Thompson 2018

PM: efectos, mecanismos (citotoxicidad, estrés oxidativo), composición, fuentes, propiedades
Journal of Occupational and Environmental Medicine, Publish Ahead of Print
DOI : 10.1097/JOM.0000000000001277
Airborne Particulate Matter: Human Exposure & Health Effects.
Jonathan E. Thompson, Ph.D.
Associate Professor, Department of Chemistry & Biochemistry,
Texas Tech University, Lubbock, TX 79409-1061 USA
Email: jon.thompson@ttu.edu, Phone: (806)834-6206
Orcid id: orcid.org/0000-0003-1550-2823
Scopus Author ID: 7405816725
Funding Sources Statement: No sources of funding have been provided to prepare this specific
work. The author’s research is currently not funded by any agency of a government or any
private company.
Conflict of interest statement:The author(s) declare(s) that there is no conflict of interest

regarding the publication of this paper.
Running title: Particulate Matter: Human Exposure & Health Effects
Copyright © 2018 American College of Occupational and Environmental Medicine. Unauthorized reproduction of this article is prohibited
Structured Abstract
Objective: Exposure to airborne particulate matter (PM) is estimated to cause millions of

premature deaths annually. This work conveys known routes of exposure to PM and resultant
health effects.
Methods: Review of available literature.
Results: Estimates for daily PM exposure are provided. Known mechanisms by which insoluble
particles are transported and removed from the body are discussed. Biological effects of PM,
including immune response, cytotoxicity, and mutagenicity are reported. Epidemiological studies
that outline the systemic health effects of PM are presented.
Conclusions: While the integrated, per capita, exposure of PM for a large fraction of the first-
world may be < 1 mg per day, links between several syndromes including ADHD, autism, loss of
cognitive function, anxiety, asthma, COPD, hypertension, stroke and PM exposure have been
suggested. This article reviews and summarizes such links reported in the literature.
Keywords: particulate matter; PM2.5; PM10; health effects of pollution, inflammation, immune
response, aerosol
List of Abbreviations
8-oxodG 7-hydro-8-oxo-2’-deoxyguanosine
A549 adenocarcinomic human alveolar basal epithelial cell line
AECOPD acute exacerbation of chronic obstructive pulmonary disease
ADHD attention deficit hyperactivity disorder
AMAD activity median aerodynamic diameter
Ax exposed skin surface area (cm2)
A(t) surface area of the skin contaminated
BAL bronchoalveolar lavage
BEAS-2B human bronchial epithelium cell line
CB carbon black
CC creative commons
COPD chronic obstructive pulmonary disease
COX-2 cyclooxygenase-2
CFD computational fluid dynamics models
CGRP calcitonin gene-related peptide receptor
C(t) particle mass concentration (g cm-3)
CSK(t) the concentration gradient across the SC
DEPs Diesel engine exhaust particles
Dp(t) depositional mass flux (g s-1)
DNA deoxyribonucleic acid
DTT dithiothreitol
EFTEM energy filtering transmission microscopy
GDP gross domestic product
GI gastrointestinal
HO-1 heme oxygenase-1
IFN-γ interferon gamma
IL-n where n is an integer, cytokine from the interleukin family
K(t) compound specific permeability coefficient
LDH lactate dehydrogenase
LPS lipopolysaccharide
logKow base-10 logarithm of the octanol-water partition coefficient
mRNA messenger RNA
miRNA micro RNA
MPPD multiple-path-particle-deposition model
MRSA methionine sulfoxide reductase A
MSRB3 methionine sulfoxide reductase B3
MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
MW molecular weight
NAC N-acetylcysteine
NPL nose, pharynx, larynx; head airways
PAH polycyclic aromatic hydrocarbon
PM particulate matter
PMx PM with aerodynamic diameter <x
PSK(t) rate of mass transport through the SC
QSPR quantitative structure activity relationship
ROS reactive oxygen species
RBC red blood cell
SC stratum corneum
SPR see TACR1
TACR1 tachykinin receptor 1, neurokinin 1 receptor, substance P receptor
TB,TCB tracheobronchial region
TBLN tracheobronchial lymph nodes
TLR2 toll-like receptor 2
TLR4 toll-like receptor 4
TNF-α tumor necrosis factor alpha
TRPV1 capsaicin receptor
UFP ultrafine particles
UD urban dust
USD US Dollars
US EPA United States Environmental Protection Agency
v(t) particle deposition velocity (cm s-1)
WBC white blood cell
INTRODUCTION.
Acute exposure to large quantities of airborne particulate matter (a.k.a atmospheric

aerosol) has long been recognized as being deleterious to human and animal health. Dramatic
events, such as the 1952 London smog, 1948 Donora event, or the immediate aftermath of the
World Trade Center building collapse create significant public awareness of the impact of
particulate pollution on health.1-5However, while less obvious to citizen observers, recent
research has suggested significanthealth impacts of chronic exposure to atmospheric particulate
matter.6-9 For instance, Pope et al. found that reducing the PM2.5 loading by 10 g / m3 led to
an increase of 0.61±0.20 year (P=0.004) in life expectancy in the United States during the 1980-
1990s.10Such a change in ambient concentration may barely be experientially noticeable to an
average observer, however, more and more empirical evidence has suggested that such low-level
chronic exposure to particulate pollution has profound human health effects contributing to a
variety of ailments. This has led some investigators to suggest that there is no ‘safe’ level of
exposure to either PM10 or PM2.5particulate pollution.11Some estimates suggest a global burden
of 4.2 million premature deaths due to particulate pollution for the year 2015.12Future projections
suggest outdoor air pollution could cause as many as 6-9 million premature deaths annually, and
a financial cost of 1% of global GDP (approx. $2.6 trillion USD) by the year 2060.13
Atmospheric aerosols have long been of interest due to reduction of visibility in urban
environments, and the aerosols role in affecting Earth’s climate by scattering or absorbing solar
radiation.14-16 These impacts have driven considerable research into delineation of the chemical
composition and size distribution of atmospheric particulate matter (PM).17 PM is often
classified into categories based upon size.18 Particles greater than 2.5 micrometers aerodynamic
diameter are called coarse mode particles. Particles between 0.1 – 2.5 micrometers are referred
to as accumulation mode particles, given their tendency to grow larger during their atmospheric
lifetime owing to deposition of materials that have undergone gas-phase reactions that reduced
volatility of the parent compound. Ultrafine particles are those that take the form of molecular
clusters up to about 100 nm in aerodynamic diameter. The chemical composition of the aerosol
strongly depends upon location and distance from sources. The global aerosol consists of both
natural and anthropogenic sources. A significant mass burden of wind-dispersed crustal material
(wind blown dust) and sea-salt spray that forms when white-caps break or from escaping
bubbles, are examples of natural sources. Inorganic ammonium sulfates or nitrates, and organic
aerosol are largely thought to be pollution derived, although natural precursors do exist. Derived
from incomplete combustion, black carbon or soot aerosol also has both natural and
anthropogenic sources. One overarching characteristic of particulate matter is its relative
chemical complexity. Atmospheric particles are typically internally mixed, with hundreds or
thousands of chemical compounds potentially being present within a single particle.19-21Many
chemical components to particulate matter are toxic, carcinogenic, or able to generate reactive
oxygen species (ROS) that are deleterious to health.22-23
Given the broad social impact, the routes of human exposure to particulate pollution are
summarized within this review article. In addition, I review existing knowledge of mechanisms
with which particles are removed or excreted from mammals, the associated immunological
responses that have been observed following exposure to particles within experimental animals,
and emerging evidence of systemic health effects of particulate pollution. Thus, the manuscript
serves to chronicle recent developments as the field of research continues to evolve.
2. DISCUSSION.
2.1 Routes of Exposureto Particulate Matter.
As with any chemical contaminant, components of particulate matter may enter the
human body through four mechanisms including inhalation, dermal absorption, injection, and
ingestion. Inhalation and dermal absorption present clear and often recognized routes to
exposure. In addition, ingestionshould be recognized as a very important mechanism by which
particulate matter may enter the body. However, the author is unaware of any mechanism
through which direct injection of aerosol materials through skin is encountered, and this route of
exposure will not be considered further.
2.1.1 Ingestion. Particulate matter can be ingested through the direct consumption of
contaminated beverages and food24and through clearance of particles removed from the lungs via
mucociliary transport. Interestingly, roughly 50% of micron-sized aerosol inhaled by
experimental animals is rapidly removed from the tracheobronchial airways within the first few
hours after inhalation, with mucociliary transport being the major mechanism of removal.25-
26
Much smaller particles penetrate deeper into the lungs where mucosal transport may not be as
an effective removal mechanism.27Experiments with sub-100 nm particles also showed very
rapid clearance of a similar fraction of particles that was consistent with mucociliary transport.28
If not removed from the body through other mechanisms, the expunged mucus may be
introduced into the gastrointestinal tract through swallowing, creating an indirectroute
toingestion of aerosol. While the exact mass fraction of particulate material that reaches the
intestinal tract is unclear and very likely variable, roughly 50% of the inhaled dose appears to be
a reasonable estimate. Clearly, this represents a significant fraction of total exposure, and
ingestion should be recognized as an important route of human exposure to particulate pollution.
Additional research on both the mechanisms of ingestion, and constraints on ingested dose by
each is required.
An emerging research theme within this area is a potential link between ingestion of
aerosol materials and a broad array of digestive conditions such as Crohn’s disease,
inflammatory bowel disease, ulcerative colitis, appendicitis, and even cancer.29-32Several groups
have found direct ingestion (gavage) of particulate matter leads to inflammatory responses and
increased oxidative stress in the gut of experimental animals.Mutlu et al. found increased levels
of the immune stimulating interleukin-6 hormone, increased intestinal permeability, and
increased apoptosis in the colon of mice after gavage administration of 200 g of particulate
matter collected from Washington, DC.33Kish et al. also found increased permeability,
inflammatory cytokine secretion, and colitis in mice that were either gavaged at 18 g / g /day or
fed particulate matter laced chow at 0.09 g/kg.34While the does used in these studies are
considered very high, such results are of physiological interest as Arrieta et al. notes that
abnormal gut permeability may play important roles in diabetes, Crohn’s disease, coeliac
disease, multiple sclerosis, irritable bowel syndrome.35
In terms of the effects of ambient aerosol on digestive health, at present conclusive data
leading to definitive evidence of health effects in humans is elusive.36Ananthakrishnanet al. have
reported observing a 40% increase in the rate of hospitalizations for inflammatory bowel disease
associated with a 1-log increase in the density of total criteria pollutant emissionsfor a limited
study of 72 counties in the state of Wisconsin.37However, Opstelten et al. did not find consistent
links between air pollution and the digestive disorders in a study carried out in Europe.38 While
not immediately obvious, ingestion of aerosol material may prove to be an important route of
human exposure. Further research is neededto better quantitate the fraction of inhaled aerosol
that becomes ingested, the relative importance / magnitude of aerosol ingested fromfood, and the
related health effects following ingestion.
2.1.2 Inhalation.The inhalation of aerosol particles is a rather obvious route of exposure.

To further understand the risks posed by this route of exposure, the anatomy of the human
airway, patterns of particle size-dependent deposition, and the fate of particles that have been
inhaled are considered in this section.
The Human Airway.The human airway is often described by three regions, the head
airways (nose, mouth pharynx and larynx), the tracheobronchial (TCB) region, and the
pulmonary or aveolar region as illustrated in Figure 1A. Air containing particles is initially
warmed and humidified upon inhalation in the head airways. The airstream then passes into the
trachea, bifurcated into left and right primary bronchus at the carina, and finally divided into the
many bronchioles. As such, the tracheobronchial region is often described as an inverted tree.
The head airways and TCB regions are very important to raise the temperature and relative
humidity of the airstream to 37 degrees Celsius and saturation (relative humidity approx. 100%).
For most adults, this condition occurs near the carina.39 This fact is of significance to aerosol
deposition and removal within the lungs because it is well-known that certain aerosol
components can undergo deliquescence and hygroscopic growth at high relative humidity.40-42
Growth will significantly alter the size distribution of particles (compared to that inhaled) and
possibly increase depositioninto mucus within the TCB region. The surfaces of the head airways
and tracheobronchial region are covered with mucus upon which particles can deposit and
rapidly be removed to the pharynx through action of cilia.43However, small, non-hygroscopic
particles, such as fresh soot44-46 may be able to escape this protective mechanism and penetrate
further into the lungs.
After the TCB region, exchange of gases between the air and blood occurs in the
pulmonary region. This occurs within hollow sacs called alveoli. Interestingly, while the linear
velocity of air streams within the head airways and TCB region can be quite high during
inhalation, the flow velocity within the alveolar region is believed to be much slower as residual
gases within the alveolar sacs compress ahead of the incoming breath. For instance, the model
of Weibel47suggests particle residence times of 200 ms within the entire TCB region and approx.
700 ms or more in the alveolar region during an inhalationmodeled at a high respiratory rate of
3.6 m3/hr.48An important consequence is at such low flow velocity, the diffusion of gases and
particles becomes the predominant mechanism of translation through the alveolar space. Due to
the increased residence times, both diffusion and gravitational settlingaffect retention and
removal of particles from the airstream in the pulmonary region.
Deposition within the Airway.The study of deposition within the human respiratory tract
is, of course, complicated by the lack of suitable experimental subjects. Historically, this
challenge has been met through computational modeling of deposition within airway
compartments with validation through experiments in animal models.According to Rostami,
computational models fall into two general categories.49 The first class is those models that
consider the entire airway from oro-nasal cavity to the alveolar region. These models generally
treat airway deposition from a classical viewpoint of aerosol impaction, Brownian diffusion,
settling, and filtration based upon the airway model of E.R. Weibel or an extension thereof.47-53
Over time, these models have been enhanced through the use of empirical airway deposition
data, so the models are often referred as semi-empirical. These models have the advantages of
being relatively easy to use and having the ability to estimate deposition throughout the entire
airway as demonstrated in Figure 2A. Conversely, caveats are related to the general inflexibility
of the model – the inability to treat special circumstances or details of aerosol administration or
physiological differences in airway dimensions or airway performance.
For end-users, several models are available for community use. The Respiratory
Deposition Calculator54-56 of the Aerosol Research Laboratory of Alberta
(http://www.mece.ualberta.ca/arla/deposition_calculator.html) offers a simple online interface to
estimate deposition in a variety of airway compartments. The multiple-path-particle-deposition
model (MPPD)57-58 can also be obtained free of charge online
(https://www.ara.com/products/multiple-path-particle-dosimetry-model-mppd-v-304). The
MPPD model considers airway deposition of particles between 0.01 – 20 micrometers and has
modules to consider particle deposition in murine models as well as in human children and adults
from 3 months of age to 21 years. While such models are commonly employed in the literature
and often yield acceptable results when averaged over many experimental subjects, recent
conventions of model users have concluded that future efforts should focus on wider access to
detailed anatomical data on the mammalian respiratory tract and inter-subject variability as a
means to improve the existing models further.59
This need is highlighted by the recent work of Jakobsson et al. who have described an
experimental apparatus for measurement of the total recovery of inhaled, monodisperse
polystyrene nanospheres with diameters < 100 nm.60 In this work the authors made
measurements on 7 human volunteers and successfully characterized recoveries of 50, 75, and
100 nm particles after inhalation. The authors found that person-to-person variability was quite
large, some 26-50 times larger than measurement imprecision. However, on average the results
for 75, and 100 nm polystyrene particles agreed very well with the MPPD deposition model. Of
note is that data presented for the average recovery of 50 nm spheres was only approx. 50% of
the MPPD model’s prediction. It is not clear whether the underestimate of deposition of very
small ultrafine particles should be attributed to the model, the limitednumber of experimental
subjects, or limitations of the apparatus.
The second type of model is computational fluid dynamics (CFD) models. CFD models
aim to discretely describe aerosol particle deposition within airways through consideration of the
Navier-Stokes equations governing fluid flow and transport of the particles.61 In this approach,
3D airway geometries are often described accurately through CT scans and equations of motion
governing particle behavior rigorously solved from first principles. Owing to its exacting nature,
CFD has the ability to consider more complex conditions for particle initial velocity, trajectory,
and particle dynamics (e.g. airspeed, sprays, use of inhalers, hygroscopic growth etc…), but
solving the equations for particle motion in a complex system is computationally intense.
Consequently, the CFD model is typically applied to certain regions or sections of the airway
rather than the entire respiratory system. So while more exact conditions can be considered, a
significant limitation of CFD is the inability to model the integrated airway.
Regardless of the exact model used, the focus of the current section of this review is
exposure to PM via inhalation. Considering Figure 2A and 2B, we see that deposition within the
head airways, TCB region, and pulmonary region is particle size dependent. Figure 2A
illustrates that deposition is high within the head airways (labeled NPL in figure) for particles
which are > 1 micrometer or < 10 nm. Super-micron particles tend to deposit onto airway
surfaces via impaction or settling while the smallest ultrafine fraction can diffuse very rapidly
and be removed. The TCB region also provides additional surface area for the smallest ultrafine
particles to diffuse into and be removed. However, particles between about 20 nm and several
hundred nanometer aerodynamic diameter are not removed effectively within the head or TCB
regions and can penetrate into the pulmonary region. This fraction of particles is often believed
to present the largest health risk since particle removal kinetics are not as rapid from the deep
lung for insoluble materials, and the particles may interfere with gas-exchange at alveolar
junctions. For instance, Anderson et al. report that at least 1/3 of 20 or 110 nm silver particles
administered intra-nasally to rats were retained within the lungs 56 days after dosing, with silver
accumulations at the terminal bronchial/alveolar duct junctions noted.62
Size dependent, post-inhalation deposition within baboon airways is illustrated in Figure

