed normally). The geometric mean is the median of the distribution, 

and the variability around the median is the geometric standard deviation (GSD or σg) and is given 

by: 

%16

%50

%50

%84

d

d

d

d GSD σ g ===

di, 

: 

Equation 4-1 

where: d16%, d50%, d84% are the particle diameters associated with the 16th, 50th (i.e., the median), 

and the 84th percentiles from the cumulative frequency distribution of particle sizes. By definition, 

GSD must be greater than one. The particle size associated with any percentile of the distribution, 

is given by

(Pz )

i = dd %50 σ g

Equation 4-2 

where: z(P) is the normal standard deviate for a given probability. In most cases, the aerosols to 

which people are naturally exposed are polydisperse. By contrast, most experimental studies of 

particle deposition and clearance in the lung use monodisperse particles (GSD <1.15). Ambient 

aerosols may also be composed of multiple size modes, each mode should be described by its 

specific median diameter and GSD. 

Aerosol size distributions may be measured and described in various ways. When a 

distribution is described by counting particles, the median is called the count median diameter 

(CMD). On the other hand, the median of a distribution based on particle mass in an aerosol is the 

mass median diameter (MMD). Impaction and sedimentation of particles in the respiratory tract 

depend on a particle’s aerodynamic diameter (dae), which is the size of a sphere of unit density that 

has the same terminal settling velocity as the particle of interest. The size distribution is frequently 

described in terms of dae as the mass median aerodynamic diameter (MMAD), which is the median 

of the distribution of mass with respect to aerodynamic equivalent diameter. Alternative descriptions 

should be used for particles with actual physical sizes below ≈ 0.5 μm because, for these sized 

particles, aerodynamic properties become less important and diffusion becomes ever more important. 

For these smaller particles, their physical diameter or CMD are typically used since diffusivity is not 

a function of particle density. For small irregular shaped particles and aggregates, the diameter of a 

spherical particle that has the same diffusion coefficient in air as the particle in question is 

appropriate. 

December 2009 4-2 
4.1.2. Structure of the Respiratory Tract 

The basic structure of the human respiratory tract is illustrated in Figure 4-1. In the literature, 

the terms extrathoracic (ET) region and upper airways are used synonymously. The term lower 

airways is used to refer to the intrathoracic airways, i.e., the combination of the tracheobronchial 

(TB) region which is the conducting airways and the alveolar region which is the functional part or 

parenchyma of the lung. A recent review of interspecies similarities and differences in the structure 

and function of the respiratory tract is provided by Phalen et al. (2008, 156865). Although the 

structure varies, the illustrated anatomic regions are common to all mammalian species with the 

exception of the respiratory bronchioles. Respiratory bronchioles, the transition region between 

ciliated and fully alveolated airways, are found in humans, dogs, ferrets, cats, and monkeys. 

Respiratory bronchioles are absent in rats and mice and abbreviated in hamsters, guinea pigs, oxen, 

sheep, and pigs. The branching structure of the ciliated bronchi and bronchioles also differs between 

species from being a rather symmetric and dichotomous branching network of airways in humans to 

a more monopodial branching network in other mammals. 

Source: Based on ICRP (1995, 006988). 

Figure 4-1. Diagrammatic representation of respiratory tract regions in humans. Structures 

are anterior nasal passages, ET1; oral airway and posterior nasal passages, ETT

2; 

bronchial airways, BB; bronchioles, bb; and alveolar interstitial, AI. 

Another species difference relevant to particle dosimetry is the route of breathing. For 

instance, rodents are obligate nose breathers, whereas most humans are oronasal breathers who 

breathe through the nose when at rest and increasingly through the mouth with increasing activity 

December 2009 4-3 
level. There is inter-individual variability in the route by which people breathe. Most people, 87% 

(26 of 30) in the Niinimaa et al. (1981, 071758) study, breathed through their nose until an activity 

level was reached where they switched to oronasal breathing. Thirteen percent (4 of 30) of the 

subjects, however, were oronasal breathers even at rest. These two subject groups are commonly 

referred to in the literature (e.g. ICRP, 1995, 006988) as “normal augmenters” and “mouth 

breathers,” respectively. In contrast to healthy subjects, Chadha et al. (1987, 037365) found that the 

majority (11 of 12) of patients with asthma or allergic rhinitis breathe oronasally even at rest. 

Source: Panel (a) reprinted with permission from McGraw Hill (Fishman and Elias, 1980, 156436) 

Figure 4-2. Structure of lower airways with progression from the large airways to the 

alveolus. Panel (a) illustrates basic airway anatomy. Structures are epithelial 

cells, EP; basement membrane, BM; smooth muscle cells, SM; and 

fibrocartilaginous coat, FC. Panel (b) illustrates the relative amounts of liquid, 

tissue, and blood with distal progression. 

December 2009 4-4 
The site of particle deposition within the respiratory tract has implications related to lung 

retention and surface dose of particles as well as potential systemic distribution of particles or their 

constituents. Figure 4-2 illustrates the progressive change in airway anatomy with distal progression 

into the lower respiratory tract. In the bronchi there is a thick liquid lining and mucociliary clearance 

rapidly moves deposited particles toward the mouth. In general, in the bronchi, only highly soluble 

materials moving from the air into the liquid layer will have systemic access via the blood. With 

distal progression, the protective liquid lining diminishes and clearance rates slow. Soluble 

compounds and some poorly soluble UFPs may cross the air-liquid interface to enter the tissues and 

the blood especially in the alveolar region. 

4.2. Particle Deposition 

Inhaled particles may be either exhaled or deposited in the ET, TB, or alveolar region. A 

particle becomes deposited when it moves from the airway lumen to the wall of an airway. The 

deposition of particles in the respiratory tract depends primarily on inhaled particle size, route of 

breathing (nasal or oronasal), tidal volume (VT), breathing frequency (f), and respiratory tract 

morphology. The distinction between air passing through the nose versus the mouth is important 

since the nasal passages more effectively remove inhaled particles than the oral passage. Respiratory 

tract morphology, which affects particle transport and deposition, varies between species, the size of 

an animal or human, and health status. 

The fraction of inhaled aerosol becoming deposited in the human respiratory tract has been 

measured experimentally. Studies, using light scattering or particle counting techniques to quantify 

the amount of aerosol in inspired and expired breaths, have characterized total particle deposition for 

varied breathing conditions and particle sizes. The vast majority of in vivo data on the regional 

particle deposition has been obtained by scintigraphic methods where external monitors are used to 

measure gamma emissions from radiolabeled particles. These scintigraphic data have shown highly 

variable regional deposition with sites of highly localized deposition or “hot spots” in the obstructed 

lung relative to the healthy lung. Even in the healthy lung, “hot spots” occur in the region of airway 

bifurcations. Mathematical models aid in predicting the mixed effects of particle size, breathing 

conditions, and lung volume on total and regional deposition. Experimentally, however, there is 

considerable inter-individual variability in total and regional deposition even when inhaled particle 

size and breathing conditions are strictly controlled. Section 4.2.4 on Biological Factors Modulating 

Deposition provides more detailed information on factors affecting deposition among individuals. 

In order to potentially become deposited in the respiratory tract, particles must first be inhaled. 

The inspirable particulate mass fraction of an aerosol is that fraction of the ambient airborne particles 

that can enter the uppermost respiratory tract compartment, i.e., the head (Soderholm, 1985, 

156992). The American Conference of Governmental Industrial Hygienists (ACGIH) and the 

International Commission on Radiological Protection (ICRP) have established inhalability criteria 

for humans (ACGIH, 2005, 156188; ICRP, 1995, 006988). These criteria are indifferent to route of 

breathing and assume random orientation with respect to wind direction. They are based on 

experimental inhalability data for dae ≤ 100 μm at wind speeds of between 1 and 8 m/s. For the 

ACGIH criterion, inhalability is 97% for an dae = 1 μm, 87% for an dae = 5 μm, 77% for an 

dae = 10 μm, and plateaus at 50% for dae above ~40 μm. The ICRP criterion, which also plateaus at 

50% for very large dae, does not become of real importance until an dae = 5 μm where inhalability is 

97%. Dai et al. (2006, 156377) reported slightly lower nasal particle inhalability in humans during 

moderate exercise than rest (e.g., 89.2 versus 98.1% for 13 μm particles, respectively). Nasal particle 

inhalability is similar between an adult and 7-year-old child (Hsu and Swift, 1999, 155855). 

Inhalability into the mouth from calm air in humans also becomes important for dae >10 μm 

(Anthony and Flynn, 2006, 155659; Brown, 2005, 156299). Unlike the inhalability from high wind 

speeds which plateaus at 50% for dae greater than ~40 μm, particle inhalability from calm air 

continues to decrease toward zero with increasing dae. Inhalability data in laboratory animals, such as rats, are only available for breathing from 

relatively calm air (velocity ≤ 0.3 m/s). For nasal breathing, inhalability becomes an important 

consideration for dae of above 1 μm in rodents and 10 μm in humans (Ménache et al., 1995, 006533). 

The inhalability of particles having dae of 2.5, 5, and 10 μm is 80, 65, and 44% in rats, respectively, 

whereas it only decreases to 96% for an dae of 10 μm in humans during nasal breathing (Ménache et 

December 2009 4-5 
al., 1995, 006533). Asgharian et al. (2003, 153068) suggested that an even more rapid decrease in 

inhalability with increasing dae may occur in rats. Inhalability is a particularly important 

consideration for rodent exposures. Section 4.2.3 provides additional discussion of interspecies 

patterns of particle deposition. 

4.2.1. Mechanisms of Deposition 

Particle deposition in the lung is predominantly governed by diffusion, impaction, and 

sedimentation. Most discussion herein focuses on these three dominant mechanisms of deposition. 

Simple interception, which is an important mechanism of fiber deposition, is not discussed in this 

chapter. Electrostatic and thermophoretic forces as mechanisms of deposition have not been 

thoroughly evaluated and receive limited discussion. Some generalizations with regard to deposition 

by these mechanisms follows, but should not be viewed as absolute rules. Both experimental studies 

and mathematical models have demonstrated that breathing patterns can dramatically alter regional 

and total deposition for all sized particles. The combined processes of aerodynamic and diffusive (or 

thermodynamic) deposition are important for particles in the range of 0.1 μm to 1 μm. Aerodynamic 

processes predominate above and thermodynamic processes predominate below this range. 

Diffusive deposition, by the process of Brownian diffusion, is the primary mechanism of 

deposition for particles having physical diameters of less than 0.1 μm. For particles having physical 

diameters of roughly between 0.05 and 0.1 μm, diffusive deposition occurs mainly in the small distal 

bronchioles and the pulmonary region of the lung. However, with further decreases in particle 

diameter below ~0.05 μm, increases in particle diffusivity shift more deposition proximally to the 

bronchi and ET regions. 

Governed by inertial or aerodynamic properties, impaction and sedimentation increase with 

dae. When a particle has sufficient inertia, it is unable to follow changes in flow direction and strikes 

a surface thus depositing by the process of impaction. Impaction occurs predominantly at 

bifurcations in the proximal airways, where linear velocities and secondary eddies are at their 

highest. Sedimentation, caused by the gravitational settling of a particle, is most important in the 

distal airways and pulmonary region of the lung. In these regions, residence time is the greatest and 

the distances that a particle must travel to reach the wall of an airway are minimal. 

The electrical charge on some particles may result in an enhanced deposition over what would 

be expected based on size alone. With an estimated charge of 10-50 negative ions per 0.5 μm 

particle, Scheuch et al. (1990, 006948) found deposition in humans (VT = 500 mL, f = 15 min-1) to 

increase from 13.4% (no charge) to 17.8% (charged). This increase in deposition is thought to result 

from image charges induced on the surface of the airway by charged particles. Yu (1985, 006963) 

estimated a charge threshold level above which deposition fractions would be increased of about 12, 

30, and 54% for 0.3, 0.6, and 1.0 μm diameter particles, respectively. Electrostatic deposition is 

generally considered negligible for particles below 0.01 μm because so few of these particles carry a 

charge at Boltzmann equilibrium. This mechanism is also thought to be a minor contributor to 

overall particle deposition, but it may be important in some laboratory studies due to specific aerosol 

generation techniques such as nebulization. Laboratory methods such as passage of aerosols through 

a Kr-85 charge neutralizer prior to inhalation are commonly used to mitigate this effect. 

The National Radiological Protection Board (NRPB) recently evaluated the potential for 

corona discharges from high voltage power lines to charge particles and enhance particulate doses 

(NRPB, 2004, 156815). They concluded that electrostatic effects would be the most important for 

particles in the size range from about 0.1-1 μm, where deposition may theoretically increase by a 

factor of three to ten. However, given that only a small fraction of ambient particles would pass 

through the corona to become charged, the small range of relevant particle sizes (0.1-1 μm), and the 

subsequent required transport of charged particles to expose individuals; the NRPB concluded that 

effects, if any, of electric fields on particle deposition in the human respiratory tract would likely be 

minimal. 

Thermophoretic forces on particles occur due to temperature differences between respired air 

and respiratory tract surfaces. Temperature gradients of around 20°C are thought to produce 

sufficient thermophoretic force to oppose diffusive and electrostatic deposition during inspiration 

and to perhaps augment deposition by these mechanisms during expiration (Jeffers, 2005, 156608). 

Thermophoresis is only relevant in the extrathoracic and large bronchi airways and reduces to zero 

as the temperature gradient decreases deeper in the lung. Theoretical analysis of thermophoresis has 

been done for smooth walled tubes and is important over distances that are several orders of 

December 2009 4-6 
magnitude smaller than the diameter of the trachea. The alteration of the flow patterns by airway 

surface features such as cartilaginous rings may affect particle transport and deposition over far 

greater distances than thermophoretic force. 

4.2.2. Deposition Patterns 

Knowledge of sites where particles of different sizes deposit in the respiratory tract and the 

amount of deposition therein is necessary for understanding and interpreting the health effects 

associated with exposure to particles. Particles deposited in the various respiratory tract regions are 

subjected to large differences in clearance mechanisms and pathways and, consequently, retention 

times. Deposition patterns in the human respiratory tract were described in considerable detail in 

dosimetry chapters of prior PM AQCD (U.S. EPA, 1996, 079380; U.S. EPA, 2004, 056905); as such, 

they are only briefly described here. 

Predicted total and regional deposition for an adult male during rest and light exercise are 

illustrated in Figure 4-3 and Figure 4-4, respectively. Note that a large proportion of inhaled coarse 

particles in the 3-6 μm (dae) range can reach and deposit in the lower respiratory tract, particularly 

the TB airways. Although these figures were provided in Chapter 6 of the 2004 PM AQCD, they are 

reproduced here to illustrate changes in deposition as a function of particle size and breathing 

conditions. The predictions were based on two publicly available particle deposition models, the 

ICRP (1995, 006988) and the Multi-Path Particle Dosimetry model (MPPD; Version 1.0, ©2002). 

The ICRP (1995, 006988) model was implemented by Lung Dose Evaluation Program (LUDEP; 

Version 2.07, June 2000). The MPPD1

 model was developed by the CIIT Centers for Health 

Research with support from the Dutch National Institute of Public Health and the Environment. 

Figure 4-3. Comparison of total and regional deposition results from the ICRP and MPPD 

models for a resting breathing pattern (VT = 625 mL, f = 12 min-1) and corrected 

for particle inhalability. Regions are extrathoracic, ET; tracheobronchial, TB; and 

alveolar, A. Panels a-b are for nose breathing; panels c-d are for mouth breathing. 

 

1

 For more information about this model, the reader is referred to: http://www.ara.com/products/mppd_capabilities.htm. 

December 2009 4-7 
Figure 4-4. Comparison of total and regional deposition results from the ICRP and MPPD 

models for a light exercise breathing pattern (VT = 1250 mL, f = 20 min-1) and 

corrected for particle inhalability. Regions are extrathoracic, ET; 

tracheobronchial, TB; and alveolar, A. Panels a-b are for nose breathing; panels 

c-d are for mouth breathing. 

4.2.2.1. Total Respiratory Tract Deposition 

The efficiency of deposition in the respiratory tract may generally be described as a 

“U-shaped” curve on a plot of deposition efficiency versus the log of particle diameter. Total 

deposition shows a minimum for particle diameters in the range of 0.1 to 1.0 μm, where particles are 

small enough to have minimal sedimentation or impaction and sufficiently large so as to have 

minimal diffusive deposition. Total deposition does not decrease to zero for any sized particle, in 

part, because of mixing between particle laden tidal air and residual lung air. The particles mixed 

into residual air remain in the lung following a breath and are removed on subsequent breaths or 

gradually deposited. Total deposition approaches 100% for particles of roughly 0.01 μm (physical 

diameter) due to diffusive deposition and for particles of around 10 μm (dae) due to the efficiency of 

sedimentation and impaction. 

Total human lung deposition, as a function of particle size, is depicted in Figure 4-5. These 

experimental data were obtained by using monodisperse spherical test particles in healthy adults 

during controlled breathing on a mouthpiece. Despite the control of inhaled particle size and 

breathing conditions, this figure illustrates variability in deposition efficiencies due to interindividual differences in lung size and anatomical variability in airway dimensions and branching 

patterns. 

December 2009 4-8 
Source: Data from Kim and Hu (1998, 086066) and Kim and Jaques (2000, 012811). 

Figure 4-5. Total lung deposition measured in healthy adults (UF, 11 M, 11 F, 31 ± 4 yr; fine 

and coarse, 11 M, 11 F, 25 ± 4 yr) during controlled breathing on a mouthpiece. 

Deposition calculated from aerosol bolus measurements between 50 and 500 mL 

into a breath with 50 mL increments. Illustrated data are means and standard 

errors. Asterisk indicates significantly greater total deposition in females versus 

males. 

4.2.2.2. Extrathoracic Region 

The first line of defense for protecting the lower respiratory tract from inhaled particles is the 

nose and mouth. Particle deposition in the ET region, especially the nasal passages, reduces the 

amount available for deposition in the TB and alveolar regions. Recent data have become available, 

but are largely derived from computational fluid dynamics (CFD) modeling and experimental 

measurements in casts. As most of these studies do not substantially improve our understanding of 

deposition in the ET region they are not reviewed here. 

