Introduction

Since the onset of the industrial revolution some

150 years ago, people are exposed to ele-

vated concentration of arbitrarily shaped ul-

trafine particles along with the chemical by-

products such as carbon monoxide (CO), nitric

oxide (NO), semi-/volatile organic compounds

(VOCs) of anthropogenic origin – mostly in the

form of incomplete combusted by-products that

leave stacks or tailpipes as macromolecular

clusters. In addition, recent advances in

nanotechnology, even more refined designed

and engineered nanoparticles (in the range

from 1 – 100 nm) are also being introduced in

the form of scratch-proof paints, lotus-effect

stained glass, suntan lotion, etc. Although their

release into the environment is not intended in

the first place, it will occur sooner rather than

later, especially once wear and tear along

with product degradation releases contained

ultrafine particles into the environment where

they easily can enter the food chain either via

aerosolization or washing-out from dumping

sites. Regardless of the particle‟s origin, the

young research field of nano-toxicology deals

with effects and potential risks of particle

structures <1 μm in size. Yet, within these di-

mensions, the well-known quote of Paracelsus

“the dose makes the poison”, needs to be re-

vised into “the dose determines the mechanism”. 1 This is particular true for nano-sized particles

as the greater surface area per unit volume

compared with their larger-sized siblings ren-

ders them biologically more active. 2 The abil-

ity of these particles to cross cell barriers and

to interact with intracellular structures is well

established, and has yielded the various path-

ways leading to oxidative stress effects. Here

in particular insoluble ultrafine particles can

extend their multiple adverse effects even fur-

ther when redistributed from one line of de-

fence to the next as metabolites or cellular

debris are released into the interstitial upon

cell death. In continuation to Part-I, 3 this short

review aims to provide an overview in the un-

derstanding of the hazardous effects relevant

to humans and at the same time to promote a

better understanding of how most contempo-

rary diseases are related to ultrafine particle

exposure.

Lung deposition predictions of airborne particles and the emergence of contemporary diseases - Part II

Mankind has been exposed to airborne nanosized particles (<100 nm) for eons, yet

mechanization and industrialization of societies has increased the overall load to which humans

are exposed to. Ultrafine-particles (below 1 µm in diameter) can thus be incorporated via any

organic surface structure and in particular when the area available is large enough – as is the

case with the skin (approx. 1.5-2 m2), the digestive tract (intestinal villi, approx. 200 m2) or the

lungs (approx. 140 m2). Since aerosolised particles are readily inhaled rather than ingested, the

lungs represent an ideal gateway with high penetration efficiency rates. If seen from a

toxicological rather than from a therapeutic point of view, deposited xenobiotic particles that

interact with biological tissues do so first on a cellular level where they are readily translocated

into the cell to interfere with metabolic pathways and eventually induce inflammatory cellular

responses. At an organismic level and in response to long-term exposure, these particles become

redistributed via the lymphatic or the blood circulatory system to reach sensitive organs or tissues

such as the central nervous system, bone marrow, lymph nodes, spleen, and heart. At this

organismic level, the persistent particle exposure may trigger or even modulate the severity of

chronic diseases.

Madl P1, Hussain M1,2 1Division of Physics and Biophysics, Department of Materials Research and Physics, University of Salzburg, Austria, 2Higher Education Commission, Islamabad, Pakistan

theHealth 2011; 2(3): 101-107

Correspondence

Pierre Madl

Division of Physics and

Biophysics, Department of

Materials Research and Physics,

University of Salzburg,

Hellbrunnerstrasse 34, A-5020

Salzburg, Austria

E-mail:

pierre.madl@sbg.ac.at

Keywords:

Nanoparticle deposition,

Bioreactivity, Lung Disease,

Chronic Disease, Epigenetics

Funding

This work was funded in part

by EU contract no. 516483

(Alpha Risk) and Higher

Education Commission of

Pakistan under the scholarschip

program (Overseas

Scholarships for Pakistani

Nationals)

Competing Interest

None declared.

