Institute of Technology Assessment

of the Austrian Academy of Sciences No. 003en • November 2010

Myrtill Simkó*,
Michael Nentwich,
How Nanoparticles Enter the
André Gazsó, Ulrich Fiedeler Human Body and Their Effects There

Summary Introduction Entry sites into the

human body
Nanomaterials have a wide range of ap- Nanotechnology and the respective nano-
plications, leading to highly diverse ex- materials are employed in the research sec-
Nanoparticles can enter the body directly
posure scenarios for humans. This calls tor and also contained in many commer-
through body openings, for example by in-
for an analysis of how nanoparticles en- cially available products. This means that
haling or swallowing. There is also an on-
ter the human body and what health the general public is currently being ex-
going discussion about a potential indirect
hazards they pose there. Current evi- posed to nanomaterials. This raises the
uptake through the skin pores. The human
dence indicates that the smaller the na- question whether such materials enter the
skin, the gastrointestinal tract and the
noparticles, the more pronounced their human body and whether they can trigger
lungs are always in direct contact with the
toxic effects. Beyond size, however, the health effects. The potential health risks are
environment. Whereas the skin serves as
shape and chemical composition of poorly investigated. A number of studies
a barrier, the gastrointestinal tract and
nanoparticles contribute to their biolog- have reported that free nanoparticles, due
lungs allow the (active or passive) trans-
ical impacts. Nanoparticles are known to their small size, can penetrate into the
port of various substances such as water,
to induce inflammation in the lung, and finest lung structures by breathing, can
nutrients or oxygen. It seems likely that
some reports of pulmonary fibrosis are cause inflammatory reactions, and subse-
nanoparticles can also enter the human
available. There are indications that quently can enter the bloodstream. The cir-
body via these routes. Due to their small
nanoparticles penetrate vascular tissue culatory system distributes such particles
size, such particles can penetrate the cell
and therefore trigger certain dysfunc- throughout the body, where they can en-
membrane and show activity at the sub-
tions or influence the cardiovascular sys- ter other organs. Nanoparticles can also
cellular level. How this takes place is cur-
tem. One recent study involving an an- be actively or passively incorporated in
rently being investigated.
imal model demonstrates that needle- cells, and harmful effects cannot be exclud-
shaped, asbestos-like nanotubes can in- ed. The biological effects are not based on
duce chronic inflammations. Only few chemical composition alone: size, shape,
The skin
data are available on effects on the di- surface texture, aggregation state and
gestive tract and the nervous system or surface charge also play an important role. The human skin is a true barrier against
on the uptake into the bloodstream via The present dossier examines the poten- the environment (except for solar radiation,
the skin. This contribution presents the tial entry sites of nanoparticles into the hu- which is essential for vitamin D production);
key data and outlines the potential path- man body and describes several biologi- no essential elements are absorbed
ways by which nanoparticles can enter cal effects which can be triggered. through it. The human skin has an aver-
the human body. age surface area of 1.5-2 m2, whereby the
uppermost layer consists of a relatively thick
layer of dead cells (so-called keratinized
cell layer, 10 μm) (Fig. 1)1.

Hair
Epidermis

Opening of
Sweat Gland
Capillaries
Sebaceous
Gland
Dermis

Muscle

Nerve

Sweat Gland
Subkutis

* Corresponding author Figure 1:

Structure of the human skin1

1
 No. 003en • November 2010

Nanoparticles composed of titanium- or zinc

oxides are currently contained in a wide Colon
range of cosmetic products such as sun- Stomach
screen lotions, where they function as high-
Intestinal
ly effective UV-absorbers. This raises the pits
Villi
question whether these products or the na- Duodenum Circular fold
nomaterials penetrate the upper skin layers Colon
and enter underlying tissue. To date, there Colon descendes
is no concrete evidence to support this sce- ascendens
Jejunum
nario. Nonetheless, there are indications that Microvilli
Ileum
such particles can accumulate around the
hair roots, in the so-called hair follicles. Dur- Appendix
ing hair growth, these follicles are open: this
would provide a route for nanoparticles to Layer of
reach deeper layers. Studies have shown that muscle
the components of particle-free lotions that Serosa
have been rubbed in are completely absent M+

