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Nanoparticles Toxicity and Their Routes of Exposures

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REVIEW

Nanoparticles toxicity and their routes of exposures

Clarence Suh Yah1*, Geoffrey Simate Simate2 and Sunny Esayegbemu Iyuke2
1
Biochemistry and Toxicology Section, National Institute for Occupational Health NIOH), 25 Hospital Road, Constitutional Hill,
Johannesburg, Gauteng, South Africa
2
School of Chemical and Metallurgical Engineering, University of the Witwatersrand, Johannesburg,
P/Bag 3, Wits 2050, South Africa

Abstract: The new scientific innovation of engineering nanoparticles (NPs) at the atomic scale of 100 nm or less, has led
to numerous novel and useful wide applications in electronics, chemicals, environmental protection, biological medicine.
Manufacturers and consumers of the nanoparticles-related industrial products however, are likely to be exposed to these
engineered nanomaterials which have various physical and chemical properties. These nanosize particles are likely to
increase an unnecessary infinite toxicological effect on animals and environment, although their toxicological effects
associated with human exposure are still unknown. In order to understand the effects of these exposures, this review
seeks to examine the various toxicological portal routes associated with NPs exposures. These NPs can enter the host
systems via skin spores, debilitated tissues, injection, olfactory, respiratory and intestinal tracts. These uptake routes of
NPs may be intentional or unintentional. Their entry may lead to various diversified adverse biological effects. Until a
clearer picture emerges, the limited data available suggest that caution must be exercised when potential exposures to
NPs are encountered. Methods used in determining NPs portal of entry into experimental animals include pharyngeal
instillation, injection, inhalation, cell culture lines and gavage exposures. This review also provides a step by step
systematic approach for the easy identification and addressing of occupational health hazards arising from NPs.

Keywords: Nanoparticles, exposure, routes.

INTRODUCTION diameters < 100nm are termed as engineered. These

particles can be compared to sizes of living things (fig. 1).
The term nanotechnology encompasses the production of Also NPs like diesel particles are incidentally generated
new materials at atomic scale. It builds nanoparticles while living things such as bacteria and larger viruses are
(NPs) whose diameter is below 100nm by manipulating natural living cells with diameter < 100nm (fig. 1).
matter (Mohanpuria et al., 2008; Simate et al., 2010;
Ngoy et al., 2011; Yah et al., 2011a, b). According to The technology can be applied to biological systems, or
Stern & McNeil (2008) NPs can be classified into two derivatives thereof, to make nanomaterials for specific
groups depending on the nature of the particle (i.e., use. It incorporates a wider range of useful industrial and
engineered or incidental). NPs such as the quantum dots, biological processes that modify the needs of humanity at
carbon nanotubes, dendrimers and fullerene which have the nanoscale level. Studies have also shown that

Living things sizes Engineered nanosize particles (< 100nm)

Fig. 1: Structures of some nanoparticles (Stern and McNeil, 2008; Mohanpuria et al., 2008).

*Corresponding author: e-mail: [email protected]

Pak. J. Pharm. Sci., Vol.25, No.2, April 2012, pp.477-491 477
Review: Nanoparticles toxicity and their routes of exposures

microorganisms can as well be used as potential The ability of nanoscale materials to enter the host
developers of NPs (Roco and Bainbridge, 2005; Andrew system, however, is amongst the numerous features that
et al., 2004; Deendayal et al., 2006; Jail et al., 2007; researchers need to observe in ascertaining whether such
Sadowski et al., 2008). In view of these developments, substances may pose any hazards. Ultrafine materials
nanotechnological companies (fig. 2) are gaining new (e.g., agglomerates, aggregates) have the highest
prospects that enable them to improve the performance of probability of entering the system especially when they
products and life with uncertain health safety issues. are airborne (Ku and Maynard, 2005). Once NPs are in
the body they can transverse the cells by persorption,
However, the benefits of nanotechnology have been offset intermingle with the tissue cells causing malfunctioning
by substantial discussion about the health issues arising of the organs (Oberdorster et al., 2005). Studies have
from nanotechnologies (Giles, 2003; Maynard and shown that airborne nanomaterials can be deposited in the
Kuempel, 2005). Occupational illnesses, however, do respiratory tract when inhaled. From there, the NPs can
occur as a result of respiratory dust particle. This is transverse the blood stream, and be relocated to other
attributed mainly to ultrafine NPs (Donaldson et al., organs (Warheit et al., 2004; Zhang et al., 2005). In order
2006). These occupational diseases tend to be to understand the effects of NPs exposures on health, this
characterized by temporal or permanent physiological review seeks to examine the various toxicological portal
dysfunction with only a few visible symptoms. On the routes associated with nanoparticles exposures. Until a
other hand, there is a possibility that they may gain access clearer picture emerges, the limited data available suggest
to the body and pose serious toxicological problem. These that caution must be exercised when potential exposures
NPs might enter the host via the lungs, dermal, wound to NPs arise. Previous studies have shown decrements in
tissues, intestinal tract either intentionally or the functioning of the lungs and adverse respiratory
unintentionally (Peter et al., 2004; Oberdorster et al., symptoms to workers that were exposed to NPs (Borm et
2005; Chen et al., 2006; Mayank and Mansoor, 2007). al., 2004; Beck-Speier et al., 2005; Bottini et al., 2006;
NPs can enter the environment and animals system Donaldson et al., 2006). Therefore, the portal routes of
through different pathways. For instance, it could be entry of engineered NPs need to be understood.
through effluent, spillage, consumer products and
disposal. The intake is usually tolerated by the organism Health exposure concerns of nanoparticles
system but when a certain range is exceeded, it would As earlier stated, NPs have diameters between 1 and
cause toxic effect and even deaths. Since NPs have 100nm that may be in the gas, liquid, powder or
environmental and animal health risks, it is, therefore, embedded in matrix. The precise meaning can be
inevitable to carry out research so as to understand and determined by the shape as well as the diameter of the
anticipate such risk through risk assessment and risk NPs measured. The morphologies might differ
management. However, in view of scarce health informa- extensively at the nanoscale. For instance, fullerene are
tion arising from NPs, it is paramount to take some spherical whereas single-wall-carbon nanotubes
remedial actions so as to reduce the hazards to workers (SWCNTs) are cylindrical (Warheit, 2006; Tanta and
and the environment. Cumpson, 2007; Aihong et al., 2008; Kaiser et al., 2008;
Witzmann and Monteriro-Riviere, 2008).