Received: March 30, 2011

Accepted: August 9, 2011

Abstract

ISSN (print): 2218-3299

ISSN (online): 2219-8083

Review

theHealth | Volume 2 | Issue 3 | 101

Potential health effects

Experimental investigations have shown that size and the

associated surface area indeed do make a difference,

thereby significantly extending the retention time of inhaled

nanosized compared with larger particles in alveolar macro-

phages. 1, 2 Although macrophages is the most important de-

fense mechanism in the alveolar region for fine and coarse

particles, this mechanism is impaired in the case of inhaled

ultrafine particles as they are not efficiently phagocytized.

Animal studies have revealed that bronchio-alveolar lavage

after aerosol exposure reveal that only about 20% of nano-

sized particle fraction (15 - 20 nm) can be flushed out along

with the macrophages, whereas lavage-efficiency increased

to approximately 80% in particles >0.5 μm in size. 1, 2 As

demonstrated in Figure 4 (see part-I), 3 removal of these par-

ticles then can only occur via redistribution into the lymphatic

or blood stream. With regards to the coarser particle frac-

tion, the larger numbers of ultrafine siblings leads to particle

dispersion into other tissues and organs to ultimately burden

the entire organism (compare with Figure 2). Due to their

minute size, these particles are routed through the interstitial

compartment between cells or straight through the cells via

caveolae - openings of around 40 nm in diameter that engulf

these particles, forming vesicles that are thought to function

as transport vehicles for macromolecules across the cells. A

similar observation is known with particle translocation across

the olfactoric bulb into the brain, thereby short-cutting the

blood-brain-barrier (Fig. 1). Already research done in the

1940 dealt with this challenge as it was possible to document

how 30 nm polio viruses use these nerves as portals of entry

into the central nervous system. 4 It is estimated that ~20%

of ultrafine particles deposited onto the olfactoric epithelium

translocate the olfactory bulb within seven days after expo-

sure. 5

The challenge with ultrafine particle exposure attains an even

more dramatic aspect when considering that most incom-

pletely combusted particles are hydrophobic in nature. Thus,

hygroscopicity and growth via condensation of water vapour

is almost inexistent, thereby increasing penetration efficien-

cies even further - particularly into the alveolar regime of the

lungs. In addition, the fractal nature of these particle ag-

glomerates are ideal substrates for volatile chemicals or ra-

dionuclides to adsorb onto. 6 In combination, both their low

solubility and their role as a “Trojan horse” act threefold: (i)

as known with asbestos, insoluble or low soluble matter exerts

chronic irritation onto the target cells, 6 while (ii) the ad-

sorbed substances on the particle surface unfold their biore-

active properties once in contact with or dissolved by tissues,

7 and finally (iii) are known to be more toxic than their

coarser siblings. 2, 8 Indeed, experimental studies confirm that

ultrafine particles measuring 20 nm and administered di-

rectly into the lungs trigger stronger inflammatory reactions

than 250 nm particles that are chemical identical, which im-

plies that the toxicological property of the particle is deter-

mined by the surface area per unit volume rather than mass. 1

Toxicity at the cellular level

Figure 3 revels the cytotoxicological potential of ultrafine

particles by emphasising the potential oxidative stresses in-

duced by these xenobiotic substances. 10 Due to the potential

oxidative properties (step “a” in Figure 3), ultrafine particles

are capable to induce lipid peroxidation. Upon endocytosis

(step “b”) these particles exert intracellular oxidative stress

and increased cytosolic calcium ion concentration, besides

triggering the activation of NADPH oxidase and generation

of reactive oxygen species (ROS). Although the latter is es-

sential for normal vital activity, 11 improper timing of ROS

formation at the wrong location is known to play a crucial

role in the initial stage of carcinogenesis. 12 Together, both

the particles and the induced inappropriate oxidative stress,

can activate cell receptors (step “c”), thereby triggering sev-

eral cellular signaling cascades where non are actually re-

quired at the expense of the cells energy reservoir. Yet

these cascades, along with transcription factors activate tran-

scription of pro-inflammatory genes and the corresponding

protein production (step “e”). Apart from interfering with

102 | theHealth | Volume 2 | Issue 3

Lung deposition predictions of airborne particles

Figure 1: Particle translocation across the olfactoric bulb into the brain.