63
2B. In this work, the authors generated polydisperse aerosols using three different nebulizers
from a solution that was laced with 74 MBq of technetium 99m (99mTc). The resulting aerosols
from different nebulizers featured different particle size distributions. The aerosol was
administered to anesthesized baboons during normal breathing and the deposition patterns within
the animal airways studied by acquiring a posterior static view with a gamma camera. As
expected, the authors found deposition of particles was strongly influenced by particle size. For
the smallest size range tested, the activity median aerodynamic diameter (AMAD) was 230 nm.
These particles preferentially accumulated within the lungs (84% in thoracic region) compared to
only 16% depositing within the head airways. Deposition within the trachea was minimal.
Particles from a nebulizer producing much larger particles (AMAD = 2.8 micrometers)
preferentially deposited within the head airways of the baboons, with only 28% reaching the
lungs. For an intermediate size range (AMAD = 550 nm), nearly equal deposition was found in
lungs and head airways.
Given an average adult tidal volume is 0.5 – 1.5 L and about 12 breaths per minute, and
average adult will inhale a volume of 10-20 m3 of air daily. The ambient concentration of
particulate matter is highly variable, but if we consider the range of 10 – 300 g / m3 we can
estimate a range of ~100 – 6000 micrograms of aerosol material being inhaled daily. It is noted
that a concentration of 300 g / m3 is exceedingly high, double the current USEPA National
Ambient Air Quality Standard for 24h exposure. A typical atmospheric aerosol particle mass
distribution exhibits large peaks in both the accumulation mode (0.1 – 1 m) and coarse modes
(> 1 m), but very little mass is typically present in the ultrafine (despite very large number
concs.) mode owing to the miniscule mass of these particles.64 Fig. 1A suggests accumulation
mode particles are often captured at approx. 20-40% total efficiency, primarily in the alveolar
and head airways. Supermicron, coarse mode particles can be deposited in airways at
efficiencies of 50-80%, with the majority of deposition occurring in the head airways. If the
rough estimate of 40-50% of the total mass is retained in airways, a daily deposition of 50-3000
micrograms may be expected as a range of daily dose of particulate matter to the respiratory
system. Of course, individual exposure is likely to vary significantly due to circumstantial
events such as occupation, time spent indoors vs. outdoors, place of residency, time spent near
cooking operations, even the mode of transport or route taken during a daily commute. This
underscores the need for the development and implementation of portable sensors to better
constrain and understand human exposure to airborne pollution sources.65-72
Fate of Inhaled Particulate Matter.Several routes of particle removal from the airway
after inhalation have been identified. After deposition of particles onto the airway epithelium,
the particles will be wetted by epithelial lining fluid.73-74 Soluble fractions can dissolve in this
fluid, and surfactants or biomoleculesmay adsorb to the surfaces of insoluble matter. The major
route of removal (approx. 50% of deposited particles) in the upper airways and TCB region
appears to be a rapid clearance (< 24 hours) to the throat via mucociliary transport. Kreyling et
al. recognizes three mechanisms by which insoluble particles that deposit within the lung
periphery are removed at a slower pace: (a) macrophage mediated transport from the alveolar
region to the ciliated airways in which mucociliary transport is active; (b) particle transport to
lung associated lymph nodes; and (c) translocation into the blood.75
Alveolar macrophages are white blood cells tasked with phagocytosis of particulate
matter or microorganisms that have been inhaled. Often, the macrophages deactivate and
dissolve microorganisms. For particles that cannot be dissolved, the macrophages internalize the
particle and promote transport to the mucociliary escalator for removal from the lung.If the
macrophage is present within conducting airways, removal may require only 1-2 days. However,
macrophages that capture particles in the alveolar region may require weeks or months for
removal with clearance times being species dependent.76-77
The kinetics of phagocytosis in the lungs is frequently studied by bronchoalveolar

lavage(BAL) with subsequent study and quantitation of the fraction of recovered particles
associated with macrophages. The uptake of particles into alveolar macrophages can be
remarkably rapid and efficient, with 50-75% of micrometer-sized particles captured within 2-3
hours, and nearly 100% by 24 hours after exposure.78-83Capture by macrophages is particle size-
and shape- dependent.84 When particle geometric diameter is either <0.5 m or >5 m,
phagocytosis into macrophages is not as effective.85-86This is best highlighted through the work
of Geiser et al., who administered 20 nm titanium dioxide particles to rats and studied particle
uptake into macrophages using energy filtering transmission microscopy (EFTEM) after BAL.87
Remarkably, the authors found that < 0.12% of the nanoparticles were taken into macrophages
and less than 2% of the macrophages studied contain nanoparticles. When present, the
nanoparticles within the cells were located in large vesicles that also contained other materials.
The result suggests as if the TiO2 nanoparticles were captured non-specifically, essentially by
accident, by the macrophages. This result suggests that macrophages do not effectively target,
capture, and remove the smallest ultrafine particles from the lung. Takenaka et al. performed
similar experiments using 16 nm gold particles in a rat model.88 These authors also found
vesicles within alveolar macrophages that contained gold particles, but report capture by the
macrophages as being very limited. Additional work with iridium particles of 15-20 and 80 nm
diameter reflect only 10-20% capture by macrophages.89 Taken together, capture and subsequent
removal of particles between 0.5 - 5 micrometer appears to be an efficient process. However,
particles < 100 nm may not be captured by macrophages specifically or effectively. Particle
removal half-lives for the iridium nanoparticles from the lung were several hundred days, which
is considerably longer than the 40-60 day half-lives that have been reported for particles of
alternate compositions.90-92 It is clear that particles not removed by the mucociliary escalator or
translocation may remain in the lung for extended periods of time.
Insoluble inhaled particles can also be transported to the tracheobronchial lymph nodes
(TBLN) in experimental animals.93In 1981, Vostal et al. allowed rats and guinea pigs to inhale
diesel exhaust.94 Upon pathological examination, these authors found darkening of the regional
lymph nodes in the early stages of exposure. During later stages of the experiment, the
mediastinum and pulmonary hilus lymph nodes were described as being “a black color” due to
the diesel soot accumulation. These authors suggested a macrophage dependent pathway from
the alveolar region was responsible for transport, and a significant residence time of the soot
within the lymph nodes. Later experiments with micrometer-sized particles have also
demonstrated such a macrophage mediated pathway.95Ferin and Feldstein96 administered 1.5-
micron aerodynamic diameter TiO2 particles to rats and found that for “low-dose experiments”
(< 1 mg administered) less than 1% of particles accumulated in the hilar lymph nodes after 25
days. However, in higher dose experiments about 4% of particles were found in lymph tissue.
Kreyling and Scheuch report that select authors have found 1-20 fold higher concentrations
(particles / g tissue) of particles in lymph nodes compared to the lungs.97 Chan et al. found that
about 6% of diesel exhaust particles originally deposited in the lungs of male Fischer rats were
present in the mediastinal lymph nodes 28 days after administration.98
In more recent experiments in which the particle size and surface charge was rigorously
controlled, Choi et al. observed very rapid (<3 min) translocation of 5 nm diameter quantum dot
nanoparticles into lymph nodes of rats.99Representative data reproduced with permission from
Choi et al. is shown in Figure 3A-CLarger particles (27 nm) took slightly larger times (approx.
10 min) to be detected in lymphatic tissue. Experiments with larger particles (34 nm and above)
did not exhibit the rapid translocation, which led the authors to suggest a size dependent effect
with a cutoff diameter of <34 nm. The very rapid transport led the authors to suggest a trans-
epithelial mechanism by which particles move from the alveolar surface to septal interstitum
followed by draining to lymph nodes. Larger particles may still be transported at lower rate
through the macrophage-mediated channel, but this was not studied. While an exciting
mechanism, only approx. 2% of the particles below the size threshold were found to translocate
into lymph tissue. A larger fraction of particles below the 34 nm cut-off were also translocated
into blood, but most particles remained in the lung during the first hour after administration.
Another important finding from this work is that particles < 10 nm (but not 27 nm diameter) are
able to easily enter the bloodstream from the lung and ultimately be removed through renal
pathways in urine. In addition, the authors show that particle surface charge is an important
factor for physiological fate. Particles with cationic surface charges were / are preferentially
taken up into cells (macrophages or epithelial cells) and prevented from the rapid translocation
pathways.100However, particles with anionic, zwitterionic, or polar surfaces were able to be
effectively translocated.
Additional experiments conducted withinsoluble, chemically stable, ultrafine particles
have suggested that, on occasion, a fraction of inhaled ultrafine particles can be translocated
from lungs into the blood stream (this does not occur for larger particles).101 Particles which
reach the blood are known to subsequently accumulate in the liver, spleen, and potentially
kidneys of experimental animals and can remain there for significant periods of time.102-106In
similar experiments, both Buckley et al.28and Kreyling et al.107allowed rats to inhale iridium
nanoparticles of several sizes< 80 nm in diameter. The researchers then tracked the distribution
of the particles within the animal and in excrement. Both studies concluded the fraction of
nanoparticles translocated into blood from the lungs was very small (<< 1%). However, both
articles reported particle size-dependent translocation, with smaller diameters being transported
to blood more effectively. Data illustrating the size-dependency is reproduced from Buckley et
al. in Figure 3D and 3E.Both papers also report roughly 40-50% of particle dose inhaled is
rapidly excreted from the experimental animals predominantly through feces after swallowing
the material cleared via mucociliary transport. Particle absorption into the body through the G.I.
tract was not observed. This appears to be a consistent result for insoluble particles in the GI
tract-they do not appear to be absorbed. In a separate experiment, gavaged barium sulfate
particulate matter (15 nm diameter) was rapidly cleared from experimental animals – primarily
via feces.108 Only 0.15% of the gavaged dose was retained at 7 days post exposure. This
suggests that barium from the nanoparticles did not effectively cross from the G.I. tract into other
tissues.
In addition to particle size dependence, translocation into blood may depend strongly on
particle composition, surface charge, or protein binding to particle surfaces. While the previous
studies found a very small fraction of translocated iridium particles, Oberdorster et al. have
reported 13C ultrafine particles (20-30 nm) produced from a spark discharge were rapidly and
effectively translocated from lung into blood within 30 minutes of exposure.109 In addition, their
account suggests that 24h after exposure, five-fold greater 13C was found in liver compared to the
residual in the lungs. It is not immediately clear what is responsible for the dramatic difference
between the result for carbon particles and that discussed within the previous paragraph for
iridium particles. However, the particle composition may play a large role. Further research is
necessary to more adequately describe the ‘rules’ for pulmonary translocation into blood.
2.1.3 Dermal Absorption.Another possible route of exposure to airborne particulate

matter is impaction or deposition to the skin. Estimates of mass flux (Dp(t); g s-1) to skin
surfaces have been provided through Eqn.1 if particle deposition velocity (v(t); cm s-1), particle
mass concentration (C(t); g cm-3),and exposed skin surface area (Ax, cm2) are known.110
· · (1)
Deposition velocities are influenced by substrate surface properties (roughness, wetness,
temperature, surface charge etc.) and are known to be particle size dependent. Particles within
the accumulation mode typically have smaller deposition velocities compared to those within the
ultrafine range and larger particles.111-112In an early study, Fogh et al.measured particle
deposition velocities under a variety of conditions and found typical values in the range of 0.01 –
0.05 cm s-1 for 500 nm particles depositing on skin of personnel within a simulated office
environment.113 These authors also found v(t) increased by a factor of > 10 – fold when
experiments were conducted within a wind – tunnel simulating 2-4 m/s wind speeds. Additional
factors such as hair coverage, skin temperature, and skin surface charge also played large roles.
In a more recent work, Shi et al. found deposition velocities increased from 0.048–0.074cm s−1
to 0.033–0.24 cm s−1 as air speed increased from 0.4 - 1.2 m s−1 for ultrafine particles depositing
onto a mannequin within a test chamber.114Deposition velocities of approaching 0.5 cm s-1may
be expected for the smallest ultrafine particles due to their rapid diffusion.
Considering the highest possible dermal exposure imaginable (C(t)= 100 g m3; Ax = 2
m for adult male with no garments; v(t)=0.5 cm s-1) daily depositional flux to skin would total
2
about 86 mg. However, this estimate is unreasonably large sinceexposed skin surface area is
reduced by clothing, mean deposition velocity would certainly be smaller, and the average
concentration of particles would likely be considerably lower. All factors considered it is
conceivable that a dermal depositional flux of particles similar to 50 - 100 g per day may be
encountered for someadults. These estimates appear to bear some reflection of reality as
Väänänen et al. found polycyclic aromatic hydrocarbons (PAHs) at roughly 70 ng cm-2 deposited
on the wrists of road pavers after a typical work shift.115 Scaled to the larger skin area used in
the previous estimate, a dermal deposition exposure of 140 g would be expected during the
workers shift, however, a portion of this deposition may be directly from the gas-phaseas many
PAHs exhibit significant volatility.
Giventhat many chemical compounds present within particulate matter (including PAHs)
are harmful to human health, it is instructive to consider the pathway that deposited materials are
absorbed through skin and enter the blood. The outermost layer of skin (approx. 10 - 40 m
thick) is a lipophilic protective layer referred to as the stratum corneum (SC) or epidermis (see
Fig. 1B).116The current working model for the SC layer is that of protein enriched cells
embedded within a lipid-laden intercellular domain (often called ‘brick and mortar’ model). As
cells continually move from the base layer to the skin surface where they are shed, the lipid
composition shifts from a more polar profile to a much more neutral, non-polar lipid profile with
an accompanying loss of phospholipids.117 This creates a barrier to prevent loss of water from
underlying layers, but also makes permeation of non-polar substances more likely. Under the SC
is the dermis and hypodermis that contains connective tissue, sweat glands, follicles, and the
vasculature.The broad working model for exposure is that a contaminant deposits onto the SC,
moves into the dermis, before diffusing into the blood via either intercellular clefts or directly
through endothelial cell membranes.
Permeation through the skin is believed to be a passive process, with the rate limiting step
beingmodeled by diffusionthrough the stratum corneum. Mass transport of materials into the
dermis is complicated by the microstructure of skin. While the SC presents a formidable, but not
impenetrable barrier, hair follicles or sweat ducts that project through the SC create shunts for
enhanced mass transport of compounds deposited onto skin.118These shunts or gaps offer low
resistance paths through the epidermis, however, they only make up about 1% or less of skin
surface area. There has been great debate about the relative efficacies of the shunt vs.
transcellular mechanism of transport through the SC. The early model of Scheuplein118 suggests
that the shunt mechanism is responsible for the majority of material transported across the
epidermis over the first few minutes after application of material upon skin. However, at later
times after exposure diffusion through the transcellular route becomes more crucial. There is
significant evidence that both routes of transport can play important roles to transport materials
into the dermis.119-124 Regardless of mechanism, the rate of mass transport through the SCfor a
particular substance (PSK(t)) is often modeled through Eqn. 2.125
· · (2)
In this equation, K(t) is a compound specific permeability coefficient, CSK(t) is the concentration
gradient across the SC, and A(t) is the surface area of the skin contaminated with the component
of interest. While CSK(t) and A(t) are related to conditions of exposure, the skin permeability
coefficient for a particular chemical compound must be known. This is not trivial since the
coefficients can vary based upon water content, temperature, skin location / type, mechanism of
transport, pH, ionization state,polarity,and molecular weight of molecules and the associated
environment. Fortunately, there is no shortage of permeability coefficient data in the literature,
from both experiments126-130 and QSPR style models.131-137 A Java-based estimator is even
available online that estimates permeability coefficients from molecular weight (MW) and the
base-10 logarithm of the octanol-water partition coefficient (logKow) of the compound.138 In
general, lipophilic molecules are able to partition into and diffuse through the SC layer the
fastest.
The impact of PM on skin is not publicly well-recognized, however, Magnani et al.