For particles >1 μm dae, deposition efficiency in the oral and nasal passages has been generally 

described as a function of an impaction parameter (Stokes number) with the addition of a flow 

regime parameter (Reynolds number) for the oral passages (Finlay and Martin, 2008, 155776; Grgic 

et al., 2004, 155810; Kelly et al., 2005, 155894; Schroeter et al., 2006, 156076). For an adult male, 

the CFD simulations of Schroeter et al. (2006, 156076) predicted nasal deposition of 10 μm dae

particles was 90%, and 100% for a VE of 7.5 L/min (rest) and 15 L/min (light activity), respectively. 

Thus, relatively few large coarse particles will pass through the nasal passages into the lungs. Since 

the nasal passages are more efficient at removing inhaled particles than the oral passage, an 

individual’s mode of breathing (i.e., oral versus nasal) influences the quantity of particles penetrating 

to the lung. 

In limited studies, it has been shown that children tend to have more oral breathing both at rest 

and during exercise and also displayed more variability than adults (Becquemin et al., 1999, 155679; 

Bennett et al., 2008, 156269; James et al., 1997, 042422). In contrast to adults, there is little data on 

the uptake of particles for oral or nasal breathing in children. Theoretical calculations by Xu and Yu 

(1986, 072697) predict enhanced deposition of particles (>2 μm) in the head region for children 

when compared to adults. Studies of fine particle deposition in physical models of the nose, scaled to 

adult versus children sizes, predict that deposition efficiency in the nose is a function of pressure 

drop across the nose (Phalen et al., 1989, 156023). Consequently, these model analyses suggest that, 

when properly scaled physiological flows are used in the calculation of nasal deposition, children, 

who have higher nasal resistance than adults, should have higher nasal deposition compared to 

adults. Surprisingly, the few studies reporting measures of nasal deposition in children, found lower 

nasal deposition efficiencies for fine particles (1-3 μm dae) as compared to adults, despite their 

higher nasal resistances (Becquemin et al., 1991, 009187; Bennett et al., 2008, 156269). These 

findings of lesser nasal versus oral breathing and less efficient nasal deposition suggest that 

children’s lower respiratory tract (i.e., the TB and alveolar regions) may receive a higher dose of 

December 2009 4-9 
ambient PM compared to adults. Normalized to lung surface area, the dose rate to the lower airways

of children versus adults is increased further because children breathe at higher minute ventilations 

relative to their lung volumes (see Section osition). 

4.2.

4.2.4.2 on age as a factor modulating dep

2.3. Tracheobronchial and Alveolar Region 

Inhaled particles passing the ET region enter and may become deposited in the lungs. For any 

given particle size, the pattern of particle deposition influences clearance by partitioning deposited 

material among lung regions. Deposition in the tracheobronchial airways and alveolar region cannot 

be directly measured in vivo. Much of the available deposition data for the TB and alveolar regions 

have been obtained from experiments with radioactively labeled, poorly soluble particles (U.S. EPA, 

1996, 079380) or by use of aerosol bolus techniques (U.S. EPA, 2004, 056905). In general, the 

ability of these experimental data to define specific sites of particle deposition is limited to 

anatomically large regions of the respiratory tract such as the head, larynx, bronchi, bronchioles, and 

alveolar region. Mathematical modeling can provide more refined predictions of deposition sites. 

Comparisons of the modeling results obtained with two publicly available models were provided in 

Figure 4-3 and Figure 4-4. Highly localized sites of deposition within the bronchi are described in 

Section 4.2.2.4. Both experimental and modeling techniques are based on many assumptions that 

may be relatively good for the healthy lung but not for the diseased lung. For discussion of these 

issues, the reader is referred to Sections 4.2.4.4 and 4.2.4.5. 

4.2.2.4. Localized Deposition Sites 

From a toxicological perspective, it is important to realize that not all epithelial cells in an 

airway will receive the same dose of deposited particles. Localized deposition in the vicinity of 

airway bifurcations has been analyzed using experimental and mathematical modeling techniques. In 

the 1996 PM AQCD, experimental data were available illustrating the peak deposition of coarse 

particles (3, 5, and 7 μm dae) in daughter airways during inspiration and the parent airway during 

expiration, but always near the carinal ridge (Kim and Iglesias, 1989, 078539; Kim et al., 1989, 

078538). In the 2004 PM AQCD, mathematical models predicted distinct “hot spots” of deposition 

in the vicinity of the carinal ridge for both coarse (10 μm) and UF (0.01 μm) particles (Heistracher 

and Hofmann, 1997, 047514; Hofmann et al., 1996, 047515). In a model of lung generations 4-5 

during inspiration, hot spots occurred at the carinal ridge for 10 μm dae particles due to inertial 

impaction and for 0.01 μm particles due to secondary flow patterns formed at the bifurcation. During 

expiration, preferential sites of deposition for both particle sizes occurred 1) approaching the 

juncture of daughter airways on the walls forming and across the lumen from the carinal ridge; and 

2) the top and bottom (visualizing the Y-shaped geometry laying horizontal) of the parent airway 

downstream of the bifurcation. 

Recent studies further support these findings (Balashazy et al., 2003, 155671; Farkas and 

Balásházy, 2008, 157358; Farkas et al., 2006, 155771; Isaacs et al., 2006, 155861). Most of these 

studies quantified localized deposition in terms of an enhancement factor. Typically, the 

enhancement factor is the ratio of the deposition in a pre-specified surface area (e.g., 100 × 100 μm 

which corresponds to ~10 × 10 epithelial cells) to the average deposition density for the whole 

airway geometry. These enhancement factors are very sensitive to the size of the surface considered 

(Balashazy et al., 1999, 043201). The studies by Farkas et al. (2006, 155771) and Farkas and 

Balásházy (2008, 157358) investigated the phenomena of localized deposition down to 0.001 μm 

particles. The deposition of 0.001 μm was rather uniform, however, the deposition pattern became 

increasingly less uniform with increasing particle size. These studies indicate that, for particles 

greater than ~0.01 μm, some cells located near the carinal ridge of bronchial bifurcations may 

receive hundreds to thousands times the average dose (particles per unit surface area) of the parent 

and daughter airways. Furthermore, the inertial impaction of particles ≥ 1 μm dae at the carinal ridge 

of large bronchi will increase with increasing inspiratory flows. In a comparison of constricted 

versus healthy airways, Farkas et al. (2006, 155771) also reported that the overall deposition 

efficiency of 10 μm dae particles at bifurcations downstream of a constriction may be increased by 

18 times. Given these considerations, Phalen and Oldham (2006, 156024) noted that substantial 

doses of particles (≥ 1 μm dae) may be justified for in vitro studies using tracheobronchial epithelial 

cell cultures. 

December 2009 4-10 
4.2.3. Interspecies Patterns of Deposition 

The primary purpose of this document is to assess the health effects of particles in humans. As 

such, human dosimetry studies have been stressed in this chapter. Such studies avoid the 

uncertainties associated with the extrapolation of dosimetric data from laboratory animals to humans. 

However, animal models have been and continue to be used in evaluating PM health effects because 

of ethical considerations regarding the types of studies that can be performed with human subjects. 

Thus, there is a considerable need to understand dosimetry in animals and dosimetric differences 

between animals and humans. Limited new data are becoming available. Similar deposition 

efficiencies have been reported in nasal casts of human and rhesus monkey for 1-10 μm dae for 

inspiratory flows mimicking resting breathing patterns (Kelly et al., 2005, 155894). Oldham and 

Robinson (2007, 156003) recently provided morphological data and predicted particle deposition in 

an asthma mouse model. 

Interspecies similarities and differences in deposition were described in detail in the last two 

PM AQCDs (U.S. EPA, 1996, 079380; U.S. EPA, 2004, 056905). It was concluded that the general 

pattern of total particle deposition efficiency was similar between laboratory animals and humans: 

deposition increases on both sides of a minimum that occurs for particles of 0.2-1 μm. There are, 

however, marked interspecies differences in uptake into the respiratory tract and regional deposition. 

For instance, the nasal inhalability of 10 μm dae particles is predicted to be 96% in humans, whereas 

it is only 44% in rats (Ménache et al., 1995, 006533). In most laboratory animal species (rat, mouse, 

hamster, guinea pig, and dogs), deposition in the ET region is near 100% for particles >5 μm dae

(Raabe et al., 1988, 001439), indicating greater efficiency than that seen in humans. Detailed 

presentation of dosimetric difference between rats and humans are available elsewhere (Brown et al., 

2005, 089308; Jarabek et al., 2005, 056756). 

Brown et al. (2005, 089308) conducted a thorough evaluation of extrapolations between rats 

and humans in relation to PM exposures. One of many factors they considered was the choice of a 

dose metric appropriate for comparison between species. For example, deposited mass may be an 

appropriate PM indicator for health effects associated with soluble PM constituents. For health 

effects associated with insoluble PM, the particle number, surface area, or mass may be appropriate 

indicators. Given interspecies differences in deposition patterns and clearance rates, the question of 

retained versus deposited dose was also discussed. It was concluded that for acute effects, the 

incremental dose may be the appropriate type of dose metric. For chronic effects, long-term burden 

may be more appropriate. For various dose metrics, estimates of particle concentration and exposure 

duration required for a rat to receive the same dose as received by a human were obtained with 

consideration of activity levels, mode of breathing, and particle size distributions. It was noted that 

high PM exposures over the period of months can lead to particle overload in rats (see 

Section 4.3.4.4). Exposure regimes were derived as a function of particle size and exposure duration 

that should avoid overwhelming macrophage mediated clearance achieving particle overload in rats 

(see Table 12 in Brown et al., 2005, 089308). The dosimetric calculations indicated that to achieve 

nominally similar acute doses per surface area in rats, relative to humans undergoing moderate to 

high exertion, PM exposure concentrations for rats would need to be somewhat higher than for 

humans. Since particle clearance from the lungs of rats is faster than humans, much higher exposure 

concentrations are required for the rat to simulate retained burdens of humans. Illustrating the 

complexity of such analyses, in some cases, rats were found to require lower exposures than humans 

to have comparable doses (generally when considering a scenario of humans at rest). 

4.2.4. Biological Factors Modulating Deposition 

Evaluation of factors affecting particle deposition is important to help understand potentially 

susceptible subpopulations. Differences in biological response following pollutant exposure may be 

caused by dosimetry differences as well as by differences in innate sensitivity. The effects of 

different biological factors on deposition were discussed in the 2004 PM AQCD (U.S. EPA, 2004, 

056905) and are summarized briefly here. 

December 2009 4-11 
4.2.4.1. Physical Activity 

The activity level of an individual is well recognized to affect their minute ventilation and 

route of breathing. Changes in minute ventilation during exercise are accomplished by increasing 

both VT and f (Table 4-1). Humans are oronasal breathers tending to breathe through the nose when 

at rest and increasingly through the mouth with increasing activity level. There is considerable interindividual variability in both the route by which people breathe and the way breathing pattern 

changes occur. 

Table 4-1. Breathing patterns with activity level in adult human male. 

Activity Awake 

Rest a Slow Walk a Light Exertion a Moderate Exertion a Heavy Exertion b

Breaths/min 

Tidal volume, mL 

Minute ventilation, L/min 

12 

625 

7.5 

16 

813 

13 

19 

1000 

19 

28 

1429 

40 

26 

1923 

50 

Sources: aWinter-Sorkina and Cassee (2002, 043670); bICRP (1995, 006988)

Individuals typically breathe through their nose while at rest, switching to oronasal breathing 

as ventilation increases (Bennett et al., 2003, 191977; Niinimaa et al., 1981, 071758). The role of the 

nose in filtering particles is diminished as airflow is diverted from the nose to the mouth during 

exercise, bringing more particles to the lower respiratory tract. A recent study in adults (Bennett et 

al., 2003, 191977) found that nasal ventilation during exercise varied as a function of both race and 

gender. African-Americans possessed a greater nasal contribution to breathing during exercise than 

Caucasians. At similar exercise efforts (i.e., normalized to a % maximum work capacity) the females 

also had a greater nasal contribution to breathing during exercise than males. 

In addition, when individuals increase their ventilation with activity the total number of 

particles inhaled per unit time (i.e., exposure rate) increases, but the fractional deposition of particles 

in each breath also changes with breathing pattern. Figure 4-3 and Figure 4-4 illustrate predicted 

deposition fractions in the respiratory tract during rest versus light exercise, respectively. During 

exercise, both VT and f increase. Fractional deposition for all particles increases with increased VT. 

Increasing the f, however, decreases the fractional deposition of fine and UFPs due to decreased time 

for gravitational and diffusive deposition. For particles larger than a dae of roughly 3 μm, increasing f 

can increase the deposition fraction due to increased impaction in the extrathoracic and TB airways. 

Thus, it should be expected that the change in deposition fraction with activity will vary among 

individuals depending on the relative influences of these two variables (i.e., VT and f ) in a given 

subject and the particle size to which they are exposed. Experimentally, the lung deposition fractions 

of fine particles during moderate exercise and mouth breathing are unchanged between rest and 

exercise (Bennett et al., 1985, 190034; Morgan et al., 1984, 190035). Kim (2000, 013112) evaluated 

differences in deposition of 1, 3, and 5 μm (MMAD) particles under varying breathing patterns 

(simulating breathing conditions of sleep, resting, and mild exercise). Total lung deposition increased 

with increasing VT at a given flow rate and with increasing flow rate at a given breathing period. 

These experimental studies suggest that the total deposited dose rate (i.e., deposition per unit time) 

of particles will generally increase in direct proportion to the increase in minute ventilation 

associated with exercise. 

The changes in ventilation, i.e., breathing pattern and flow rate, may also alter the regional 

deposition of particles. Coarse particle deposition increases in the TB and ET regions during exercise 

due to the increased flow rates and associated impaction. A rapid-shallow breathing pattern during 

exercise may result in more bronchial airway versus alveolar deposition, while a slow-deep pattern 

will shift deposition to deeper lung regions (Valberg et al., 1982, 190019). Bennett et al. (1985, 

190034) showed for 2.6 μm particles that moderate exercise shifted deposition from the lung 

periphery towards ET and larger, bronchial airways. Similarly, Morgan et al. (1984, 190035) showed 

that even for fine particles (0.7 μm) TB deposition was enhanced with exercise. This shift in 

deposition toward the bronchial airways results in a much greater dose per unit surface area of tissue 

in those regions. Morgan et al. (1984, 190035) also found that the apical-to-basal distribution of fine 

December 2009 4-12 
particles increased with exercise, i.e., a shift towards increased deposition in the lung apices. This 

shift may be less likely for larger particles, however, whose deposition in large airway bifurcations 

may preclude their transport to these more apical regions (Bennett et al., 1985, 190034). 

4.2.4.2. Age 

Airway structure and respiratory conditions vary with age, and these variations may alter the 

amount and site of particle deposition in the respiratory tract. It was concluded in the 2004 PM 

AQCD (U.S. EPA, 2004, 056905) that significant differences between adults and children had been 

predicted by mathematical models and observed in experimental studies. Studies generally indicated 

that ET and TB deposition was greater in children and that children received greater doses of 

particles per lung surface area than adults. Deposition studies in the elderly are still quite limited. 

A few studies have attempted to measure oronasal breathing in children as compared to adults 

(Becquemin et al., 1999, 155679; Bennett et al., 2008, 156269; James et al., 1997, 042422). This is 

important since particles deposit with greater efficiency in the nose relative to the mouth, thereby 

affecting exposure of the lower respiratory tract. James et al. (1997, 042422) found that children (age 

7-16 yr, n = 10) displayed more variability than adults with respect to their oronasal pattern of 

breathing with exercise. However, it was not possible to predict the pattern of the partitioning of 

ventilation during exercise based on age, gender, or nasal airway resistance. Further, in a limited 

number of children (age 8−16 yr, n = 10), Becquemin et al. (1999, 155679) found that the children 

tended to display more oral breathing both at rest and during exercise than the adults. The highest 

oral fractions were also found in the youngest children. None of these studies, however, was able to 

show a relationship between nasal resistance and the relative contribution of nasal breathing in 

children. Bennett et al. (2008, 156269) made preliminary measurements of the relative contributions 

of oral versus nasal breathing at rest and during incrementally graded submaximal exercise on the 

cycle ergometer for children (age 6-10 yr, n = 12) and adults (age 18-27 yr, n = 11). There was a 

trend for children to have a lesser nasal contribution to breathing at rest and during exercise, but the 

differences from adults were not statistically significant. 

Breathing patterns are well recognized to change with increasing age, i.e., VT increase and 

respiratory rates decrease (Tabachnik et al., 1981, 157036; Tobin et al., 1983, 156122). Bennett and 

Zeman (1998, 076182) measured the deposition fraction of inhaled, fine particles (2 μm dae) in 

children (age 7-14 yr, n=16) and adults (age 19-35 yr, n=12) as they breathed the aerosol with their 

natural, resting breathing pattern. Among the children, variation in deposition fractions, measured by 

photometry at the mouth, was highly dependent on intersubject variation in VT. On the other hand, 

they found no difference in deposition fractions between children versus adults for these fine 

particles. This finding and the modeling predictions (Hofmann et al., 1989, 006922) are explained in 

part by the smaller VT and faster breathing rate of children relative to adults for natural breathing 

conditions. Bennett et al. (2008, 156269) also recently reported measures of fine particle (1 and 2 μm 

dae) deposition at ventilation rates typical of light exercise in children (age 6-10 yr, n=12) and adults 

(age 18-27 yr, n=11) and showed that, like with resting breathing, deposition fractions were 

predicted by breathing pattern and did not differ or tended to be less in children compared to adults. 

On the other hand, because children breathe at higher minute ventilations relative to their lung 

volumes, the rate of deposition of fine particles normalized to lung surface area may be greater in 

children versus adults (Bennett and Zeman, 1998, 076182). 

Bennett and Zeman (2004, 155686) expanded their measures of fine particle deposition during 

resting breathing to a larger group of healthy children (6-13 yr; 20 boys, 16 girls) and found again 

that the variation in total deposition was best predicted by VT (r = 0.79, p < 0.001). But both VT and 

resting minute ventilation increased with both height and body mass index (BMI) of the children. 