Figure 2: Exposure of human lung fibroblast cells to ceria particles of

20-50 nm in diameter. (a) Vesicles inside a fibroblast cell with ceria

agglomerates. (b) A cluster of particles agglomerates close to the cell

membrane. (c) Particles both inside the cell (vesicle) and outside are

exclusively found in the form of agglomerates.(modified after 9)

also enter the cell by passive diffusion and remain non-

membrane bound from where they may penetrate mitochon-

dria (step “f”) and disrupt normal electron transport, leading

to additional oxidative stress. Free particle translocation may

also occur into the nucleus where they interact with the ge-

netic material (step “g”). Eventually, lipid peroxide-derived

products form DNA adducts may lead to genotoxicity and

mutagenesis (step “h”). In less severe cases the cell may be

prompted Into the apoptotic pathway, thereby inducing pre-

mature cell death. 13 However, apoptosis leaves cellular de-

bris along with the toxic particle load for clean-up to other

cells, which from an organismic point of view must be consid-

ered just as a redistributing pathway.

Short term exposure to airborne pollutants

At the organismic level - as shown in Table 1- acute exposure

to airborne particles is associated with increased mortality

and morbidity. 14 Epidemiological studies have shown a de-

crease in pulmonary function associated with short-term ex-

posure to these particles. Ware et al. 15 showed that the

prevalence of cough and bronchitis positively correlates with

elevated ambient particle concentrations. These decrements

in lung function appear to persist for several weeks after

exposure even when the distressing particle load is no longer

present. Yet, short-time exposure also adversely affects the

cardiovascular system, among which thrombogenesis, ische-

mia (shortage of oxygen supply to target organs due to

plaque destabilization and blood clothing) and arrhythmia

(disturbance of the electrical activity of the heart muscle) are

noteworthy as they can in severe cases end fatally. 16

Long-term exposure to airborne pollutants

As outlined above, the olfactoric system represents a very

imminent way. Apart of the deteriorating effects of the olfac-

tory bulb and alterations of the blood-brain barrier of

chronic exposure to ultrafine particles, some neuropathologic

effects have been observed and include (i) degeneration of

cortical neurons, (ii) apoptotic glial white matter cells, (iii)

non-neuritic plaques, and (iv) neurofibrillary tangles. 18 In

effect, evidence mounts that neurodegenerative disorders

such as Multiple Sclerosis, 21 Alzheimer‟s, 22, 23 Parkinson‟s, 24

Amyotropic Lateral Sclerosis 25 and even Creutzfeldt-Jakob

disease 26 are favoured or at least adversely affected by

chronic exposure to ultrafine particles along and their associ-

ated chemical by-products involved in the cellular response

patterns as highlighted in Figure 3.

Beside short-cutting the blood-brain barrier, ultrafine parti-

cles also exert a wider organismic response upon chronic ex-

theHealth | Volume 2 | Issue 3 | 103

Lung deposition predictions of airborne particles

Figure 3: Hypothetical cyto-toxicological effects of ultrafine particles

range from membrane peroxidation (a), once incorporated formation

of reactive oxygen species (b), activation of cell-receptors (c)

triggering unnecessary cell-metabolic functions, activate expression of

inflamatory responses (d), interaction with organelles, such a

mitochondria (e), disruption of the electron transport chain (f),

interaction with the DNA itself (g) and unfolding genotoxic potentials

(h).(modified after 10)