studied how an ambient aerosol concentrate (100 g / mL) affected a reconstructed human
epidermis model.139 The authors reported an increase in ROS due to particle associated metals
and the increased ROS led to lipid oxidation. The aerosol concentrate also invoked apoptosis in
the cells studied. Results of interest for personal vanity include the report of Vierkotter et al.140
In this manuscript, the authors studied the skin of 400 Caucasian women and found that air
pollution was correlated to signs of aging, including pigment spots and wrinkles.
2.1.4Translocation to Brain via Olfactory Nerve. Evidence also exists for another
potentially important route of exposure that occurs within the nasal cavity after inhalation. In
this mechanism, insoluble ultrafine particles deposit upon the olfactory mucosa in the nasal
region and translocate along axons of the olfactory nerve directly into the olfactory bulb of the
brain. For ultrafine 13C particles of count mean diameter 36 nm, Oberdörster et al. found particle
concentrations of 0.35 μg/g in olfactory bulbs of rats one day after exposure to 160 g/m3 for 6
hours via inhalation.141 The authors suggested approx. 20% of particles deposited on the
olfactory mucosal lining were translocated to the brain via the nerve.These authors also pointed
out earlier studies with poliovirus (30 nm) and colloidal gold nanoparticles (50 nm) that also
directly describe transport of particles along olfactory nerves at a velocity of approx. 2.5
mm/hr.142-144
Several additional authors have reported particle translocation to the olfactory bulb.
Patchin et al. found rapid translocation of 20 nm Ag nanoparticles into the olfactory bulb, with
slower and less effective transport of 110 nm silver particles after a 6 h exposure.145 Kao et al.
have reported a translocation pathway for ZnO nanoparticles following in vivo nasal exposure to
rats, and have suggested that endocytosis is required for further interneuron translocation of the
particles.146 Several other publications have documented olfactory nerve transport of ultrafine
nanoparticles for metal particles containing Ni, Mn, Co, Cd, and Hg.147-152This mechanism of
particle transport is significant for several reasons. First, because transport from blood-to-brain
(e.g. across blood-brain barrier) is generally prohibited for nanoparticles the olfactory nerve
route offers the particles direct access to the brain.153-154 Secondly, since the particles (in some
cases) are able to influence local chemistry through generation of ROS or broadly defined
cytotoxicity, serious health implications could result from even small numbers of particles
chronically being transported into the brain.
2.2. Physiological Responses to Particulate Matter.
2.2.1 Inflammatory Response to Particulate Matter within the Airway. It has long been
noted that particulate matter can produce an inflammatory response in airways. The
inflammation response is mediated chemically by several small proteins, called cytokines, that
are produced and excreted by neutrophils, macrophages, and epithelial cells in the airway.155-157
Severalpro-inflammatory cytokines have been studied and include include tumor necrosis factor
alpha (TNF-α), interferon gamma (IFN-γ), cyclooxygenase-2 (COX-2), and several interleukins
(IL-1, IL-6, IL-8, IL-18, and IL-32). Thus, many investigators have studied the dose-dependent
expression or release of cytokines in the presence or absence of particulate matter as an
experimental strategy for better understanding the inflammatory response. Further experimental
elegance can be achieved through monitoring cytokine levels after blocking G-protein coupled
receptor mediated responses or use of ‘knock-out’ animal models that lack the ability to respond
through a certain biochemical pathway. These studies allow investigators insights into the
cellular mechanisms involved in inflammation response caused by particulate matter.Table 1 and
the remaining text of section 2.2.1 provides an overview of select research reports describing
inflammatory responses to particulate matter.158-191
Early work in the field focused on understanding the size and material dependence of
immune responses. For instance, Veronesi et al. reported that when human bronchial epithelial
cells are exposed to residual oil fly ash particulate matter intracellular Ca2+ rapidly increases and
cells release IL-6, IL-8 and TNF- within 4 hours of exposure.158 Further experiments aimed to
uncover the molecular mechanism of the immune response using antagonists for SPR (TACR1),
CGRP and the capsaicin (TRPV1) receptors.159-160A role for the SPR could be expected given its
role mediating pro-inflammatory responses in immune and epithelial cells.161The SPR and CGRP
antagonists were found to reduce fly ash related IL-6 production by 25-50%. However, a
capsaicin channel antagonist reduced IL-6, IL-8, and TNF- response to baseline – indicating a
significant potential role for TRPV1. The exact chemical component of the fly ash responsible
for action was not elucidated in this manuscript, however TRPV1 is known to be sensitive to
protons and it was noted within the manuscript that the fly ash particles were acidic. Additional
work by Carter et al. provides evidence that implicates metal ions as a potential cause of immune
response to fly ash.162 In this work, the authors found that cytokine production was inhibited by
the inclusion of a metal chelator (deferoxamine) or a free-radical scavenger
(dimethylthiourea).As discussed later, metal ions are known to catalytically produce reactive
oxygen species (ROS) in aqueous solutions through Fenton chemistry.163-164Additional early
laboratory experiments with polystyrene, titanium dioxide, and carbon black particles of varying
sizes led to the belief that ultrafine particles, by virtue of their large surface areas, increase
immune response in the lungs of animals.165,187-190 However, the research results reflected most
particles induced some inflammatory responses in the animal models considered. It appears as if
multiple channels and mechanisms may be responsible for inflammatory responses.
Later experiments began considering atmospheric particulate matter. Becker et al.

collected particulate matter at Chapel Hill, NC into fine and coarse fractions prior to studying
cytokine production in human alveolar macrophages and epithelial cells.166The pro-inflammatory
response of cells was quantified by tracking expression of TNF- , IL-6, IL-8, and COX-2 after
exposure to re-suspended particulate matter. Interestingly, the authors found that 90-95% of the
stimulatory material causing inflammatory response in alveolar macrophages was found in the
coarse particle fraction. This result appears consistent with the earlier discussion of more
efficient recognition and endocytosis of micron-sized particles by macrophages compared to
ultrafine particles and is reported frequently in literature (see table 1).For human bronchial
epithelial cells, all size fractions of particulate matter elicited inflammation response, but again
the coarse fraction yielded higher levels of IL-8 and COX-2. However, it was the fine fraction
that produced the highest levels of hemoxygenase-1, a biomarker of oxidant-induced stress.
The authors suggested that macrophages and epithelial cells produce inflammatory response to
particles through the TLR4 and TLR2 receptor channels, respectively.
Figure 4A illustrates a dose-response relationship for the release of IL-8 from BEAS-2B
cells following exposure to particulate matter collected from Milan as reported by Gualtieri et al.
in their 2010 work. Several data series are plotted in the figure. Notice that the traces for PM2.5
for both winter and summer months did not produce a measureable increase in IL-8 over
baseline. However, both winter and summer PM10 fractions produced increases in IL-8, with the
summer fraction increasing concentrations 15-20 fold at highest doses. Such behavior is
frequently encountered in the literature (e.g. PM10> PM2.5 in terms of inflammatory response).
Endotoxins present in PM10 fractions are believed to play a major role in establishing
consistently higher inflammatory responses caused by coarse mode particles.167 Endotoxin is
generallymost abundant within the coarse mode of PM. Endotoxin is lipopolysaccharide (LPS)
material found intheouter membranes of gram-negative bacteria. Endotoxins are large, stable,
hydrophobic molecules, approximately 10 kDa in size. Bacteria will commonly shed endotoxin
in significant quantities when cells die or when actively growing and dividing and the
hydrophobic nature of the material allow endotoxin to ‘stick’ to particle surfaces well. It is
certainly logical that mammals have evolved a strong inflammatory response to the presence of
these molecules as a defense mechanism, and this may be responsible for the strong
inflammatory responses observed.
Investigators often attempt to discern the role of endotoxin in producing inflammatory

response to PM by completing experiments in the presence of polymyxin B, which binds
endotoxin and renders it unable to produce inflammatory response. Figure 4B illustrates one
such experiment in which the authors demonstrated a 50% reduction in expression of IL-8 by
human BEAS-2B cells exposed to the summertime PM10 fraction collected in Milan. It has been
shown that the summertime aerosol in Milan has approximately 3-fold higher endotoxin
compared to winter, and this difference was postulated as the causative agent for the result.168
However, no such reduction in inflammatory behavior was observed for the winter aerosol
sample. This may suggest an alternate biochemical pathway by which the winter PM10 elicits a
response. Nonetheless, endotoxins present in the PM10 fraction have become recognized as
being a crucial factor causing airway inflammation. The very significant inflammatory role of
endotoxins present within particulate matter has led to several recent reports that aim to improve
understanding of the concentrations and seasonal dependence of endotoxin in particulate
materials.169-171 No doubt, detecting particulate endotoxin in real time will continue to be a focus
of additional research in future years.
2.2.2 Oxidative Stress. Particulate matter is known to contain several redox-active

compounds that include transition metals, quinones, phenols from a variety of natural and
anthropogenic combustion sources and even dispersed crustal materials.192 Recent work has
even indicated particle-phase material that originates from simulated atmospheric processing of
aerosol precursors (SOA; secondary-organic aerosol) also exert an oxidative potential.193-194Shen
and Anastasio have shown authentic particulate matter collected in the San Joaquin Valley also
generates H2O2 and OH in surrogate lung fluid.195-196 These results are not terribly surprising as
many reactions germane to atmospheric chemistry proceed via a free-radical mediated
mechanism.
After inhalation and deposition onto airway epithelium, the redox-active materials can
sustain, catalyze, or induce reactions within the epithelial lining fluid that produce reactive
oxygen species (ROS)such ashydroxyl radical (OH), superoxide (O2−), singlet oxygen,
hydroperoxy radical (HO2), alkoxy radicals (RO), alkylperoxy (ROO), ozone (O3), and
hydrogen peroxide (H2O2). These compounds differ in reactivity, but ROS often exhibit
reduction potentials of E0> +0.9 V, making them highly reactive and largely indiscriminate of
reaction partner.197To complicate matters further, ROS often undergo reaction with transition
metals, oxygen, or other substances to form catalytic cycles that increase oxidative stress and
regenerate mediators of the reactions. Such reaction cycles hypothesized to occur in epithelial
lining fluid has recently been summarized by Lakey et al. and are illustrated in Figure 5.198
These authors suggest an initial step of a redox-cycle is transfer of electrons to transition metals
or quinones. Superoxide radicals then form when the reduced semiquinone or metal ion reacts
with molecular oxygen. The superoxide reacts to form hydrogen peroxide, and hydroxyl radicals
(OH) can then form through Fenton reactions catalyzed by transition metal ions. As the most
reactive ROS, formation of OH can be considered highly destructive to airway tissue since its
reduction potential is E0>2.3 V and OH consequently reacts rapidly with nearly all organic
substances to abstract a proton yielding a secondary organic radical.
Thus, not surprisingly many investigators have reported on oxidative stress induced by
exposure to particulate matter and the subject has been previously reviewed.199-201In 2002,
Gurgueira et al. demonstrated significant oxidative stress in both the lungs and heart of rats that
breathed PM.202Interestingly, increases in stress showed strong association with the amount of
iron, manganese, copper, and zinc present within the PM concentrate applied. For an elderly
population of human volunteers, Delfino et al. found that ambient PM2.5 levels were positively
associated with IL-6 levels and that corresponding PM2.5 extracts produced reactive oxygen
species in rat macrophages.203 These results are consistent with the possibility of transition
metals present in PM acting as redox mediators after inhalation. Additional evidence for the
involvement of transition metals in generation of ROS, and subsequent physiological effects can
be found in experiments in which investigators find a partial reduction in expression of
inflammation biomarkers (such as IL-6 or IL-8) in lung epithelial cells or macrophages after
chelation of metal ions (studies cited in section 3.1).
Several studies have reported an association between PM and oxidative damage to

204-205
DNA. While such oxidative lesions in DNA are usually rapidly repaired, a very small
fraction of unrepaired lesions may lead to mutations or carcinogenesis.206-207Novotna et al. report
a significant increase in oxidative DNA damage among policeman in Prague that correlated with
exposure to PAH bound to the PM2.5 aerosol fraction.208 Additionally, PM2.5 and PM10 levels
within three days prior to sampling correlated to levels of aurinary marker of oxidative damage
to DNA in a cohort of bus drivers in Prague.209 In follow up work, Bagryantseva et al. reported
oxidative damage to DNA, lipids, and proteins in a group of 70 bus drivers and garagemen also
from Prague.210 Interestingly, damage observed was negatively correlated with the anti-oxidant
vitamin C.
Sorenson et al. studied the oxidative damage on DNA as mediated by the redox effects of
transition metal ions.211 In their study, urine and lymphocytes from 49 students was collected
and analyzed for 7-hydro-8-oxo-2’-deoxyguanosine (8-oxodG), which is believed to be the major
product of hydroxyl radical attack on DNA. In addition, personal sampling of exposure to PM
was accomplished and chemical analysis of the PM matter carried out. The authors found the 8-
oxodGconcentration within lymphocytes (but not urine) was significantly associated with
vanadium and chromium concentration in the PM samples. This report is consistent with
additional reports of increased concentrations of 8-oxodG following exposure to transition
metals within PM and resultant mutations of DNA.212-216
Shi et al. investigated the hydroxyl radical generating capability of coarse and fine PM
fractions, and the resultant ability to form 8-oxodG in calf thymus DNA and within A549
epithelial cells.217 The authors found both fine and coarse fractions generate OH and lead to
formation of 8-oxodG. Coarse mode PM collected in the fall/winter season led to the highest
OH generation rate. The OH generation rate was not proportional to the concentration of several
transition metals present in the PM (with exception of copper), however, the transition metal
often plays a catalytic role in Fenton chemistry (rather than being consumed via reaction) and
very small quantities can exert large redox roles. Taken together, the results implicate certain
transition metals, most notably Cr and V, acting as redox mediators within airways and such
action can lead to oxidative DNA defects. The extent to which the lesions lead to health effects
remains a subject of further research.
In addition to metal ions, polycyclic aromatic hydrocarbons (PAHs) may play significant
roles in redox chemistry within the lungs. Li et al. demonstrated that ultrafine particles collected
in the Los Angeles basin were most effective at inducing heme oxygenase-1 (HO-1) and the
depletion of glutathione within macrophages and epithelial cells.218 These results are consistent
with oxidative taxing of the cells. In addition, the ultrafine particles exhibited the highest ROS
activity of any particle fraction collected as measured via a dithiothreitol (DTT) assay. The HO-
1 expression, glutathione depletion, and ROS activity were all associated with the PAH content
of the PM samples tested.
In addition to producing oxidative lesions in DNA, reactive oxygen species introduced

via PM may exert additional biochemical impacts. Chirino et al. carried out a very interesting
study in which the authors treated human A549 epithelial cells with extracts of PM10 from
Mexico City.219 The authors found that the PM10fraction did induce oxidative damage in cells.
The PM10 also decreased glutathione levels by 55%, and reduced the activity of superoxide
dismutase (65% reduction), catalase (31% reduction), glutathione reductase (62% reduction) and
glutathione-S-transferase (42% reduction). These results are fascinating because glutathione
exerts a significant anti-oxidant property to prevent damage due to ROS in cells. The enzymes
also play crucial roles in the apparatus that prevents cellular damage caused by ROS. In this
case, the PM10 extract increased ROS, and simultaneously negatively affected the cells ability to
respond to the oxidative stressor.
Additional work has found PM2.5 extracts collected in Asia results in significant oxidation
of methionine residues of bovine serum albumin in vitro and albumin present in mouse BAL
fluid.220 This is of significance to health because albumin is believed to play an anti-oxidant
role. Lai et al. performed experiments in which human epithelial (A549) cells were exposed to
diesel exhaust particles (DEPs), urban dust (UD), and carbon black (CB).221 All particle types
induced oxidation of methionine residues in human albumin protein. The repair mechanism that
uses enzymes (MRSA and MSRB3) to convert the methionine to its unoxidized form was
inhibited in the case of exposure to the urban dust particles, suggesting oxidized protein can
accumulate in cells in certain circumstances. These authors also suggest evidence for different
pathways with which oxidized proteins are degraded (autophagy) depending upon the type of
PM the cells were exposed to. The result of inhibited protease action is consistent with the work
of Kipen et al. who allowed healthy human volunteers to inhale diesel exhaust and secondary
organic aerosol to study the effect upon white blood cell (WBC) or red blood cell (RBC)
proteasome activity.222 The authors observed an 8-12% decline in proteasome activity in the test
subjects after a 2 h inhalation exposure. The results suggest the redox activity of inhaled PM
may play important roles in protein homeostasis. More research is necessary to better
understand particulate matters effects on oxidative stress.
2.2.3 Cytotoxicity and Apoptosis.The toxicity and mutagenicity of particulate matter on

cells has also been the subject of significant study.223-224Table 2 lists selected manuscripts from
recent literature that consider cytotoxicity induced by aerosol particles and their contents.225-243 A
major theme that consistently appears in recent literature is studies aimed to unravelhow the size
and composition effects of how PM affects cells. Frequently, lung epithelial cells (A549, BEAS-
2B) or macrophages are used for this type of study, and size-fractionated aerosol samples and /or
aqueous and organic extracts are applied to the cells to ascertain a response. Cell viability is
usually tracked via either the LDH assay or the MTT assay. The MTT assay is based upon
NADPH-dependent enzymespresent in viable cells reducing a dye 3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide (a.k.a. MTT) to an insoluble purple colored form. The LDH
cell viability assay relies upon the release of the enzyme lactate dehydrogenase (LDH) into the
extracellular media. The principle relies upon the cell membrane becoming permeable or
outright break-down which is a symptom of a necrotic cell.Therefore, thepresence of
extracellular LDH is an indicator of membrane disruption / loss of viability in cells.244
An example of such work can be found in Deng et al.226Exposing human A549 cells to
PM2.5 collected in China at doses between 8 – 64 g / cm2 led to a dose-dependent cytotoxicity.
A dose-dependent, moderate loss of cell viability 6-48 hours after exposure is a commonly
reported result in the literature (14/18 papers in table 2 report such result).
An obvious extension upon simply demonstrating cytotoxicity is developing an