Interestingly, these data suggest that for a given height and age, children with higher BMI have 

larger minute ventilations and VT at rest than those with lower BMI. These differences in breathing 

patterns as a function of BMI translated into increased deposition of fine particles in the heaviest 

children. The rate of deposition (i.e., particles depositing per unit time) in the overweight children 

was 2.8 times that of the leanest children (p < 0.02). Among all children, the rate of deposition was 

significantly correlated with BMI (r = 0.46, p < 0.004). Some of the increase in deposition fractions 

of heavier children may be due to their elevated VT, which was well correlated with BMI (r = 0.72, 

p < 0.001). 

In 62 healthy adults with normal lung function aged 18-80 yr, Bennett et al. (1996, 083284) 

showed there was no effect of age on the whole lung deposition fractions of 2-μm particles under 

December 2009 4-13 
natural breathing conditions. Across all subjects, the deposition fractions were found to be 

independent of age, depending on breathing period (r = 0.58, p < 0.001) and airway resistance 

(r = 0.46, p < 0.001). In the same adults breathing with a fixed pattern (360 mL VT, 3.4 sec breathing 

period), there was a mild decrease in deposition with increasing age, which could be attributed to 

increased peripheral airspace dimensions in the elderly. 

4.2.4.3. Gender 

Males and females differ in body size, conductive airway size, and ventilatory parameters; 

therefore, gender differences in deposition might be expected. In some of the controlled studies, 

however, the men and women were constrained to breathe at the same VT and f. Since women are 

generally smaller than men, the increased minute ventilation of women compared to their normal 

ventilation could affect deposition patterns. This may help explain why gender related effects on 

deposition have been observed in some studies. 

Kim and Hu (1998, 086066) assessed the regional deposition patterns of 1-, 3-, and 5-μm 

MMAD particles in healthy adult males and females using controlled breathing. The total fractional 

deposition in the lungs was similar for both genders with the 1-μm particle size, but was greater in 

women for the 3- and 5-μm particles. Deposition also appeared to be more localized in the lungs of 

females compared to those of males. Kim and Jaques (2000, 012811) measured deposition in healthy 

adults using sizes in the UF mode (0.04-0.1 μm). Total fractional lung deposition was greater in 

females than in males for 0.04- and 0.06-μm particles. The region of peak fractional deposition was 

shifted closer to the mouth and peak height was slightly greater for women than for men for all 

exposure conditions. The total lung deposition data from these studies are illustrated in Figure 4-5. These differences were generally attributed to the smaller size of the upper airways, particularly of 

the laryngeal structure, in females. 

In another study (Bennett et al., 1996, 083284), the total respiratory tract deposition of 2-μm 

particles was examined in adult males and females aged 18-80 yr who breathed with a normal resting 

pattern. There was a tendency for greater deposition fractions in females compared to males. 

However, since males had greater minute ventilation, the deposition rate (i.e., deposition per unit 

time) was greater in males than in females. More recently, Bennett and Zeman (2004, 155686) found 

no difference in the deposition of 2-μm particles in boys versus girls aged 6-13 yr (n = 36). 

4.2.4.4. Anatomical Variability 

Anatomical variability, even in the absence of respiratory disease, can affect deposition 

throughout the respiratory tract. The ET region is the first exposed to inhaled particles and, therefore, 

deposition within this region would reduce the amount of particles available for deposition in the 

lungs. Variations in relative deposition within the ET region will, therefore, propagate through the 

rest of the respiratory tract, creating differences in calculated doses among individuals. 

The influence of variations in nasal airway geometry on particle deposition has been 

investigated. Cheng et al. (1996, 047520) examined nasal airway deposition in healthy adults using 

particles ranging in size from 0.004 to 0.15 μm and at 2 constant inspiratory flow rates, 167 and 

333 mL/s. Inter-individual variability in deposition was correlated with the wide variation of nasal 

dimensions; in that, greater surface area, smaller cross-sectional area, and increasing complexity of 

airway shape were all associated with enhanced deposition. Bennett and Zeman (2005, 155687) have 

also shown that nasal anatomy influences the efficiency of particle uptake in the noses of adults. For 

light exercise breathing conditions in adults, their study demonstrated that nasal deposition 

efficiencies for both 1- and 2-μm monodisperse particles were significantly less in African 

Americans versus Caucasians. The lesser nasal efficiencies in African-Americans were associated 

with both lower nasal resistance and less elliptical nostrils compared to Caucasians. 

Within the lungs, the branching structure of the airways may also differ between individuals. 

Zhao et al. (2009, 157187) recently examined the bronchial anatomy of the left lung in patients 

(132 M, 84 W; mean age 47 yr) that underwent conventional thoracic computed tomography scans 

for various reasons. At the level of the segmental bronchus in the upper and lower lobes, a 

bifurcation occurred in the majority of patients. A trifurcation, however, was observed in 23% of the 

upper and 18% of the lower lobes. Other more unusual findings were also reported such as four 

bronchi arising from the left upper lobe bronchus. As described in Section 4.2.2.4, deposition can be 

highly localized near the carinal ridge of bifurcations. The effect of a bifurcation versus other 

December 2009 4-14 
branching patterns on airflow patterns and particle deposition has not been described in the literature. 

Martonen et al. (1994, 000847) showed that a wide blunt carinal ridge shape dramatically affected 

the flow stream lines relative to a narrower and more rounded ridge shape. Specifically, there were 

high flow velocities across the entire area of the blunt carinal ridge versus a smoother division of the 

airstream in the case of the narrow rounded ridge shape. The implication may be that localized 

particle deposition on the carinal ridge would increase with ridge width. A similar situation might be 

expected for a trifurcation versus a bifurcation. These differences in branching patterns provide a 

clear example of anatomical variability among individuals that might affect both air flow patterns 

and sites of particle deposition. 

4.2.4.5. Respiratory Tract Disease 

The presence of respiratory tract disease can affect airway structure and ventilatory 

parameters, thus altering deposition compared to that occurring in healthy individuals. The effect of 

airway diseases on deposition has been studied extensively, as described in the 1996 and 2004 PM 

AQCD (U.S. EPA, 1996, 079380; U.S. EPA, 2004, 056905). Studies described therein showed that 

people with chronic obstructive pulmonary disease (COPD) had very heterogeneous deposition 

patterns and differences in regional deposition compared to healthy individuals. People with 

obstructive pulmonary diseases tended to have greater deposition in the TB region than did healthy 

people. Furthermore, there tended to be an inverse relationship between bronchoconstriction and the 

extent of deposition in the alveolar region, whereas total respiratory tract deposition generally 

increased with increasing degrees of airway obstruction. 

The vast majority of deposition studies in individuals with respiratory disease have been 

performed during controlled breathing, i.e., all subjects breathed with the same VT and f. However, 

although resting VT is similar or elevated in people with COPD compared to healthy individuals, the 

former tend to breathe at a faster rate, resulting in higher than normal tidal peak flow and resting 

minute ventilation. Thus, given that breathing patterns differ between healthy and obstructed 

individuals, particle deposition data for controlled breathing may not be appropriate for estimating 

respiratory doses from ambient PM exposures. 

Bennett et al. (1997, 078839) measured the fractional deposition of insoluble 2-μm particles in 

moderate-to-severe COPD patients (n = 13; mean age 62 yr) and healthy older adults (n = 11; mean 

age 67 yr) during natural resting breathing. COPD patients had about a 50% greater deposition 

fraction and a 50% increase in resting minute ventilation relative to the healthy adults. As a result, 

the patients had an average deposition rate of about 2.5 times that of healthy adults. Similar to 

previously reviewed studies (U.S. EPA, 1996, 079380; U.S. EPA, 2004, 056905), these investigators 

observed an increase in deposition with an increase in airway resistance, suggesting that deposition 

increased with the severity of airway disease. 

Brown et al. (2002, 043216) measured the deposition of an UF aerosol (CMD = 0.033 μm) 

during natural resting breathing in 10 patients with moderate-to-severe COPD (mean age 61 yr) and 

9 healthy adults (mean age 53 yr). The COPD group consisted of 7 patients with chronic bronchitis 

and 3 patients with emphysema. The total deposition fraction in the bronchitic patients (0.67) was 

significantly (p < 0.02) greater than in either the patients with emphysema (0.48) or the healthy 

subjects (0.54). Minute ventilation increased with disease severity (healthy, 5.8 L/min; chronic 

bronchitic, 6.9 L/min; emphysema, 11 L/min). Relative to the healthy subjects, the average dose rate 

was significantly (p < 0.05) increased by 1.5 times in the COPD patients, whereas the average 

deposition fraction only tended to be increased by 1.1 times. These data further demonstrate the need 

to consider dose rates (which depend on minute ventilation) rather than just deposition fractions 

when evaluating the effect of respiratory disease on particle deposition and dose. 

December 2009 4-15 
Source:Data from Tu and Knutson (1984, 072870). 

Figure 4-6. Total deposition of hygroscopic sodium chloride and hydrophobic 

aluminosilicate aerosols during oral breathing (VT = 1.0 L; f = 15 min-1). 

4.2.4.6. Hygroscopicity of Aerosols 

Experimental and modeling studies of hygroscopic aerosol growth and deposition in the lung 

were extensively discussed in Section 10.4.3.1 of the 1996 PM AQCD (U.S. EPA, 1996, 079380). 

Hygroscopic ambient aerosols include sulfates, nitrates, some organics, and aerosols laden with 

sodium or potassium. The high relative humidity in the lungs contributes to rapid growth of 

hygroscopic particles and dramatically alters the deposition characteristics of ambient hygroscopic 

aerosols relative to nonhygroscopic aerosols. Nonhygroscopic particles in the range of 0.3 μm have 

minimal intrinsic mobility and low total deposition in the lungs. However, a 0.3 μm salt particle 

(dry) will grow in vivo to nearly 2 μm and deposit to a far greater extent (Anselm et al., 1990, 

156217). The hygroscopic growth of particles in the respiratory tract decreases diffusive deposition 

and increases aerodynamic deposition as illustrated in Figure 4-6. 

4.2.5. Summary 

Particle deposition in the respiratory tract occurs predominantly by diffusion, impaction, and 

sedimentation. Deposition is minimal for particle diameters in the range of 0.1 to 1.0 μm, where 

particles are small enough to have minimal sedimentation or impaction and sufficiently large so as to 

have minimal diffusive deposition. In humans, total respiratory tract deposition approaches 100% for 

particles of roughly 0.01 μm (physical diameter) due to diffusive deposition and for particles of 

around 10 μm dae due to the efficiency of sedimentation and impaction. 

The first line of defense for protecting the lower respiratory tract from inhaled particles is the 

nose and mouth. Nasal deposition approaches 100% in the average human for 10 μm dae particles. 

Experimental studies show lower nasal particle deposition in children than adults. Relative to adults, 

children also tend to breathe more through their mouth which is less efficient for removing inhaled 

particles than the nose. These findings suggest that the lower respiratory tract of children may 

receive a higher dose of ambient PM compared to adults. Since children breathe at higher minute 

ventilations relative to their lung volumes, the rate of particle deposition normalized to lung surface 

area may be further increased relative to adults. 

People with COPD generally have greater total deposition and more heterogeneous deposition 

patterns compared to healthy individuals. The observed increase in deposition correlates with 

increases in airway resistance, suggesting that deposition increases with the severity of airway 

disease. COPD patients also have an increased resting minute ventilation relative to the healthy 

adults. This demonstrates the need to consider dose rates (which depend on minute ventilation) 

December 2009 4-16 
rather than just deposition fractions when evaluating the effect of respiratory disease on particle 

deposition and dose. 

 Modeling studies indicate that, for particles greater than ~0.01 μm, some cells located near the 

carinal ridge of bronchial bifurcations may receive hundreds to thousands times the average dose 

(particles per unit surface area) of the parent and daughter airways. The inertial impaction of 

particles ≥ 1 μm dae at the carinal ridge of large bronchi increases with increasing inspiratory flows. 

Airway constriction can further augment the overall deposition efficiency of coarse particles at 

downstream bifurcations. These findings suggest that substantial doses of particles (≥ 1 μm dae) may 

be justified for in vitro studies using tracheobronchial epithelial cell cultures. 

Our ability to extrapolate between species has not generally changed since the 2004 PM 

AQCD (U.S. EPA, 2004, 056905). However, some considerations related to coarse particles warrant 

comment. The inhalability of particles having dae of 2.5, 5, and 10 μm is 80, 65, and 44% in rats, 

respectively, whereas it remains near 100% for a dae of 10 μm in humans. In most laboratory animal 

species (rat, mouse, hamster, guinea pig, and dogs), deposition in the extrathoracic region is near 

100% for particles greater than 5 μm dae. By contrast, in humans nasal deposition approaches 100% 

for 10 μm dae. Oronasal breathing versus obligate nasal breathing further contributes to greater 

penetration of coarse particles into the lower respiratory tract of humans than rodents. 

4.3. Clearance of Poorly Soluble Particles 

This section discusses the clearance and translocation of poorly soluble particles that have 

deposited in the respiratory tract. The term “clearance” is used here to refer to the processes by 

which deposited particles are removed by mucociliary action or phagocytosis from the respiratory 

tract. “Translocation” is used here mainly to refer to the movement of free particles across cell 

membranes and to extrapulmonary sites. In the literature, translocation may also refer to the extraand intracellular dissolution of particles and the subsequent transfer of dissociated material to the 

blood through extra- and intracellular fluids and across the various cell membranes and lung tissues. 

The clearance and distribution of soluble particles and soluble constituents of particles are discussed 

in Section 4.4. 

A basic overview of biological mechanisms and clearance pathways from various regions of 

the respiratory tract are presented in the following sections. Then regional kinetics of particle 

clearance are addressed. Subsequently, an update on interspecies patterns and rates of particle 

clearance is provided. The translocation of UFPs is also discussed. Finally, information on biological 

factors that may modulate clearance is presented. 

4.3.1. Clearance Mechanisms and Kinetics 

For any given particle size, the deposition pattern of poorly soluble particles influences 

clearance by partitioning deposited material between lung regions. Tracheobronchial clearance of 

poorly soluble particles in humans, with some exceptions, is thought (in general) to be complete 

within 24-48 h through the action of the mucociliary escalator. Clearance of poorly soluble particles 

from the alveolar region is a much slower process which may continue from months to years. 

4.3.1.1. Extrathoracic Region 

Particles deposited in either the nasal or oral passages are cleared by several mechanisms. 

Particles depositing in the mouth may generally be assumed to be swallowed or removed by 

expectoration. Particles deposited in the posterior portions of the nasal passages are moved via 

mucociliary transport towards the nasopharynx and swallowed. Mucus flow in the most anterior 

portion of the nasal passages is forward, toward the vestibular region where removal occurs by 

sneezing, wiping, or nose blowing. 

December 2009 4-17 
4.3.1.2. Tracheobronchial Region 

Mucociliary clearance in the TB region has generally been considered to be a rapid process 

that is relatively complete by 24-48 h post-inhalation in humans. Mucociliary clearance is frequently 

modeled as a series of “escalators” moving material proximally from one generation to the next. As 

such, the removal rate of particles from an airway generation increases with increasing tracheal 

mucus velocity. Assuming continuity in the amount of mucus between airway generations, mucus 

velocities decrease and transit times within an airway generation increase with distal progression. 

Although clearance from the TB region is generally rapid, experimental evidence discussed in the 

1996 and 2004 PM AQCD (U.S. EPA, 1996, 079380; U.S. EPA, 2004, 056905) showed that a 

fraction of material deposited in the TB region is retained much longer. 

The slow-cleared TB fraction (i.e., the fraction of particles deposited in the TB region that are 

subject to slow clearance) was thought to increase with decreasing particle size. For instance, Roth et 

al. (1993, 156928) showed approximately 93% retention of UFPs (30 nm median diameter) thought 

to be deposited in the TB region at 24 h post-inhalation. The slow phase clearance of these UFPs 

continued with an estimated half-time (t1/2) of around 40 days. Using a technique to target inhaled 

particles (monodisperse 4.2 μm MMAD) to the conducting airways, Möller et al. (2004, 155987) 

observed that 49 ± 9% of particles cleared rapidly (t1/2 of 3.0 ± 1.6 h), whereas the remaining 

fraction cleared considerably slower (t1/2 of 109 ± 78 days). The ICRP (1995, 006988) human 

respiratory tract model assumes particles ≤ 2.5 μm (physical diameter) to have a slow-cleared TB 

fraction of 50%. The slow-cleared fraction assumed by the ICRP (1995, 006988) decreases with 

increasing particle size to <1% for 9 μm particles. Considering the UF data of Roth et al. (1993, 

156928) in addition to data considered by the ICRP (1995, 006988), Bailey et al. (1995, 190057) 

estimated a slow-cleared TB fraction of 75% for UFPs. At that time, they (Bailey et al. 1995) also 

estimated the slow-cleared fraction to decrease with increasing particle size to 0% for particles ≥ 6

μm. Recent experimental evidence from the same group (Smith et al., 2008, 190037) showed no 

difference in TB clearance among humans for particles with geometric sizes of 1.2 versus 5 μm, bu

the same d

t 

s, 

s 

an expected. 

ae (5 μm) so as to deposit similarly in the TB airways. For at least micron-sized particle

these recent findings do not support the particle size dependence of a slow-cleared TB fraction. A

discussed further below, much of the apparent slow-cleared TB fraction may be accounted for by 

differences in deposition patterns, i.e., greater deposition in the alveolar region th

A portion of the slow cleared fraction from the TB region appears to be associated with small 

bronchioles. For large particles (dae = 6.2 μm) inhaled at a very slow rate to theoretically deposit 

mainly in small ciliated airways, 50% had cleared by 24 h post-inhalation. Of the remaining 

particles, 20% cleared with a t1/2 of 2.0 days and 80% with a t1/2 of 50 days (Falk et al., 1997, 

086080). Using the same techniques, Svartengren et al. (2005, 157034) also reported the existence of 

long-term clearance in humans from the small airways. It should be noted that the clearance rates for 

the slow-cleared TB fraction still exceeds the clearance rate of the alveolar region in humans. 