Fig. 2: A perspective of nanotechnology applications as related to discipline.

478 Pak. J. Pharm. Sci., Vol.25, No.2, April 2012, pp.477-491
 Clarence Suh Yah

The scarcity of scientific data obliges us to face According to Borm and Kreyling (2004) the effects of
uncertainty of the risks arising from NPs. Therefore, the ultrafine particles absorbed by inhalation were influence
processes of generating nanoscale materials in the gas by dose, deposition, dimension, durability and defence
phase, or using or producing nanoscale materials as mechanisms. Toxicity of NPs often will depend on the
powders or solutions pose the risk for releasing NPs efficiency of these mechanisms. The dose, deposition,
(Oberdorster et al., 2005). Potential exposure may arise dimension, and durability link toxicity to surface
during their production, development, use, or discarding concentration. On the other hand, the T and B
(Stern and McNeil, 2008). Also there is likely exposure to lymphocytes at the respiratory site help to reduce the
NPs if it involves disturbing deposited nanoscale material. potential effect of the surface concentration and toxicity
There are likely possibilities that the resultant environ- of NPs (IRSST, 2006).
ment may increase NPs hazards to:
Engineered nanoparticles
• Working with ultrafine particles in solution without Engineered NPs are nanoscale particles which are
adequate protection (gloves, gowns, masks) will products of processes involving combustion and
increase the risk of skin exposure. vaporization which are designed with very specific
• Working with nanoscale materials in solution during physical and chemical properties that make them very
pouring or mixing operations, where a high degree of attractive for commercial development (Medina et al.,
agitation is involved, will lead to an increase 2007). They have found applications in cosmetics, clothes
possibility of inhaling droplets being formed. electronics, biomedicine, aerospace and computer
• Generating NPs in the gas phase in non-enclosed industry. Due to their small size and large surface area,
systems will enhance the likelihood of aerosol expose engineered NPs may have a high rate of pulmonary
to the workplace. deposition and, translocation ability to travel from the
• Using ultrafine powders will lead to the risk of aero- lung to systemic sites, penetrate dermal barriers, and a
solization. high inflammatory potency per mass (Medina et al.,
• Maintenance on equipment and processes used to 2007). Therefore, engineered NPs just like ultrafine
produce or fabricate nanosize materials or the clean- particles need to be studied to determine if they pose
up of spills or waste material will pose a potential for health risks similar to those that have been associated
exposure to workers performing these tasks (Cross et with the ultrafine particles. In biomedical field,
al., 2007). engineered NPs application as drug delivery system is on
• Cleaning of dust collection systems used to capture the increase due to the vast physiochemical properties that
NPs can pose a potential for both skin and inhalation make them very accessible to be conjugated with various
exposure. drugs and molecules (Ngoy et al., 2011). However, the
NPs bio-conjugates cellular toxicity needs to be validated
• Machining, sanding, drilling, or other mechanical
before human applications.
disruptions of materials containing nanoscale
materials can potentially lead to aerosol of NPs. Nano-aerosol
• The transfer of nanomaterials in open systems is Aerosol is a suspension of fine solid particles or liquid
likely to increase exposure potentials even for droplets in a gas. It includes smoke, air pollutants, and
relatively hydrophobic NPs (Lam et al., 2006). Open perfume spray. A nanoaerosol, therefore, comprise of NPs
systems during NPs processing may increase suspended in a gas, and may be present as discrete
exposure to human beings. particles, or as clusters of NPs (Heim et al., 2005). These
assemblies may have diameters larger than 100 nm. In the
Ultrafine particles case of an aerosol consisting of micrometer-diameter
Ultrafine particles are not purposefully manufactured nor particles formed as assemblies of NPs, the definition of
are they necessarily of a constant composition or size nanoaerosol is open to interpretation. It is generally
although they are less than 100nm, so they are nano-sized. accepted that if the nanostructure associated with the NPs
The ultrafine particles have been used to define aerosol is accessible through physical, chemical, or biological
and airborne particles less than 100 nm in diameter. There interactions, then the aerosol may be considered a
is no clear distinction between ultrafine particles and nanoaerosol. However, if the nanomaterial within
nanoparticles. The two terms are used so as to make a individual micrometer-scale diameter does not directly
distinction between engineered (nanoparticle) and influence particle activity, the aerosol would not be
incidental (ultrafine) nanoscale particles (Nemmar et al., described as aerosols (Dreher, 2004). There are not many
2001; Jacobson and Seinfelf, 2004; Beck-Speier et al., literatures on health implication of gaseous nanoparticles,
2005; IRSST, 2006). However, this does not imply that however studies are needed to identify mechanisms by
significant differences exist among their properties in which nano-aerosols induce cellular damage and generate
relation to measurement, risk assessment, and control of oxidative stress (Quadros and Marr, 2010). Airborne such
exposures. as silver nanoparticles exert toxic effects mainly through