understanding of the substances responsible for such effects. The study of the impact of reactive
oxygen species (ROS) on cytotoxicity is also a very commonly studied phenomenon. As
illustrated in Figure 6, Deng et al.also demonstrated a significant reduction (approx. 25%) in
cytotoxicity when the ROS scavenger N-acetylcysteine (NAC) was present within media,
indicating a role of reactive oxygen species in cytotoxicity. Frequently, either a radical scavenger
or a metal ion chelator is added to the experimental medium in an effort to mitigate ROS
production. It is commonly observed that reducing the ROS potential mitigates, but does not
eliminate, cytotoxicity. In terms of attributing cytotoxicity to other specific chemical
components of the aerosol, much more work is needed. Enhanced toxicity of engineered metal
oxide (ZnO) nanoparticles has been demonstrated, and PAHs present within aerosol collected
during winter has been linked to increased cellular toxicity.225,228 However, PM of various
compositions prove cytotoxic to cells at significant concentrations, and many cellular pathways
are likely responsible for cell death. Therefore, the current consensus invokes a summative
model of cytotoxicity in which multiple components exert compounding effects. The extent to
which any singular component influences cytotoxicity,and how chemical components may
interact has yet to be constrained.
In addition to cytotoxicity studies many authors have begun considering the cellular /
molecular pathways responsible for the demise of cells after exposure to PM. Several
mechanisms of cellular death have been identified that include apoptosis, necroptosis, pyroptosis,
necrosis, and autophagic cell death.245Understanding the cell-death mechanism is important to
design intervention strategies to ameliorate the detrimental effects of PM on human health.
Apoptosis is the most studied form of auto-induced cell death, and this process requires
the activation of caspase proteases to degrade cellular components.246 Cells then undergo a rapid
death while displaying distinct morphological changes (blebbing) and biochemical markers.
Apoptosis can easily be studied by virtue of the wide variety of analytical methods available to
probe the phenomenon.247-250
Evidence for cell death through apoptotic channels following exposure to PM has been
demonstrated. Deng et al.226 demonstrated that increased PM dose led to higher levels of Bax
protein, and increase cleavage of Caspases 3, 7, 8, 9. These protein expression levels are
consistent with promoting and initiating apoptosis – programmed cell death. In a subsequent
work, Li et al. found PM2.5 induces cellular apoptosis through a mitochondria-dependent
pathway.251 Downregulation of the miR-1228-5p microRNA was associated with PM2.5 induced
apoptosis while up-regulation of this miRNA offered a protection against apoptosis. Seriani et al.
reported that mRNA coding for caspase-3 exhibited a 4-fold increase after exposure to Diesel
PM.234Wang et al. found that exposing A549 cells to PM led to large increases in cleaved
caspase 3 present.240 These authors also developed a ‘knock-out’ cell line that decreased
expression of dimethylargininase (DDAH-1) by 90%. This enzyme degrades methylarginines in
cells that inhibit nitric oxide synthase formation. The knockout cell line exhibited decreased
apoptosis rate. In addition, a knock-out cell line with reduced inducible nitric oxide synthase
(iNOS) also had higher viability after being treated with PM. These results may suggest a nitric
oxide dependent pathway to cell death. Taken together, the experimental results strongly suggest
PM2.5exposure can lead to cell death through apoptosis, although this may not be the only
channel of cell death.
Macroautophagy (a.k.a autophagy) is a more recently discovered mode of lysosome-

meditedcell death process. In autophagy, a membrane forms within the cell cytoplasm and this
membrane surrounds and engulfs material to be degraded creating an autophagosome. The
autophagosome fuses with lysosome and the captured material is degraded. When Jeon and Lee
exposed neuronal cells to ultrafine particles (PM0.1) collected in Korea they found that cell death
occurred, however, protein markers of apoptosis were unchanged in the cells.241Further
investigation led to the realization that the Atg7 and Atg3 proteins implicated in cell autophagy
were up-regulated after exposure to PM. This led the authors to suggest possible role for
autophagy as a mechanism of cell death in some cases after cells are exposed to PM. In addition,
An et al.242 exposed A549 cells to black carbon and ozone treated black carbon and considered
differential gene expression after exposure. The authors found genes for autophagy were
affected, providing circumstantial evidence for a possible role for autophagy in cell death after
exposure to PM.Additional authors have very recently demonstrated additional roles for
autophagy in PM mediated cell death, yet additional research in this area is still needed.212-216
Necroptosis may possibly be initiated by PM under conditions in which caspases are

inhibited because the process is induced by tumor necrosis factor (TNF). TNF is known to be
elevated in cells after exposure to PM. Pyroptosis is a death mechanism that involves cell
swelling and membrane lysis. To best of my knowledge the existing literature does not
conclusively describe observation of either necroptosis or pyroptosis death mechanism after
exposure to PM.
2.3. Systemic Effects of PM.
In recent years, investigators have begun researching links between PM and a variety of
systemic ailments that include autism, Parkinson’s disease, Alzheimer’s, olfactory deficits,
cognitive deficits, ADHD, COPD, depression, and cancer.The remaining text of section 2.3 and
table 3 lists publications that outline recent results in these fields.257-319Many of the publications
data sets appear to suggest relatively weak trends between exposure to air pollution and the
condition under study that seem like promising leads. However in many cases obtaining
statistical significance linking variables has proven difficult. In this section, I will briefly
summarize recent epidemiological results describing links between PM and these conditions. If
additional studies relate specific biochemical results germane to the physiological conditions to
PM exposure, they may also be considered within this section. Future work linking pollutant
exposure to health conditions may be aided through more precise monitoring of human exposure
to pollutants.
2.3.1 Links Between PM Exposure Parkinson’s, Alzheimer’s, and Cognitive

Function.One area that has received significant interest in the literature is potential links
between PM exposure, reduced cognitive function, and neuro-degenerative disease. The effect
of PM on cognitive function has recently been reviewed.320One positive result is that of Power et
al. who studied cognition in 680 elderly men, and how exposure to BC affected scores on a Mini-
mental state cognition examination.321 The authors found that a doubling of the natural log of
black carbon concentration (ln [BC]) level led to a significantly increased odds ratio (1.3 fold
more likely) for a participant to score low (< 25) on the cognition examination. The doubling of
BC led to a 0.054 standard deviation lower test score, leading authors to conclude exposure to
traffic related PM leads to decreased cognitive function. Weuve et al.262 also found a 0.02
fractional reduction in cognitive score for each 10 g/m3 increase in PM2.5-10 during a long-term
exposure (7-14 years) study. Ranft et al. report a mild cognitive impairment for subjects living
near a busy roadway.260Gatto et al. have suggested increasing exposure to PM2.5 could be
associated with lower verbal learning scores.268 Other studies have reported possible cognitive
deficits due to PM for children263,294, the elderly267, and even infants or children in
utero.290,291,296,299 Additional studies have rejected the hypothesis of a link between PM and
cognitive deficiencies.259 Given the abstract nature of cognition, and memory it is difficult to link
declines in cognition with empirically observable physiological, biochemical, or pathological
changes within the brain.
Other groups have focused on studying potential links between PM and

neurodegenerative diseases like Parkinson’s and Alzheimer’s. Several epidemiological studies
listed in Table 3 report increased exposure to PM is associated with increased hospitalization for
Parkinson’s270and Alzheimer’s274,277however, others reject a link between PM and
Parkinson’s.275The neuropathology of these disease states have been researched more
extensively. Consequently, it is possible to directly search for links between PM exposure and
physiological changes consistent with the diseased state.
Levesque et al. exposed male rats to various levels (0-1000 g PM / m3) of Diesel
exhaust over a 6 month period to investigate minimum levels required to illicit markers of
neuropathy.322 Results suggested that high concentration of Diesel exhaust led to elevated levels
of TNF in most brain regions tested.The protein α Synuclein was found to be elevated at highest
does of PM. Tangles or clumps of this protein is a pathological indicator of Parkinson’s
disease.The amyloid peptide (Aβ42) levels were found to be the highest in the frontal lobe for
animals exposed to highest levels of PM. The phosphorylated tau [pS199] protein was elevated
in animals exposed to higher DE concentrations (992 and 311 μg PM/m3). These results indicate
that proteins linked to Alzheimer's disease were also affected by PM exposure. Calderon-
Garciduenas et al. found greater neuronal and astrocytic accumulation of Aβ42 during autopsies
of patients from high pollution areas compared to residents of low air pollution cities.257 Aβ
protein is the main component of amyloid plaque that lead to development of Alzheimer’s
disease. Calderon-Garciduenas et al. also autopsied the brains of children and young adults of
subjects from very polluted urban environments and less polluted places (control).263
Remarkably, 40% of test subjects exhibited tau-hyper-phosphorylation and 51% had amyloid-β
(Aβ) diffuse plaques. This compared with 0% of controls. In addition a 15-fold down-regulation
of the prion-related protein (PrP(C)) was observed in subjects from highly polluted urban
environments. The paper’s authors suggested that down-regulation of the PrP(C) is significant
because of the proteins “important roles for neuroprotection, neurodegeneration, and mood
disorder states.” At present, limited biochemical evidence has emerged that suggests a possible
link between PM and the increased abundance of biomarkers relevant to neurodegenerative
disorders.
2.3.2 Links Between PM Exposure, Impulsivity, Anxiety, ADHD, and Autism.

Another popular venue of research is linking PM exposure to several emerging neurological
disorders such as ADHD, autism, anxiety, or behavioral impulsivity. Several reports describe an
increase in the rate of autism for children of mothers who lived in proximity to a freeway, or
otherwise were believed to experience higher levels of PM based upon spatiotemporal modeling
of environmental monitoring data during pregnancy.285,292,293 Results were even more
convincing for exposure during the third trimester of the pregnancy.However, other research
found no link between autism and air pollution in the maternal prenatal period.298
In additional work, Siddique et al found that even after correcting for a potential
confounding variables, ambient PM₁₀ level was positively correlated with ADHD with an odds
ratio of OR = 2.07 (95% CI, 1.08-3.99).284 The data of Perera et al. suggested a possible link
between PM and PAHs with ADHD in African American and Dominican youth living in New
York.323An interesting lab study relevant to these results was presented by Allen et al. who
exposed mice to concentrated ambient ultrafine particulate matter (CAPS) during the first 2
weeks of life, and (for certain cohorts) again in adulthood, to determine whether exposure to PM
altered the delayed reward response.324 Preference for immediate reward is an important factor
contributing to several psychiatric disorders, including addiction, impulsive behavior, and
attention deficit hyperactivity disorder (ADHD). The manuscript reports that the mice that
received the postnatal CAPS dose exhibited bias towards receiving immediate rewards / positive
reinforcement. The research suggests a possible link between PM and mammalian impulsivity of
relevance to ADHD.
Other researchers have begun considering links between PM exposure and anxiety related
symptoms. It has long been known that exposure to cigarette smoke increases anxiety in
smokers.325 Pun et al.301 examined the possible link between PM2.5 and level of depressive and
/or anxiety symptoms in 4,008 older adults living in the United States. Their results suggested
thatan increase in PM2.5level was significantly associated with anxiety symptoms. Considering a
180-day moving average of PM, the odds-ratio was 1.61(95% CI: 1.35, 1.92) after adjustment for
socio-economic status. PM2.5 was also associated with depressive symptoms with a statistically
significantodds-ratio (O.R.) when considering a 30-day moving average (OR = 1.16; 95% CI:
1.05, 1.29). Interestingly, exposure to PM may affect depressive states and anxiety
symptoms.Power et al. also considered links between PM2.5 and anxiety outcomes in older
women.302 These authors found a significant increase in odds ratio predicting high anxiety
symptoms per 10 μg/m3 increasein prior one month averagePM2.5 (1.12, 95% confidence interval
1.06 to 1.19). Interestingly, no association between anxiety and exposure to larger particles
(PM2.5-10) was found. In 2015, Zijlema et al. found individuals living in urban or semi-urban
areas (presumably higher PM levels) had poorer lung function and exhibited a higher prevalence
of major depressive disorder (OR 1.65, 95% CI 1.35;2.00), and generalized anxiety disorder (OR
1.58, 95% CI 1.35;1.84).303Datasets which call into question the association between PM and
anxiety or depression also exist. For instance, Zijlema et al.also conducted a study of over
70,000 participants using data from 4 European countries.304 Certain data sets considered
yielded positive associations between pollutant levels and depressed mood, yet data from other
locations yielded negative associations. The authors concluded that they could not find
consistent evidence for association between ambient air pollution and depression based upon
their study.
Of note to this discussion is the ability for ultrafine particles to translocate to the
olfactory bulb in the brain following inhalation as discussed in section 2.4.Should such
translocation occur after inhalation, and the ultrafine particles interfere with neurochemistry in
the brain, significant side effects may occur. It is known that the olfactory bulb is responsible for
additional duties beyond just smell. For instance, removal of the olfactory bulb in rodent models
leads to anxiety and depression-like behaviors.326In humans, it has been shown that reduced
olfactory bulb volume leads to not only reduced olfactory function but also major depressive
disorder.327 As a result, PM translocated into the olfactory bulb may play a major influence on
such conditions and additional research is warranted in this area.
2.3.3Effect of PM on Cardiovascular Health & Stroke. Another body system

potentially affected by PM is the cardiovascular system. In 2014, Shin et al. conducted a meta
analysis of 20 studies appearing in the literature and concluded that strong evidence exists for a
link between short-term exposure to PM and ischemic stroke.328In years since, several more
reports have appeared in literature describing links between stroke and PM. Lin et al. have
reported on the incidence of stroke in 45,625 participants from low-income countries.305 Using
satellite data, the concentration of PM was estimated and multilevel regression used to examine
associations between PM and stroke. The authors report that the odds of stroke were 1.13 (95%
confidence interval, 1.04-1.22) for each 10 μg/m3 increase in PM2.5. These authors also estimate
1.97-12% of stroke cases in the study population could be attributed to PM.Matsuo et al.
considered the cases of 6885 ischemic stroke patients in Japan and tracked the PM level prior to
onset of the stroke event.329 Results suggested that ambient PM2.5 at a lag time of 0-1 day was
associated with subsequent ischemic stroke. Per 10 μg/m3 increase in suspended PM, the odds-
ratio for occurance of stroke was 1.02 with a 95% confidence interval of 1.00-1.05.
PM2.5exhibited a slightly stronger effect with an odds-ratio of 1.03 [95% conf. int. 1.00-1.06]. In
contrast, ambient suspended PM and PM2.5 at longer lag times showed no significant association
with stroke occurrence, indicating acute exposure to high pollution events may be important for
rapidly triggering ischemic stroke. Detection of the effect of chronic PM exposure on stroke, is
more difficult.
Lin et al. considered the effect of peak PM2.5 concentrations on cardiovascular mortality
in Guangzhou, China from January 2013-June 2015.306 The authors report a significant
association between hourly peak concentrations of PM2.5 and cardiovascular mortality was
found. Ischemic heart diseases and cerebrovascular diseases were particularly apparent. For
every 10 μg/m3 increment of hourly peak PM2.5 a 1.15% (95% CI: 0.67%, 1.63%); 1.02% (95%
CI: 0.30%, 1.74%) and 1.09% (95% CI: 0.27%, 1.91%) increase in mortality from total
cardiovascular diseases, ischemic heart disease, and cerebrovascular disease was observed,
respectively. Xia et al. have also reported on a possible link between PM and cardiovascular
distress.307The authors adjusted data for relative humidity and temperature, and found the highest
odds ratios of cardiac arrest corresponding to a 10 µg/m3 increase in PM2.5 was 1.07 (95%
confidence interval (CI): 1.04–1.10), at a lag time of 1 day post exposure. Given the short lag
time, the results support the hypothesis that acute elevated PM2.5 exposure contributes to
triggering cardiac arrest - especially in those patients who are advanced in age and have a history
of stroke. Kang et al. and Yorifuji et al. have also published recent manuscripts describing
increased risk of cardiac arrest when PM was elevated.330-331 Finally, Lin et al. considered
correlations between ambient PM2.5 and hypertension in 12,665 participants >50 years of age.332
Satellite data was used to estimate PM2.5 concentrations that participants were exposed to. For a
10 μg/m3 increase in ambient PM2.5, the adjusted odds ratio for hypertension was 1.14 (with 95%
confidence interval of 1.07-1.22). Hypertension is considered a risk condition for heart disease.
Significant evidence has been presented in the literature attributing PM exposure to
cardiovascular distress.
2.3.4Effect of PM on Respiratory Health.Perhaps the most obvious body system that