in the hair follicles after 7 days, but that the

Figure 2: Structure of the human gastrointestinal tract.
number of particles in the nanoparticle-con-
(Left: overview right: enlarged view of the mucous lining of the gut along with the microvilli7)
taining lotion only dropped by half. No up-
take into the blood (translocation) through
healthy skin has yet been demonstrated. Nano-scale structures can involuntarily en- venously injected material was deposited in
ter the gastrointestinal tract with food or the liver after one week12. This is evidence
In contrast, studies on healthy skin have when swallowing material cleared from the that nanoparticle uptake via the gut could
shown that various so-called quantum dots bronchi via mucociliary clearance. The oral play a subordinate role. Only few studies
can penetrate the skin. (Quantum dots are intake of an average person is estimated to have examined the uptake and residence
produced from semiconductor materials and be 1012 to 1014 nano- and microparticles time of nanoparticles in the gastrointestinal
absorb certain wavelengths of light. In life daily8, with the overwhelming majority be- tract, hindering definitive conclusions.
sciences they find use as biomarkers, or al- ing silicates and titanium dioxide. In animal
so in LEDs and displays.) experiments, 50-100 nm-sized polystyrene
The lung
Research is currently being conducted on particles pass through the gut wall and en-
whether particle uptake differs in injured or ter the lymphatic system9; fullerenes, in con- The lung consists of two different function-
diseased skin (psoriasis etc.). There is con- trast, tend not to be absorbed. Other stud- al areas, namely of the respiratory tract,
sensus, however, that the barrier function is ies, however, show no uptake into the vas- where air is transported into or out of the
compromised and nanoparticle penetration cular system via the gastrointestinal tract10,11. lung, and the gas exchange area (bronchi,
possible. There is clearly no consensus about how bronchioli, alveoli), where oxygen and car-
nanoparticles behave in the gastrointestinal bon dioxide are exchanged with the environ-
system. One study examined the uptake of ment. The human lung consists of about 2300
The digestive system radioactively marked, intravenously inject- kilometers of respiratory tract and about 300
ed fullerenes compared with uptake through million alveoli (Fig. 3)13. The surface area
The entire gastrointestinal tract is in direct the gastrointestinal tract in rats. However, of the human lung is nearly 140 m2 and rep-
contact with all ingested materials, and all 98 % of the orally ingested material was ex- resents an enormous exposure surface. The
the necessary nutrients for the body (with the creted, whereas about 80 % of the intra- respiratory tract functions as a relatively ro-
exception of gases) are absorbed here. The
whole surface of the gastrointestinal tract
serves as a complex barrier; at the same time,
it is the key gate for the macromolecules the Larynx
body needs. Only small molecules can dif- Air tube Deoxygenated blood
fuse through the stomach epithelium. The ep-
Collar bone Oxygenated blood
ithelium of the intestine is in immediate con-
tact with the partially digested material, en- Thorax
abling direct nutrient absorption. The food
in the small intestine is already digested and Radix pulmoni
consists of a mixture of molecules such as Bronchi
disaccharides, peptides, fatty acids and mo-
Alveoli
noglycerides. These are converted in the in-
testinal villi and then absorbed (Fig. 2)7. In Pleura Alveoli
(visceralis)
order to increase the surface of the epithe-
lium, the intestinal villi are further covered
by even smaller villi (microvilli). This yields Pleura
(parietalis)
a surface of about 200 m2 for nutrient up-
take in the gastrointestinal tract.
Figure 3: Structure of the human lung. (Left: overview; right: enlarged view of the alveoli13)