Pak. J. Pharm. Sci., Vol.25, No.2, April 2012, pp.477-491 479

Review: Nanoparticles toxicity and their routes of exposures

the aqueous phase and the complication depend on the are through the skin, lungs or intestinal tract causing
particle size and the concentration of the silver particles. adverse biological effects (Peter et al., 2004; Warheit et
Although National Institute for Occupational Health has al., 2004; Oberdorster et al., 2005; Davoren et al., 2007;
set airborne at concentration of 10 mg m_3, inhaled Silver Li et al., 2007). Other potential routes of NPs in the case
nanoparticles have been found to show inflammatory of biomedical applications include parental administration
reaction of the respiratory and cardiovascular systems, such as intravenous, intradermal and peritoneal exposures
leading to asthma complications, chronic bronchitis into experimental Stern and McNeil, 2008; De Jong et al.,
(Quadros and Marr, 2010). According to Quadros and 2008). Factors that my influence NPs entry includes size,
Marr, (2010) NPs are capable penetrating more into the charge, surface area and shape (Auffan et al., 2008).
cellular tissues of the respiratory tract causing According to Auffan et al (2008) nanosize particles have
intracellular reactions and oxidative stress. an elevated surface/volume ratio of approximately 35-
40% of atoms localized at the surface of a 10nm NPs
Nano-agglomerate compared with less than 20% for particles larger than
Agglomerate is a group of coarse accumulations of 30nm. These NPs represent a target for the potential
material particles held together by weak forces such as toxicity. The toxicity of these materials depends on their
van der Waals forces, electrostatic forces and surface persistence or clearance from the different organs due to
tension (Ku and Maynard, 2005; ISO, 2006). These the immune response of the host (Jeffrey et al., 2008).
agglomerates of NPs have the potential to enter the body
or skin if they are in the form of airborne. The agglom- Nano-respiratory route
erate are usually deposited according to their diameter Much research has been done with NPs toxicity of the
(18), resulting in inflammation and later the development respiratory tract. These nanomaterials can be inhaled
of interstitial fibrosis and granulomas (Jacobson and (Peter et al., 2004; Warheit et al., 2004; Oberdorster et
Seinfeld, 2004; Seaton and Donaldson, 2005; Warheit, al., 2005) naturally in the form of aerosol, powders or
2006). However, more research needs to be done in order artificially by instillation into the respiratory tract for
to ascertain other health effects of these NPs. toxicity studies. For instance, findings by Warheit et al
(2004) and Li et al (2007) found that NPs can be instilled
Nano-aggregate via intratracheal, oropharyngeal and intrapharyngeal
Unlike nano agglomerates, nano aggregates are respectively when determining the toxicity of NPs in
heterogeneous particles held together by relatively strong animals respiratory tract. The respiratory system is the
forces, and as a result cannot easily breakup (IRSST, part of the organs that deal with the process of respiration
2006; ISO, 2006). Furthermore, these aggregates can that is, moving from the nose through the trachea to the
adhere to each other through Van der Waals forces to bronchioles (fig. 3). The system is responsible for taking
form agglomerates (Friedlander and Pui, 2003). For in and sending out air from living animals. The lungs are
example, Murr et al (2004) clearly showed that airborne part of the respiratory tract responsible for exchange of
particles are agglomerates of aggregates of aerodynamic gases.
diameters ranging from a few nanometres to several
micrometres.

Aggregates NPs have been shown to cross the cellular

membrane barrier causing inflammatory and cytokines
activities, however, their activities have not been able to
display serious cytotoxicity effect to cells (Peter et al.,
2004). Furthermore, aggregates of SWCNTs have been
found to induce dose interstitial inflammation in mice
(Maynard and Kuempel, 2005). The health effect of these
carbon nanotubes however, depends on the concentration
and size of the clumps or aggregates of the NPs. The
aggregate NPs when in the lungs have the ability to
disaggregate and form smaller particles. The hazards
created by the small particles in the lugs can catalysts
inflammatory responses (Maynard and Kuempel, 2005).
Fig. 3: Passage way of NPs of the lungs.
Nano-portal routes http://en.wikipedia.org/wiki/Upper_respiratory-tract
Due to the increased use of nanomaterials, and the
envisaged potential risks associated with exposure, it is Inhalation is the most common route of exposure to NPs
inevitable that the potential routes of entry are well in the workplaces. Once inhaled, these materials are
understood. As alluded to earlier, the main routes of entry carried by electrostatic force of the air from the upper to
480 Pak. J. Pharm. Sci., Vol.25, No.2, April 2012, pp.477-491
 Clarence Suh Yah