could be affected by exposure to PM is the lungs and airways. Various investigative teams have
considered links between respiratory problems like asthma, and COPD with PM exposure.
McCreanor et al. studied asthmatic volunteers walking on a street where only Diesel vehicles
producing BC aerosol were allowed.308 The authors found that exposure to the fine particle
pollution resulted in a significant reduction in lung function, and increase in immune response
(IL-8 and myeloperoxidase), but often no symptoms presented in the test subjects.Weichenthal et
al. have conducted a case-crossover study and found that among Canadian children (<9 year
age), an increase of 5.92 μg/m3in 3-day mean PM2.5concentration was associated with a 7.2%
(95% confidence interval, 4.2-10) increased risk of emergency room visits for asthma.309 The
results suggest PM pollution can exacerbate asthma symptoms. Mirabelli et al. also considered
the effect of PM pollution on asthma symptomsamong adults in the United States. It was found
that a 4–5% higher asthma symptom prevalence among asthmatics was observed in regions
where PM2.5 ≥ 7.07 μg/m3.310 When PM was in the range of 4.00–7.06 μg/m3, a 1-μg m-3 increase
was associated with a 3.4% [95% conf. int.: 1.1, 5.7] increase in symptom prevalence. Pothirat
et al. conducted a cross-sectional study between 1/2006 – 3/2009 to understand the effect of PM
on asthma and COPD symptoms in Chiang Mai, Thailand.333 A limited number of cases (917)
were considered, however, the authors report significant risk-ratio increases when lag times of 6-
7 days are considered. Pope et al. considered the effect of PM2.5 levels on asthma related
hospital admissions in Phoenix, AZ.311 After controlling for several possible confounding
variables (influenza, temperature, humidity, rain) the authors estimate a risk ratio for adults of
1.19 (95% C.I. 1.06, 1.34) and 1.20 (95% C.I. 1.05, 1.37) for days 2 and 3 after high exposure.
Hwang et al. investigated links between hospital emergency room visits due to respiratory
problems and PM in Taiwan during 2012.312 For the Kao-Pung air quality zone, the authors
report convincing risk-ratios of 1.23 [95% conf. int., 1.05–1.45] for AECOPD (1.07 (95% CI =
1.01–1.13) for asthma, and 1.07 (95% CI = 1.01–1.13) for pneumonia for each 10 μg/m3 increase
in PM2.5. Requia et al. considered the impact of PM levels on human health in Canada between
2007-2014.313 The authors report that a two-year increase of 10 μg/m3 in PM2.5level was
associated with an increased risk in diabetes incidence, in asthma incidence, and in high blood
pressure incidence of 5.34% (95% Conf. Int., 2.28%; 12.53%), 2.24% (95% C.I.: 0.93%; 5.38%),
and 8.29% (95% C.I.: 3.44%; 19.98%), respectively. Zhao et al. studied the effect of fine and
coarse PM on hospital visits due to respiratory disease in Dongguan, China during 2013-
2015.314Over 44,800 cases were considered. Both coarse and fine-mode PM were significantly
associated with morbidity of respiratory disease, COPD, and asthma. Although the authors did
not find any link between PM and pneumonia, they did find that an increase in PM equivalent to
an inter-quartile range of their study led to a 15.41% (95% CI, 10.99%, 20.01%) increase in
respiratory morbidity at the third lag day after exposure. The authors estimate that PM2.5 may be
responsible for approx. 8.3% of hospital outpatient visits due to respiratory morbidity at their
location.Clearly, many investigators have considered the effect of PM on respiratory distress. To
summarize work in the field, Khreis et al. have very recently published a meta-analysis of
existing literature and found a risk estimate of 1.08 (95% conf. int. 1.03, 1.14) for children
developing asthma per 5 Mm-1 increase in BC.334 In addition, the authors summarized a risk
estimate of 1.03 (1.01, 1.05) per 1 μg/m3increase in PM2.5, and 1.05 (1.02, 1.08) per 2 μg/m3
PM10.
The landscape of literature considering links between COPD and AECOPD and PM is
similar to that encountered for asthma. Investigators frequently can exhibit loose links between
PM and incidence of COPD or AECOPD, however, unraveling the physiology remains
complex.335-338Hwang et al. found correlation between hospital admissions for COPD and the
level of PM2.5 in southwestern Taiwan.315For this study, the relative risk (RR) for every 10 μg/m³
increase in ambient PM2.5during the spring and winter months was found to beabout 1.25 (95%
Conf. Int. 1.22-1.27) with a lag time of zero days (immediate presentation of symptoms).In a
second paper from Hwang et al. 38,715 hospital admissions for AECOPD were studied for
association with PM2.5.316The authors report risk ratios for hospital admission for AECOPD for
every 10 µg/m3 increase in PM2.5to be 1.02 (95% Conf. Int. = 1.007- 1.04). Patients >65 years of
age were affected the most. Tsai et al. studied hospital admissions for COPD in Taiwan to find
possible associations with PM levels.317 The authors split the data set into warmer days (>23 °C)
and cooler weather and found that an interquartile range increase in PM concentration led to
increases of 12% (95% Conf. Int. = 8-16%) and 3% (95% Conf. Int. = 0-7%) in COPD
admissions, respectively.Of particular note is the relationship between COPD and biomass
burning smoke. Exposure to biomass smoke is believed to be a major factor in promoting
COPD.339-340One example of a study linking biomass burning smoke to COPD is found in Hu et
al. who published a meta-analysis study that established an odds ratio of 2.44 (95% Conf. Int.
1.9-3.33) for individuals developing COPD, relative to those individuals not exposed to biomass
smoke.318 Finally, Li et al. conducted a meta-analysis of 12 studies from the literature to evaluate
the effect of PM on COPD hospitalizations and mortality.341 The authors found that a 10-μg/m3
increase in daily PM2.5 was associated with a 3.1% (95% Conf. Int. 1.6%-4.6%) increase in
COPD hospitalizations and a 2.5% (95% C.I., 1.5%-3.5%) increase in COPD mortality.
3. CONCLUSION.
This review article has outlined mechanisms of exposure to particulate matter,

physiological responses on a cellular level, and has presented some epidemiological-level
evidence for the broader systemic effects of PM. PM has been shown to elicit an immune
response on a cellular level, and frequently exhibits some degree of cytotoxicity – especially at
high exposure dose. Many investigators have presented data that suggests a link between
ambient PM levels and a variety of health ailments, including cognitive losses, anxiety &
depression, ADHD, autism, stroke, cardaic arrest, and hypertension. The epidemiological
studies are of considerable societal value because they have provided estimates of the health
impacts of PM exposure. This allows projection of economic cost related to the morbidity and
mortality caused by PM.
After considering dermal deposition and typical rates of breathing, the daily dose of PM
that many individuals are exposed to is likely just a few hundred micrograms. This is far less
than the pharmacological dose of many prescribed medications. It is truly remarkable that
exposure to such low quantities of PM can elicit measureable responses to human health. The
required societal investment in healthcare response and resulting deaths attributed to PM create a
large societal burden. Additional research should be conducted to better understand how to
reduce exposure to particulate pollution, and better treat patients that present with symptoms
related to PM exposure.
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FIGURE CAPTIONS
Figure 1. (A) Anatomy of human lung showing the three regions. (B) Anatomy of human skin.
Hair follicles and sweat glands create shunts through which deposited particulate matter may
permeate skin through the stratum corneum (epidermis). Figures are adapted with minor labeling
changes from W.C. Hinds64 and the National Institute of General Medical Sciences with
permission.
Figure 1. (A) Anatomy of human lung showing the three regions. (B) Anatomy of human skin. Hair follicles and sweat glands create shunts
through which deposited particulate matter may permeate skin through the stratum corneum (epidermis). Figures are adapted with minor
labeling changes from W.C. Hinds64 and the National Institute of General Medical Sciences with permission.
Figure 2.(A) Modeled deposition of inhaled particles in the upper and lower human respiratory
tract as a function of particle size for nose breathing. A = alveolar; TB = tracheobronchial; NPL
= nasal, pharynx, larynx. Figure A reproduced from Oberdorster with permission.342(B) In vivo
inhalation experiments using baboons. Representative scintigraphic images of head airways,
trachea, and lungs obtained for the threepolydisperse aerosol samples. All images are for the
same baboon. Relative aerosol depositions (%) for the extrathoracic (ET) and thoracic (TH)
regions are indicated. Activity median aerodynamic diameter (AMAD) and [d16, d84] were
noticed for each aerosol sample generated. It is observed that aerosol particles with Dp < 500
nm more effectively accumulate within the lungs while larger micrometer sized particles deposit
in head airways. Figure B is reproduced from Albuquerque-Silva et al. under CCBY license.63
Figure 2. (A) Modeled deposition of inhaled particles in the upper and lower human respiratory tract as a function of particle size for nose
breathing. A = alveolar; TB = tracheobronchial; NPL = nasal, pharynx, larynx. Figure A reproduced from Oberdorster with permission.342 (B) In
vivo inhalation experiments using baboons. Representative scintigraphic images of head airways, trachea, and lungs obtained for the three
polydisperse aerosol samples. All images are for the same baboon. Relative aerosol depositions (%) for the extrathoracic (ET) and thoracic (TH)
regions are indicated. Activity median aerodynamic diameter (AMAD) and [d16, d84] were noticed for each aerosol sample generated. It is
observed that aerosol particles with Dp < 500 nm more effectively accumulate within the lungs while larger micrometer sized particles deposit
in head airways. Figure B is reproduced from Albuquerque‐Silva et al. under CCBY license.63
Figure 3.(a) Translocation into lymph node (LN), blood, and urine during the first hour after 5
nm and 27 nm diameter nanoparticles were administered to rats. (b) Color images, near-infrared
fluorescence images of tissue sections, and histological slices obtained from organs Sprague-
Dawley rats at 1 h after instillation. Scale bars, on left are 5 mm, on right 200 μm. (c)
Quantitative biodistribution and clearance using Tc-conjugated nanoparticles administered
intratracheally into Sprague-Dawley rats. Translocation from lung to blood over
time.Translocation from lung to lymph nodes 1 h after injection, and total body distribution of
nanoparticles.Each data point represents the mean ± s.d. of n = 3 animals. The ion TcO4− was
used as a control. Note in A and C the nanoparticles have different surface charges. (D, E)
Fraction of iridium particles within the liver and kidney of rats normalized to the lung tissue
post-exposure. Particles achieving this fate have been translocated into blood from the lungs.
Notice, the fraction of particles is well < 1 % of lung loading and a strong size-dependence is
noted with the 10 nm particles being translocated most efficiently. Figure A-C is reproduced
from Choi et al.99with permission and Figures D,E is reproduced from Buckley et al. under CC
license.28
Figure 3. (a) Translocation into lymph node (LN), blood, and urine during the first hour after 5 nm and 27 nm diameter nanoparticles were administered to
rats. (b) Color images, near‐infrared fluorescence images of tissue sections, and histological slices obtained from organs Sprague‐Dawley rats at 1 h after
instillation. Scale bars, on left are 5 mm, on right 200 μm. (c) Quantitative biodistribution and clearance using Tc‐conjugated nanoparticles administered
intratracheally into Sprague‐Dawley rats. Translocation from lung to blood over time. Translocation from lung to lymph nodes 1 h after injection, and total
body distribution of nanoparticles. Each data point represents the mean ± s.d. of n = 3 animals. The ion TcO4− was used as a control. Note in A and C the
nanoparticles have different surface charges. (D, E) Fraction of iridium particles within the liver and kidney of rats normalized to the lung tissue post‐
exposure. Particles achieving this fate have been translocated into blood from the lungs. Notice, the fraction of particles is well < 1 % of lung loading and a
strong size‐dependence is noted with the 10 nm particles being translocated most efficiently. Figure A‐C is reproduced from Choi et al.99 with permission and
Figures D,E is reproduced from Buckley et al. under CC license.28
Figure 4. (A) IL-8 cytokine increases as a function of particulate matter dose, season of
collection, and PM size fraction (PM2.5 vs. PM10). (B) IL-8 production after exposure to PM
collected in winter and summer for experiments with and without polymyxin B, a substance
known to bind endotoxin, inhibiting its inflammatory response. Approximately 50% of the
summer PM inflammatory response was attributable to endotoxin for this experiment. While the
winter aerosol produced a smaller IL-8 response, it was unaffected by polymyxin B. The
experiment illustrates the complex mechanisms required to elicit an inflammatory response.
Figures reproduced from Gualtieri et al. with permission.184
Figure 4. (A) IL‐8 cytokine increases as a function of particulate matter dose, season of collection, and PM size fraction (PM2.5 vs. PM10). (B) IL‐
8 production after exposure to PM collected in winter and summer for experiments with and without polymyxin B, a substance known to bind
endotoxin, inhibiting its inflammatory response. Approximately 50% of the summer PM inflammatory response was attributable to endotoxin
for this experiment. While the winter aerosol produced a smaller IL‐8 response, it was unaffected by polymyxin B. The experiment illustrates
the complex mechanisms required to elicit an inflammatory response. Figures reproduced from Gualtieri et al. with permission.184
Figure 5. Summary of reactions involving reactive oxygen species (ROS) occurring in epithelial
lining fluid. Figure reproduced under C.C. license from Lakey et al.198
Figure 5. Summary of reactions involving reactive oxygen species (ROS) occurring in epithelial lining fluid. Figure reproduced under C.C. license
from Lakey et al.198
Figure 6.(A)Effect of PM2.5 on the expression of apoptosis-related proteins in A549 cells.
Relative protein band densities from gels after treatment with various concentrations of PM2.5 for
48 h or at 32 μg/cm2 of PM2.5 for 0, 6, 12, 24 or 48 h. Bar graph summarizes results
quantitatively. (B) Effect of PM2.5 dose on cell cytotoxicity in the presence (+NAC) or absence
(-NAC) of the anti-oxidant N-acetylcysteine. (C) Apoptotic cell rate in the presence of PM2.5
relative to control and case in which NAC was present. Figures reprinted from Deng et al. with
permission.226
Figure 6. (A) Effect of PM2.5 on the expression of apoptosis‐related proteins in A549 cells. Relative protein band densities
from gels after treatment with various concentrations of PM2.5 for 48 h or at 32 μg/cm2 of PM2.5 for 0, 6, 12, 24 or 48 h. Bar
graph summarizes results quantitatively. (B) Effect of PM2.5 dose on cell cytotoxicity in the presence (+NAC) or absence (‐
NAC) of the anti‐oxidant N‐acetylcysteine. (C) Apoptotic cell rate in the presence of PM2.5 relative to control and case in
which NAC was present. Figures reprinted from Deng et al. with permission.226
Table 1. Select Literature Detailing Immune Responses to PM.
Substance In vitro or Summary of Results Citation

Administered in vivo
Residual oil fly In vitro BEAS-2B cells, exposed to residual oil fly Veronesi
ash (ROFA) ash particles (ROFA), responded with an et al.158
immediate (<30 s) increase in intracellular
calcium levels ([Ca2+]), increases of key
inflammatory cytokine transcripts (i.e., IL-
6, IL-8, TNF- ) within 2 h exposure, and
subsequent release of IL-6 and IL-8
cytokine protein after 4 h exposure.
Pretreatment of BEAS-2B cells with
pharmacological antagonists selective for
the SP or CGRP receptors reduced the
ROFA-stimulated IL-6 cytokine production
by approximately 25 and 50%,
respectively. However, pretreatment of
these cells with capsazepine (CPZ), an
antagonist for capsaicin (i.e., vanilloid)
receptors, inhibited the immediate increases
in [Ca2+]i, diminished transcript (i.e., IL-6,
IL-8, TNF- ) levels and reduced IL-6
cytokine release to control levels.
Residual oil fly In vitro 0, 5, 50, or 200 μg/ml ROFA was admin. Carter et
ash (ROFA) IL-8, IL-6, and TNF-α proteins all al.162
produced. Chelating metal ions or
scavenging free radicals reduced response.
Residual oil fly In vitro IL-6 and TNF production in macrophages Becker et
ash, diesel dust, after administering fly ash, diesel dust, and al. 172
ambient particles ambient particles
material
Residual oil fly In vitro Residual oil fly ash inhibited tyrosine Samet et
ash (ROFA) phosphatase activity in human epithelial al173
BEAS cells. Suggests possible mechanism
through which pro-inflammatory proteins
accumulate.
Residual oil fly In vitro Cultures of dorsal root ganglion (DRG) Veronesi
ash (ROFA), sensory neurons of mice were exposed to
woodstove, Mt. oil fly ash, woodstove, coal fly ash, et al.174
St. Helen, St. ambient particles and volcanic PM.
Louis, Ottawa, Authors found neurons released significant
coal fly ash levels of the pro-inflammatory cytokine IL-
6 into media. Also found reduced release
with an antagonist of capsaicin receptor. In
addition, strong species dependence of
effects between strains of mice.
Ambient PM, In vitro Human macrophages and endothelial cells Becker et

Diesel particles used. Coarse mode particles more al.175
important for inflammation response,
TLR4 and TLR2 mediates response, diesel
particles exhibited lower inflammatory
response by interfering with cytokine
release from cells
PM2.5 collected in In vitro PM2.5 significantly increased the expression Bekki et

China levels of inflammatory (interleukin-1β and al.176
cyclooxygenase-2) and oxidative stress
(heme oxygenase1) genes in mouse
Polymixin B, an endotoxin neutralizer, and
TLR4 knock-out mice strongly surpressed
inflammatory responses. but not oxidative
responses. However, when antioxidant was
added (acetylcystein) oxidative stress was
surpressed but not inflammatory response.
The paper successfully illustrates two
distinct pathways to inflammatory
response.
PM collected in In vivo Coarse PM from both rural and industrial Schins et

Germany locations in Germany was collected and al. 2004.177
applied intratrachaelly to rats. Again, the
coarse mode cause neutrophilic
inflammation of lungs. Also observed an
increase in TNF- for one coarse sample.
Responses were reported to be associated
with endotoxin content.
Ambient PM In vitro Human epithelial like cells and murine Thomson

macrophage like cells were exposed to PM et al.178
collected at several industrial sites.
Authors studied cytotoxicity, inflammation.
Significant site specific responses were
observed. Metals and PAHs correlated
with cytotoxicity, but inflammatory
responses were associated primarily with
endotoxin content within coarse particles.
Size-selected PM In vitro Authors found that coarse mode ambient Kumar et

collected in particles more effective for eliciting an al.179
Australia and inflammatory response in mouse tracheal
traffic related cells. This was evidenced by increased IL-
aerosol (soot) 6, IL-8, IL- 1 and CXCL1 secretion in
mouse and human epithelial cells. The
traffic aerosols did not produce
inflammatory response as measured by
cytokines. The authors suggest a role for
iron, but they did not consider endotoxins.
PM collected in In situ The authors used human bronchial Ortiz-