2
 No. 003en • November 2010

bust barrier consisting of an active epithe- remain in the brain and potentially accumu- sorbed particles. Some are taken up (inter-
lial layer that is protected by a viscous mu- late there18,19. Nanoparticles have also been nalized) by epithelial cells, as has been de-
cus layer (air-blood tissue barrier). In the gas demonstrated to penetrate into higher brain scribed for nano-scale titanium dioxide,
exchange area, the barrier between the alve- centers though this route (cortex, thalamus gold, polystyrene and zirconium)22,25. The
olar wall and the capillaries is very thin. The and cerebellum), with electroencephalograms underlying explanatory model states that the
air inside (in the lumen) of the alveoli is on- showing an altered pattern. released free radicals possibly trigger so-
ly a few nanometers away from the flowing called oxidative stress and irreparably dam-
blood. Animal experiments show that nano- age the cells (cytotoxicity). Other authors dis-
particles can cross this air-blood tissue bar- cuss the potential deposition of the nanopar-
rier. This introduces nanomaterials into the Effects on ticles directly onto the DNA, which can lead
body’s circulatory system14. Due to the large to a genotoxic effect20. Absorbed nanopar-
surface area of the alveoli and the intensive
the human body ticles can translocate from the lung into the
air-blood contact, the alveoli are more ex- blood10,14,27,28, whereby these results are be-
Animal experiments demonstrate that inflam-
posed to environmental influences than is the ing hotly debated. There is agreement that,
mations of the bronchi and alveoli can be
respiratory tract. The bronchi are coated with beyond the size of the particles, their surface
triggered by nanometer-sized carbon-, poly-
a mucociliary layer that removes particles de- texture and charge or coating can influence
styrene-, iron-, titanium dioxide- and iridi-
posited in the lungs (mucociliary clearance). the biological effectivity12,15.
um particles17,20. In individual cases, inflam-
This mucociliary clearance is sufficient to re-
matory reactions in occupationally exposed
move most of the nanoparticles deposited
persons have been described for nanoscale Conclusions
along the bronchi. The effectiveness of this
indium-zinc-oxides21 and zirconium particles
mechanism, however, decreases as particle Nanoparticles with a diameter of up to
from welding fumes22.
size decreases. This means that nanoparti- 100 nm, such as carbon or metallic ox-
cles enter the alveoli and are deposited on A range of data is available on the effects ide particles, are already present in the en-
the epithelium, after which a direct exchange of nanoparticles, whereby a close correla- vironment. They can induce biological ef-
with the alveolar epithelia can take place. tion exists between surface texture and bio- fects via cell membrane penetration and
So-called feeding cells (macrophages) take logical effects. In rats and mice, for exam- are more reactive than larger particles. The
over the task of removing foreign bodies be- ple, titanium dioxide (or nickel- and vana- use of nanoparticles, however, can im-
cause the alveoli lack a mucociliary clear- dium dioxide particles) measuring 20 nm ad- prove the efficiency of cosmetic products
ance mechanism. ministered directly into the lungs triggered for example, and makes it possible to cre-
stronger inflammatory reactions than 250 ate new coatings (e.g. scratch-proof
The minute size of the particles plays a key
nm particles. These and other results show paints). Moreover, they are considered as
role here as well. Animal experiments demon-
that toxicity is influenced more by the sur- candidates for new and promising med-
strate that the normal cleaning mecha-
face than by mass12. Moreover, beyond the ical applications and therapies. The in-
nisms can fail because insoluble nanopar-
size of the surface, its features (for example creasing use of nanoparticles, however,
ticles can be deposited for months to years
the presence of reactive groups on the sur- calls for further research in order to be able
in the bronchi and alveoli15. Higher depo-
face) determine the toxicity. In a special to conduct risk assessments. In particular,
sition rates have been reported in patients
mouse model, a recent pilot study shows that it is important to investigate the actual ex-
with chronic bronchitis and bronchial asth-
intraperitoneally administered (area of the posure of different groups such as con-
ma, whereby the reduced clearance and the
body covered by peritoneum), long (ca. sumers, occupationally exposed persons,
elevated breathing rates in these patients
20 μm), needle-shaped nanotubes can trig- and patients as well as both users and pro-
have been discussed as causes15,16.
ger chronic inflammation, while short and/or ducers of nanoparticles. In addition, the
How long the absorbed nanoparticles re- curved nanotubes induce no such effects. material uptake mechanisms need to be
main in the body (kinetics) remains unknown. Since their features (form, length and insol- investigated for a better understanding of
Some studies indicate that, after inhaling the ubility) resemble those of asbestos fibers, a the effects.
nanoparticles, these can enter other organs. comparable mechanism of action has been
Thus, after 7 days, inhaled nanoparticles were discussed23.
detected in the liver, spleen, brain, kidneys,
A key issue is a potential carcinogenic effect
heart and bone marrow12,17. A metaboliza-
of inhaled nanoparticles. The administration
tion of absorbed inorganic nanoparticles (for
of high doses of granular and biologically
example titanium dioxide) appears to be un-
stable nanodust (inert bulk material) in rats
likely, whereas organic nanomaterials (e.g.
was shown to be correlated with an elevat-
fullerenes) are more likely to be modified by
ed tumor frequency24. It remains unclear,
metabolic processes. Whether the particles
however, whether this involves a direct geno-
translocate into the lymphatic/blood circu-
toxic effect of the nanoparticles or whether
lation and become distributed and poten-
it reflects secondary reactions such as the re-
tially accumulate in the body, and whether
lease of free radicals, as is the case in chron-
they affect the cardiovascular system, is the
ic inflammations. The question of how small
subject of ongoing study.
amounts of nanoparticles behave in humans
Research is also being conducted on whether and whether they can induce cancer cannot
particles that reach the brain via breathing, be answered at this point. There is also un-
for example by way of the olfactory nerve, certainty about what happens with the ab-