the lower respiratory tract (Oberdorstern et al., 2005; region have been found to enter the brain by translocation
Cross et al., 2007). The particles are usually inhaled in to the olfactory nerve of experimental animals (Flesken et
the form of airborne NPs, systemic administration of al., 2007). Other reports by Oberdorster et al (2005)
drugs, chemicals and other compounds to the lungs confirmed that inhaled MnO2 NPs (30nm) can be
through direct cardiac output to the pulmonary arteries translocated from the lungs into the olfactory organ after a
(Jeffrey et al., 2008). Immediately the NPs are in the 7 day post exposure in experimental rats. The olfactory
pulmonary sites, translocation to blood circulation system is the sensory organ used for olfaction, or the
through the lymphatic pathways can occur depending on sense of smell (fig. 4), the prominent part of the face of
the nanomaterial size. Earlier reports by Berry et al mammals.
(1977) described the translocation of 30nm gold NPs
across the alveolar epithelium of rats by interstitial It receives stimuli interpreted as odours from volatile and
instillation. This report was further supported by Ballou et soluble substances and lies in the upper part of the nasal
al (2004) when they showed quantum dots (10nm) in cavity, and that forms a mucous membrane continuous
liver, lymph and bone marrow of experimental mouse. with the rest of the lining of the nasal cavity. This reveals
Also when the NPs are deposited in the alveolar, they are that the nerve endings of the nasal olfactory mucosa are
usually attacked by the process of phagocytosis. This also portal entry of nanomaterials into the host. According to
led to chemotactic activities which trigger the earlier findings by De Lorenzo (1970) silver coated
complement system cascade and the inflammatory cell colloidal gold particles of upto 50nm can be transported
response to the site of NPs. According to Oberdorster et through olfactory nerves as well as across the synapses of
al (2005) the effect of the inflammatory and the the dendrite cells. Taking into cognizance the nano-
complement cascade may take upto two month 10 days in respiratory tract toxicity studies from non human animals
rat and roughly two years in humans to be cleared. there is likely possibility that these translocation pathways
According to earlier reports of Borm and Kreyling (2004) can exist in human highly dependent on the chemical and
the interstitial translocation of NPs across the lung physical properties of the NPs. It can be concluded
alveolar cells are more common in primate’s species but therefore, the unbridled growth and use of ultrafine
they assumed that the high translocation can occur in particles (carbon nanotubes) in medical and human health
humans. Gwinn and Vallyathan (2006) reported that could possibility become the “asbestos” of the 21st
inhaled nanosize particles may trigger phagocytosis and century.
cause systemic health effects in experimental animals.
Other animal studies, have also shown that discrete NPs The deposition of NPs in the respiratory tract is
may enter the body from the lungs and translocate the influenced by the particle’s size. According to NIOSH
bloodstream to other organs (Obordorster et al., 2005; (2006) agglomerates of NPs can be deposited in the
Nemmar et al., 2001; Das et al., 2007). respiratory tract according to the diameter of the
agglomerate. In addition, reports by ICRP (1994) have
There are also reports that nanoscale viruses (30nm) such shown that discrete NPs are deposited in the lungs to a
as the polio virus found in the lungs can enter the sensory greater extent than larger particles. Studies by Daigle et al
nerve endings of the olfactory organ (Yakovenko et al., (2003) have shown that increase in breathing rate and
2009). The discrete NPs that are deposited in the nasal mechanism (e.g., nasal or mouth) affects the rate of NPs

The olfactory system

1. Olfactory build, 2. Mittral cells, Bone, 4. Nasal epithelium, 5. Glomerulus, 6. Olfactory receptor cells.

Fig. 4: The olfactory nerve passage of nanoparticles. http://en.wikipedia.org/wiki/File:Olfactory_system.svg

Pak. J. Pharm. Sci., Vol.25, No.2, April 2012, pp.477-491 481

Review: Nanoparticles toxicity and their routes of exposures

deposition. Persons with existing lung diseases or respiratory system through the mucociliary escalator
conditions are also susceptible to increase in NPs (Obordorster et al., 2005; Chen et al., 2006; Li et al.,
deposition. 2007). Nanomaterials can also be exposed into the GI viz
water, food, cosmetics, drugs, drug delivery devices.
Nano-gastrointestinal route Some studies have investigated the potential intestinal
The gastrointestinal tract is the system of organs in absorption and the translocation of NPs and generally
animals that takes in food substances, and expels the found uptake within the GT. Studies by Jani (1990) have
remains as waste (fig. 5). The functions are for digestion, showed that gastrointestinal absorption of titanium
absorption and defecation and differ from species to particles ranging from 150-500 nm are larger than those
species. Fig. 5 below demonstrates a simple illustration of typically used in sunscreen into the lymph, liver and
primates’ intestinal tract. spleen. More critical findings concerning the fate of
ingested NPs can be viewed from radioactive metal
Ingestion is another route whereby NPs may enter the studies, where NPs have been shown to translocate from
body. Most of the toxicity studies pertaining to NPs are the gastrointestinal tract to other organs (Borm and
focused mainly on respiratory tract (RT) exposures with Kreyling, 2004).
few studies describing the gastrointestinal tract (GI)
exposures. The gastrointestinal tract (GI) exposures Furthermore, NPs administered orally are usually
usually occur either unintentional from hand to mouth absorbed, through the epithelial cells of the Peyer’s
transfer or from traditional materials. Furthermore, it patches in the gut-associated lymphoid tissue (GALT) and
could occur during handling of the materials that contain also through the gut enterocytes (Chen et al., 2006;
the NPs. Other possible gastrointestinal tract (GI) Alexander, 2005). Earlier reports by Jani et al (1990)
exposures may come from particles cleared from the indicated that oral administration of NPs can be absorbed