Puerto Rico- both epithelial cells. Urban PM10 extracts were Martinez
urban and rural cytotoxic, and promoted IL-6/IL-8 et al.180
secretion. Endotoxins were found to
contribute to inflammatory repsonse.
Wood In vitro THP-1 and A549 cells produced IL-8 after Corsini et
Combustion PM exposure to ultrafine particle matter al.181
produced from wood burning. Soft or hard
woods largely performed similarly. Diesel
exhaust particles were more effective at
inducing IL-8 production on a per mass
basis.
Resuspended In vivo (IT Four fold increase in IL-1 and doubling Farina et
Urban PM10 from instillation) of TNF in bronchoalveolar lavage fluid al.182
Milan for mice who were exposed to PM.
Resuspended In vivo (IT PM10 and PM2.5 collected in Milan was Farina et
Urban PM10 and instillation) aerosoloizedintratrachaelly in mice. The al.183
PM2.5 from authors screened for several inflammatory
Milan markers and found all (PMNs percentage,
TNF-α, Hsp70 in the BALf, HO-1 in lung
parenchyma) were increased after summer
PM10 administration. Conversely, winter
PM10 and PM2.5 increased the amount of
Cyp1B1, a protein involved in the
induction of pro-carcinogenic effect. The
study demonstrates seasonally different
responses to PM, but not all response from
endotoxins.
PM10 and PM2.5 In vitro Authors found that summer PM10 exhibited Gualtieri
collected in highest inflammatory response in human et al.184
Milan BEAS-2B and A549 epithelial cells.
Inflammation was reduced by approx.. 50%
through Polymixin B – indicating a partial
role of endotoxins. Winter PM was more
cytotoxic to cells – this was attributed to
increased PAH content.
PM2.5 and PM10 In vitro The authors used bone marrow derived Ferguson
collected at mouse macrophages to study immune et al.185
Missoula, MT response of fine and coarse mode aerosol.
The authors found IL-1 increased linearly
with coarse mode aerosol in both summer
and winter months. However, endotoxin
content did not correlate with the observed
increases.
PM2.5-10 collected In vivo Authors observed increase in IL-6, IL-8, Alexis et

in Chapel Hill, TNF- , neutrophils, and macrophages after al.186
NC human volunteers inhaled nebulized PM
extracts.
TiO2, SiO2, fly In vitro All PM types produced dose-dependent Tao and
ash, urban air PM increases in TNF- and a macrophage Kobzik187
inflammatory protein (MIP-2) when
alveolar macrophages and epithelial cells
were co-cultured.
Polystyrene In vivo The authors instilled 64, 202, and 535 nm Brown et
(multiple sizes) polystyrene particles into rat lungs. Found al.188
ultrafine polystyrene led to highest IL-8
release from A549 cells with decreasing
release for larger particles.
TiO2 (multiple In vivo Results indicate fine and ultrafine TiO2, Hohr et
sizes and with both native surfaces and methylated al.189
surfaces) surfaces produced similar increases in
MIP-2 protein over controls in BAL fluid
of tracheal instilled rats. Activity of
enzymes studied and cell counts related to
total particle surface area.
TiO2 and Carbon In vivo Rats were instilled with fine and ultrafine Renwick
Black (fine and TiO2 and carbon black. Authors found et al.190
ultrafine) instillation of large does of ultrafine
particles of both compositions led to
increased fraction of neutrophils in BAL
fluid. However, dosing equivalent mass of
fine particles did not produce response.
Diesel PM In vitro Authors used A549 epithelial cell line to Mazzarella

study the effect of diesel PM on immune et al.191
response. Results show exposure to Diesel
PM led to increased expression of IL-6 and
IL-8. The Diesel PM immune response
was even larger than that observed for a
lipopolysaccharide derived from E. Coli.
Table 2. Select Literature Detailing Cytotoxicity Responses to PM.
Substance In vitro or Summary of Results Citation

Administered in vivo
PM collected In vitro Authors collected PM0.3-PM2.5 and PM2.5 Landkocz et

in France fractions in the city of Dunkerque, in northern al.225
France. They extracted the samples using
dichloromethane and water, representing
‘organic’ and ‘aqueous’ extracts. Results
indicated that very high concentrations of
material from the very fine particle (<0.3
micron) organic extract exhibited mutagenic
activity. The authors attributed this to PAHs,
especially nitro-, amino- and hydroxylamino-
PAHs in the sample. Other size fractions and
aqueous extracts did not exhibit mutagenicity.
A similar result occurred when cell viability was
evaluated using the lactate dehydrogenase
(LDH) release assay for the BEAS-2B cells
after 24, 48 or 72 h of exposure to PM extracts.
The organic extract fraction led to statistically
significant loss of cell viability within 24 h at a
dose of 20 g PM/cm2 while the aqueous
extracts demonstrated an effect only at doses >
40 g PM/cm2 after 72 hours of exposure.
While the dose used in this study far exceed
likely deposition in airways or skin, the results
do emphasize the importance of the organic
fraction in cytotoxicity.
PM2.5 In vitro Exposing human A549 cells to PM2.5 collected Deng et al.226
collected in in China at doses between 8 – 64 g / cm2 led
China to a dose-dependent cytotoxicity. A significant
reduction (approx. 25%) in cytotoxicity when
the ROS scavenger N-acetylcysteine (NAC) was
present within media, indicating a role of
reactive oxygen species in cytotoxicity. These
authors also demonstrated that increase PM
dose led to higher levels of Bax protein, and
increase cleavage of Caspases 3, 7, 8, 9. These
protein expression levels are consistent with
promoting and initiating apoptosis –
programmed cell death. Taken together, the
results suggest PM2.5 can lead to the cell death.
In a subsequent work, Li et al. found PM2.5
induces cellular apoptosis through a
mitochondria-dependent
pathway.211Downregulation of the miR-1228-5p
microRNA was associated with PM2.5 induced
apoptosis while upregulation of this miRNA
offered a protection against apoptosis.
PM2.5 In vivo w/ Authorsintratracheally instilled mice with a Jin et al.227

collected in suspension of PM at a concentration of 4 mg/kg
China lavage body weight and collected BAL fluid for
analysis. The authors found an inflammatory
response, as evidenced by significantly
increased levels of ROS, iNOS, EGF, and
CXCL1 compared to controls. The
concentration of IL-1 and IL-18 was found to
increase, but not at statistical significance
(P<0.05). The authors also reported significant
increases in expression of two proteins in the
NF- B family, indicating a potential pathway
for the observed inflammatory response.
ambient PM In vitro Lu et al. tested the cytotoxicity of ambient PM Lu et al.228

size fractions size fractions as well as engineered
and ZnO, nanoparticles made from ZnO, NiO, and CeO2.
NiO, and The ZnO particles proved to be the most potent,
CeO2 in terms of cytotoxicity. However, all particles
tested negatively impacted cytotoxicity at high
doses (200 g /mL). The foremost toxicity of
the ZnO nanoparticles was also reflected via the
MTT and LDH cytotoxicity assays and the
highest intracellular ROS intensity and
apoptotic induction fraction was observed for
the sample containing the water-soluble fraction
of ambient fine particles (PM1.8) present at 200
μg/mL.
Automotive In vitro Particles produced during automotive braking Gasser et

braking are an important component of urban particulate al.229
particles matter. In the work of Gasser et al., the
cytotoxicity and immune response of such
particles were investigated in epithelial lung
cells. The authors found that at the doses used
during braking experiments, the brake particles
induced no significant difference in cytotoxicity
compared to controls. However, cultures
exposed to brake PM did exhibit increased
ROS, as measured through a fluorescence-based
assay. In subsequent experiments, the authors
did find increasing IL-8 concentration at
elevated organic carbon content, indicating a
possible link between variables.
Black carbon In vivo w/ Authors compared lung response in mice which Chu et al.230
and O3 aged were intratracheally instilled fresh-black carbon
particles lavage (fBC) and ozone treated black carbon. These
results suggested a higher expression of IL-1 ,
IL-6, IL-33, and CD3 in the lungs of mice
which were given the ozone treated black
carbon. In addition, the authors studied
phosphorylation of several proteins including
PI3K, AKT1/2/3, IKKα/β, IκB and ERK, and
determined it was increased after exposure to
both BC and oxidized BC. Phosphorylation was
higher in the oxidized BC case. The authors
results consistently demonstrated oxidized BC
caused additional lung inflammation / damage
compared with untreated BC.
Carbon In vitro Reported on the cytotoxicity of both native and Liu et al.231
nanotubes surface oxidized carbon nanotubes. While
nanotubes specifically may not be a major
concern as a component of airborne particulate
matter, the material serves as a proxy for aerosol
carbon. In this work, the surfaces of single wall
carbon nanotubes were oxidized with OH and
ozone in an attempt to link chemical evolution
with toxicology. The authors observed
functionalization of the nanotube surface
reflective of carboxylate groups forming.
However, the cytotoxicity and redox activity of
the particles were not related to
functionalization.
PM2.5 In vitro Investigated the effect of water soluble (WS) Zou et al.232
components and insoluble (WIS) PM2.5 components on A549
cells. The authors found a dose-dependent
decrease in cell viability between 50-400 g /
mL for both WS and WIS fractions. In addition,
when the LDH assay was performed, it was
found that the WIS fraction was far more
effective at disrupting the cellular membrane
compared to the WS fraction. Only at highest
dose of WS fraction did a significant difference
in LDH emerge. This suggests a strong
composition dependence on cytotoxicity via
membrane disruption.
PM10 in In vitro Used size-selective sampling of PM10 in Velali et al.233

Thessaloniki, Thessaloniki, northern Greece. Results from an
northern urban aerosol suggested particles between 0.49
Greece – 3 m yielded the highest ROS generating
potential on a per-mass basis as measured by the
dithiothreitol assay. In terms of cytotoxicity,
the authors used both the mitochondrial
dehydrogenase (MTT) and lactate
dehydrogenase (LDH) assays. The MTT
method suggested particles in the 0.49 – 1.5
micron range were most cytotoxic on a per-mass
basis, however, the LDH assay yielded results
inconsistent with this conclusion. For the LDH
assay, particles in all size ranges did not
produce LDH release significantly different
from the control. In many cases, LDH release
noted was actually lower than the control
experiment.
Diesel In vitro Studied the effects of diesel exhaust on human Seriani et

exhaust bronchial epithelial cells (BEAS-2B). Cells al.234
particles exposed to diesel exhaust particles were found
to have a significant loss in cell stiffness,
membrane stability, and mitochondrial activity.
In addition, genes involved in apoptosis were
differentially expressed after exposure to
particles. mRNA coding for caspase-3
exhibited nearly a 4-fold increase shortly after
exposure to PM extract, while mRNA for bcl-2
decreased approx. 10-fold over same period.
These results suggest increased apoptosis after
exposure to the diesel PM.
Baghdad In vitro Report on the biological effects of particulate Hamad et

material collected from the Baghdad aerosol. In
aerosol their experiments, gene expression and ROS al.235
was tracked in alveolar macrophages. The
authors concluded that pro-inflammatory
proteins Cxcl1, IL-1 , TNF-α, Ccl2 and Ccl7
were upregulated after exposure to PM. In
addition, ROS was correlated to bulk PM mass
concentration, organic carbon content,
levoglucosan (biomass burning tracer), PAHs,
and metals.
Wind-blown In vitro Naimabadi et al. considered the cytotoxicity of Naimabadi et

dust PM10 collected during dust storms in Iran al.236
through use of the LDH assay. The authors
determined that wind-blown dust exhibits
cellular toxicity, and that its magnitude is very
similar to ‘normal’ background ambient aerosol
on a per-mass basis. This result is significant to
many residents of Earth’s dust-belt, because the
mass concentration of dust aerosol can reach
levels 1000-fold higher than typical ambient
levels during intense dust events.269 This
suggests the potential for significant
cytotoxicity in the aftermath of dust storms.
PM10 – 3 μm; In vitro Authors collected size segregated PM(PM10 – 3 T. Schilirò et

PM3 – 0.95μm; μm; PM3 – 0.95μm; PM< 0.95μm) in Torino, Italy and al.237
PM< 0.95μm exposed organic and aqueous extracts of PM to
from Torino, THP-1 cells. The authors considered the
Italy inhibition of cell proliferation. Both the
aqueous and organic extracts were found to
inhibit cell proliferation with similar efficacy
(30.8 ± 6.0% for summer aerosol and 28.4 ±
6.9% for winter aerosol). The authors also used
the LDH assay to study cell membrane integrity
and found interesting seasonal dependence. For
summer, PM extracts induced a larger release of
LDH compared to winter samples (54.3 ±
36.5% and 22.6 ± 17.7%) and LDH values were
highest for the coarse aerosol fraction in
summer. However, in winter the finest aerosol
fraction yielded most significant increases in
LDH. Results suggest variability in toxicity by
seasonally influence composition.
PM<0.2, PM0.2- In vitro Cao et al. sampled particles into several size Cao et al.238
2.5, and PM2.5- fractions (PM<0.2, PM0.2-2.5, and PM2.5-10) near an
10near incinerator in Shanghai, China and evaluated
incinerator cell viability and generation of ROS in A549
cells. The viability assay revealed an inverse
relationship between particle size and toxicity -
the smallest size fraction induced highest cell
loss after 6h exposure. The authors found
higher concentrations of anthopogenically
generated elements (V, Ni, Cu, Zn, Cd and Pb)
in the smallest size fraction.
Wood-smoke In vivo w/ Aimed to study the effects of wood smoke by Muala et

BAL allowing 14 human volunteers to breathe wood al.239
smoke at a PM1 concentration of 314 g / m3
for 3 h in a chamber. A follow up bronchoscopy
with bronchial wash (BW), bronchoalveolar
lavage (BAL) and endobronchial mucosal
biopsies was then performed after 24 h. The
authors report an unexpected finding, that
lymphocytes in BAL fluid and macrophage,
neutrophil and lymphocytes in BW were
reduced following exposure compared to
controls. Cells present sub-mucosally were
found to increase after exposure, with epithelial
CD3+, CD8+ and mast cells increasing
abundance. The authors conclude that the
wood-smoke may contain cytotoxic components
that influenced the immune response.
PM2.5 extract In vitro Considered the role of dimethylarginine Wang et al.240

dimethylaminohydrolase-1 (DDAH1), an
enzyme tasked with degrading asymmetric
dimethylarginine (ADMA), which is an
endogenous nitric oxide synthase (NOS)
inhibitor. These authors found that exposing
A549 cells to 100 g/mL of PM2.5 led to large
increase in cleaved caspase-3, cleaved PARP,
iNOS and reduced expression of DDAH1 and
DDAH2. These results are consistent with
triggering an apoptotic channel of cell death,
and indeed reduced cell viability at 48h was
clearly observed. The authors then generated a
‘knock-out’ cell line that drastically reduced
expression of DDAH-1 (by 90%). Upon
exposure to PM2.5 extract, the knock-out cell
line demonstrated a reduced apoptosis rate,
indicating down regulating DDAH-1 offered a
protective effect against PM2.5. The authors also
found iNOS knockout cells treated with PM2.5
extract had significantly higher viability after 24
h. The knockout cells exhibited less PARP
cleavage, significantly increased anti-apoptotic
protein Bcl-2 expression, and decreased pro-
apoptotic protein Bax expression in the PM2.5-
exposed cells. Interestingly, overexpression of
DDAH1 in the test cells also significantly
attenuated PM2.5 attributed cell death.
PM0.1 in In vitro Jeon and Lee collected PM0.1 in Korea using an Jeon and
Korea inertial impactor. They performed cell viability Lee241
assays after exposing the SH-SY5Y neuronal
cells to PM extracts. Exposure to 35, 150 and
250 µg mL–1 of PM0.1 for 24 h resulted in
approximately 28%, 48% and 67% cell death,
respectively. However, when the reactive
oxygen species (ROS) scavenger NAS was
present at 600 M the cell viability improved
dramatically. The authors tracked Bax, Bcl-2
and caspase-3 (markers of apoptosis) and the
levels were not significantly changed after PM0.1
administration, indication apoptotic death was
not responsible. The research team did find that
the levels of Atg7 and Atg3 proteins were
significantly up-regulated after PM0.1 treatment.
Atg7 and Atg3 are proteins implicated in cell
autophagy. Thus, under this set of conditions,
PM induced loss of cell viability apparently
through autophagy.
Black carbon In vitro Treated human epithelial A549 cells either fresh An et al.242
or ozone BC (FBC) or ozone-oxidized BC (OBC) and
treated black examined resulting cell viability and gene
carbon expression. Treating black carbon with ozone is
believed to alter the particles surface polarity
which may change health impacts. After
−1
treatment with 20 μg mL of FBC and OBC for
24 h, the cell viability reduced to 91.0 ± 4.2%,
84.7 ± 6.3%, and the LDH elevated 2.1-2.4 fold.
They also examined the expression of approx.
47, 000 genes, and about 1,500 were
significantly changed by the FBC and OBC.
Interestingly, less than half of genes related to
oxidative stress, inflammation, and autophagy
were identical for the FBC and OBC samples.
This suggests significant complexity in the
cellular response to PM and leads the authors to
believe different molecular pathways were
activated.
PM2.5 and In vitro The authors collected PM2.5 and PM>2.5 in Fresnel-
PM>2.5 in Cotonou (Benin). BEAS-2B (bronchial Cachon et
Benin epithelial cells) were treated at PM al.243
concentrations of 1.5–96 μg/cm2 and
cytotoxicity, and inflammatory response
studied. The authors found dose-dependent
increases inIL-1β, IL-6,and IL-8.
Table 3. Select Literature Detailing Observed Systemic Effects of PM.
Study Pollutant Results Citation