3
 No. 003en • November 2010

Notes and References 11 Kanapilly, G. M. and Diel, J. H., 1980, Ultra- 20 Elder, A. C., Gelein, R., Finkelstein, J. N., Cox,
fine 239PuO2 aerosol generation, character- C. and Oberdorster, G., 2000, Pulmonary in-
1 www.qualimedic.de/Haut.html (translated). ization and short-term inhalation study in the flammatory response to inhaled ultrafine parti-
2 Lademann, J., Weigmann, H., Rickmeyer, C., rat, Health Phys 39(3), 505-19. cles is modified by age, ozone exposure, and
Barthelmes, H., Schaefer, H., Mueller, G. and 12 Oberdorster, G., Oberdorster, E. and Ober- bacterial toxin, Inhal Toxicol 12 Suppl 4, 227-46.
Sterry, W., 1999, Penetration of titanium diox- dorster, J., 2005, Nanotoxicology: an emerg- 21 Homma, S., Miyamoto, A., Sakamoto, S., Kishi,
ide microparticles in a sunscreen formulation ing discipline evolving from studies of ultrafine K., Motoi, N. and Yoshimura, K., 2005, Pul-
into the horny layer and the follicular orifice, Skin particles, Environ Health Perspect 113(7), monary fibrosis in an individual occupational-
Pharmacol Appl Skin Physiol 12(5), 247-56. 823-39. ly exposed to inhaled indium-tin oxide, Eur
3 Lademann, J., Richter, H., Schaefer, U. F., 13 www.medizinfo.de/gastro/images/ Respir J 25(1), 200-4.
Blume-Peytavi, U., Teichmann, A., Otberg, N. duendarm.jpg (translated). 22 Kotter, J. M. and Zieger, G., 1992, Sarcoid
and Sterry, W., 2006, Hair follicles – a long- 14 granulomatosis after many years of exposure
Nemmar, A., Hoet, P. H., Vanquickenborne, B.,
term reservoir for drug delivery, Skin Pharma- to zirconium, “zirconium lung“, Pathologe 13(2),
Dinsdale, D., Thomeer, M., Hoylaerts, M. F.,
col Physiol 19(4), 232-6. 104-9.
Vanbilloen, H., Mortelmans, L. and Nemery,
4 Lademann, J., Schaefer, H., Otberg, N., Teich- 23
B., 2002, Passage of inhaled particles into the Poland, C.A., Duffin, R., Kinloch, I., Maynard,
mann, A., Blume-Peytavi, U. and Sterry, W., blood circulation in humans, Circulation 105(4), A., Wallace, W.A.H., Seaton, A., Stone, V.,
2004, Penetration of microparticles into human 411-4. Brown, S., William, M., Donaldson, K. 2008,
skin, Hautarzt 55 (12), 1117-9. 15 Carbon nanotubes introduced into the abdom-
Borm, P. J., Robbins, D., Haubold, S., Kuhl-
5 Ryman-Rasmussen, J. P., Riviere, J. E. and Mon- busch, T., Fissan, H., Donaldson, K., Schins, inal cavity of mice show asbestos-like patho-
teiro-Riviere, N. A., 2006, Penetration of in- R., Stone, V., Kreyling, W., Lademann, J., Krut- genicity in a pilot study, Nature Nanotechnol-
tact skin by quantum dots with diverse physic- mann, J., Warheit, D. and Oberdorster, E., ogy, Published online: 20 May 2008.
ochemical properties, Toxicol Sci 91(1), 159-65. 2006, The potential risks of nanomaterials: a 24 Roller, M. and Pott, F., 2006, Lung tumor risk
6 Rouse, J. G., Yang, J., Ryman-Rasmussen, J. review carried out for ECETOC, Part Fibre, Tox- estimates from rat studies with not specifical-
P., Barron, A. R. and Monteiro-Riviere, N. A., icol 3, 11. ly toxic granular dusts, Ann N Y Acad Sci 1076,
2007, Effects of mechanical flexion on the pen- 16 Frampton, M. W., Utell, M. J., Zareba, W., 266-80.
etration of fullerene amino acid-derivatized Oberdorster, G., Cox, C., Huang, L. S., Mor- 25 Geiser, M., Rothen-Rutishauser, B., Kapp, N.,
peptide nanoparticles through skin, Nano Lett row, P. E., Lee, F. E., Chalupa, D., Frasier, L. Schurch, S., Kreyling, W., Schulz, H., Semm-