Fig 5: Intestinal passage of nanoparticle orally and by gavage feeding respectively

(http://en.wikibooks.org/wiki/File:Digestive_system_diagram_en.svg

482 Pak. J. Pharm. Sci., Vol.25, No.2, April 2012, pp.477-491

 Clarence Suh Yah

across the GI tract via the lymph nodes to the liver and larger particles (0.5-7µm) as reported by Blundell et al
spleen. Reports of Yoshifumi (2002) showed that NPs (1989). These studies found large accumulation of soil
substances are easily taken up by the recticuloendothelial particles in lymph nodes of bear footed human associated
cells during drug transfer. The uptake of these particles of with elephantiasis. Findings by North Carolina State
different sizes can lead to different toxicological effects. University have shown that quantum dot NPs skin
Studies on polystyrene latex NPs in the range of 3 µm to penetration was as a result of skin abrasion therefore
50 nm have shown that maximal absorption can occur raising the workers safety issues arising from workplace
with particle size of approximately 50-100 nm in diameter activities especially of those involved with quantum dot
(Hussain et al., 2001). However, further studies by manufacturing and others NPs (Hagens et al., 2007;
Hussain et al (2001) found that even latex particles above Monteiro-Riviere et al., 2008). Earlier reports by Kim et
1 mm can be retained in the Peyer’s patches. The al (2004) showed that mice injected intradermally with
ingestion of ultrafine particles by the GI tract can quantum dots can localize in the lymph nodes and can
stimulate phygaocytosis at the GI mucosa and cause systematically spread to other organs as previously
antigen-antibody mediated reactions and inflammatory described. The United Kingdom Royal Society and Royal
responses and from there systematically to other organs of Academy of Engineers have reported that NPs of titanium
the body (Hussain et al., 2001). dioxide used in sunscreens do not go through the skin
especially beyond the epidermis (The Royal Society,
Studies by Chen et al (2006) have shown that copper NPs 2004). However, the societies have made several
can cytotoxically trigger injuries on the lymph, payer’s recommendations concerning further and more in-
patches, liver, spleen and kidney of experimental animals. formation on dermal nanoparticles skin penetration.
In these studies by Chen et al (2006) after gavaging mice Findings by Tinkle et al (2003) have shown that NPs less
with copper NPs, they discovered that the GI tract toxicity than 1 µm in diameter may penetrate skin mechanically.
belongs to Hodge and Sterner Scale (3 classes of Recent studies by Zhang et al (2008) reported the
moderately toxicity). Other symptoms associated with the penetration of quantum dot (QD621) NPs (i.e., NPs
toxicity were alimentary canal include loss of appetite, containing cadmium and selenium core with cadmium
vomiting and diarrhea. Others included hypopnea, tremor sulphite) when topically applied to weaning porcine skin
and arching of the back. (of Yorkshire pigs). The same group also used the same
QD621 and found that the quantum dot could penetrate
Nano-dermal route neonatal human epidermal kerationcytes leading to
The dermal organ is the outer surface covering of the skin inflammatory responses. The QD621 were depicted in the
(epidermis and dermis) and the largest organ of the body. intercellular lipid bilayers of the stratum corneum by
It guards the underlying internal organs (figs. 6a and 6b). transmission electron microscopy (Zhang et al., 2008) by
Apart from its interface with the environment, it also elevating cytokines (interleukin-6 and interleukin 8).
protects the body against external interferences and acts Monteiro-Riviere (2008) reported that quantum dot
as an insulator and synthesis of vitamin D. penetration was a function of intercellular lipid structure
or hair follicle density which could modify these
Skin barrier alterations (such as the wounds, scrapes, or penetration processes. Previous studies by Ryman-
dermatitis) could act as exposures routes to NPs into the Rasmussen et al (2007) showed that quantum dot could
body and should not be overlooked. Debilitated skin penetrate through the epidermal layers synthesized with
represents a good channel for entry of finer and even the same core/shell and with similar surface coatings

Fig. 6a: Cross section of the skin. Fig. 6b: Debilitated tissue
Fig. 6: Dermal passage of nanoparticles showing the anatomy of the skin (a) and debilitated skin (b) respectively.
http://www.essentialdayspa.com/Skin_Anathomy_and_Physiology.htm, http://en.wikipedia.org/wiki/Wound

