health effects of nanoparticles

7/29/2019 health effects of nanoparticles

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Institute of Technology Assessmentof the Austrian Academy of Sciences No. 003en November 2010

Introduction

Nanotechnology and the respective nano-materials are employed in the research sec-tor and also contained in many commer-cially available products. This means that

the general public is currently being ex-posed to nanomaterials. This raises thequestion whether such materials enter thehuman body and whether they can triggerhealth effects. The potential health risks arepoorly investigated. A number of studieshave reported that free nanoparticles, dueto their small size, can penetrate into thefinest lung structures by breathing, cancause inflammatory reactions, and subse-quently can enter the bloodstream. The cir-culatory system distributes such particlesthroughout the body, where they can en-ter other organs. Nanoparticles can also

be actively or passively incorporated incells, and harmful effects cannot be exclud-ed. The biological effects are not based onchemical composition alone: size, shape,surface texture, aggregation state andsurface charge also play an important role.The present dossier examines the poten-tial entry sites of nanoparticles into the hu-man body and describes several biologi-cal effects which can be triggered.

Entry sites into thehuman body

Nanoparticles can enter the body directlythrough body openings, for example by in-haling or swallowing. There is also an on-

going discussion about a potential indirectuptake through the skin pores. The humanskin, the gastrointestinal tract and thelungs are always in direct contact with theenvironment. Whereas the skin serves asa barrier, the gastrointestinal tract andlungs allow the (active or passive) trans-port of various substances such as water,nutrients or oxygen. It seems likely thatnanoparticles can also enter the humanbody via these routes. Due to their smallsize, such particles can penetrate the cellmembrane and show activity at the sub-cellular level. How this takes place is cur-rently being investigated.

The skin

The human skin is a true barrier againstthe environment (except for solar radiation,which is essential for vitamin D production);no essential elements are absorbedthrough it. The human skin has an aver-age surface area of 1.5-2 m2, whereby theuppermost layer consists of a relatively thicklayer of dead cells (so-called keratinized

cell layer, 10 m) (Fig. 1)

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.

Summary

Nanomaterials have a wide range of ap-plications, leading to highly diverse ex-posure scenarios for humans. This callsfor an analysis of how nanoparticles en-

ter the human body and what healthhazards they pose there. Current evi-dence indicates that the smaller the na-noparticles, the more pronounced theirtoxic effects. Beyond size, however, theshape and chemical composition ofnanoparticles contribute to their biolog-ical impacts. Nanoparticles are knownto induce inflammation in the lung, andsome reports of pulmonary fibrosis areavailable. There are indications thatnanoparticles penetrate vascular tissueand therefore trigger certain dysfunc-tions or influence the cardiovascular sys-

tem. One recent study involving an an-imal model demonstrates that needle-shaped, asbestos-like nanotubes can in-duce chronic inflammations. Only fewdata are available on effects on the di-gestive tract and the nervous system oron the uptake into the bloodstream viathe skin. This contribution presents thekey data and outlines the potential path-

ways by which nanoparticles can enterthe human body.

1

* Corresponding author

How Nanoparticles Enter theHuman Body and Their Effects There

Myrtill Simk*,Michael Nentwich,

Andr Gazs, Ulrich Fiedeler

Figure 1:Structure of the human skin1

Hair

Opening ofSweat Gland

Capillaries

SebaceousGland

Muscle

Nerve

Sweat Gland

Dermis

Epidermis

Subkutis


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No. 003en November 2010

Nanoparticles composed of titanium- or zincoxides are currently contained in a widerange of cosmetic products such as sun-screen lotions, where they function as high-ly effective UV-absorbers. This raises the

question whether these products or the na-nomaterials penetrate the upper skin layersand enter underlying tissue. To date, thereis no concrete evidence to support this sce-nario. Nonetheless, there are indications thatsuch particles can accumulate around thehair roots, in the so-called hair follicles. Dur-ing hair growth, these follicles are open: thiswould provide a route for nanoparticles toreach deeper layers. Studies have shown thatthe components of particle-free lotions thathave been rubbed in are completely absentin the hair follicles after 7 days, but that thenumber of particles in the nanoparticle-con-

taining lotion only dropped by half. No up-take into the blood (translocation) throughhealthy skin has yet been demonstrated.

In contrast, studies on healthy skin haveshown that various so-called quantum dotscan penetrate the skin. (Quantum dots areproduced from semiconductor materials andabsorb certain wavelengths of light. In lifesciences they find use as biomarkers, or al-so in LEDs and displays.)

Research is currently being conducted onwhether particle uptake differs in injured or

diseased skin (psoriasis etc.). There is con-sensus, however, that the barrier function iscompromised and nanoparticle penetrationpossible.

The digestive system

The entire gastrointestinal tract is in directcontact with all ingested materials, and allthe necessary nutrients for the body (with theexception of gases) are absorbed here. Thewhole surface of the gastrointestinal tractserves as a complex barrier; at the same time,

it is the key gate for the macromolecules thebody needs. Only small molecules can dif-fuse through the stomach epithelium. The ep-ithelium of the intestine is in immediate con-tact with the partially digested material, en-abling direct nutrient absorption. The foodin the small intestine is already digested andconsists of a mixture of molecules such asdisaccharides, peptides, fatty acids and mo-noglycerides. These are converted in the in-testinal villi and then absorbed (Fig. 2)7. Inorder to increase the surface of the epithe-lium, the intestinal villi are further coveredby even smaller villi (microvilli). This yields

a surface of about 200 m2 for nutrient up-take in the gastrointestinal tract.