Kreyling et al. (1999, 039175) targeted inhaled particle (dae = 2.2 and 2.5 μm) deposition to the TB 

airways of adult beagle dogs and subsequently quantified particle retention using scintigraphic and 

morphometric analyses. Despite the use of shallow aerosol bolus inhalation to a volumetric lung 

depth of less than the anatomic dead space, 2.5-25% of inhaled particles deposited in alveoli. At 24 

and 96 h post-inhalation, more than 50% of the retained particles were in alveoli. However, 40% of 

particles present at 24 and 96 h were localized to small TB airways of between 0.3 and 1 mm in 

diameter. Collectively, these studies suggest that although mucociliary clearance is fast and effective 

in healthy large airways, it is less effective and sites of longer retention exist in the smaller TB 

airways. 

The underlying sites and mechanisms of long-term TB retention in the smaller airways remain 

largely unknown. Several factors may contribute to the existence or experimental artifact of slow 

clearance from the smaller TB airways. Even when inhaled to very shallow lung volumes, some 

particles reach the alveolar region (Kreyling et al., 1999, 039175). Therefore, experiments utilizing 

bolus techniques to target inhaled particle deposition to the TB airways may have had some 

deposition in the alveolar region. This may occur due to variability in path length and the number of 

generations to the alveoli (Asgharian et al., 2001, 017025) and/or differences in regional ventilation 

(Brown and Bennett, 2004, 190032). Nonetheless, the experimentally measured clearance rates 

measured for the slow cleared TB fraction are faster than that of the alveolar region in both humans 

and canines. Thus, although experimental artifacts likely occur, they do not discount the existence of 

a slow cleared TB fraction. To some extent, it is possible that the slow cleared TB fraction may be 

due to bronchioles that do not have a continuous ciliated epithelium as in the larger bronchi. Neither 

December 2009 4-18 
path length, ventilation distribution, nor a discontinuous ciliated epithelium explains an apparently 

slow cleared TB fraction with decreasing particle size below 0.1 μm. As discussed in Section 4.3.3

on Particle Translocation, UFPs cross cell membranes by mechanisms different from larger (~1 μm) 

particles. Based on that body of literature, particles smaller than a micron may enter epithelial cells 

resulting in their prolonged retention, particularly in the bronchioles where the residence time is 

longer and distances necessary to reach the epithelium are shorter compared to that in the bronchi. 

4.3.1.3. Alveolar Region 

The primary alveolar clearance mechanism is macrophage phagocytosis and migration to 

terminal bronchioles where the cells are cleared by the mucociliary escalator. Alveolar macrophages 

originate from bone marrow, circulate briefly as monocytes in the blood, and then become 

pulmonary interstitial macrophages before migrating to the luminal surfaces. Under normal 

conditions, a small fraction of ingested particles may also be cleared through the lymphatic system. 

This may occur by transepithelial migration of alveolar macrophage following particle ingestion or 

free particle translocation with subsequent uptake by interstitial macrophages. Snipes et al. (1997, 

156092) have also demonstrated the importance of neutrophil phagocytosis in clearance of particles 

from the alveolar region. Rates of alveolar clearance of poorly soluble particles vary between species 

and are briefly discussed in Section 4.3.2. The translocation of particles from their site of deposition 

is discussed in Section 4.3.3. The efficiency of macrophage phagocytosis is thought to be greatest for particles between 1.5 

and 3 μm (Oberdörster, 1988, 006857). The decreased efficiency of alveolar macrophage for 

engulfing UFPs increases the time available for these particles to be taken up by epithelial cells and 

moved into the interstitium (Ferin et al., 1992, 044401). Consistent with this supposition 

(i.e., translocation increases with time), an increase in titanium dioxide (TiO2) particle transport to 

lymph nodes has been reported following inhalation of a cytotoxin to macrophages (Greenspan et al., 

1988, 045031). Interestingly, the long-term clearance kinetics of the poorly soluble UF (15-20 nm 

CMD) iridium (Ir) particles were found to be similar to the kinetics reported in the literature for 

micrometer-sized particles (Semmler et al., 2004, 055641; Semmler-Behnke et al., 2007, 156080). 

Semmler-Behnke et al. (2007, 156080) concluded that UF Ir particles are less phagocytized by 

alveolar macrophage than larger particles, but are effectively removed from the airway surface into 

the interstitium. Particles are then engulfed by interstitial macrophages which then migrate to the 

airway lumen and are removed by mucociliary clearance to the larynx. The major role of 

macrophage-mediated clearance was supported by lavage of relatively few free particles versus 

predominantly phagocytized particles at time-points of up to 6 mo. It is also possible that some free 

particles as well as particle-laden macrophages were carried from interstitial sites via the lymph flow 

to bronchial and bronchiolar sites, including bronchial-associated lymphatic tissue, where they were 

excreted again into the airway lumen. 

4.3.2. Interspecies Patterns of Clearance and Retention 

There are differences between species in both the rates of particle clearance from the lung and 

manner in which particles are retained in the lung. For instance, based on models of mucociliary 

clearance from un-diseased airways, >95% of particles deposited in the tracheobronchial airways of 

rats are predicted to be cleared by 5 h post deposition, whereas it takes nearly 40 h for comparable 

clearance in humans (Hofmann and Asgharian, 2003, 055579). As noted in Section 4.3.1.2, however, 

there is considerable evidence that a sizeable fraction of particles deposited at the bronchiolar level 

of the ciliated airways in humans (as well as canines) are cleared at a far slower rate. The slow 

cleared TB fraction appears to increase with decreasing particle size. 

December 2009 4-19 
0.10

1.00

0 100 200 300 400

Days after inhalation

Fraction Retained

F-344 rat

Dog

Human

L-E rat

Hamster

HTM rat

Guinea Pig

Source: Data from Kreyling and Scheuch (2000, 056281). 

Figure 4-7. Retention of poorly soluble particles (0.5-5 μm) in the alveolar region of the lung 

over time in various mammalian species. 

Figure 4-7 illustrates rates of alveolar clearance for 0.5-5 μm particles in various mammalian 

species. The alveolar clearance rate of particles smaller than 0.1 μm and larger than 5 μm is slower 

than that of particles in the 0.5-5 μm range. From interspecies comparisons of alveolar clearance, the 

path length from alveoli to ciliated terminal bronchioles may affect the particle transport rate 

(Kreyling and Scheuch, 2000, 056281). The average path length from alveoli to ciliated terminal 

bronchioli is longer in humans, monkeys, and dogs, than in sheep, rats, hamsters, and mice. 

Transport time and hence retention times may increase with path length. This hypothesis fits with all 

species in this comparison, except guinea pigs, which have a short path length yet particle retention 

that is nearly as long as in humans, monkeys, and dogs. However, sheep have a short path length and 

particle transport as fast as rodents. In general, alveolar clearance rates appear to increase with 

increasing path length from the alveoli to ciliated airways. 

There are also distinct differences in the sites of particle retention between species. Large 

mammals retain particles in interstitial tissues under normal conditions, whereas rats retain particles 

in alveolar macrophages (Snipes, 1996, 076041). In rats with chronic high doses there is a shift in 

the pattern of dust accumulation and response from that observed at lower doses in the lungs (Snipes, 

1996, 076041; Vincent and Donaldson, 1990, 002462). Rats chronically exposed to high 

concentrations of insoluble particles experience a reduction in their alveolar clearance rates and an 

accumulation of interstitial particle burden (Bermudez et al., 2002, 055578; Bermudez et al., 2004, 

056707; Ferin et al., 1992, 044401; Oberdörster et al., 1994, 046203; Oberdörster et al., 1994, 

056285; Warheit et al., 1997, 086055). The influence of exposure concentration on the pattern of 

particle retention in rats (exposed to diesel soot) and humans (exposed to coal dust) was examined 

by Nikula et al. (2001, 016641). In rats, the diesel particles were found to be primarily in the lumens 

of the alveolar duct and alveoli; whereas in humans, retained dust was found primarily in the 

interstitial tissue within the respiratory acini. 

4.3.3. Particle Translocation 

Mucociliary and macrophage mediated clearance of poorly soluble particles from the 

respiratory tract was discussed in Section 4.3.1. There is evidence that particles may cross cell 

membranes and move from their site of deposition by other mechanisms. The following subsections 

discuss the movement of particles from the luminal surfaces of the alveolar region and from the 

olfactory mucosa. The clearance and distribution of soluble particles and soluble constituents of 

particles are discussed in Section 4.4. 

December 2009 4-20 
4.3.3.1. Alveolar Region 

Numerous studies have examined the translocation of UFPs from their site of deposition in the 

lung. Traditionally viewed as a relatively inert particle type, UF TiO2 has received the most study. At 

the time the 2004 PM AQCD was released, there were conflicting results regarding the rate and 

magnitude of UF carbon translocation from the human lung. Since that time, it has become wellestablished that the transport of UF carbon particles from the human lung is far slower than that of 

soluble materials. However, it has also been shown in animal studies (primarily of rats) that UFPs 

cross cell membranes by mechanisms different from larger (~1 μm) particles and that a small 

fraction of these particles enter capillaries and may distribute systemically. Described in brief below, 

details of selected new studies investigating the disposition of poorly soluble particles are provided 

in Annex B. 

There has been some contention regarding ability of UF carbon particles to rapidly diffuse 

from the lungs into the systemic circulation. Based on their study of 5 healthy volunteers, Nemmar et 

al. (2002, 024914) suggested that UF carbon particles (<100 nm) pass rapidly into the systemic 

circulation. However, Brown et al. (2002, 043216) found that the majority of UF carbon particles 

(CMD, 33 ± 2 nm) were still in the lungs of healthy human adult volunteers (n = 9; aged 40-67 yr) 

and COPD patients (n = 10; 45-70 yr) at 24 h post-inhalation. Brown et al. (2002, 043216) and 

Burch (2002, 056754) contended that the findings reported by Nemmar et al. (2002, 024914) were 

consistent with soluble pertechnetate clearance, but not insoluble UF carbon particles. Highly 

soluble in normal saline, pertechnetate clears rapidly from the lung with a half-time of ~10 min and 

accumulates most notably in the bladder, stomach, thyroid, and salivary glands. Three recent studies 

have confirmed that the majority (>95%) of UF carbon particles deposited in the lungs of human 

volunteers are retained at 24 h post-inhalation (Mills et al., 2006, 088770; Wiebert et al., 2006, 

157146; Wiebert et al., 2006, 156154). Wiebert et al. (2006, 157146) modified their aerosol 

generation system to reduce leaching of the 99mTc radiolabel from carbon particles. Except for a 

small amount of radiotracer leaching from particles (1.0 ± 0.6% of initially deposited activity in 

urine by 24 h), these investigators found negligible radiolabel and associated particle clearance from 

the lungs by 70 h. The available data show that there is not a rapid or significant amount of UF 

carbon particle migration into circulation (Brown et al., 2002, 043216; Burch, 2002, 056754; Mills et 

al., 2006, 088770; Möller et al., 2008, 156771; Wiebert et al., 2006, 157146; Wiebert et al., 2006, 

156154). 

Although human studies show that the vast majority of UF carbon particles are retained in the 

lungs until at least 24 h post-inhalation, both in vitro and in vivo studies support the rapid (≤ 1 h) 

translocation of free UF TiO2 particles across pulmonary cell membranes (Churg et al., 1998, 

085815; Ferin et al., 1992, 044401; Geiser et al., 2005, 087362). Peculiar to TiO2 aerosols, there is 

evidence that particle aggregates may disassociate once deposited in the lungs. This disassociation 

makes inhaled aggregate size the determinant of deposition amount and site, but primary particle size 

the determinant of subsequent clearance (Bermudez et al., 2002, 055578; Ferin et al., 1992, 044401; 

Takenaka et al., 1986, 046210). Following disaggregation, the UF TiO2 particles are cleared more 

slowly and cause a greater inflammatory response (neutrophil influx) than fine TiO2 particles 

(Bermudez et al., 2002, 055578; Ferin et al., 1992, 044401; Oberdörster et al., 1994, 046203; 

Oberdörster et al., 1994, 056285; Oberdorster et al., 2000, 039014). The differences in inflammatory 

effects and possibly lymph burdens between fine and UF TiO2 in many studies appear related to lung 

burden in terms of particle surface area and not particle mass or number (Oberdorster, 1996, 039852; 

Oberdörster et al., 1992, 045110; Oberdorster et al., 2000, 039014; Tran et al., 2000, 013071). More 

recently, others have noted that particle surface area is not an appropriate metric across all particle 

types (Warheit et al., 2006, 088436). Surface characteristics such as roughness can also affect protein 

binding and potentially clearance kinetics, with smoother TiO2 surfaces being more hydrophobic 

(Sousa et al., 2004, 089866). 

Geiser et al. (2005, 087362) conducted a detailed examination of the disposition of inhaled UF 

TiO2 in 20 healthy adult rats. They found that distributions of particles among lung tissue 

compartments appeared to follow the volume fraction of the tissues and did not significantly differ 

between 1 and 24 h post-inhalation. Averaging 1- and 24-h data, 79.3 ± 7.6% of particles were on the 

luminal side of the airway surfaces, 4.6 ± 2.6% were in epithelial or endothelial cells, 4.8 ± 4.5% 

were in connective tissues, and 11.3 ± 3.9% were within capillaries. Particles within cells were not 

membrane bound. It is not clear why the fraction of particles identified in compartments such as the 

capillaries did not differ between 1 and 24 h post-inhalation. These findings were consistent with the 

smaller study of 5 rats by Kapp et al. (2004, 156624) who reported identifying TiO2 aggregates in a 

December 2009 4-21 
type II pneumocyte; a capillary close to the endothelial cells; and within the surface-lining layer 

close to the alveolar epithelium immediately following a 1-h exposure. These studies effectively 

demonstrate that some inhaled UF TiO2 particles, once deposited on the pulmonary surfaces, can 

rapidly (≤ 1 h) translocate beyond the epithelium and potentially into the vasculature. 

Extrapulmonary translocation has also been described for poorly soluble UF gold and Ir 

particles. In male Wistar-Kyoto rats exposed to UF gold particles (5-8 nm), Takenaka et al. (2006, 

156110) reported a low but significant fraction (0.03 to 0.06% of lung concentration) of gold in the 

blood from 1 to 7 days post-inhalation. Semmler et al. (2004, 055641) also found small but 

detectable amounts of poorly soluble Ir particle (15 and 20 nm CMD) translocation from the lungs of 

male Wistar-Kyoto rats to secondary target organs like the liver, spleen, brain, and kidneys. Each of 

these organs contained about 0.2% of deposited Ir. The peak levels in these organs were found 7 days 

post-inhalation. The translocated particles were largely cleared from extrapulmonary organs by 20 

days and Ir levels were near background at 60 days post-inhalation. Particles may have been 

distributed systemically via the gastrointestinal tract. Immediately after the 6-h inhalation exposure, 

18 ± 5% of the deposited Ir particles had already cleared into the gastrointestinal tract. After 3 wk, 

31 ± 5% of the deposited particles were retained in the lung. By 2 and 6 mo post-inhalation, lung 

retention was 17 ± 3 and 7 ± 1%, respectively. The particles appeared to be cleared predominantly 

from the peripheral lung via the mucociliary escalator into the GI tract and were found in feces. 

A few recent studies have characterized differences in the behavior of fine and UF particles in 

vitro. Geiser et al. (2005, 087362) found that both UF and fine (0.025 μm gold, 0.078 μm TiO2, and 

0.2 μm TiO2) particles cross cellular membranes by non-endocytic (i.e., involving vesicle formation) 

mechanisms such as adhesive interactions and diffusion, whereas the phagocytosis of larger 1 μm 

TiO2 particles is ligand-receptor mediated. Edetsberger et al. (2005, 155759) found that UFPs 

(0.020 μm polystyrene) translocated into cells by first measurement (~1 min after particle 

application). Intracellular agglomerates of 88-117 nm were seen by 15-20 min and of 253-675 nm by 

50-60 min after particle application. These intracellular aggregates were thought to result from 

particle incorporation into endosomes or similar structures since Genistein or Cytochalasin treatment 

generally blocked aggregate formation. Interestingly, particles did not translocate into dead cells, 

rather they attached to the outside of the cell membrane. Amine- or carboxyl-modified surfaces (46 

nm polystyrene) did not affect translocation across cultures of human bronchial epithelial cells with 

about 6% regardless of the surface characteristics (Geys et al., 2006, 155789). 

4.3.3.2. Olfactory Region 

Numerous studies have demonstrated the translocation of soluble and poorly soluble particles 

from the olfactory mucosa via the axons to the olfactory bulb of the brain. The vast majority of these 

studies were conducted in rodents. However, DeLorenzo (1970, 156391) observed the rapid (within 

30-60 min) movement of 50 nm silver-coated colloidal gold particles instilled on the olfactory 

mucosa into the olfactory bulb of squirrel monkeys. The specifics of this and other key studies that 

have investigated the translocation of particles to the olfactory bulb are provided in Annex B. 

Two recent studies reported the movement of UFPs deposited in the olfactory region of the 

nose along the olfactory nerve and into the olfactory bulb of the brain in rats. Oberdörster et al. 

(2004, 055639) exposed rats to UF carbon particles (36 nm CMD, 1.7 σg) containing 13C in a wholebody chamber for 6 h. The distribution of 13C was followed for 7 days postexposure. There was a 

significant increase in 13C in the olfactory bulb on Day 1 with persistent and continued increase 

through Day 7. Elder et al. (2006, 089253) exposed rats to manganese (Mn) oxide (~30 nm 

equivalent sphere with 3-8 nm primary particles) via whole-body inhalation exposure for 12 days (6 

h/day, 5 days/wk) with both nares open or Mn oxide for 2 days (6 h/day) with right nostril blocked. 

After the 12 days exposure via both nostrils, Mn in the olfactory bulb increased 3.5-fold. After the 

2-day exposure with the right nostril blocked, Mn was found mainly in the left olfactory bulb (2.4-

fold increase). These studies suggest the neuronal uptake and translocation of UFPs without particle 

dissolution and in the absence of mucosal injury. 