Table 1: Confirmed deaths of the short-term London smog event (5th - 9th Dec. 1952) with analysis of autopsy, demographics and cause of

death. (*) Autopsy note: condition worsened during smog event. 17 Inlet: Reduced visibility due to smog-related light scattering and absorption

at Nelson's Column during the London Smog event. 18 DoD: Death on Arrival

exposure that extends far beyond respiratory ailments men-

tioned above. The ability of these particles to translocate

from their portal of entry to secondary target tissues is high-

lighted by some investigations. These wider organismic ef-

fects involve structurally higher hierarchic levels such as or-

gans and ultimately the entire organism. At these levels, im-

munological and inflammatory effects decrease the overall

stress-tolerance and pave the way for cascades of events

that culminate into the commonly known chronic disease pat-

tern - viewed at a first glance - seem to be decoupled from

exposure to particles and their chemical associates. Aside

from a few experimental studies focusing on the eco-

toxicological effects, 1, 27 little effort has been made to study

the collateral effects on organs other than the lungs, in par-

ticular studies that highlight for example the conditioning

effect of airborne pollutants onto the immune system. 28 A

particular set of epidemiological studies even focus on the

combined effect of administered chemicals and the environ-

mental setting the organism is embedded in. Here it was

observed that patients have become so ingrained that the

mere sight of a given location was enough to trigger a de-

crease in immune activity without even exposing them to

imuno-suppressing agents - a phenomenon known as immune

conditioning. 29 Investigations of this kind emphasize the fact

that suppression of the immune system is a controlled process

underlying the subconscious regime of our mind. In this re-

gard, the animal study of Sepolsky et al. 30 is quite interest-

ing as they could show how the continuous activation of the

acute phase response pattern eventually can lead to a state

of chronic inflammation, in which “sickness behavior” becomes

a way of life. In the context of aerosol exposure, the com-

plex interaction of various regulatory layers with different

hierarchical preferences makes it very difficult to assign a

single toxic agent (i.e. ultrafine particle) the full adverse po-

tential. It‟s important to keep in mind that in most cases the

cocktail of distressing influences of various kinds synergisti-

cally act on the exposed organism. To shed just some light on

this intrinsically interwoven network, synergism between two

types of aerosols shall be demonstrated – the combined ef-

fect of carbonaceous ultrafine particles and pollen allergens.

In such cases it was found that exposure to carbonaceous

particles before allergen challenge exerts strong adjuvant

effects on the manifestation of allergic airway inflammation. 31 Hence, allergen-sensitized individuals are more susceptible

to the detrimental health effects of ultrafine aerosol expo-

sure. Similar experiments investigating the conditioning ef-

fects of soot particles with adsorbed volatile organics on the

immune system confirm the proallergic potential. This implies

a crucial role of airborne pollutants for an allergic break-

through in atopic individuals, who have not developed an

allergic disease yet. 32 In this regard it is crucial to stress, that

the conditioning effects of the immune system can occur within

short periods of time. It is sufficient that the triggering event

is a coordinated with a immuno-suppressive eposode of the

exposed individual, thereby the extra stress excerted by the

aerosol burden induces - as emphasized further below in

Figure 3-a distressing response pattern.

On the other hand, extended exposure without synergistic

agents likewise induce adverse health effects. Such well-

investigated aerosols regard vaporized heavy metals that

tend to bioaccumulate if inhaled over longer time. Lead tox-

icity, for example is associated with deficits in central nervous

system functioning especially in younger ages. Absorption

into blood from lung can cause high blood pressure and

damage to renal function. 33 Inhalation of Cadmium fumes is

identified as a potential human carcinogen, causing lung

104 | theHealth | Volume 2 | Issue 3

Lung deposition predictions of airborne particles

Table 2: Clinical data for control and exposed subjects due to long-term exposure. The primary causes of death included accidents resulting in

immediate death (death on arrival, DOA), arrhythmias, myocardial infarctions, and carcinomas including: gastric, lung, colon, breast, and

cervical.19 Inlet: Aerial view of Mexico City revealing reduced visibility due to ultrafine particles from combustion sources. 20

cancer. Breathing lower levels for years leads to a build-up

of cadmium in the kidneys that can cause kidney disease.

Other effects that may occur after breathing cadmium for a

long time are lung damage and fragile bones. 33 It is difficult

to distinguish mercury toxicity symptoms from those of some

bronchial irritation and pneumonitis (see also Table 1). 33 In

the field of occupational exposure, where threshold-levels

are generally higher, inhalation for example to arsenic

fumes, is causally associated with lung cancer. 34 Other com-

mon ailments however acute exposure to mercury (e.g. in the

organo-metallic form of methyl-mercury) has shown adverse

effects on the central nervous system, kidneys and thyroid.