Pak. J. Pharm. Sci., Vol.25, No.2, April 2012, pp.477-491 483

Review: Nanoparticles toxicity and their routes of exposures

having similar hydrodynamic diameters but different of nanomaterials. This raises the question whether
penetration rates. Apart from quantum dot, Zhang et al nanomaterials could penetrate the dermis, be eventually
(2008) also showed the interactions of functionalized absorbed systemically, and be responsible for an
SWCNTs in human epidermal keratinocytes stimulating acute/chronic and local/systemic potential health risk. We
lymphokines and cytokines. already know that the skin is nanoporous at the nanoscale,
having orifices of hair follicles and glands open on skin
Other NPs such as TiO2 and ZnO have also been reported surface therefore, providing alternative entrance routes.
as key particles that are capable of penetrating the skin
when applied topically to human skin in vitro (Friedlander Nano-ocular route
and Pui, 2003). Studies by Tan et al (1996) showed The eyes are used to detect light and sending of signals
absorption of titanium through human skin with micro along the optic nerve to the visual areas of the brain
fine TiO2, while studies with microfine zinc and TiO2 (Frentiu and Adriana, 2008) as shown in fig.7
particles applied to porcine skin did not show penetration.
This is because pig porcine skin has collagenate
(Mediskin), which can provide limited adhesion of NPs.
Other studies by Rodney and Barbara (1972) have shown
that porcine skin has limited wound adhesion and
therefore, limited bacterial infection. Other studies have
shown that quantum dots of different sizes, shapes, and
surface coatings have varying physicochemical properties
when they do penetrate intact skin of pigs (Ryman-
Rasmussen et al., 2007). The mode of the NPs penetration
was mediated by passive diffusion and was found localize
within the dermal layers of the stratum corenum within 8
to 24 hours. Another experiment carried out by Baroli
(2008) with excised human ski healthy female abdominal
skin samples, exposed to NPs for a maximum of 24 hours
showed that penetration of NPs to the skin occurred
through the stratum corneum lipidic matrix and hair
follicle orifices, allowing NPs to reach the deepest layers
of the stratum corneum, hair follicles and the stratum
granulosum. He also showed that in some exceptional
cases, the NPs were found in viable epidermis (Baroli,
2008).
Fig. 7: Optical passage of nanoparticle showing the
In vitro studies concerning cultured human skin cells have anatomy of an the eye
shown that both SWCNT and MWCNT can enter cell http://commons.wikimedia.org/wiki/File:Schematic_diagr
membranes and trigger the release of pro-inflammatory am_of_the_human_eye_no.svg
molecules (lymphokines cytokines) resulting into
oxidative stress, and decreased viability (Monteiro- The eye is divided into the anterior and posterior
Riviere et al., 2008). Actually there no clear cut NPs segments. There are few literatures reports in indicating
adverse effect studies on experimental animals yet. that the eye as route of entry of NPs into animals. Drug
Studies on the dermal exposure of NPs are still ongoing delivery is achieved through topical application
and it is still unknown. (Aniruddha et al., 2008). However, topical treatment of
posterior eye infection is not effective due to the rapid
Most of the penetration and distribution of nanomaterials precorneal elimination due to solution drainage, long
in skin and toxicity are minimal and limited to the diffusional path length, induced lacrimation, and corneal
uppermost stratum corneum layers and areas near hair epithelial impermeability (Jarvinen et al., 1995).
follicles. This usually led to irritation of the inflammation
area in experimental animals. This is because the stratum However, NPs have generated considerable interest for
corneum is the primary barrier for skin and that any type drug delivery into the eye (Aniruddha et al., 2008).
of perturbations to the skin such as an open wound, cut, or According to Herrero-Vanrell and Refojo (Herrero-
alteration to this skin barrier could expose NPs to viable Vanrell and Refojo, 2001), intravitreally administrations
skin cells (Cross et al., 2007; Zhang et al., 2008). of NPs have shown to sustain drug delivery to the eye.
Therefore, more toxicological assessment such as The subconjunctival administrations of Fluorescent NPs
abrasion should be conducted to determine if penetration (Fluospheres TM, 20 nm) to male Sprague-Dawley rats
to this barrier would allow an enhancement of absorption containing sodium fluorescein, NPs, were detected within