Location Concentration
Mexico High level air-polluted Brain inflammation Calderon-

area vs. low levels.cIn biomarkers: COX-2 Garciduenas et
high level air-polluted expression and Aβ42 al.257
area, ozone and PM accumulation.
levels exceed the U.S.
standards most of the
year. In the cities with
low levels of air
pollution, pollutant
concentrations are below
the current U.S.
standards.
UK Diesel exhaust produced Increase in median Cruts et al.258

by an engine. Dilute power frequency in the
diesel exhaust frontal cortex in response
(300 μg/m3). to exposure to diesel
exhaust for 30 min.
USA Annual PM10 and ozone Cognitive functions and Chen and
level at the county of reaction time display no Schwartz259
residence determined by significant findings for
inverse distance PM10.
weighting. The
estimated annual
average exposure was
37.2 ± 12.8 μg/m3 for
PM10 and 26.5 ± 5.2 ppb
for ozone. 1-year PM10
Urban: 39.0 ± 13.4
Rural: 33.6 ± 10.6
(μg/m3).
Ruhr district, Traffic-related PM. Living near busy streets Ranft et al.260
Germany Exposure to background within 50 m was
PM10 concentration in associated with mild
ambient air during cognitive impairment:
1980–1993 (min, mean, CERAD-Plus test: −3.8
max.): Ruhr district: (95% CI: −7.8, 0.1);
44.4,48.6,53.6 μg/m3 Stroop test: −5.1 (95%
Rural county Borken: CI: −8.2, −2.0); Sniffing
39.3, 45.0, 49.0 μg/m3 test: −1.3 (95% CI: −2.4,
during 2002–2006: Ruhr −0.2).
district: 25.8, 28.3,
30.5 μg/m3 Rural county
Borken: 25.0, 25.0,
25.0 μg/m3.
Mexico High level air-polluted Subjects in Mexico had Calderon-

area vs. low levels. Air significantly lower Garciduenas et
pollutants of control University of al.261
town were below the Pennsylvania Smell
current Environmental Identification Test
Protection Agency (UPSIT)
(EPA) standards. scores:34.24 ± 0.42 vs.
controls 35.7 ± 0.40,
p = 0.03.
USA PM2.5–10, and PM2.5 For long-term exposure Weuve et al.262

determined by US (7–14 years): PM2.5–10
Environmental exposure: The 2-year
Protection Agency change in standardized
(USEPA) spatiotemporal cognitive scores for each
smoothing models. 10 μg/m3 increment in
PM2.5–10 exposure is:
−0.020, 95% CI: −0.032,
PM2.5–10 −0.008 PM2.5 exposure:
The 2-year change in
Lowest: 6.7–19.6 standardized cognitive
scores for each 10 μg/m3
Second: 19.7–21.8 increment in PM2.5
exposure is: −0.018
Third: 21.9–24.2
(95% CI: −0.035,
Fourth: 24.3–27.2 −0.002).
Highest: 27.3–
68.2 μg/m3
PM2.5
Lowest: 1.9–11.5
Second: 11.6–13.2
Third: 13.3–15.0
Fourth: 15.1–16.8
Highest: 16.9–
25.5 μg/m3.
Mexico City O3, PM10, PM2.5, SO2, Presence of neocortical Calderon-

NO2, CO, and Pb. hyperphosphorylated tau Garciduenas et
with pretangle material al.263
and amyloid-β diffuse
plaques in the frontal
cortex of individuals
exposed to urban air
pollution suggests a link
between oxidative stress,
neuroinflammation,
neurodegeneration, and
chronic exposure to high
concentrations of air
pollution.
Mexico High level air-polluted COX2 in the frontal Calderon-

area vs. low levels. cortex was significantly Garciduenas et
elevated in Mexico City al.264
subjects vs. control,
p = 0.008. Exposed
subjects also had higher
IL1β expression in the
frontal cortex,
p = 0.0002. COX2 in
olfactory bulb was
significantly elevated vs.
control, p = 0.005.
USA Satellite-derived A 10- g/m3 increase in Loop et al.265

estimate of 1-year mean PM2.5 concentration was
PM2.5 concentration. not reliably associated
with an increased odd of
Quartile of PM2.5: incident impairment (OR
=1.26, 95% CI: 0.97,
First: 6.6–12.2
1.64).
Second: 12.2–13.6
Third: 13.6–14.8
Highest: 14.8–
21.0 μg/m3
Mexico City Impaired cognitive Calderon-

metropolitan functions; altered Garciduenas et
area PM2.5, 35 μg/m3 immune responses al.266
include significant
decreases in the numbers
of natural killer cells and
increased numbers of
mCD14+ monocytes and
CD8+ cells.
USA Average Older adults living in Ailshire and

PM2.5concentration from areas with higher PM2.5 Crimmins267
each monitoring station concentrations (highest
were weighted using the quartile) had worse
inverse of the distance. cognitive function
(β = −0.26, 95% CI:
PM2.5 ranged from 4.500 −0.47, −0.05)
to 9.942 μg/m3 in the
first and lowest quartile,
9.943 to 12.184 μg/m3 in
the second quartile,
12.185 to 13.796 μg/m3
in the third quartile, and
13.797 to 20.661 μg/m3.
Los Angeles Average O3, PM2.5, and Increasing exposure to Gatto et al.268
NO2 concentration from PM2.5 was associated
2000 to 2006 estimated with lower verbal
using monitoring data learning (β = −0.32 per
and inverse distance 10 μg/m3; 95% CI:
weighing PM2.5 −0.63, 0.00).
(20.2 ± 3.5) of men
versus (16.5 ± 3.3) μg
/m3 of women.
Tehran, Iran PM10, SO2, NO, NO2, Prevalent MS cases had Heydarpour et
NOx concentration a clustered pattern in al.269
during the year 2010 Tehran. A significant
estimated using land use difference in exposure to
regression (LUR). PM10 (p < 0.001) was
observed in MS cases
PM10 in Multiple compared with controls.
sclerosis (MS) cases
were 99.1 μg/m3, while
the mean exposures for
PM10 were 93 μg/m3 in
random controls.
USA PM2.5: 6.1–18.0 μg/m3 in Short-term exposure to Zanobetti et al.270

121 US communities. PM2.5 is significantly
associated with an
increase in
hospitalization risks for
Parkinson's disease
(3.23%, 1.08, 5.43).
11 states Particulate matter. The relative risk (RR) Palacios et al.271

(California, comparing the top
Connecticut, Quartiles of PM10: quartile to the bottom
Florida, quartile of PM exposure
3.8–21.0, 21.0–24.3,
Maryland, was 0.99 (95%
24.3–28.3, 28.3-
Massachusetts, 88.3 μg/m3 Confidence Intervals
Michigan, (CI):0.84, 1.16) for PM10
New York, Quartiles of PM2.5: (≤10 microns in
New Jersey, diameter), 1.08 (95% CI:
Pennsylvania, 1.2–12.6, 12.6–15.0, 0.81, 1.45) for PM2.5
Ohio and 15.0–17.4, 17.4- (≤2.5 microns in
Texas), USA 73.9 μg/m3 diameter), and 0.92 (95%
CI: 0.71, 1.19) for PM2.5–
Quartiles of PM2.5–10:
10 (2.5 to 10 microns in
0–7.2, 7.2–9.2, 9.2–12.0, diameter)

12.0–67.1 μg/m3
London, Average PM10 and PM2.5 Higher PM2.5 of Tonne et al.272

England concentration estimated 1.1 μg/m3 was
by dispersion model at associated with a 0.03
home address. During (95% CI: −0.06 to 0.002)
the 5 years between 5-year decline in
2002 and 2004 and standardized memory
2007–2009, average score and a 0.04 (−0.07
exposure to total PM10 to −0.01) decline when
was 23.4 μg/m3 and to restricted to participants
total PM2.5, 14.9 μg/m3. remaining in London
Average exposures from between study waves.
vehicle exhaust were
0.72 μg/m3 for PM10
and 0.64 μg/m3 for
PM2.5.
Annual PM2.5 levels Those living in areas Ailshire and

based on air monitoring with greater exposure to Clarke273
USA data. Average PM2.5 PM2.5 had an error rate
concentration in areas 1.5 times greater than
where respondents lived those exposed to lower
was 13.8 ± 3.1 μg/m3 PM2.5 concentrations
(IRR = 1.53; 95% CI:
1.02, 2.30 for 10 μg/m3
increment).
O3 and PM2.5 exposure There was a 138% Jung et al.274

estimated using inverse increase Alzheimer's
Taiwan distance weighting. The disease risk per increase
mean of annual average of 4.34 μg/m3 in PM2.5
of PM10 was over the follow-up
59.25 ± 15.76 μg/m3 period (95% CI: 2.21,
with a range of 18.18 to 2.56).
108.35 μg/m3; The mean
of annual average of
PM2.5 was
33.5 ± 69.20 μg/m3 with
a range of 10.36 to
61.76 μg/m3 during
2000–2010.
North Carolina Ozone and fine No statistically Kirrane et al.275

and Iowa USA particulate matter. significant association of
Parkinson's disease with
The maximum of the 4- fine particulate matter
year average predicted (OR = 1.34; 95% CI:
PM2.5 concentration 0.93, 1.93) in North
assigned to an Iowa Carolina but not in Iowa.
participant was
11.5 μg/m3 compared to
17.7 μg/m3 in North
Carolina.
Lombardy A higher RR of hospital Angelici et al.276

region, Italy admission for MS
Particulate matter relapse was associated
42.48 ± 28.6 μg/m3 with exposure to PM10 at
different time intervals.
Hospital admission for
MS increased 42% (95%
CI: 1.39–1.45) on the
dayspreceeded by
1 week with PM10 levels
in the highest quartile.
The p-value for trend
across quartiles was
<0.001.
Northeastern Long-term PM2.5 Hazard ratio (HR) of Kioumourtzoglou

USA exposure. 1.08 (95% CI: 1.05, et al.277
1.11) for dementia, an
The average PM2.5 HR of 1.15 (95% CI:
concentration was 1.11, 1.19) for AD, and
12.0 ± 1.6 μg/m3 an HR of 1.08 (95% CI:
(IQR = 3.8 μg/m3) 1.04, 1.12) for PD
admissions per 1 μg/m3
increase in annual PM2.5
concentrations
Mexico City Exposure to high Major findings in MC Calderon-

Metropolitan concentrations of air residents included Garciduenas et
Area (MCMA) pollutants: PM2.5 and leaking capillaries and al.278
and small cites ozone. small arterioles with
in Mexico extravascular lipids and
erythrocytes, lipofuscin
in pericytes, smooth
muscle and EC,
thickening of
cerebrovascular
basement membranes
with small deposits of
amyloid, patchy absence
of the perivascular glial
sheet, enlarged
Virchow–Robin spaces
and nano-size particles
(20–48 nm) in
endothelial cells,
basement membranes,
axons and dendrites. The
integrity of the
neurovascular unit, an
interactive network of
vascular, glial and
neuronal cells is
compromised in MC in
young residents.
Long-term exposures to Tzivian et al.279

air pollution and traffic
German Ruhr Long-term air pollution noise were positively
Area and traffic noise associated with Mild
exposures. cognitive impairment
PM2.5:18.39 ± 1.05 μg/m3 (MCI), mainly with
amnestic subtype
(aMCI). An interquartile
range increase in PM2.5
were associated with
overall MCI (OR: 1.16,
95% CI:1.05–1.27) and
aMCI (1.22, 96% CI:
1.08–1.38). In two-
exposure models, Air
pollution and noise
associations were
attenuated, for aMCI:
PM2.5 1.13 (0.98, 1.30)
Highly exposed children Calderon-

had: Poorer performance Garciduenaset
Mexico High level air-polluted in the digit span al.280
area vs. low levels. (p = 0.014), information
(p = 0.019), and
arithmetic (p = 0.031).
Higher proportion of
prefrontal white matter
hyperintense lesions than
low exposed groups.
Compared high to low Wang et al.281
exposure schools, odds
Quanzhou, Traffic-related air of lower performance:
China pollution: low vs. visual response speed:
exposed school based on visual simple reaction
NO2 and PM10 levels time-preferred hand test
(ecologically determined (OR =1.67, p = 0.044);
by air monitors and visual simple reaction
passive samplers). time-non-preferred hand
test (OR =1.83,
Average concentrations
of NO2, and PM10 were, p = 0.017); Speed and
attention, measured by
respectively, 22 μg/m3
the continuous
and 80 μg/m3 in the
polluted area and performance test (OR
=2.40, p = 0.001);
7 μg/m3 and 68 μg/m3 in
the clear area. Accuracy and speed,
measured by the digit
symbol test (OR =1.38,
P = 0.019); Psychomotor
stability, measured by
the pursuit aiming test
(OR =1.61, P < 0.001);
motor coordination,
measured by the sign
register test (OR =1.94,
P < 0.001).
Mexico Mexico residents had Calderon-

significantly lower Garciduenaset
High level air-polluted UPSIT scores: al.282
area vs. low levels. 34.24 ± 0.42 vs. controls
Air pollutants of control 35.7 ± 0.40, p = 0.03.
The exposed groups
town were below the
exhibited remarkable
current Environmental
Protection Agency immunoreactivity to
Aβ42 and α-synuclein,
(EPA) standards.
and OB endothelial
hyperplasia, and
neuronal accumulation
of particles.
Mexico High level air-polluted Highly exposed healthy Calderon-

area vs. low levels. children had exhibited Garciduenaset
selective impairment in al.283
IQ subscales tapping on
attention, short-term
memory and learning
abilities.
Delhi, India PM10 estimated by Ambient PM10 level was Siddiqueet al.284
surrounding monitoring positively correlated
stations.The annual with ADHD (OR = 2.07;
average concentrations 95% CI, 1.08–
of PM10 were 3.99).<120 μg/m3: 1.00
161.3 ± 4.9 μg/m3.The (referent); 120–
concentrations of PM10 139 μg/m3: 1.824
were significantly lower (1.070–3.629); 140–
in control areas, 200 μg/m3: 2.201
74.6 ± 3.3 μg/m3. (1.162–5.032);
>200 μg/m3: 2.770

(1.381–5.555).
California, Proximity to Autism was associated Volk et al.285

USA freeways.Exposure with residential
category:< 309 m from proximity to a freeway
freeway,309–647 m during the third trimester
from freeway, 647– (OR =2.22; CI, 1.16–
1419 m from freeway, 4.42). Adjusting for
>1419 m from freeway sociodemographic
factors and maternal
smoking, maternal
residence at the time of
delivery was more likely
be near a freeway (<
309 m) for cases than for
controls [odds ratio
(OR) = 1.86; 95%
confidence interval (CI),
1.04–3.45].
Los Angeles, CO, NO2, NO, O3, For an IQR increase, Becerra et al.286
California PM2.5, PM10 from there was 12–15%
nearest monitoring increase in odds of
stations and land use autism for O3 [odds ratio
regression (LUR) (OR) = 1.12, 95% CI:
models. 1.06, 1.19; per 11.54 ppb
increase] and PM2.5 (OR
Per interquartile range =1.15; 95% CI: 1.06,
(IQR): 1.24; per 4.68 μg/m3
increase).
PM10 8.25 μg/m3
PM2.5 4.68 μg/m3.
USA Traffic-related air Exposure to the highest Newman et al.287

pollution, elemental tertile of ECAT during
carbon attributed to the child's first year of
traffic (ECAT). life was significantly
associated with
High vs. low ECAT Hyperactivity T-scores
(≥40 μg/m3 vs. < in the “at risk” range at
0.40 μg/m3). 7 years of age, after
adjustment [adjusted
odds ratio (aOR) = 1.7;
95% CI: 1.0, 2.7].
California, Traffic-related air Regional exposure Volk et al.288

USA pollution (TRP), NO2, measures of particulate
PM2.5, and PM10.TRP matter less than 2.5 and
levels of 31.8 ppb or 10 microns in diameter
greater (4th quartile), (PM2.5 and PM10) were
16.9–31.8 ppb (3rd also associated with
quartile), and 9.7– autism during gestation
16.9 ppb (2nd quartile), (PM2.5 OR = 2.08/2SD,
compared to 9.7 ppb or 95%CI 1.93–2.25; PM10
less (1st quartile, OR = 2.17/2SD, 95%CI
reference group). 1.49–3.16) and the first
year of life (PM2.5
OR = 2.12, 95%CI 1.45–
3.10; PM10 OR = 2.14,
95% CI 1.46–3.12).
Stockholm, Residence time- No clear or consistent Gong et al.289

Sweden weighted concentration associations were found
of PM10 and NOx during between air pollution
pregnancy, the first year, exposure during any of
and the ninth year of life the three time windows
using dispersion and any of the
modeling. neurodevelopmental
outcomes.
The yearly average
levels of PM10 were
relatively constant (3.3–
4.2 μg/m3).
South Korea PM10 and NO2 during There were negative Kim et al.290
entire pregnancy associations between
estimated by inverse maternal exposure to
distance weighting. PM10 and mental
developmental index
The average (β = −2.83; p = 0.003)
concentration of PM10 and psychomotor
was 53.19 μg/m3 (range, developmental index
38.84–69.95) which was (β = −3.00; p = 0.002)
slightly higher than the throughout the first
annual standard of Korea 24 months of life as
(50 μg/m3). determined by the
generalized estimating
The concentration of
equation (GEE)
NO2 was 26.30 ppb
(range, 13.08–45.12) model.Maternal NO2
exposure was related
which was lower than
with impairment of
the annual standard of
Korea (30 ppb) and the psychomotor
development (β = −1.30;
USA EPA (53 ppb).
p = 0.05) but not with
cognitive function
(β = −0.84; p = 0.20).
Massachusetts, Black carbon (BC) and Compared with children Harris et al.291
USA PM2.5 exposures, and living ≥200 m from a
residential proximity to major roadway at birth,
major roadways, and those living <50 m away
near-residence traffic had lower non-verbal IQ
density during late (−7.5 points; 95% CI:
pregnancy and −13.1, −1.9); somewhat
childhood.PM2.5 lower verbal IQ (−3.8
exposure: points; 95% CI: −8.2 to
0.6); visual motor
Third trimester: abilities (−5.3 points;
12.3 ± 2.6 95% CI: −11.0 to 0.4).
Birth-6 years: 11.3 ± 1.7
Year before cognitive

testing: 9.4 ± 1.9 μg/m3
North Carolina PM10: PM10 exposure during Kalkbrenneret

and California, the third trimester was al.292
North Carolina: associated with Autism
USA 24.0 ± 4.0 μg/m3 spectrum disorder (OR
=1.36, 95% CI: 1.13–
California: 1.63) Temporal patterns
22.9 ± 3.1 μg/m3 in PM10 were
pronounced, leading to
an inverse correlation
between the first- and
third-trimester
concentrations (r = −0.7).
Adjusted ORs were, for

the first trimester, 0.86
(95% CI = 0.74–0.99),
second trimester, 0.97
(0.83–1.15), and third
trimester, 1.36 (1.13–
1.63); and after
simultaneously including
first- and third-trimester
concentrations to
account for the inverse
correlation, were: first
trimester, 1.01 (0.81–
1.27) and third trimester,
1.38 (1.03–1.84).
USA PM2.5–10 and PM2.5 PM2.5 exposure during Razet al.293

concentration before, pregnancy was
during, and after associated with increased
pregnancy estimated by odds of ASD, with an
validated spatiotemporal adjusted odds ratio (OR)
models.The average for ASD per interquartile
levels of PM2.5 and range (IQR) higher PM2.5
PM10–2.5 during (4.42 μg/m3) of 1.57
pregnancy were (95% CI: 1.22, 2.03)
14.6 ± 3.3 and among women with the
9.9 ± 4.9 μg/m3. same address before and
after pregnancy (160
cases, 986 controls).
Association with the
9 months of pregnancy
was (OR =1.63; 95% CI:
1.08, 2.47).The
association between
ASD and PM2.5 was
stronger for exposure
during the third trimester
(OR =1.42 per IQR
increase in PM2.5; 95%
CI: 1.09, 1.86) than
during the first two
trimesters (ORs = 1.06
and 1.00) when mutually
adjusted. There was little
association between
PM2.5–10 and ASD.
Catalonia, Elemental carbon (EC), Children attending Sunyeret al.294