Yet, long term low level exposure to mercury, as a byproduct

of coal combustion, is known to cause Having made the tran-

sition from milder to more severe, chronic disease patterns, it

is not difficult to understand that genotoxic properties of

long-term aerosol exposure replaces the acute symptoms by

unfolding the full pathogenic spectrum and include even can-

cer cases. Table 2 summarizes some of the major findings of

the epidemiological investigation made in Mexico City,

known for its notorious pollutant laden air. 19 Although the list

is not extensive, the high occurrence of various types of can-

cers is striking. Just by considering the fact that only about

5-10% of cancer and cardiovascular cases can be attributed

to heredity, it becomes obvious that 90-95% are controlled

by our lifestyles. 35 Hence, malignancies are derived from

environmentally-induced epigenetic alterations and not de-

fective genes. 36, 37, 38 While genetic factors determine the

tendency towards malignancy, environmental factors largely

contributes to cardiovascular diseases, cancers, and other

major causes of mortality. 35 Environmental factors are repre-

sented by one‟ lifestyle and includes diet, exposure to biore-

active toxins as well as psychic stress.

Epigenetics

With every breath, bite, and sip, we introduce countless ul-

trafine particles, viruses and bacteria into our body. Due to

the orchestrated surveillance and countermeasures carried

out by our immune system, the delicate balance between a

healthy and a diseased state is normally biased towards a

state of wellbeing (Figure 4). In order to maintain this ho-

meostasis, the immune system along with specialized white

blood cells have to track and phagocytose xenobiotic aero-

sols, harmful viruses and opportunistic bacteria before they

do any harm. In the process of such an organismic response,

every interaction of theses substances on a cellular level aids

in the fine-tuning of cell-metabolic pathways, thereby en-

training or conditioning each cell for an optimal response. If

chronic disturbances (multiple stress exposure on a cellular

level) favour down-turning developments, in that every tip-

ping point at a bifurcation unit (Figure 4) biases the system

towards a distressing path. If this series of distressing devel-

opments is not reversed, this eventually will lead to differen-

tiation of abnormal cell types (i.e. cancer precursor cells). On

the other hand, upon cessation or neutralization of one or

more distressing events and at any new bifurcation point in

time, the system can flip back to a more eustress-like equilib-

rium, with an improved response pattern when dealing with

individual stress burdens as a result of aerosol exposure. To

enable the immune system to differentiate between foreign

entities and “itself”, certain membrane markers are used to

facilitate dendritic cell recognition. During one‟s lifetime

these membrane markers are enriched by cellular experi-

ence; that is, exposure to pathogens triggers for example a

cellular response that utilizes the NF-κB signalling pathway in

which the resulting endproducts of the immuno-proteasome

activity are displayed along with the original ID-recognition

markers on the lipid bilayer. 40 In order to memorize this ex-

perience at a cellular level, the information has to pass on the

progeny cells. 41, 42 This is the moment where epigenetics

comes into effect. Cells can learn in predominantly two ways,

they either do it via “bookmarking” or via “paramutation”. 43,

44 The former transmits cellular memory in the pattern of

gene expression via mitosis to somatic progeny cells within

the same generation and kind (i.e. somatic liver stem-cells

divide into liver cells and not some other cell type). The lat-

ter on the other hand, regard the quasi “inheritance” of char-

acteristic of a gene that is "remembered" and seen in later

generations (e.g. via the germ cell linage), even if the

stressor that caused the epigenomic modification is no longer

present.