484 Pak. J. Pharm. Sci., Vol.25, No.2, April 2012, pp.477-491

 Clarence Suh Yah

15 minutes. Recent reports by Farjo et al (2006) explained that project out into the fluid medium and reduce NPs
how DNA NPs can be implored to transfer genes into the chances of penetrating the ear. Some preliminary reports
mouse retina. Jani et al (2007) reported that albumin NPs by Mamedova et al (2005) of the Hough Ear Institute
encapsulating pCMV.Flt23K when injected into the showed that superparamagnetic NPs can be used as drug
corneas of uninjured mice the NPs were detected in the delivery into the inner ear of guinea pigs and into the
corneal keratocyte cytoplasm. The albumin NPs can be prilymphatic fluid. Another pilot report by Xianxi et al
used to express intraceptors for extended periods that are (Xianxi et al., 2007) of San Diego CA also showed that
effective in suppressing injury-induced corneal polylactic/glycolic acid (PLGA) polymer coated with iron
neovascularization. The highly efficient transfer of the oxide NPs, applied to the round window membrane of
reporter gene into photoreceptor cells could lead to chinchillas, induced by magnetic field can enter the inner
effective treatments for conditions such as retinitis ear and will be found in multiple locations within the
pigmentosa. Therefore, by modifying the properties of cochlea tissue. According to the recent work by Barnes et
NPs, they could be made to target specific organs. al (2007) to compare two different physiological studies
that involve magnetic acceleration of superparamagnetic
Nano-auditory route nanoparticles (SPION) through two round window
The ear is the organ that detects sounds and plays a major membrane (RWM) models. Through electron microscopy
role in the sense of balance and body position (fig. 8). It is studies, they were able to confirm that SPION were pulled
part of the auditory system. Vertebrates have a pair of through the RWM of anesthetized guinea pigs.
ears, which are symmetrically placed on opposite sides of
the head. Their arrangement and the ability to localize Nano-intravenous routes
sound sources (waves) can passively facilitate the entry of In biological assessment, intravenous administration of
NPs into the inner ear and to the other vital parts of the NPs is very important route used in determining
body via blood. toxicological assessment in experimental animals. In the
study of De Jong et al (2008) to determine particle size-
However, very few researches have been made public that dependent organ distribution of gold NPs they
the auditory pathway is a channel for NPs transport into intravenously injected experimental rat in the tail vein
the ear. This is due the complex natures of the anatomies with gold NPs with diameters of 10, 50, 100 and 250 nm,
of the ears which contains hollow channels filled with respectively. Their results gave an oxidative stress in the
fluid, and have sensory cells that are studded with hair rat’s liver cells. The 10nm gold NPs showed the most
cells. The microscopic hairs structural protein filaments widespread presence in the various organ systems

Fig. 8: Auditory passage of nanoparticles showing the anatomy of the ear.

http://www.music.sc.edu/fs/bain/vc/musc726a/MUSC%20726%20Lecture/more%20ear-brain/01-ear.gif

Pak. J. Pharm. Sci., Vol.25, No.2, April 2012, pp.477-491 485

Review: Nanoparticles toxicity and their routes of exposures

including brain, heart, kidneys, lungs, testis and thymus Nano-mucus route
(DeJong et al., 2008). Also in order to test the toxicity The nano-mucus membrane pathway is the lining of most
and biomedical imaging of layered nanohybrids endodermal cells that cover the epithelium and are
consisting of magnesium/aluminium core, Flesken et al involved in absorption and secretion. They line various
(2007) subjected the NPs subcutaneously, intra- body cells and cavities that are exposed to the external
peritoneally and intravenously injections to mice. Their environment and internal organs. It is continuous with the
histological findings showed inflammatory lesions in the skin, nostrils, lips, ears, the genital and the anus. NPs
lungs and dermis after intravenous and subcutaneous deposited on the various mucus tissues pathway,
administration respectively. Early experimental studies by encounter mucus or epithelial lining fluid. This may
Rocio et al (1997) also administered intravenously NPs at trigger phagocytosis or contact fibroblasts B cells or
single doses of 20 and 100 mg/kg for 14 days. In these endothelial cells resulting into the NPs removal (Brayden,
studies, the liver was seen as a passive target tissue for 2001; Obordorster et al., 2005a). The mucus membrane is
NPs if given intravenously, due to the phagocytosis by the first barrier that confronts NPs that are deposited in
Kupffer cells. Indeed, intravenous administration of NPs the conducting epithelium. Other reports by Moghimi et
is followed by inflammatory responses, characterized by al (2001) have shown that NPs can be translocated
an increased synthesis and secretion of cytokines. through the mucosal lining and epithelial cells of the
Experimental animals absorb NPs from the site of intestine and do associate with the GALT and the blood
injection into the lymphatic system (Thanos et al., 1999) circulatory system. According to Umamaheshwari et al
as shown in fig. 9. The subcutaneous route involves a (2004) NPs deposited on the mucus membranes might
complex sequence of nanoparticle movement, mostly lead to various types of interaction forces between
involving lymph and blood. The relevance of intravenous mucoadhesive nanomaterials and the mucus surface.
administration of NPs into experimental animals studies These forces include weak Van der Waals forces, strong
to humans have been questioned not only in drug delivery hydrogen bonding, electrostatic attraction, mechanical
but also in vaccination, a modality which requires interpenetration, and entanglement. Furthermore, methods
systematic absorption of the encapsulated active drug to such as fluorescence probe have been used to evaluate
achieve a biological response (Rocio et al., 1997) as these interactions in vitro and in vivo to measure
shown in fig. 9. mucoadhesive capacity (Umamaheshwari et al., 2004).
Depending upon the specific mucus membrane
application, NPs exposure may translocate and impart a
cytological toxic effect depending on the factors earlier
reported.