Elder et al. (2006, 089253) also addressed the issue of whether solubilization of particles was 

requisite for translocation along the olfactory nerve and into the brain. Similar amounts of soluble 

manganese chloride (MnCl2) and poorly soluble Mn oxide were instilled onto the left naris of 

anesthetized rats. At 24 h post-instillation, similar amounts of Mn were found in the left olfactory 

bulb of rats instilled with MnCl2 (8.2 ± 3.6% of instilled) and Mn oxide (8.2 ± 0.7% of instilled). If 

solubilization were required for translocation, then a lower amount of Mn oxide than MnCl2 should 

December 2009 4-22 
have reached the olfactory bulb. Following 14 consecutive days of aerosol exposure, Dorman et al. 

(2001, 055433) demonstrated that more soluble Mn sulfate reaches the olfactory bulb and striatum of 

rat brains than the poorly soluble form of Mn tetroxide. Nonetheless, the Mn levels were statistically 

increased in both the olfactory bulb and striatum following exposure to Mn tetroxide relative to 

filtered air. In a subsequent 13-wk exposure study, Dorman et al. (2004, 155752) also demonstrated 

that more soluble manganese sulfate (MnSO4) reached the olfactory bulb than was observed for the 

less soluble Mn form (hureaulite). Both the soluble and less soluble forms of Mn resulted in 

statistically increased levels of Mn in the olfactory bulb relative to air exposed controls. The soluble 

MnSO4 was also observed to reach the striatum and cerebellum. In addition, Yu et al. (2003, 156171) 

demonstrated increased Mn levels in the brains of rats exposed to welding-fumes for 60 days, 

however, the role of transport via the blood is less clear in this study. 

The translocation of zinc (Zn) and TiO2 to the olfactory bulb has also been reported in the 

literature. Persson et al. (2003, 051846) observed the translocation of Zn to the olfactory bulbs 

following instillation in both rats and freshwater pike. Wang et al. (2007, 156146) reported the 

translocation of both fine (155 nm) and UF (21 and 71 nm) TiO2 particles in mice. Interestingly, a 

qualitative analysis of the data showed that more of the fine TiO2 than UF TiO2 reached the 

olfactory bulb. Wang et al. (2007, 156146) suggested that a strong hydrophilic character and 

propensity for aggregation reduced the translocation of the UF TiO2. The importance of particle translocation to the brain is not yet understood. Translocation via 

the axon to the olfactory bulb has been observed for numerous compounds of varying composition, 

particle size, and solubility. Although the rate of translocation is rapid, perhaps less than an hour, the 

magnitude of transport remains poorly characterized. With regard to the magnitude of transport, 

Elder et al. (2006, 089253) found that as much as 8% of both soluble and insoluble forms of Mn 

were translocated to the olfactory bulb in rats following intranasal instillation. It is also still unclear 

to what extent translocation to the olfactory bulb and other brain regions may vary between species. 

The olfactory mucosa covers approximately 50% of the nasal epithelium in rodents versus only 

about 5% in primates (Aschner et al., 2005, 155663). Additionally, a greater portion of inhaled air 

passes through the olfactory region of rats relative to primates (Kimbell, 2006, 155902). These 

differences may predispose rats, more so than humans, to deposition of particles in the olfactory 

region with subsequent particle translocation to the olfactory bulb. 

4.3.4. Factors Modulating Clearance 

4.3.4.1. Age 

It was previously concluded that there appeared to be no clear evidence for any age-related 

differences in clearance from the lung or total respiratory tract, either from child to adult, or young 

adult to elderly (U.S. EPA, 1996, 079380; U.S. EPA, 2004, 056905). Studies showed either no 

change or some slowing in mucus clearance with age after maturity. Although some differences in 

alveolar macrophage function were reported between mature and senescent mice, no age-related 

decline in macrophage function had been observed in humans. A comprehensive review of the recent 

and older literature supports a decrease in mucociliary clearance with increasing age beyond 

adulthood in humans and animals. Limited animal data also suggest macrophage-mediated alveolar 

clearance may also decrease with age. 

Studies addressing the effects of age on respiratory tract clearance are provided in Annex B. 

Ho et al. (2001, 156549) demonstrated that nasal mucociliary clearance rates were about 40% lower 

in old (age >40-90 yr) versus young (age 11-40 yr) men and women. Tracheal mucus velocities in 

elderly (or aged) humans and beagle dogs are about 50% that of young adults (Goodman et al., 1978, 

071130; Whaley et al., 1987, 156153). Several human studies have demonstrated decreasing rates of 

mucociliary particle clearance from the large and small bronchial airways with increasing age 

(Puchelle et al., 1979, 006863; Svartengren et al., 2005, 157034; Vastag et al., 1985, 157088). Linear 

fits to the data show that rapid clearance (within 1 h) from large bronchi and prolonged clearance 

(between 1-21 days) from the small bronchioles in an 80-year-old is only about 50% of that in a 

20-year-old (Svartengren et al., 2005, 157034; Vastag et al., 1985, 157088). One study reported that 

alveolar particle clearance rates decreased by nearly 40% in old versus young rats (Muhle et al., 

1990, 006853). Another study has reported that older rats have an increased susceptibility to 

December 2009 4-23 
pulmonary infection due to altered alveolar macrophage function and slowed bacterial clearance 

(Antonini et al., 2001, 156219). Although data are somewhat limited, they consistently show a 

depression of clearance throughout the respiratory tract with increasing age from young adulthood in 

humans and laboratory animals. 

4.3.4.2. Gender 

Gender was not found to affect clearance rates in prior reviews (U.S. EPA, 1996, 079380; 

U.S. EPA, 2004, 056905). Studies not included in those reviews also show that human males and 

females have similar nasal mucus clearance rates (Ho et al., 2001, 156549), tracheal mucus 

velocities (Yeates et al., 1981, 095391), and large bronchial airway clearance rates (Vastag et al., 

1985, 157088). 

4.3.4.3. Respiratory Tract Disease 

At the time of the last two reviews (U.S. EPA, 1996, 079380; U.S. EPA, 2004, 056905), it was 

well recognized that obstructive airways disease may influence both the site of initial deposition and 

the rate of mucociliary clearance from the airways. When deposition patterns are matched, 

mucociliary clearance rates are reduced in patients with COPD relative to healthy controls. The 

effects of acute bacterial/viral infections and cough on mucociliary clearance were briefly 

summarized in Section 10.4.2.5 (EPA, 1996, 079380) and Section 6.3.4.4 (EPA, 2004, 056905) of 

past reviews. While cough is generally a reaction to some inhaled stimulus, in some cases, especially 

respiratory disease, it can also serve to clear the upper bronchial airways of deposited substances by 

dislodging mucus from the airway surface. One of the difficulties in assessing effects on infection on 

mucociliary clearance is that spontaneous coughing increases during acute infections. Cough has 

been shown to supplement mucociliary clearance of secretions, especially in patients with 

obstructive lung disease and primary ciliary dyskinesia. 

Using a bolus technique to target specific lung regions, Möller et al. (2008, 156771) examined 

particle clearance from the ciliated airways and alveolar region of healthy subjects, smokers, and 

patients with COPD. Airway retention after 1.5 hours was significantly lower in healthy subjects 

(89 ± 6%) than smokers (97 ± 3%) or COPD patients (96 ± 6%). At 24 and 48 h, retention remained 

significantly higher in COPD patients (86 ± 6% and 82 ± 6%, respectively) than healthy subjects 

(75 ± 10% and 70 ± 9%, respectively). However, these findings are confounded by the more central 

pattern of deposition in the healthy subjects than in the smokers and COPD patients. Alveolar 

retention of particles was similar between the groups at 48 h post-inhalation. 

The effect of asthma on lung clearance of particles may depend on disease status. Lay et al. 

(2009, 190060) found significantly (p < 0.01) more rapid particle (0.22 μm) mucociliary clearance 

over a 2-h period post-inhalation in mild asthmatics than in healthy volunteers. Although the pattern 

of deposition tended to be more central in the asthmatics, there was not a statistically significant 

difference from healthy controls. In vivo uptake by airway macrophages in mild asthmatics was also 

enhanced relative to healthy volunteers (p < 0.01). In an ex vivo study, airway macrophages from 

individuals with more severe asthma had impaired phagocytic capacity relative to less severely 

affected asthmatics and healthy volunteers (Alexis et al., 2001, 190013). Lay et al. (2009, 190060) 

concluded that enhanced uptake and processing of particulate antigens could contribute to the 

pathogenesis and progression of allergic airways disease in asthmatics and may contribute to an 

increased risk of exacerbations with particulate exposure. 

Chen et al. (2006, 147267) investigated the effect of endotoxin on the disposition of particles. 

Healthy rats and those pretreated with endotoxin (12 h before particle instillation) were instilled with 

UF (56.4 nm) or fine (202 nm) particles. In healthy rats, there were no marked differences in lung 

retention or systemic distribution between the UF and fine particles. In healthy animals, UFPs were 

primarily retained in lungs (72 ± 10% at 0.5-2 h; 65 ± 1% at 1 day; 62 ± 5% at 5 days). Particles 

were also detected in the blood (2 ± 1% at 0.5-2 h; 0.1 ± 0.1% at 5 days) and liver (3 ± 2% at 0.5-2 

h; 1 ± 0.1% at 5 days) of the healthy animals. At 1 day post-instillation, about 13% of the particles 

were excreted in the urine or feces of the healthy animals. In rats pretreated with endotoxin, by 2 h 

post-instillation, the UFPs accessed the blood (5 versus 2%) and liver (11 versus 4%) to a 

significantly greater extent than fine particles. The endotoxin-treated rats also had significantly 

greater amounts of UFPs in the blood (5% versus 2%) and liver (11% versus 3%) relative to the 

December 2009 4-24 
healthy control rats. This study demonstrates that acute pulmonary inflammation caused by 

endotoxin increases the migration of UFPs into systemic circulation. 

Adamson and Preditis (1995, 189982) investigated the possibility that particle deposition into 

an already injured lung might affect particle retention and enhance the toxicity of “inert” particles. 

Bleomycin was instilled into mice to induce epithelial necrosis and subsequent pulmonary fibrosis. 

Instilled 3 days following bleomycin treatment, while epithelial permeability was compromised, 

carbon black particles in treated mice were translocated to the interstitium and showed increased 

pulmonary retention relative to untreated mice. When instilled 4 wk post-bleomycin treatment, after 

epithelial integrity was restored, carbon black particle retention was similar between treated and 

untreated mice with minimal translocation to the interstitium. The instillation of carbon particles did 

not appear to increase lung injury in the bleomycin treated mice at either time point. This study 

shows that integrity of the epithelium affects particle retention and translocation into interstitial 

tissues. 

4.3.4.4. Particle Overload 

Unlike other laboratory animals, rats appear susceptible to “particle overload” effects due to 

impaired macrophage-mediated alveolar clearance. Numerous reviews have discussed this 

phenomenon and the difficulties it poses for the extrapolation of chronic effects in rats to humans 

(International, 2000, 002892; Miller, 2000, 011822; Morrow, 1994, 006850; Oberdorster, 1995, 

046596; Oberdorster, 2002, 021111). Large mammals have slow pulmonary particle clearance and 

retain particles in interstitial tissues under normal conditions, whereas rats have rapid pulmonary 

clearance and retain particles in alveolar macrophages (Snipes, 1996, 076041). With chronic high 

doses of PM there is a shift in the pattern of dust accumulation and response from that observed at 

lower doses in rat lungs (Snipes, 1996, 076041; Vincent and Donaldson, 1990, 002462). Rats 

chronically exposed to high concentrations of insoluble particles experience a reduction in their 

alveolar clearance rates and an accumulation of interstitial particle burden (Bermudez et al., 2002, 

055578; Bermudez et al., 2004, 056707; Ferin et al., 1992, 044401; Oberdörster et al., 1994, 046203; 

Oberdörster et al., 1994, 056285; Warheit et al., 1997, 086055). With continued exposure, some rats 

eventually develop pulmonary fibrosis and both benign and malignant tumors(Lee et al., 1985, 

067628; Lee et al., 1986, 067629; Warheit et al., 1997, 086055). Oberdörster (1996, 039852; 2002, 

021111) proposed that high-dose effects observed in rats may be associated with two thresholds. The 

first threshold is the pulmonary dose that results in a reduction in macrophage-mediated clearance. 

The second threshold, occurring at a higher dose than the first, is the dose at which antioxidant 

defenses are overwhelmed and pulmonary tumors develop. Intrapulmonary tumors following TiO2

exposures are exclusive to rats and are not found in mice or hamsters (Mauderly, 1997, 084631). 

Moreover, Lee et al. (1985, 067628) noted that the squamous cell carcinomas observed with 

prolonged high concentration TiO2 exposures developed from the alveolar lining cells adjacent to the 

alveolar ducts, whereas squamous cell carcinomas in humans which are generally linked with 

cigarette smoking are thought to arise from basal cells of the bronchial epithelium. Quoting Lee et al. 

(1986, 067629), “Since the lung tumors were a unique type of experimentally induced tumor under 

exaggerated exposure conditions and have not usually been seen in man or animals, their relevance 

to man in questionable.” 

4.3.5. Summary 

For any given particle size, the pattern of poorly soluble particle deposition influences 

clearance by partitioning deposited material between regions of the respiratory tract. Particles 

depositing in the mouth may generally be assumed to be swallowed or removed by expectoration. 

Particles deposited in the posterior portions of the nasal passages or the TB airways are moved via 

mucociliary transport towards the nasopharynx and swallowed. Although clearance from the TB 

region is generally rapid, there appears to be fraction of material deposited in the TB region of 

humans that is retained much longer. The underlying sites and mechanisms of long-term TB 

retention are not known. The primary alveolar clearance mechanism is macrophage phagocytosis and 

migration to terminal bronchioles where the cells are cleared by the mucociliary escalator. Clearance 

from both the TB and alveolar region is more rapid in rodents than humans. Mucociliary and 

macrophage-mediated clearance decreases with age beyond adulthood. 

December 2009 4-25 
Human data show that there is not a rapid or significant amount of UF carbon particle 

migration into circulation. However, both in vitro and in vivo animal studies support the rapid 

(≤ 1 h) translocation of free UF TiO2 particles across pulmonary cell membranes. Extrapulmonary 

translocation has also been described in rats for poorly soluble UF gold and Ir particles. A low, but 

statistically significant, fraction (0.03-0.06% of lung concentration) of UF gold particles has been 

observed in the blood of rats from 1 to 7 days post-inhalation. The translocation in detectable 

amounts (<1% of deposited material) of poorly soluble Ir particles (15 and 20 nm CMD) from the 

lungs of rats to secondary target organs like the liver, spleen, brain, and kidneys has also been 

reported. However, the systemic distribution of particles may have occurred via normal clearance 

from the lungs to the gastrointestinal tract. 

Although the importance of particle translocation to the brain is not yet understood, 

translocation from the olfactory mucosa via the axon to the olfactory bulb has been reported in 

primates, rodents, and freshwater pike for numerous compounds of varying composition, particle 

size, and solubility. The rate of translocation is rapid, perhaps less than an hour. In rats, as much as 

8% of material may become translocated to the olfactory bulb following intranasal instillation. It is 

unclear to what extent translocation to the olfactory bulb and other brain regions may vary between 

species. Interspecies differences may predispose rats, more so than humans, to the deposition of 

particles in the olfactory region with subsequent translocation to the olfactory bulb. 

4.4. Clearance of Soluble Materials 

Soluble particles and soluble constituents of particles may be absorbed through the epithelium 

and distributed systemically or retained in the lung. The rate of dissolution depends on a number of 

factors, including particle surface area and chemical structure. Some dissolved materials bind to 

proteins or other components in the airway surface liquid layer. In the ciliated airways, solutes are 

cleared by mucociliary transport and diffuse into underlying tissues and the blood. In the alveolar 

regions, the thin barrier between the air and blood allows for rapid transport of solutes into the blood. 

The movement of soluble materials depends on the site of deposition in the lung, the rate of material 

dissolution from particles, and the molecular weight of the solute. The rate of soluble material 

clearance from the lungs depends on epithelial permeability which may be affected by age, 

respiratory disease, and concurrent exposures. While enhanced clearance of insoluble particles acts 

to reduce dose to airway tissue, increased transport of soluble matter into the blood stream may 

enhance effects on extra-pulmonary organs. 

4.4.1. Clearance Mechanisms and Kinetics 

The rate of absorption across the epithelium for materials that dissolve in the airway or 

alveolar lining fluid is fairly rapid (minutes to hours) and is a function of their molecular size and 

their water or lipid solubility (Enna and Schanker, 1972, 155767; Huchon et al., 1987, 024923; 

Oberdörster, 1988, 006857; Schanker et al., 1986, 005100). Huchon et al. (1987, 024923) studied the 

clearance of a variety of aerosolized solutes from the lungs of dogs. Solute clearance was inversely 

related to molecular weight. Negligible clearance of the largest molecular weight solute (transferrin 

mol wt ~76,000 daltons) in their study was found over a 30-min observation period. At the other 

extreme, free pertechnetate (mol wt ~163 daltons) had a clearance rate of 6% per min. Clearance of 

hydrophilic solutes is diffusion limited by pore sizes associated with intercellular tight junctions 

(estimated at 0.6-1.5 nm). Absorption of lipophilic compounds that pass easily through cell 

membranes is perfusion limited and thus generally occurs very rapidly. However, if lipophilic 

materials are adsorbed onto insoluble particles their retention in the lung may be prolonged (Creasia 

et al., 1976, 059713). In addition to diffusion through intercellular junctions, transcellular transport 

of large solutes by pinocytosis into epithelial cells has also been observed (Chinard, 1980, 156341). 

A portion of poorly soluble particles may become dissolved with subsequent solute clearance. 

More rapid dissolution of poorly soluble nano- or UF particles relative to micro-sized particles 

occurs due to an increasing surface-to-volume ratio with decreasing particle size. Kreyling et al. 

(2002, 037332) examined the dissolution of poorly soluble UF Ir particle agglomerates (15-80 nm 

CMD) composed of 5 nm primary particles. After 7 days, <1% of the particles were dissolved in 

buffered saline, whereas 6% dissolved in 1 N hydrochloric acid after 1 day. Thus, the high surfaceDecember 2009 4-26 
to-volume ratio of UFPs should not be misconstrued to imply rapid dissolution of poorly soluble 

particles following deposition in the respiratory tract. However, poorly soluble particles that become 

phagocytosed may slowly dissolve in the acidic (pH of 4.3-5.3) environment of the phagolysosome 

to be released in their solubilized form from the cell and potential move across the epithelium into 

the bloodstream. The dissolution rate is inversely related to particle size and directly related to 

specific surface area (Kreyling and Scheuch, 2000, 056281) and facilitated by the acidic 

environment of the macrophage (Kreyling, 1992, 067243). 