This rather new field in genomic research is about to unravel

- apart from the more rigid lower genome level - a second,

very plastic level of information processing that employs the

epigenome. Mounting evidence confirms that environmental

exposure to stressors are indeed able to modulate the epige-

nome in such a way that entire cell-lines – both somatic as

well as germ cells – can pass the stress-information in a re-

versible manner extending over three generations 42 before

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Lung deposition predictions of airborne particles

Figure 4. Bifurcation patterns between health and disease: In case of

brief disturbances, homeostasis is restored once the disturbance

passes. However, if the disturbance is prolonged, a series of

irreversible distressing events force the organism to a new „steady

state‟. Inlet: the magnifying glass should highlight the sensitivity of the

tipping point of a bifurcation. At this moment in time, the system is so

sensitive to environmental stimuli that the slightest disturbance

determines the progression in the di- or eu-stress regime. (modified after 39)

it is lost again without altering the sequence of the DNA itself. 45, 46 This Lamarckian-type of inheritance is achieved via vari-

ous processes and involves in particular DNA-methylation,

histone modifications, mRNA silencing and other regulatory

interference mechanisms. 47, 48 Together these tools switch “on

or off” certain sections on the DNA, thereby enabling or in-

hibiting ribosomal activity to attain access to genetic informa-

tion. Modulating the epigenome implies that environmental

exposure (lifestyle, dietary preferences and distressing psy-

chological events – refer to Figure 5) are able to alter the

phenotypic appearance both on the cellular as well as on the

organismic level and are even passed on to future genera-

tions just in the same manner as DNA blueprints are passed

on via the double helix. 49 Studies employing both animals 50

as well as humans 51 underline the crucial role of epigenetic

modulation and the onset of chronic diseases. Although ex-

posure to ultrafine particles seem to be just one element in a

multidimensional stressphase relationship, a slight pressure

from one or the other side (e.g. via airborne pollutants) can

bring an apparently stable but labile equilibrium into a dy-

namic non-linear response pattern until a new metastable

equilibrium is reached. This also implies that diseases should

just be regarded as organismic proxy indicators in the at-

tempt to attain a new steady state. Hence, we can say that

extended environmental ultrafine particle exposure contain

distressing agents that, along with other stressors, shift the

constantly fluctuating homeostatic steady state into new fluc-

tuating instabilities. However, the difference between these

states lies in the fact that in the latter stages affected indi-

viduals increasingly feel physically less fit than in the former

from these have been kicked out of.

Exposure to anthropogenically released ultrafine particles

originating from incomplete combustion processes fully unfold

their toxicological potential – particularly in congested areas.

These particles have multitude ways to enter the body, which

include adsorption via the skin, the olfactoric nerve bundles

(inducing neurodegenerative diseases), deposition within the

respiratory tract (directly related to respiratory diseases),

ingestion of cleared particle laden mucus and redistribution

of the cellularly absorbed particle load throughout the or-

ganism - in combination with the former responsible of the

wider organismic health problems. Toxicity itself not only

depends on the nature of the particle (solubility, hydropho-

bicity, chemical properties) but also on the surface structure,

onto which volatile substances and radionuclides can adsorb.

Since nano-sized particles exert more severe distressing ef-

fects on the cellular level than their coarser siblings, these

aerosols significantly contribute to chronic disease patterns

and epigenetic imprinting, which enables acquired lifestyle-

related stress-response patterns to be passed on to subse-

quent generations. Due to the fact that these particles access

secondary target organs along with their effects on the or-

ganismic level, they definitely will attain further toxico-

medical attention in the near future. The availability of more

and more products containing designed and engineered

nano-particles and fibers, adds to this dilemma as awareness

of associated risks and benefits have not yet lead to guide-

lines in order to limit side-effects of improper production

methods, inadequate usage and irresponsible disposal of

these materials. While the exact risk of aerosolized particles

is still hard to define, current scientific evidence already

stresses the adverse effects of long-term exposure as it tilts

the balance towards the emergence of so called “civil-

society-related” diseases that so far were either considered

harmless or not yet associated to these environmental stress-

ors. While it is not always possible to assign as a single det-

rimental aerosol with a particular disease, the evidence given

so far indicates that ultrafine xenobiotic particles are rather

promoters and modulators in the emergence of chronic dis-

eases that so far were scarcely known in the past. Since

these aerosols exert their effects not only on the cellular, or-

ganic and organismic level, but also interfere with the onto-

filogenetic patterns currently investigated in the field of epi-

genetics, their ever increasing presence will disproportianally

challenges our medicare system.

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