Spain NO2, and ultrafine schools with higher
particle number (UFP) levels of EC, NO2, and
measured by air UFP both indoors and
monitors set at outdoors experienced
schools.Number per substantially smaller
cubic centimeter of UFP growth in all the
outdoor was minimum cognitive measurements.
11,939 and maximum
was 51,146.UFP indoor
were minimum 8,034
and maximum 26,665.
Pennsylvania, PM2.5 predicted by LUR Adjusted odds ratios Talbottet al.295

USA during pre-pregnancy, (AOR) were elevated for
trimesters one through specific pregnancy and
three, pregnancy, years postnatal intervals (pre-
one and two of life and pregnancy, pregnancy,
cumulative (starting and year one), and
from pre-pregnancy). postnatal year two was
significant, (AOR = 1.45,
Pre-pregnancy through 95% CI = 1.01–2.08).
pregnancy: The effect of cumulative
pregnancy periods;
15.1 ± 1.4 (case)
noting that starting with
14.8 ± 1.4 (control) pre-pregnancy through
pregnancy, the adjusted
Pre-pregnancy through odds ratios are in the
year 2: 1.46–1.51 range and
significant for pre-
14.3 ± 1.4 (case)
pregnancy through year
14.1 ± 1.4 (control) 2 (OR = 1.51, 95%
μg/m3. CI = 1.01–2.26).
Boston, MA, Exposure to prenatal The study suggests the Chiu et al.296
USA particulate air associations between
pollution.Averaged higher PM2.5 levels at
prenatal PM2.5 level was 31–38 weeks with lower
11.3 μg/m3. IQ, at 20–26 weeks
gestation with increased
Omission errors (OEs),
at 32–36 weeks with
slower Hit reaction time
(HRT), and at 22–
40 weeks with increased
Hit reaction time
standard error (HRT-SE)
percentile” among boys,
while significant
associations were found
in memory domains in
girls (higher PM2.5
exposure at 18–26 weeks
with reduced Visual
Memory Index (VIM), at
12–20 weeks with
reduced General
Memory Index
(GM).Increased PM2.5
exposure in specific
prenatal windows may
be associated with poorer
function across memory
and attention domains
with variable
associations based on
sex.
Mexico City Exposure to high Major findings in MC Calderon-

Metropolitan concentrations of air residents included Garciduenaset
Area (MCMA) pollutants, i.e., PM2.5 leaking capillaries and al.297
and small cites and ozone. small arterioles with
in Mexico extravascular lipids and
erythrocytes, lipofuscin
in pericytes, smooth
muscle and EC,
thickening of
cerebrovascular
basement membranes
with small deposits of
amyloid, patchy absence
of the perivascular glial
sheet, enlarged
Virchow–Robin spaces
and nanosize particles
(20–48 nm) in
endothelial cells,
basement membranes,
axons and dendrites. The
integrity of the
neurovascular unit, an
interactive network of
vascular, glial and
neuronal cells is
compromised in MC
young residents.
Stockholm Nitrogen oxides (NOx) Air pollution exposure Gong et al.298

county, and particulate matter during the prenatal
Sweden with diameters <10 μm period was not
(PM10).The arithmetic associated with ASD
mean levels of NOx overall (OR 1.00, 95%
from local traffic were CI 0.86–1.15) per
11.0 μg/m3 during 10 μg/m 3
increase in
mother's pregnancy, and PM10.
dropped somewhat to
9.8 μg/m3 during the
postnatal period.The
yearly arithmetic mean
levels of PM10 were
relatively constant (4.2–
4.4 μg/m3).
Japan Air pollution exposure Yorifujiet al.299

during gestation was
Prenatal exposure to positively associated
(municipality level) with the risk of some
traffic-related air developmental milestone
pollution.Suspended PM delays at both ages (2.5
(PM7) was & 5.5 years.).Air
32 ± 8.6 μg/m3. pollution associated with
verbal and fine motor
development at age
2.5 years; and with
behaviors related to
inhibition and
impulsivity at
5.5 years.ORs following
one interquartile-range
increase in nitrogen
dioxide and suspended
particulate matter were
1.24 (95% CI: 1.07–
1.43) for inability to
compose a two-phrase
sentence at ages 2.5 and
1.10 (1.05, 1.16) for
inability to express
emotions at age
5.5 years.
USA Ambient Levels of PM10 Data from the Chen and

and ozone as neurobehavioral Schwartz300
extrapolated by subject evaluation system-2
address and locations of (NES2) data (including a
US EPA monitoring simple reaction time test
stations [SRTT] measuring motor
response speed to a
visual stimulus; a
symbol-digit substitution
test [SDST] for coding
ability; and a serial-digit
learning test [SDLT] for
attention and short-term
memory) from 1764
adult participants were
considered. PM and
ozone concentrations
were estimated from
extrapolation of data
from US EPA
monitoring stations.
PM10 was associated
with decreased CNS
function, however after
adjustment for
socioeconomic factors
the association
disappeared. However
ozone reduced
performance in NES2.
Each 10 ppb increase in
ozone increased SDST
and SDLT scores by
0.16 and 0.56-
equivalent to 3.5 and 5.3
years of aging – related
decline in cognition.
USA Ambient levels of PM2.5 The association between Pun et al.301

as extrapolated though a PM2.5 and depression and
spatio-temporal model anxiety was considered.
developed by the A sample of N = 4,008
authors. older individuals living
across the United States
was the test group. An
increase in PM2.5 was
significantly associated
with anxiety symptoms
and PM2.5 was positively
associated with
depressive symptoms.
USA Ambient levels of PM2.5 Found a significant Power et al.302

as extrapolated though a increase in odds ratio
spatio-temporal model predicting high anxiety
developed by the symptoms per 10 μg/m3
authors. increase in prior one
month average PM2.5
(1.12, 95% confidence
interval 1.06 to 1.19).
Interestingly, no
association between
anxiety and exposure to
larger particles (PM2.5-10)
was found
Europe Urban vs rural Zijlema et al. found Zijlema et al.303

individuals living in
urban or semi-urban
areas (presumably higher
PM levels) had poorer
lung function and
exhibited a higher
prevalence of major
depressive disorder (OR
1.65, 95% CI 1.35;
2.00), and generalized
anxiety disorder (OR
1.58, 95% CI 1.35;
1.84).
Europe Ambient levels of PM Zijlema et al. conducted Zijlema et al.304

and NO2 estimated by a study of over 70,000
land-use model participants using data
from 4 European
countries. Certain data
sets considered yielded
positive associations
between pollutant levels
and depressed mood, yet
data from other locations
yielded negative
associations! The
authors concluded that
they could not find
consistent evidence for
association between
ambient air pollution and
depression based upon
their study.
Several low Satellite remote sensing Lin et al. have reported Lin et al.305
income used to estimate PM on the incidence of
countries concentration stroke in 45,625
participants from low-
income countries. Using
satellite data, the
concentration of PM was
estimated and multilevel
regression used to
examine associations
between PM and stroke.
The authors report that
the odds of stroke were
1.13 (95% confidence
interval, 1.04-1.22) for
each 10 μg/m3 increase
in PM2.5. These authors
also estimate 1.97-12%
of stroke cases in the
study population could
be attributed to PM.
China Hourly PM2.5 monitoring Lin et al. considered the Lin et al.306
data was used for effect of peak PM2.5
Guangzhou, Cina concentrations on
cardiovascular mortality
in Guangzhou, China
from January 2013-June
2015. The authors report
a significant
association between
hourly peak
concentrations of PM2.5
and cardiovascular
mortality was found.
Ischemic heart diseases
and cerebrovascular
diseases were
particularly apparent.
For every 10 μg/m3
increment of hourly peak
PM2.5 a 1.15% (95% CI:
0.67%, 1.63%); 1.02%
(95% CI: 0.30%, 1.74%)
and 1.09% (95% CI:
0.27%, 1.91%) increase
in mortality from total
cardiovascular diseases,
ischemic heart disease,
and cerebrovascular
disease was observed,
respectively.
Beijing, China Gas pollutants and The authors adjusted Xia et al.307
ambient PM2.5 data for relative humidity
concentrations and temperature, and
found the highest odds
ratios of cardiac arrest
corresponding to a 10
µg/m3 increase in PM2.5
was 1.07 (95%
confidence interval (CI):
1.04–1.10), at a lag time
of 1 day post exposure.
Given the short lag time,
the results support the
hypothesis that acute
elevated PM2.5 exposure
contributes to triggering
cardiac arrest - especially
in those patients who are
advanced in age and
have a history of stroke.
London Diesel PM McCreanor et al. studied McCreanor et

asthmatic volunteers al.308
walking on a street
where only Diesel
vehicles producing BC
aerosol were allowed.
The authors found that
exposure to the fine
particle pollution
resulted in a significant
reduction in lung
function, and increase in
immune response (IL-8
and myeloperoxidase),
but often no symptoms
presented in the test
subjects.
Canada PM2.5 Weichenthal et al. have Weichenthal et

conducted a case- al.309
crossover study and
found that among
Canadian children (< 9
year age), an increase of
5.92 μg/m3 in 3-day
mean PM2.5
concentration was
associated with a 7.2%
(95% confidence
interval, 4.2 - 10)
increased risk of
emergency room visits
for asthma. The results
suggest PM pollution
can exacerbate asthma
symptoms.
USA PM2.5 Mirabelli et al. also Mirabelli et al.310

considered the effect of
PM pollution on asthma
symptoms. It was found
that exceeding PM2.5 ≥
7.07 μg/m3 was
associated with an
approximate 4–5%
higher asthma symptom
prevalence among
asthmatics. When PM
was in the range of 4.00
– 7.06 μg/m3, a 1-μg m-3
increase was associated
with a 3.4% [95% conf.
int.: 1.1, 5.7] increase in
symptom prevalence.
Phoenix, AZ. PM2.5 Pope et al. considered Pope et al.311

the effect of PM2.5 levels
on asthma related
hospital admissions in
Phoenix, AZ. After
controlling for several
possible confounding
variables (influenza,
temperature, humidity,
rain) the authors estimate
a risk ratio for adults of
1.19 (95% C.I. 1.06,
1.34) and 1.20 (95% C.I.
1.05, 1.37) for days 2
and 3 after high
exposure.
Taiwan PM2.5 Hwang et al. investigated Hwang et al.312

links between hospital
emergency room visits
due to respiratory
problems and PM in
Taiwan during 2012. For
the Kao-Pung air quality
zone, the authors report
convincing risk-ratios of
1.23 [95% conf. int.,
1.05–1.45] for AECOPD
(1.07 (95% CI = 1.01–
1.13) for asthma, and
1.07 (95% CI = 1.01–
1.13) for pneumonia for
each 10 μg/m3 increase
in PM2.5.
Canada PM2.5 Requia et al. considered Requia et al.313

the impact of PM levels
on human health in
Canada between 2007-
2014. The authors report
that a two-year increase
of 10 μg/m3 in PM2.5
level was associated with
an increased risk in
diabetes incidence, in
asthma incidence, and in
high blood pressure
incidence of 5.34% (95%
Conf. Int., 2.28%;
12.53%), 2.24% (95%
C.I.: 0.93%; 5.38%), and
8.29% (95% C.I.: 3.44%;
19.98%), respectively.
China PM2.5, PM10 Zhao et al. studied the Zhao et al.314

effect of fine and coarse
PM on hospital visits due
to respiratory disease in
Dongguan, China during
2013-2015. Over 44,800
cases were considered.
Both coarse and fine-
mode PM were
significantly associated
with morbidity of
respiratory disease,
COPD, and asthma.
Although the authors did
not find any link
between PM and
pneumonia, they did find
that an increase in PM
equivalent to an inter-
quartile range of their
study led to a 15.41%
(95% CI, 10.99%,
20.01%) increase in
respiratory morbidity at
the third lag day after
exposure. The authors
estimate that PM2.5 may
be responsible for
approx.. 8.3% of hospital
outpatient visits due to
respiratory morbidity at
their location.
Taiwan PM2.5 Hwang et al. found Hwang et al.315

correlation between
hospital admissions for
COPD and the level of
PM2.5 in southwestern
Taiwan. For this study,
the relative risk (RR) for
every 10 μg/m³ increase
in ambient PM2.5 during
the spring and winter
months was found to be
about 1.25 (95% Conf.
Int. 1.22 - 1.27) with a
lag time of zero days
(immediate presentation
of symptoms).
Taiwan PM2.5 38,715 hospital Hwang et al.316

admission records for
AECOPD were studied
for association with
PM2.5. The authors report
risk ratios for hospital
admission for AECOPD
for every 10 µg/m3
increase in PM2.5 to be
1.02 (95% Conf. Int. =
1.007- 1.04). Patients
>65 years of age were
affected the most.
Taiwan PM2.5 Studied hospital Tsai et al.317

admissions for COPD in
Taiwan to find possible
associations with PM
levels. The authors split
the data set into warmer
days (>23 °C) and cooler
weather and found that
an interquartile range
increase in PM
concentration led to
increases of 12% (95%
Conf. Int. = 8 - 16%) and
3% (95% Conf. Int. = 0 -
7%) in COPD
admissions, respectively.
Various, meta Biomass smoke meta-analysis study that Hu et al.318

analysis established an odds ratio
of 2.44 (95% Conf. Int.
1.9 - 3.33) for
individuals developing
COPD, relative to those
individuals not exposed
to biomass smoke.
* A portion of this table has been adapted from Wang et al. with permission.319

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PM: efectos, mecanismos (citotoxicidad, estrés oxidativo), composición, fuentes, propiedades

Journal of Occupational and Environmental Medicine, Publish Ahead of Print

Airborne Particulate Matter: Human Exposure & Health Effects.

Jonathan E. Thompson, Ph.D.

Associate Professor, Department of Chemistry & Biochemistry,

Texas Tech University, Lubbock, TX 79409-1061 USA

Email: jon.thompson@ttu.edu, Phone: (806)834-6206

Orcid id: orcid.org/0000-0003-1550-2823

Scopus Author ID: 7405816725

Conflict of interest statement:The author(s) declare(s) that there is no conflict of interest

Running title: Particulate Matter: Human Exposure & Health Effects

Objective: Exposure to airborne particulate matter (PM) is estimated to cause millions of

Methods: Review of available literature.

A549 adenocarcinomic human alveolar basal epithelial cell line

AECOPD acute exacerbation of chronic obstructive pulmonary disease

ADHD attention deficit hyperactivity disorder

AMAD activity median aerodynamic diameter

Ax exposed skin surface area (cm2)

A(t) surface area of the skin contaminated

BAL bronchoalveolar lavage

BEAS-2B human bronchial epithelium cell line

COPD chronic obstructive pulmonary disease

CFD computational fluid dynamics models

CGRP calcitonin gene-related peptide receptor

C(t) particle mass concentration (g cm-3)

CSK(t) the concentration gradient across the SC

DEPs Diesel engine exhaust particles

Dp(t) depositional mass flux (g s-1)

DNA deoxyribonucleic acid

EFTEM energy filtering transmission microscopy

GDP gross domestic product

HO-1 heme oxygenase-1

IFN-γ interferon gamma

IL-n where n is an integer, cytokine from the interleukin family

K(t) compound specific permeability coefficient

LDH lactate dehydrogenase

logKow base-10 logarithm of the octanol-water partition coefficient

mRNA messenger RNA

miRNA micro RNA

MPPD multiple-path-particle-deposition model

MRSA methionine sulfoxide reductase A

MSRB3 methionine sulfoxide reductase B3

MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NPL nose, pharynx, larynx; head airways

PAH polycyclic aromatic hydrocarbon

PMx PM with aerodynamic diameter <x

PSK(t) rate of mass transport through the SC

QSPR quantitative structure activity relationship

ROS reactive oxygen species

RBC red blood cell

TACR1 tachykinin receptor 1, neurokinin 1 receptor, substance P receptor

TB,TCB tracheobronchial region

TBLN tracheobronchial lymph nodes

TLR2 toll-like receptor 2

TLR4 toll-like receptor 4

TNF-α tumor necrosis factor alpha

TRPV1 capsaicin receptor

UFP ultrafine particles

US EPA United States Environmental Protection Agency

v(t) particle deposition velocity (cm s-1)

WBC white blood cell

Acute exposure to large quantities of airborne particulate matter (a.k.a atmospheric

2.1 Routes of Exposureto Particulate Matter.