There is considerable evidence that soluble particles depositing in the bronchial airways are 

cleared by dual mechanisms (Bennett and Ilowite, 1989, 000835; Lay et al., 2003, 155920; Matsui et 

al., 1998, 040405; Sakagami et al., 2002, 156936; Wagner and Foster, 2001, 156143). The relative 

contribution of their removal by transepithelial absorption versus mucociliary clearance is likely a 

function of both the molecular size and water or lipid solubility of the material (Enna and Schanker, 

1972, 155767; Huchon et al., 1987, 024923; Oberdörster, 1988, 006857; Sakagami et al., 2002, 

156936). Furthermore, the rate of mucociliary transport for soluble particles may be less than that of 

insoluble particles (Lay et al., 2003, 155920). Consequently, non-permeating hydrophilic solutes 

may remain in contact with the airway epithelium for a longer period than insoluble particles. This 

may be due to diffusion of a greater portion of the solute into the periciliary sol layer which may be 

transported less efficiently than the mucus layer during mucociliary clearance. Bronchial blood flow 

has also been shown to modulate airway retention of soluble particles (Wagner and Foster, 2001, 

156143), i.e., decreasing blood flow increases airway retention of soluble particles. 

As an example of how transport of soluble components of PM may clear the lung by 

transepithelial absorption, Wallenborn et al. (2007, 156144) measured elemental content of lungs, 

plasma, heart, and liver of healthy male WKY rats (12-15 wk old) 4 or 24 h following a single 

intratracheal (IT) instillation of saline or 8.33 mg/kg of oil combustion PM containing a variety of 

transition metals with differing water and acid solubility. Metals with high water solubility and 

relatively high concentration in oil combustion PM were increased in extrapulmonary organs. 

Elements with low water or acid solubility, like silicon and aluminum, were not detected in 

extrapulmonary tissues despite decreased levels in the lung suggesting they cleared the lung 

primarily by mucociliary clearance. Thus, PM-associated metals deposited in the lung may be 

released into systemic circulation at different rates depending on their water/acid solubility. 

The amount and type of water soluble or leachable metals associated with PM varies with 

location and by source. Furthermore some metals such as Zn, Cu, and Fe are essential to body 

function while others such as vanadium and nickel are nonessential metals. Consequently the body 

and the lung have different ways of dealing with excesses in inhaled soluble metals associated with 

PM. Bioavailability, and potentially the toxicity, of leachable metals may be altered by protein 

binding within the lung and blood as well as the affinities of these binding sites. For example Zn is 

tightly regulated by a variety of metal binding proteins, including metallothionein and a family of Zn 

specific transporters. In the plasma, Zn binds to many proteins, including α2-macroglobulin and 

albumin. Zn is an example of a common abundant water soluble metal in ambient air that may 

contribute to increased respiratory and cardiovascular disease risk associated with PM exposure. 

Wallenborn et al. (2009, 191172) recently showed that soluble Zn sulfate (in the form of 70Zn, a rare 

isotope of Zn) introduced into the lungs by instillation not only reaches, but accumulates in 

extrapulmonary organs, including the heart and liver, following pulmonary exposure. However, the 

retention of greater than 50% of 70Zn in the lung at 4 h post-instillation suggested that the 

transepithelial absorption of soluble Zn was indeed slowed by binding to proteins in the lungs. While 

it could not be ascertained if 70Zn measured in the heart was replacing endogenous Zn pools, any 

accumulation in cardiac Zn levels could lead to mitochondrial dysfunction and ion channel 

disruption, possibly explaining adverse cardiac effects from inhalation of Zn-rich PM. Effects of Zn 

instillation on epithelial integrity were not evaluated. 

4.4.2. Factors Modulating Clearance 

A number of studies have evaluated the epithelial permeability by measuring the clearance of 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA), a small hydrophilic solute (492 daltons, 

0.57 nm). These studies are the basis for much of the discussion in this section. 

December 2009 4-27 
4.4.2.1. Age 

In humans, the clearance of water-soluble particles (99mTc-DTPA) from the alveolar epithelium 

generally slows with increasing age (Braga et al., 1996, 156289; Pigorini et al., 1988, 156027). 

However, Tankersley et al. (2003, 096363) recently showed enhanced permeability of soluble 

particles (99mTc-DTPA) in terminally senescent mice just before death, suggesting that a 

disintegration of the epithelial barrier may be a feature of lung homeostatic loss during this period of 

terminal senescence. 

4.4.2.2. Physical Activity 

The transepithelial transport rates of soluble particles, 99mTc-DTPA, have also been found to 

increase during exercise (Hanel et al., 2003, 155826; Lorino et al., 1989, 155946; Meignan et al., 

1986, 156752). This enhancement was linked to increases in VT associated with exercise (Lorino et 

al., 1989, 155946). Regionally, this effect was dominated by increased apical lung clearance and 

attributed to an increase in apical blood flow (Meignan et al., 1986, 156752). The increased 

permeability with exercise appears to resolve to baseline after a short period post exercise, i.e., 

within a couple hours (Hanel et al., 2003, 155826). 

4.4.2.3. Disease 

Because the integrity of the epithelial surface lining of the lungs may be damaged from lung 

disease, particles (either insoluble or soluble) may gain greater access to the interstitium, lymph, and 

blood stream. Damage to the epithelial barrier is most likely to acutely affect transepithelial transport 

rates of soluble particles. From bronchial biopsies, Laitinen et al. (1985, 037521) found various 

degrees of epithelial damage, from loosening of tight junctions to complete denudation of the airway 

epithelium, in asthmatics. Consistent with these findings, Ilowite et al. (1989, 156584) found that 

asthmatics had increased permeability of the bronchial mucosa to the hydrophilic solute 99mTc-DTPA. On the other hand, a more recent study in a sheep model showed that the presence of 

bronchial edema could slow the uptake of soluble DTPA into the blood and enhanced retention in the 

airways, likely within the expanded interstitial barrier (Foster and Wagner, 2001, 155778). Both a 

leaky epithelial barrier and expanded interstitial barrier associated with asthma may result in 

enhanced exposure of submucosal immune and smooth muscle cells to xenobiotic substances. 

Alveolar epithelial permeability was also shown to be affected by the presence of lung 

inflammation. The most common finding has been a clear increase in alveolar permeability induced 

by cigarette smoking (Jones et al., 1980, 155883). This effect appears to be dependent on the recent 

cigarette smoke exposure as indexed by carboxyhaemoglobin (Jones et al., 1983, 155884) and is 

rapidly reversible within a week of smoking cessation (Mason et al., 1983, 013169). In fact, Huchon 

et al. (1984, 156576) demonstrated that COPD patients who have stopped smoking have normal 

clearance of 99mTc-DTPA. 

In general, increased alveolar permeability to 99mTc-DTPA has been found to be associated 

with any lung syndrome characterized by pulmonary edema. While the trans-alveolar transport of a 

small solute like DTPA is very sensitive to even mild acute lung injury (such as that associated with 

even mild cigarette smoking), increased transport rates of larger molecules (>100K daltons) across 

the alveolar epithelium require more severe damage like that seen in adult respiratory distress 

syndrome (ARDS) (Braude et al., 1986, 155701; Peterson et al., 1989, 024922). Interstitial lung 

disease and pulmonary fibrosis are also characterized by increased alveolar permeability (Antoniou 

et al., 2006, 156220; Bodolay et al., 2005, 156280; Watanabe et al., 2007, 157115). Interestingly, 

these recent studies have also shown that the increased permeability in these patients could be 

corrected with immunosuppressive/steroid treatments (Bodolay et al., 2005, 156280; Watanabe et al., 

2007, 157115). Furthermore, studies of DTPA clearance in bleomycin injured dogs, a model of 

pulmonary fibrosis, suggest that the enhanced permeability is associated with the initial acute phase 

of the lung damage, with clearance rates returning to normal as chronic fibrosis developed over time 

(Suga et al., 2003, 157024). 

Finally, as evidence of lung complications associated with non-insulin dependent diabetes 

(type 2), Lin et al. (2002, 155932) found impairment of alveolar integrity as shown by increased 

transport rates of both hydrophilic and lipophilic solutes from the lungs in these patients. By 

contrast, a number of other studies have found epithelial permeability reduced, i.e., slower transport 

December 2009 4-28 
rates, in diabetes (Caner et al., 1994, 156320; Mousa et al., 2000, 156786; Ozsahin et al., 2006, 

156833) that may be related to disease duration and metabolic control (Ozsahin et al., 2006, 

156833) . These findings are consistent with thickening of alveolar basement membrane detected in 

autopsies of diabetes patients (Weynand et al., 1999, 157140). 

4.4.2.4. Concurrent Exposures 

The integrity of the alveolar epithelium may be disrupted by co-pollutants such that soluble 

components of inhaled particles can more easily enter the interstitium and blood stream. Like active 

cigarette smoking discussed previously, Beadsmoore et al. (2007, 156259) showed clearance halftimes in healthy passive smokers to be shorter compared with healthy non-smokers but still longer 

than in healthy smokers. These findings show a progressive increase in epithelial permeability with 

exposure to cigarette smoke. Similarly, acute exposure of humans to 0.4 ppm ozone for 2 h with 

intermittent exercise has been shown to alter epithelial integrity and increase clearance of soluble 

hydrophilic particles from the alveolar surfaces of the lung (Kehrl et al., 1987, 040824). This effect 

persists to at least 24 h post-exposure even following lower exposure levels (0.24 ppm average for 

130 min) of ozone (Foster and Stetkiewicz, 1996, 079920). Similarly, 0.8 ppm O3 exposure for 2 h in 

rats caused increased permeability to macromolecules at all levels of the respiratory tract (Bhalla et 

al., 1986, 040407) that persisted in the alveolar region beyond 24 h post-exposure. Cohen et al. 

(1997, 009213) may have best illustrated the competing effects of mucociliary and transepithelial 

transport by showing that coexposure to ozone affected the retention of inhaled chromium in rats 

differently depending on its solubility. In its soluble potassium chromate form, ozone decreased the 

retention of chromium, but when chromium was inhaled as insoluble barium chromate, its retention 

in the lung was increased by ozone coexposure. Similarly, a study that showed decreased clearance 

of insoluble cesium oxide particles following influenza infection also showed a virus-induced 

enhancement of clearance for a soluble cesium chloride (Lundgren et al., 1978, 155950). Chang et 

al. (2005, 097776) also recently showed that UF carbon black acts through a reactive oxygen species 

(ROS) dependent pathway to increase epithelial permeability in mice. 

Chronic exposure to other particulate or gaseous pollutants does not always led to increased 

epithelial permeability. Studying subjects with a variety of occupational exposures, Kaya et al. 

(2006, 156632) showed that nonsmoking welders actually have decreased epithelial permeability 

relative to nonsmoking control subjects, and occupational exposure of painters to isocyanates has no 

effect on bronchoalveolar epithelial permeability (Kaya et al., 2003, 156631). 

4.4.3. Summary 

The healthy airway and alveolar epithelium is generally impermeable to very large insoluble 

macromolecules and particles. Water and acid soluble particles may more rapidly move through the 

epithelium as they dissolve on the airway surface or within the phagolysomes of macrophages. The 

presence of airway inflammation in a variety of airway diseases (e.g., asthma, fibrosis, ARDS, 

pulmonary edema, inflammation from smoking) alters epithelial integrity to allow more rapid 

movement of these solutes into the bloodstream. While diabetics are another group recently shown to 

have increased susceptibility to particulate air pollution (Zanobetti and Schwartz, 2002, 034821), it 

is unclear whether transport of soluble particles across the epithelium is affected in these patients. In 

general, it appears that coexposure to irritant pollutants results in a disruption of epithelial integrity 

and macrophage function which, on the one hand, retards mucociliary and alveolar clearance, but 

also allows for a more rapid movement of soluble constituents across the epithelial surface into the 

interstitium and blood stream. Alterations in epithelial permeability by disease, pollutant exposure, 

or infection may partially explain increased susceptibility to PM associated with these co-conditions. 

December 2009 4-29 
Chapter 4 References 

ACGIH (2005). TLVs and BEIs: Based on the documentation of the threshold limit values for chemical substances and 

physical agents and biological exposure indices. American Conference of Governmental Industrial Hygienists. 

Cincinnati, Ohio. 156188

Adamson I; Prieditis H (1995). Response of mouse lung to carbon deposition during injury and repair. Environ Health 

Perspect, 103: 72-76. 189982

Alexis N; Soukup J; Nierkens S; Becker S (2001). Association between airway hyperreactivity and bronchial macrophage 

dysfunction in individuals with mild asthma. Am J Physiol Lung Cell Mol Physiol, 280: L369-L375. 190013

Anselm A; Heibel T; Gebhart J; Ferron GA (1990). In vivo studies of growth factors of sodium chloride particles in the 

human respiratory tract. J Aerosol Sci, 21: S427-430. 156217

Anthony TR; Flynn MR (2006). Computational fluid dynamics investigation of particle inhalability. J Aerosol Sci, 37: 750-

765. 155659

Antonini JM; Roberts JR; Clarke RW; Yang HM; Barger MW; Ma JYC; Weissman DN (2001). Effect of age on respiratory 

defense mechanisms: pulmonary bacterial clearance in Fischer 344 rats after intratracheal instillation of Listeria 

monocytogenes. Chest, 120: 240-249. 156219

Antoniou KM; Malagari K; Tzanakis N; Perisinakis K; Symvoulakis EK; Karkavitsas N; Siafakas NM; Bouros D (2006). 

Clearance of technetium-99m-DTPA and HRCT findings in the evaluation of patients with Idiopathic Pulmonary 

Fibrosis. BMC Pulm Med, 6: 4. 156220

Aschner M; Erikson KM; Dorman DC (2005). Manganese Dosimetry: Species Differences and Implications for 

Neurotoxicity. Crit Rev Toxicol, 35: 1-32. 155663

Asgharain B; Kelly JT; Tewksbury EW (2003). Respiratory deposition and inhalability of monodisperse aerosols in LongEvans rats. Toxicol Sci, 71: 104-111. 153068

Asgharian B; Hofmann W; Miller FJ (2001). Mucociliary clearance of insoluble particles from the tracheobronchial 

airways of the human lung. J Aerosol Sci, 32: 817-832. 017025

Bailey M; Dorrian M; Birchall A (1995). Implications of airway retention for radiation doses from inhaled radionuclides. J 

Aerosol Med, 8: 373-390. 190057

Balashazy I; Hofmann W; Heistracher T (1999). Computation of local enhancement factors for the quantification of particle 

deposition patterns in airway bifurcations. J Aerosol Sci, 30: 185-203. 043201

Balashazy I; Hofmann W; Heistracher T (2003). Local particle deposition patterns may play a key role in the development 

of lung cancer. J Appl Physiol, 94: 1719-1725. 155671

Beadsmoore C; Cheow HK; Szczepura K; Ruparelia P; Peters AM (2007). Healthy passive cigarette smokers have 

increased pulmonary alveolar permeability. Nucl Med Comm, 28: 75-77. 156259

Becquemin MH; Swift DL; Bouchikhi A; Roy M; Teillac A (1991). Particle deposition and resistance in the noses of adults 

and children. Eur Respir J, 4: 694-702. 009187

Becquemin MM; Bertholon JF; Bouchikhi A; Malarbet JL; Roy M (1999). Oronasal Ventilation Partitioning in Adults and 

Children: Effect on Aerosol Deposition in Airways. Radiat Prot Dosimetry, 81: 221-228. 155679

Bennett W; Messina M; Smaldone G (1985). Effect of exercise on deposition and subsequent retention of inhaled particles. 

J Appl Physiol, 59: 1046-1054. 190034

Bennett W; Zeman K; Jarabek A (2003). Nasal contribution to breathing with exercise: effect of race and gender. J Appl 

Physiol, 95: 497-503. 191977

Bennett WD; Ilowite JS (1989). Dual pathway clearance of 99mTc-DTPA from the bronchial mucosa. Am Rev Respir Dis, 

139: 1132-1138. 000835

 

Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and 

Environmental Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of 

developing science assessments such as the Integrated Science Assessments (ISA) and the Integrated Risk Information System (IRIS). 

December 2009 4-30 
Bennett WD; Zeman KL (1998). Deposition of fine particles in children spontaneously breathing at rest. Inhal Toxicol, 10: 

831-842. 076182

Bennett WD; Zeman KL (2004). Effect of body size on breathing pattern and fine-particle deposition in children. J Appl 

Physiol, 97: 821-826. 155686

Bennett WD; Zeman KL (2005). Effect of Race on Fine Particle Deposition for Oral and Nasal Breathing. Inhal Toxicol, 

17: 641-648. 155687

Bennett WD; Zeman KL; Jarabek AM (2008). Nasal contribution to breathing and fine particle deposition in children 

versus adults. J Toxicol Environ Health A Curr Iss, 71: 227-237. 156269

Bennett WD; Zeman KL; Kim C (1996). Variability of fine particle deposition in healthy adults: effect of age and gender. 

Am J Respir Crit Care Med, 153: 1641-1647. 083284

Bennett WD; Zeman KL; Kim C; Mascarella J (1997). Enhanced deposition of fine particles in COPD patients 

spontaneously breathing at rest. Inhal Toxicol, 9: 1-14. 078839

Bermudez E; Mangum JB; Asgharian B; Wong BA; Reverdy EE; Janszen DB; Hext PM; Warheit DB; Everitt JI (2002). 

Long-term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium 

dioxide particles. Toxicol Sci, 70: 86-97. 055578

Bermudez E; Mangum JB; Wong BA; Asgharian B; Hext PM; Warheit DB; Everitt JI (2004). Pulmonary responses of 

mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicol Sci, 77: 347-357. 