Fig. 9: Intravenous injection and transport of NPs to key and target organs (tumor cells). (a) blood vessel; (b)
adhesion to capillary wall; (c) extravagation and flow in tissue; (d) flow at vessel junction; (e) movement to target
tumours cells.
486 Pak. J. Pharm. Sci., Vol.25, No.2, April 2012, pp.477-491
 Clarence Suh Yah

The effect of Nanomaterial ligands and cell membrane influencing NPs cellular activities (Cho et al., 2009). It
interactions determines the properties and functions of NPs, i.e. how
The small size of NPs and their ‘needle-like’ penetrating negatively or positively NPs surfaces are charged. This
ability into cells have made NPs excellent carriers in makes them either very highly reactive and receptive to
biomedical and molecular biology techniques (Yum et al., cell surfaces due to either cations or anions interaction,
2010). The needle like feature has been reported by De thus, creating a net surface charge (Patra et al., 2010).
Jong et al (2008) as a means for ease of absorption,
penetration, circulation and distribution of NPs in bio- It is important to note that modifications to the NP
systems. This is due to the large surface area to volume surfaces may cause undesirable ionic interactions with
ratio that contributes to cell membrane interactions (Van- biological systems (Verma et al., 2010) due to changes in
Doren et al., 2011), thus providing easy penetration and surface charges. Many NPs are stabilized with surface
reactivity in biological system than bulk material. For charges to prevent aggregation via electrostatic repulsion
example, De Jong et al (2008) revealed that 10 nm was (Alkilany and Murph, 2010), thus playing a significant
the most widespread in the system after 24 h of AuNPs. role in membrane cell interactions. For example,
This shows that AuNPs circulations in the system are Schaeublin et al (2011) found both cationic and anionic
highly size dependent. Apart from size, ligands attached NPs responsible for mitochondrial membrane potential
to NP modify their surface activities thus increasing the disruption suggesting that both charged ligands
NP hydrophilicity and biocompatibility properties. This conjugated on NPs can lead to cellular disorders. Apart
facilitates NPs ease of penetration and membrane cells from that, the issue of NPs translocation into host tissues
interaction (Verma and Stellacci, 2010) as shown in fig and their toxicokinetics in vivo is an important underlying
10. principle in understanding NPs-cellular interactions. This
bio-distribution of NPs can serve as basses for assessing
health impact due to surface charges depending on the
route (nasal, oral or dermal) of exposure to the NPs.
These biodistribution processes after exposures are all
tied down to the surface physio-chemical properties that
make them chemically more reactive upon interaction
with biological systems (Gosens et al., 2010). Therefore,
the attributes of NPs and its coated surface charges must
be examined with care to ascertain cellular activities.

CONCLUSION
The safety issues derived from NPs routes of entry and
their potential bio-distribution are governed by surface
area, shape, agglomeration, aggregation solubility and
size with protein (opsonisation) interactions within the
host (Poland et al., 2008). The size fractions in the
nanoscale range have greater lung deposition and rapid
systemic translocation having various inflammatory,
Fig. 10: Ligands surface interaction of nanomaterials with oxidative and cytotoxic effects on experimental animals
cell membranes (Verma and Stellacci, 2010). than larger particles (Andrew et al., 2004; Obordorster et
al., 2005a). With these discussed possible potential routes
Of these ligands, PEG has gained popularity as a of NPs, nanotechnology research should proceed with
modifying agent due to its amphiphilic and solubility caution. The combination of hazard and production
characteristics (Niidome et al., 2006; Patra et al., 2010). should go hand in hand so as to reduce potential
This increases the circulation period of the NPs in the acquisition of NPs through the International Standards
blood stream. A study investigating the bio-distribution of Organisation (ISO), good manufacturing practices
PEG modified and non-modified gold nanorods in mice (GMP), and good laboratory practice (GLP). Suitable
reported a larger percentage of modified NPs in the blood quality control procedures should be part of the process so
in contrast to unmodified particles over the same time as to ensure NPs product safety and quality and hence part
period (Patra et al., 2010). Earlier studies Pan et al (2007) of the company quality assurance scheme. Also the
revealed that 1.4 nm AuNPs functionalized with TPPMS manufacturing industries of nanotechnology should work
could enter the cells very easily and bind on dsDNA hand in hand with the health and hazard risk assessment
major groove and disrupt cellular function. Surface so as to establish a lower health risk of any type
modification of NPs goes with surface charge emanating from the production and used of NPs. Though
modification as well. Surface charge is the measure of the there is limited toxicological data available at the present,
zeta potential, and is a major physical characteristic with the current review, there is hope to increase the
Pak. J. Pharm. Sci., Vol.25, No.2, April 2012, pp.477-491 487
Review: Nanoparticles toxicity and their routes of exposures

awareness and safety issues of concerning the elephantiasis of the lower legs. Ann. Trop. Med.
development of nanotechnology. Parasitol., 83(4): 381-385.
Borm PJ and Kreyling W. (2004). Toxicological hazards
ACKNOWLEDGEMENT of inhaled nanoparticles – Potential implications for
drug delivery. J. Nanosci. Nanotechnol., 4: 521-531.
The authors acknowledge the financial support from the Bottini M, Bruckner S, Nika K, Bottini N, Bellucci S,
Department of Science and Technology (DST), South Magrini A, Bergamaschi A and Mustelin T (2006).
Africa. Multi-walled carbon nanotubes induce T lymphocyte
apoptosis. Toxicol. Lett., 160: 121-126.
Brayden D (2001). Oral vaccination in man using
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