7(1), 155-60. M., Speers, D. M. and Stewart, J., 2004, Ef- ler, M., Im Hof, V., Heyder, J. and Gehr, P.,
7 www.vitanet.de/media/img/106026727254 fects of exposure to ultrafine carbon particles 2005, Ultrafine particles cross cellular mem-
267493/lungenkrebs_lungenaufbau.gif in healthy subjects and subjects with asthma, branes by nonphagocytic mechanisms in lungs
(translated). Res Rep Health Eff Inst (126), 1-47; discussion and in cultured cells, Environ Health Perspect
8 49-63. 113(11), 1555-60.
Lomer, M. C., Thompson, R. P. and Powell, J.
17 Semmler, M., Seitz, J., Erbe, F., Mayer, P., Hey- 26 Stone, V., Johnston, H. and Clift, M. J., 2007,
J., 2002, Fine and ultrafine particles of the di-
et: influence on the mucosal immune response der, J., Oberdorster, G. and Kreyling, W. G., Air pollution, ultrafine and nanoparticle toxi-
and association with Crohn’s disease, Proc Nu- 2004, Long-term clearance kinetics of inhaled cology: cellular and molecular interactions,
tr Soc 61(1), 123-30. ultrafine insoluble iridium particles from the rat IEEE Trans Nanobioscience 6(4), 331-40.
9 lung, including transient translocation into sec- 27 Oberdorster, G., Sharp, Z., Atudorei, V., Elder,
Volkheimer, G., 1974, Passage of particles
ondary organs, Inhal Toxicol 16(6-7), 453-9. A., Gelein, R., Lunts, A., Kreyling, W. and Cox,
through the wall of the gastrointestinal tract,
18 Elder, A. and Oberdorster, G., 2006, Translo- C., 2002, Extrapulmonary translocation of ul-
Environ Health Perspect 9, 215-25.
10 cation and effects of ultrafine particles outside trafine carbon particles following whole-body
Kreyling, W. G., Semmler, M., Erbe, F., May-
of the lung, Clin Occup Environ Med 5(4), 785- inhalation exposure of rats, J Toxicol Environ
er, P., Takenaka, S., Schulz, H., Oberdorster,
96. Health A 65(20), 1531-43.
G. and Ziesenis, A., 2002, Translocation of ul-
19 Elder, A., Gelein, R., Silva, V., Feikert, T., Opan- 28 Nemmar, A., Vanbilloen, H., Hoylaerts, M. F.,
trafine insoluble iridium particles from lung ep-
ithelium to extrapulmonary organs is size de- ashuk, L., Carter, J., Potter, R., Maynard, A., Ito, Hoet, P. H., Verbruggen, A. and Nemery, B.,
pendent but very low, J Toxicol Environ Health Y., Finkelstein, J. and Oberdorster, G., 2006, 2001, Passage of intratracheally instilled ul-
A 65(20), 1513-30. Translocation of inhaled ultrafine manganese trafine particles from the lung into the systemic
oxide particles to the central nervous system, circulation in hamster, Am J Respir Crit Care
Environ Health Perspect 114(8), 1172-8. Med 164(9), 1665-8.

MASTHEAD:
Owner: Austrian Academy of Sciences; legal person under public law
(BGBl 569/1921; BGBl I 130/2003); Dr. Ignaz Seipel-Platz 2, A-1010 Vienna
Editor: Institute of Technology Assessment (ITA); Strohgasse 45/5, A-1030 Vienna;
www.oeaw.ac.at/ita
Mode of publication: The NanoTrust Dossiers are published irregularly and contain the research
results of the Institute of Technology Assessment in the framework of its research project NanoTrust.
The Dossiers are made available to the public exclusively via the Internet portal “epub.oeaw” :
epub.oeaw.ac.at/ita/nanotrust-dossiers
NanoTrust-Dossier No. 003en, November 2010: epub.oeaw.ac.at/ita/nanotrust-dossiers/dossier003en.pdf
ISSN: 1998-7293
This Dossier is published under the Creative Commons
(Attribution-NonCommercial-NoDerivs 2.0 Austria)
licence: creativecommons.org/licenses/by-nc-nd/2.0/at/deed.en