056707

Bhalla DK; Mannix RC; Kleinman MT; Crocker TT (1986). Relative permeability of nasal, tracheal, and bronchoalveolar 

mucosa to macromolecules in rats exposed to ozone. J Toxicol Environ Health, 17: 269-283. 040407

Bodolay E; Szekanecz Z; Devenyi K; Galuska L; Csipo I; Vegh J; Garai I; Szegedi G (2005). Evaluation of interstitial lung 

disease in mixed connective tissue disease (MCTD). Rheumatology, 44: 656-661. 156280

Braga F; Mango JC; Souza JF; Ferrioli E; De Andrade J; Iazigi N (1996). Age-related reduction in 99Tcm-DTPA alveolarcapillary clearance in normal humans. Nucl Med Comm, 17: 971-974. 156289

Braude S; Nolop KB; Hughes JMB; Barnes PJ; Royston D (1986). Comparison of lung vascular and epithelial permeability 

indices in the adult respiratory distress syndrome. Am Rev Respir Dis, 133: 1002-1005. 155701

Brown J; Bennett W (2004). Deposition of coarse particles in cystic fibrosis: model predictions versus experimental results. 

J Aerosol Med, 17: 239-248. 190032

Brown JS (2005). Particle inhalability at low wind speeds. Inhal Toxicol, 17: 831-837. 156299

Brown JS; Wilson WE; Grant LD (2005). Dosimetric comparisons of particle deposition and retention in rats and humans. 

Inhal Toxicol, 17: 355-385. 089308

Brown JS; Zeman KL; Bennett WD (2002). Ultrafine particle deposition and clearance in the healthy and obstructed lung. 

Am J Respir Crit Care Med, 166: 1240-1247. 043216

Burch WM (2002). Comment on "Passage of inhaled particles into the blood circulation in humans". Circulation, 106: 

e141-e142. 056754

Caner B; Ugur O; Bayraktar M; Ulutuncel N; Mentes T; Telatar F; Bekdik C (1994). Impaired lung epithelial permeability 

in diabetics detected by technetium-99m-DTPA aerosol scintigraphy. J Nucl Med, 35: 204-206. 156320

Chadha TS; Birch S; Sackner MA (1987). Oronasal distribution of ventilation during exercise in normal subjects and 

patients with asthma and rhinitis. Chest, 92: 1037-1041. 037365

Chang C-C; Chiu H-F; Wu Y-S; Li Y-C; Tsai M-L; Shen C-K; Yang C-Y (2005). The induction of vascular endothelial 

growth factor by ultrafine carbon black contributes to the increase of alveolar-capillary permeability. Environ 

Health Perspect, 113: 454-460. 097776

Chen J; Tan M; Nemmar A; Song W; Dong M; Zhang G; Li Y (2006). Quantification of extrapulmonary translocation of 

intratracheal-instilled particles in vivo in rats: effect of lipopolysaccharide. Toxicology, 222: 195-201. 147267

Cheng K-H; Cheng Y-S; Yeh H-C; Guilmette RA; Simpson SQ; Yang Y-H; Swift DL (1996). In vivo measurements of 

nasal airway dimensions and ultrafine aerosol deposition in the human nasal and oral airways. J Aerosol Sci, 27: 

785-801. 047520

December 2009 4-31 
Chinard FP (1980). The alveolar-capillary barrier: some data and speculations. Microvasc Res, 19: 1-17. 156341

Churg A; Stevens B; Wright JL (1998). Comparison of the uptake of fine and ultrafine TiO2 in a tracheal explant system. 

Am J Physiol, 274: L81-L86. 085815

Cohen MD; Zelikoff JT; Chen L-C; Schlesinger RB (1997). Pulmonary retention and distribution of inhaled chromium: 

effects of particle solubility and coexposure to ozone. Inhal Toxicol, 9: 843-865. 009213

Creasia DA; Poggenburg JK Jr; Nettesheim P (1976). Elution of benzo[a]pyrene from carbon particles in the respiratory 

tract of mice. J Toxicol Environ Health, 1: 967-975. 059713

Dai YT; Juang YJ; Wu Y; Breysse PN; Hsu DJ (2006). In vivo measurements of inhalability of ultralarge aerosol particles 

in calm air by humans. J Aerosol Sci, 37: 967-973. 156377

DeLorenzo AJD (1970). The olfactory neuron and the blood-braín barríer. In Taste and Smell in Vertebrates (pp. 151-175). 

London: Churchill Livingstone. 156391

Dorman DC; McManus BE; Parkinson CU; Manuel CA; McElveen AM; Everitt JI (2004). Nasal Toxicity of Manganese 

Sulfate and Manganese Phosphate in Young Male Rats Following Subchronic (13-Week) Inhalation Exposure. Inhal 

Toxicol, 16: 481-488. 155752

Dorman DC; Struve MF; James RA; Marshall MW; Parkinson CU; Wong BA (2001). Influence of particle solubility on the 

delivery of inhaled manganese to the rat brain: manganese sulfate and manganese tetroxide pharmacokinetics 

following repeated (14-day) exposure. Toxicol Appl Pharmacol, 170: 79-87. 055433

Edetsberger M; Gaubitzer E; Valic E; Waigmann E; Köhler G (2005). Detection of nanometer-sized particles in living cells 

using modern fluorescence fluctuation methods. Biochem Biophys Res Commun, 332: 109-116. 155759

Elder A; Gelein R; Silva V; Feikert T; Opanashuk L; Carter J; Potter R; Maynard A; Ito Y; Finkelstein J; Oberdorster G 

(2006). Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health 

Perspect, 114: 1172-1178. 089253

Enna SJ; Schanker LS (1972). Absorption of drugs from the rat lung. Am J Physiol, 223: 1227-1231. 155767

Falk R; Philipson K; Svartengren M; Jarvis N; Bailey M; Camner P (1997). Clearance of particles from small ciliated 

airways. Exp Lung Res, 23: 495-515. 086080

Farkas A; Balásházy I (2008). Quantification of particle deposition in asymmetrical tracheobronchial model geometry. 

Comput Biol Med, 38: 508-18. 157358

Farkas A; Balashazy I; SzQcs K (2006). Characterization of Regional and Local Deposition of Inhaled Aerosol Drugs in 

the Respiratory System by Computational Fluid and Particle Dynamics Methods. J Aerosol Med, 19: 329-343. 

155771

Ferin J; Oberdorster G; Penney DP (1992). Pulmonary retention of ultrafine and fine particles in rats. Am J Respir Cell Mol 

Biol, 6: 535-542. 044401

Finlay WH; Martin AR (2008). Recent advances in predictive understanding of respiratory tract deposition. J Aerosol Med 

Pulm Drug Deliv, 21: 189-206. 155776

Fishman AP; Elias JA (1980). Fishman's Pulmonary diseases and disorders. New York: McGraw-Hill. 156436

Foster WM; Stetkiewicz PT (1996). Regional clearance of solute from the respiratory epithelia: 18--20 h postexposure to 

ozone. J Appl Physiol, 81: 1143-1149. 079920

Foster WM; Wagner EM (2001). Bronchial edema alters 99mTc-DTPA clearance from the airway surface in sheep. J Appl 

Physiol, 91: 2567-2573. 155778

Geiser M; Rothen-Rutishauser B; Kapp N; Schurch S; Kreyling W; Schulz H; Semmler M; Im Hof V; Heyder J; Gehr P 

(2005). Ultrafine particles cross cellular membranes by nonphagocytic mechanisms in lungs and in cultured cells. 

Environ Health Perspect, 113: 1555-1560. 087362

Geys J; Coenegrachts L; Vercammen J; Engelborghs Y; Nemmar A; Nemery B; Hoet PHM (2006). In vitro study of the 

pulmonary translocation of nanoparticles A preliminary study. Toxicol Lett, 160: 218-226. 155789

Goodman RM; Yergin BM; Landa JF; Golinvaux MH; Sackner MA (1978). Relationship of smoking history and 

pulmonary function tests to tracheal mucous velocity in nonsmokers, young smokers, ex-smokers, and patients with 

chronic bronchitis. Am Rev Respir Dis, 117: 205-214. 071130

December 2009 4-32 
Greenspan BJ; Morrow PE; Ferin J (1988). Effects of aerosol exposures to cadmium chloride on the clearance of titanium 

dioxide from the lungs of rats. Exp Lung Res, 14: 491-499. 045031

Grgic B; Finlay WH; Burnell PKP; Heenan AF (2004). In vitro intersubject and intrasubject deposition measurements in 

realistic mouth–throat geometries. J Aerosol Sci, 35: 1025-1040. 155810

Hanel B; Law I; Mortensen J (2003). Maximal rowing has an acute effect on the blood-gas barrier in elite athletes. J Appl 

Physiol, 95: 1076-1082. 155826

Heistracher T; Hofmann W (1997). Flow and deposition patterns in successive airway bifurcations. Presented at In: Cherry, 

N.; Ogden, T., eds. Inhaled Particles VIII: proceedings of an international symposium on inhaled particles organised 

by the British Occupational Hygiene Society; August 1996; Cambridge, UK. Ann. Occup. Hyg. 41(suppl.): 537-

542. 047514

Ho JC; Chan KN; Hu WH; Lam WK; Zheng L; Tipoe GL; Sun J; Leung R; Tsang KW (2001). The effect of aging on nasal 

mucociliary clearance, beat frequency, and ultrastructure of respiratory cilia. Am J Respir Crit Care Med, 163: 983-

988. 156549

Hofmann W; Asgharian B (2003). The effect of lung structure on mucociliary clearance and particle retention in human and 

rat lungs. Toxicol Sci, 73: 448-456. 055579

Hofmann W; Balashazy I; Heistracher T; Koblinger L (1996). The significance of particle deposition patterns in bronchial 

airway bifurcations for extrapolation modeling. Aerosol Sci Technol, 25: 305-327. 047515

Hofmann W; Martonen TB; Graham RC (1989). Predicted deposition of nonhygroscopic aerosols in the human lung as a 

function of subject age. J Aerosol Med, 2: 49-68. 006922

Hsu DJ; Swift DL (1999). The measurements of human inhalability of ultralarge aerosols in calm air using mannikins. J 

Aerosol Sci, 30: 1331-1343. 155855

Huchon GJ; Montgomery AB; Lipavsky A; Hoeffel JM; Murray JF (1987). Respiratory clearance of aerosolized radioactive 

solutes of varying molecular weight. J Nucl Med, 28: 894-902. 024923

Huchon GJ; Russell JA; Barritault LG; Lipavsky A; Murray JF (1984). Chronic air-flow limitation does not increase 

respiratory epithelial permeability assessed by aerosolized solute, but smoking does. Am Rev Respir Dis, 130: 457-

460. 156576

ICRP (1995). Human respiratory tract model for radiological protection: a report of a task group of the International 

Commission on Radiological Protection. Ann ICRP, 24: 1-482. 006988

Ilowite JS; Bennett WD; Sheetz MS; Groth ML; Nierman DM (1989). Permeability of the bronchial mucosa to 99mTcDTPA in asthma. Am Rev Respir Dis, 139: 1139-1143. 156584

International Life Sciences Institute (2000). The relevance of the rat lung response to particle overload for human risk 

assessment: A workshop consensus report. Inhal Toxicol, 12: 1-17. 002892

Isaacs KK; Schlesinger RB; Martonen TB (2006). Three-dimensional computational fluid dynamics simulations of particle 

deposition in the tracheobronchial tree. J Aerosol Med, 19: 344-352. 155861

ISO (2008). Nanotechnologies -- Terminology and definitions for nano-objects -- Nanoparticle, nanofibre and nanoplate. 

International Organization for Standardization. Geneva. 190066

James DS; Stidley CA; Lambert WE; Chick TW; Mermier CM; Samet JM (1997). Oronasal distribution of ventilation at 

different ages. Arch Environ Occup Health, 52: 118-123. 042422

Jarabek AM; Asgharian B; Miller FJ (2005). Dosimetric adjustments for interspecies extrapolation of inhaled poorly 

soluble particles (PSP). Inhal Toxicol, 17: 317-334. 056756

Jeffers DE (2005). Relative magnitudes of the effects of electrostatic image and thermophoretic forces on particles in the 

respiratory tract. Radiat Prot Dosimetry, 113: 189-194. 156608

Jones JG; Minty BD; Lawler P; Hulands G; Crawley JC; Veall N (1980). Increased alveolar epithelial permeability in 

cigarette smokers. Lancet, 1: 66-68. 155883

Jones JG; Minty BD; Royston D; Royston JP (1983). Carboxyhaemoglobin and pulmonary epithelial permeability in man. 

Thorax, 38: 129-133. 155884

December 2009 4-33 
Kapp N; Kreyling W; Schulz H; Im Hof V; Gehr P; Semmler M; Geiser M (2004). Electron energy loss spectroscopy for 

analysis of inhaled ultrafine particles in rat lungs. Microsc Res Tech, 63: 298-305. 156624

Kaya E; Fidan F; Unlu M; Sezer M; Tetik L; Acar M (2006). Evaluation of alveolar clearance by Tc-99m DTPA 

radioaerosol inhalation scintigraphy in welders. Ann Nucl Med, 20: 503-510. 156632

Kaya M; Salan A; Tabakoglu E; Aydogdu N; Berkarda S (2003). The bronchoalveolar epithelial permeability in house 

painters as determined by Tc-99m DTPA aerosol scintigraphy. Ann Nucl Med, 17: 305-308. 156631

Kehrl HR; Vincent LM; Kowalsky RJ; Horstman DH; O'Neil JJ; McCartney WH; Bromberg PA (1987). Ozone exposure 

increases respiratory epithelial permeability in humans. Am J Respir Crit Care Med, 135: 1124-1128. 040824

Kelly JT; Asgharian B; Wong BA (2005). Inertial Particle Deposition in a Monkey Nasal Mold Compared with that in 

Human Nasal Replicas. Inhal Toxicol, 17: 823-830. 155894

Kim CS (2000). Methods of calculating lung delivery and deposition of aerosol particles. Respir Care, 45: 695-711. 013112

Kim CS; Hu SC (1998). Regional deposition of inhaled particles in human lungs: comparison between men and women. J 

Appl Physiol, 84: 1834-1844. 086066

Kim CS; Iglesias AJ (1989). Deposition of inhaled particles in bifurcating airway models: I inspiratory deposition. J 

Aerosol Med, 2: 1-14. 078539

Kim CS; Iglesias AJ; Garcia L (1989). Deposition of inhaled particles in bifurcating airway models: II expiratory 

deposition. J Aerosol Med, 2: 15-27. 078538

Kim CS; Jaques PA (2000). Respiratory dose of inhaled ultrafine particles in healthy adults. Philos Transact A Math Phys 

Eng Sci, 358: 2693-2705. 012811

Kimbell JS (2006). Nasal Dosimetry of Inhaled Gases and Particles: Where Do Inhaled Agents Go in the Nose? Toxicol 

Pathol, 34: 270-273. 155902

Kreyling WG (1992). Intracellular particle dissolution in alveolar macrophages. Environ Health Perspect, 97: 121-126. 

067243

Kreyling WG; Blanchard JD; Godleski JJ; Haeussermann S; Heyder J; Hutzler P; Schulz H; Sweeney TD; Takenaka S; 

Ziesenis A (1999). Anatomic localization of 24- and 96-h particle retention in canine airways. J Appl Physiol, 87: 

269-284. 039175

Kreyling WG; Scheuch G (2000). Clearance of particles deposited in the lungs. In Gehr, P.; Heyder, J. (Ed.),Particle-lung 

interactions (pp. x). New York, NY: Marcel Dekker, Inc. 056281

Kreyling WG; Semmler M; Erbe F; Mayer P; Takenaka S; Schulz H; Oberdorster G; Ziesenis A (2002). Translocation of 

ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. 

J Toxicol Environ Health A Curr Iss, 65: 1513-1530. 037332

Laitinen LA; Heino M; Laitinen A; Kava T; Haahtela T (1985). Damage of the airway epithelium and bronchial reactivity 

in patients with asthma. Am Rev Respir Dis, 131: 599-606. 037521

Lay J; Alexis N; Zeman K; Peden D; Bennett W (2009). In vivo uptake of inhaled particles by airway phagocytes is 

enhanced in patients with mild asthma compared with normal volunteers. Thorax, 64: 313-320. 190060

Lay JC; Stang MR; Fisher PE; Yankaskas JR; Bennett WD (2003). Airway Retention of Materials of Different Solubility 

following Local Intrabronchial Deposition in Dogs. J Aerosol Med, 16: 153-166. 155920

Lee KP; Henry NW III; Trochimowicz HJ; Reinhardt CF (1986). Pulmonary response to impaired lung clearance in rats 

following excessive TiO2 dust deposition. Environ Res, 41: 144-167. 067629

Lee KP; Trochimowicz HJ; Reinhardt CF (1985). Transmigration of titanium dioxide (TiO2) particles in rats after 

inhalation exposure. Exp Mol Pathol, 42: 331-343. 067628

Lin CC; Chang CT; Li TC; Kao A (2002). Objective Evidence of Impairment of Alveolar Integrity in Patients with NonInsulin-Dependent Diabetes Mellitus Using Radionuclide Inhalation Lung Scan. Lung, 180: 181-186. 155932

Lorino AM; Meignan M; Bouissou P; Atlan G (1989). Effects of sustained exercise on pulmonary clearance of aerosolized 

99mTc-DTPA. J Appl Physiol, 67: 2055-2059. 155946

Lundgren DL; Hahn FF; Crain CR; Sanchez A (1978). Effect of influenza virus infection on the pulmonary retention of 

inhaled 144Ce and subsequent survival of mice. Health Phys, 34: 557-567. 155950

December 2009 4-34 
Martonen TB; Yang Y; Xue ZQ (1994). Effects of carinal ridge shapes on lung airstreams. Aerosol Sci Technol, 21: 119-

136. 000847

Mason GR; Uszler JM; Effros RM; Reid E (1983). Rapidly reversible alterations of pulmonary epithelial permeability 

induced by smoking. Chest, 83: 6-11. 013169

Matsui H; Randell SH; Peretti SW; Davis CW; Boucher RC (1998). Coordinated clearance of periciliary liquid and mucus 

from airway surfaces. J Clin Invest, 102: 1125-1131. 040405

Mauderly JL (1997). Relevance of particle-induced rat lung tumors for assessing lung carcinogenic hazard and human lung 

cancer risk. Environ Health Perspect, 105 (Suppl 5): 1337-1346. 084631

Meignan M; Rosso J; Leveau J; Katz A; Cinotti L; Madelaine G; Galle P (1986). Exercise increases the lung clearance of 

inhaled technetium-99m DTPA. J Nucl Med, 27: 274-280. 156752

Ménache MG; Miller FJ; Raabe OG (1995). Particle inhalability curves for humans and small laboratory animals. Ann 

Occup Hyg, 39: 317-328. 006533

Miller FJ (2000). Dosimetry of particles in laboratory animals and humans in relationship to issues surrounding lung 

overload and human health risk assessment: a critical review. Inhal Toxicol, 12: 19-57. 011822

Mills NL; Amin N; Robinson SD; Anand A; Davies J; Patel D; de la Fuente JM; Cassee FR; Boon NA; Macnee W; Millar 

AM; Donaldson K; Newby DE (2006). Do inhaled carbon nanoparticles translocate directly into the circulation in 

humans? Am J Respir Crit Care Med, 173: 426-431. 088770

Möller W; Felten K; Sommerer K; Scheuch G; Meyer G; Meyer P; Haussinger K; Kreyling WG (2008). Deposition, 

retention, and translocation of ultrafine particles from the central airways and lung periphery. Am J Respir Crit Care 

Med, 177: 426-432. 156771

Möller W; Haussinger K; Winkler-Heil R; Stahlhofen W; Meyer T; Hofmann W; Heyder J (2004). Mucociliary and longterm particle clearance in the airways of healthy nonsmoker subjects. J Appl Physiol, 97: 2200-2206. 155987

Morgan W; Ahmad D; Chamberlain M; Clague H; Pearson M; Vinitski S (1984). The effect of exercise on the deposition of 

an inhaled aerosol. Respir Physiol, 56: 327-338. 190035

Morrow PE (1994). Mechanisms and significance of "particle overload". In Mohr U (Ed.),Toxic and Carcinogenic Effects 

of Solid Particles in the Respiratory Tract (pp. 17-25). Washington, DC: ILSI Press . 006850

Mousa K; Onadeko BO; Mustafa HT; Mohamed M; Nabilla A; Omar A; Al-Bunni A; Elgazzar A (2000). Technetium 

99mTc-DTPA clearance in the evaluation of pulmonary involvement in patients with diabetes mellitus. Respir Med, 

94: 1053-1056. 156786

Muhle H; Creutzenberg O; Bellmann B; Heinrich U; Mermelstein R (1990). Dust overloading of lungs: investigations of 

various materials, species differences, and irreversibility of effects. J Aerosol Med, 1: S111-S128. 006853

Nemmar A; Hoet PHM; Vanquickenborne B; Dinsdale D; Thomeer M; Hoylaerts MF; Vanbilloen H; Mortelmans L; 

Nemery B (2002). Passage of inhaled particles into the blood circulation in humans. Circulation, 105: 411-414. 

024914

Niinimaa V; Cole P; Mintz S; Shephard RJ (1981). Oronasal distribution of respiratory airflow. Respir Physiol Neurobiol, 

43: 69-75. 071758

Nikula KJ; Vallyathan V; Green FHY; Hahn FF (2001). Influence of exposure concentration or dose on the distribution of 

particulate material in rat and human lungs. Environ Health Perspect, 109: 311-318. 016641

NRPB (2004). Particle deposition in the vicinity of power lines and possible effects on health: Report of an independent 

advisory group on non-ionising radiation and its ad hoc group on corona ions. National Radiological Protection 

Board. Oxfordshire, England. 156815

Oberdörster G (1988). Lung clearance of inhaled insoluble and soluble particles. J Aerosol Med, 1: 289-330. 006857

Oberdorster G (1995). Lung particle overload: implications for occupational exposures to particles. Regul Toxicol 

Pharmacol, 27: 123-135. 046596

Oberdorster G (1996). Significance of particle parameters in the evaluation of exposure-dose-response relationships of 

inhaled particles. Inhal Toxicol, 8 Supplement: 73-89. 039852

Oberdorster G (2002). Toxicokinetics and effects of fibrous and nonfibrous particles. Inhal Toxicol, 14: 29-56. 021111

December 2009 4-35 
Oberdörster G; Ferin J; Gelein R; Soderholm SC; Finkelstein J (1992). Role of the alveolar macrophage in lung injury: 

studies with ultrafine particles. Environ Health Perspect, 97: 193-199. 045110

Oberdörster G; Ferin J; Lehnert BE (1994). Correlation between particle size, in vivo particle persistence, and lung injury. 

Environ Health Perspect, 102 : 173-179. 046203

Oberdörster G; Ferin J; Soderholm S; Gelein R; Cox C; Baggs R; Morrow PE (1994). Increased pulmonary toxicity of 

inhaled ultrafine particles: due to lung overload alone? Ann Occup Hyg, 38: 295-302. 056285

Oberdorster G; Finkelstein JN; Johnston C; Gelein R; Cox C; Baggs R; Elder ACP (2000). Acute pulmonary effects of 

ultrafine particles in rats and mice. Health Effects Institute. Boston. Report Number 96. 039014

Oberdörster G; Sharp Z; Atudorei V; Elder A; Gelein R; Kreyling W; Cox C (2004). Translocation of inhaled ultrafine 

particles to the brain. Inhal Toxicol, 16: 437-445. 055639

Oldham MJ; Robinson RJ (2007). Predicted tracheobronchial and pulmonary deposition in a murine asthma model. Anat 

Rec, 290: 1309-1314. 156003

Ozsahin K; Tugrul A; Mert S; Yüksel M; Tugrul G (2006). Evaluation of pulmonary alveolo-capillary permeability in Type 

2 diabetes mellitus Using technetium 99mTc-DTPA aerosol scintigraphy and carbon monoxide diffusion capacity. J 

Diabetes Complications, 20: 205-209. 156833

Persson E; Henriksson J; Tallkvist J; Rouleau C; Tjalve H (2003). Transport and subcellular distribution of intranasally 

administered zinc in the olfactory system of rats and pikes. Toxicology, 191: 97-108. 051846

Peterson BT; Dickerson KD; James HL; Miller EJ; McLarty JW; Holiday DB (1989). Comparison of three tracers for 

detecting lung epithelial injury in anesthetized sheep. J Appl Physiol, 66: 2374-2383. 024922

Phalen RF; Oldham MJ (2006). Aerosol dosimetry considerations. Clin Occup Environ Med, 5: 773-784. 156024

Phalen RF; Oldham MJ; Mautz WJ (1989). Aerosol Deposition in the Nose As a Function of Body Size. Health Phys, 57: 

299-305. 156023

Phalen RF; Oldham MJ; Wolff RK (2008). The relevance of animal models for aerosol studies. J Aerosol Med Pulm Drug 

Deliv, 21: 113-124. 156865

Pigorini F; Maini CL; Pau F; Giosue S (1988). The influence of age on the pulmonary clearance of 99Tcm-DTPA 

radioaerosol. Nucl Med Comm, 9: 965-971. 156027

Puchelle E; Zahm J-M; Bertrand A (1979). Influence of age on bronchial mucociliary transport. Scand J Respir Dis, 60: 

307-313. 006863

Raabe OG; Al-Bayati MA; Teague SV; Rasolt A (1988). Regional deposition of inhaled monodisperse, coarse, and fine 

aerosol particles in small laboratory animals. In Inhaled particles VI: Proceedings of an international symposium 

and workshop on lung dosimetry (pp. 53-63). Cambridge, U.K.: Pergamon Press. 001439

Roth C; Scheuch G; Stahlhofen W (1993). Clearance of the human lungs for ultrafine particles. J Aerosol Sci, 24: S95-S96 

. 156928

Sakagami M; Byron PR; Venitz J; Rypacek F (2002). Solute disposition in the rat lung in vivo and in vitro: determining 

regional absorption kinetics in the presence of mucociliary escalator. J Pharmacol Sci, 91: 594-604. 156936

Schanker LS; Mitchell EW; Brown RA Jr (1986). Species comparison of drug absorption from the lung after aerosol 

inhalation or intratracheal injection. Drug Metab Dispos, 14: 79-88. 005100

Scheuch G; Gebhart J; Roth C (1990). Uptake of electrical charges in the human respiratory tract during exposure to air 

loaded with negative ions. J Aerosol Sci, 21: S439-S442. 006948

Schroeter JD; Kimbell JS; Asgharian B (2006). Analysis of particle deposition in the turbinate and olfactory regions using a 

human nasal computational fluid dynamics model. J Aerosol Med Pulm Drug Deliv, 19: 301-313. 156076

Semmler M; Seitz J; Erbe F; Mayer P; Heyder J; Oberdorster G; Kreyling WG (2004). Long-term clearance kinetics of 

inhaled ultrafine insoluble iridium particles from the rat lung, including transient translocation into secondary 

organs. Inhal Toxicol, 16: 453-459. 055641

Semmler-Behnke M; Takenaka S; Fertsch S; Wenk A; Seitz J; Mayer P; Oberdörster G; Kreyling WG (2007). Efficient 

elimination of inhaled nanoparticles from the alveolar region: evidence for interstitial uptake and subsequent 

reentrainment onto airways epithelium. Environ Health Perspect, 115: 728-733. 156080

December 2009 4-36 
Smith JR; Bailey MR; Etherington G; Shutt AL; Youngman MJ (2008). Effect of particle size on slow particle clearance 

from the bronchial tree. Exp Lung Res, 34: 287-312. 190037

Snipes MB (1996). Current information on lung overload in nonrodent mammals: contrast with rats. Inhal Toxicol, 8: 91-

109. 076041

Snipes MB; Harkema JR; Hotchkiss JA; Bice DE (1997). Neutrophil Involvement in the Retention and Clearance of Dust 

Intratracheally Instilled into the LUNGS of F344/N Rats. Exp Lung Res, 23: 65-84. 156092

Soderholm SC (1985). Size-selective sampling criterial for inspirable mass fraction. In Particle size-selective sampling in 

the workplace : report of the ACGIH Technical Committee on Air Sampling Procedures (pp. 27-32). Cincinnati, 

Ohio: American Conference of Governmental Industrial Hygienists. 156992

Sousa SR; Moradas-Ferreira P; Saramango B; Viseu ML; Barbosa MA (2004). Human serum albumin adsorption on TiO2 

from single protein solutions and from plasma. Langmuir, 20: 9745-9754. 089866

Suga K; Yuan Y; Ogasawara N; Tsukuda T; Matsunaga N (2003). Altered Clearance of Gadolinium 

Diethylenetriaminepentaacetic Acid Aerosol from Bleomycin-injured Dog Lungs: Initial Observations. Am J Respir 

Crit Care Med, 167: 1704-1710. 157024

Svartengren M; Falk R; Philipson K (2005). Long-term clearance from small airways decreases with age. Eur Respir J, 26: 

609-615. 157034

Tabachnik E; Muller N; Toye B; Levison H (1981). Measurement of ventilation in children using the respiratory inductive 

plethysmograph. J Pediatr, 99: 895-899. 157036

Takenaka S; Dornhofer-Takenaka H; Muhle H (1986). Alveolar distribution of fly ash and of titanium dioxide after longterm inhalation by Wistar rats. J Aerosol Sci, 17: 361-364. 046210

Takenaka S; Karg E; Kreyling W; Lentner B; Möller W; Behnke-Semmler M; Jennen L; Walch A; Michalke B; Schramel P 

(2006). Distribution Pattern of Inhaled Ultrafine Gold Particles in the Rat Lung. Inhal Toxicol, 18: 733-740. 156110

Tankersley CG; Shank JA; Flanders SE; Soutiere SE; Rabold R; Mitzner W; Wagner EM (2003). Changes in lung 

permeability and lung mechanics accompany homeostatic instability in senescent mice. J Appl Physiol, 95: 1681-

1687. 096363

Tobin MJ; Chadha TS; Jenouri G; Birch SJ; Gazeroglu HB; Sackner MA (1983). Breathing patterns. 1. Normal subjects. 

Chest, 84: 202-205. 156122

Tran CL; Buchanan D; Cullen RT; Searl A; Jones AD; Donaldson K (2000). Inhalation of poorly soluble particles II 

Influence of particle surface area on inflammation and clearance. Inhal Toxicol, 12: 1113-1126. 013071

Tu KW; Knutson EO (1984). Total deposition of ultrafine hydrophobic and hygroscopic aerosols in the human respiratory 

system. Aerosol Sci Technol, 3: 453-465. 072870

U.S. EPA (1996). Air quality criteria for particulate matter. U.S. Environmental Protection Agency. Research Triangle Park, 

NC. EPA/600/P-95/001aF-cF. 079380

U.S. EPA (2004). Air quality criteria for particulate matter. U.S. Environmental Protection Agency. Research Triangle Park, 

NC. EPA/600/P-99/002aF-bF. 056905

Valberg P; Brain J; Sneddon S; LeMott S (1982). Breathing patterns influence aerosol deposition sites in excised dog lungs. 

J Appl Physiol, 53: 824-837. 190019

Vastag E; Matthys H; Kohler D; Gronbeck L; Daikeler G (1985). Mucociliary clearance and airways obstruction in 

smokers, ex-smokers and normal subjects who never smoked. Eur J Respir Dis, 139: 93-100. 157088

Vincent JH; Donaldson K (1990). A dosimetric approach for relating the biological response of the lung to the 

accumulation of inhaled mineral dust. Br J Ind Med, 47: 302-307. 002462

Wagner EM; Foster WM (2001). Interdependence of bronchial circulation and clearance of 99mTc-DTPA from the airway 

surface. J Appl Physiol, 90: 1275-1281. 156143

Wallenborn JG; Kovalcik KD; McGee JK; Landis MS; Kodavanti UP (2009). Systemic translocation of (70)zinc: kinetics 

following intratracheal instillation in rats. Toxicol Appl Pharmacol, 234: 25-32. 191172

Wallenborn JG; McKee JK; Schladweiler MC; Ledbetter AD; Kodavanti UP (2007). Systemic translocation of particulate 

matter-associated metals following a single intratracheal instillation in rats. J Toxicol Sci, 98: 231-239. 156144

December 2009 4-37 
December 2009 4-38 

Wang JX; Chen CY; Yu HW; Sun J; Li B; Li YF; Gao YX; He W; Huang YY; Chai ZF (2007). Distribution of TiO 2 

particles in the olfactory bulb of mice after nasal inhalation using microbeam SRXRF mapping techniques. Journal 

of Radioanal Chem, 272: 527-531. 156146

Warheit DB; Hansen JF; Yuen IS; Kelly DP; Snajdr SI; Hartsky MA (1997). Inhalation of high concentrations of low 

toxicity dusts in rats results in impaired pulmonary clearance mechanisms and persistent inflammation. Toxicol 

Appl Pharmacol, 145: 10-22. 086055

Warheit DB; Webb TR; Sayes CM; Colvin VL; Reed KL (2006). Pulmonary instillation studies with nanoscale TiO2 rods 

and dots in rats: Toxicity is not dependent upon particle size and surface area. Toxicol Sci, 91: 227-236. 088436

Watanabe N; Tanada S; Sasaki Y (2007). Pulmonary clearance of aerosolized 99mTc-DTPA in sarcoidosis I patients. Q J 

Nucl Med Mol Imaging, 51: 82-90. 157115

Weynand B; Jonckheere A; Frans A; Rahier J; Saint-Luc CU (1999). Diabetes mellitus Induces a Thickening of the 

Pulmonary Basal Lamina. Respiration, 66: 14-19. 157140

Whaley SL; Muggenburg BA; Seiler FA; Wolff RK (1987). Effect of aging on tracheal mucociliary clearance in beagle 

dogs. J Appl Physiol, 62: 1331-1334. 156153

Wiebert P; Sanchez-Crespo A; Falk R; Philipson K; Lundin A; Larsson S; Möller W; Kreyling W; Svartengren M (2006). 

No Significant Translocation of Inhaled 35-nm Carbon Particles to the Circulation in Humans. Inhal Toxicol, 18: 

741-747. 156154

Wiebert P; Sanchez-Crespo A; Seitz J; Falk R; Philipson K; Kreyling WG; Moller W; Sommerer K; Larsson S; Svartengren 

M (2006). Negligible clearance of ultrafine particles retained in healthy and affected human lungs. Eur Respir J, 28: 

286-290. 157146

Winter-Sorkina Rde; Cassee FR (2002). From concentration to dose: factors influencing airborne particulate matter 

deposition in humans and rats. National Institute for Public Health and the Environment. Bilthoven, Netherlands. 

650010031/2002. www.rivm.nl/bibliotheek/rapporten/650010031.html. 043670

Xu GB; Yu CP (1986). Effects of age on deposition of inhaled aerosols in the human lung. Aerosol Sci Technol, 5: 349-357. 

072697

Yeates DB; Gerrity TR; Garrard CS (1981). Particle deposition and clearance in the bronchial tree. Ann Biomed Eng, 9: 

577-592. 095391

Yu CP (1985). Theories of electrostatic lung deposition of inhaled aerosols. Ann Occup Hyg, 29: 219-227. 006963

Yu IJ; Park JD; Park ES; Song KS; Han KT; Han JH; Chung YH; Choi BS; Chung KH; Cho MH (2003). Manganese 

distribution in brains of Sprague-Dawley rats after 60 days of stainless steel welding-fume exposure. 

Neurotoxicology, 24: 777-785. 156171

Zanobetti A; Schwartz J (2002). Cardiovascular damage by airborne particles: are diabetics more susceptible? 

Epidemiology, 13: 588-592. 034821

Zeidler-Erdely PC; Calhoun WJ; Ameredes BT; Clark MP; Deye GJ; Baron P; Jones W; Blake T; Castranova V (2006). In 

vitro cytotoxicity of Manville Code 100 glass fibers: Effect of fiber length on human alveolar macrophages. Part 

Fibre Toxicol, 28: 3:5. 190967

Zhao X; Ju Y; Liu C; Li J; Huang M; Sun J; Wang T (2009). Bronchial anatomy of left lung: a study of multi-detector row 

CT. Surg Rad Anat, 31: 85-91. 157187