Nano-scale structures can involuntarily en-ter the gastrointestinal tract with food orwhen swallowing material cleared from thebronchi via mucociliary clearance. The oralintake of an average person is estimated tobe 1012 to 1014 nano- and microparticlesdaily8, with the overwhelming majority be-ing silicates and titanium dioxide. In animalexperiments, 50-100 nm-sized polystyreneparticles pass through the gut wall and en-ter the lymphatic system9; fullerenes, in con-trast, tend not to be absorbed. Other stud-ies, however, show no uptake into the vas-cular system via the gastrointestinal tract10,11.There is clearly no consensus about hownanoparticles behave in the gastrointestinalsystem. One study examined the uptake ofradioactively marked, intravenously inject-ed fullerenes compared with uptake throughthe gastrointestinal tract in rats. However,98 % of the orally ingested material was ex-creted, whereas about 80 % of the intra-

venously injected material was deposited inthe liver after one week12. This is evidencethat nanoparticle uptake via the gut couldplay a subordinate role. Only few studieshave examined the uptake and residencetime of nanoparticles in the gastrointestinaltract, hindering definitive conclusions.

The lung

The lung consists of two different function-al areas, namely of the respiratory tract,where air is transported into or out of thelung, and the gas exchange area (bronchi,bronchioli, alveoli), where oxygen and car-bon dioxide are exchanged with the environ-ment. The human lung consists of about 2300kilometers of respiratory tract and about 300million alveoli (Fig. 3)13. The surface areaof the human lung is nearly 140 m2 and rep-resents an enormous exposure surface. Therespiratory tract functions as a relatively ro-

2

Figure 2:Structure of the human gastrointestinal tract.(Left: overview right: enlarged view of the mucous lining of the gut along with the microvilli7)

Appendix

Colonascendens

ColonStomach

Circular fold

Villi

Intestinalpits

Microvilli

Layer ofmuscle

Serosa

DuodenumColondescendes

Jejunum

Ileum

M+

Figure 3:Structure of the human lung. (Left: overview; right: enlarged view of the alveoli13)

Larynx

Air tube

Collar bone

Thorax

Radix pulmoni

Bronchi

Alveoli

Pleura(visceralis)

Pleura

(parietalis)

Oxygenated blood

Deoxygenated blood

Alveoli


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bust barrier consisting of an active epithe-lial layer that is protected by a viscous mu-cus layer (air-blood tissue barrier). In the gasexchange area, the barrier between the alve-olar wall and the capillaries is very thin. The

air inside (in the lumen) of the alveoli is on-ly a few nanometers away from the flowingblood. Animal experiments show that nano-particles can cross this air-blood tissue bar-rier. This introduces nanomaterials into thebodys circulatory system14. Due to the largesurface area of the alveoli and the intensiveair-blood contact, the alveoli are more ex-posed to environmental influences than is therespiratory tract. The bronchi are coated witha mucociliary layer that removes particles de-posited in the lungs (mucociliary clearance).This mucociliary clearance is sufficient to re-move most of the nanoparticles deposited

along the bronchi. The effectiveness of thismechanism, however, decreases as particlesize decreases. This means that nanoparti-cles enter the alveoli and are deposited onthe epithelium, after which a direct exchangewith the alveolar epithelia can take place.So-called feeding cells (macrophages) takeover the task of removing foreign bodies be-cause the alveoli lack a mucociliary clear-ance mechanism.

The minute size of the particles plays a keyrole here as well. Animal experiments demon-strate that the normal cleaning mecha-

nisms can fail because insoluble nanopar-ticles can be deposited for months to yearsin the bronchi and alveoli15. Higher depo-sition rates have been reported in patientswith chronic bronchitis and bronchial asth-ma, whereby the reduced clearance and theelevated breathing rates in these patientshave been discussed as causes15,16.

How long the absorbed nanoparticles re-main in the body (kinetics) remains unknown.Some studies indicate that, after inhaling thenanoparticles, these can enter other organs.Thus, after 7 days, inhaled nanoparticles were

detected in the liver, spleen, brain, kidneys,heart and bone marrow12,17. A metaboliza-tion of absorbed inorganic nanoparticles (forexample titanium dioxide) appears to be un-likely, whereas organic nanomaterials (e.g.fullerenes) are more likely to be modified bymetabolic processes. Whether the particlestranslocate into the lymphatic/blood circu-lation and become distributed and poten-tially accumulate in the body, and whetherthey affect the cardiovascular system, is thesubject of ongoing study.

Research is also being conducted on whether

particles that reach the brain via breathing,for example by way of the olfactory nerve,

remain in the brain and potentially accumu-late there18,19. Nanoparticles have also beendemonstrated to penetrate into higher braincenters though this route (cortex, thalamusand cerebellum), with electroencephalograms

showing an altered pattern.

Effects onthe human body

Animal experiments demonstrate that inflam-mations of the bronchi and alveoli can betriggered by nanometer-sized carbon-, poly-styrene-, iron-, titanium dioxide- and iridi-um particles17,20. In individual cases, inflam-matory reactions in occupationally exposed

persons have been described for nanoscaleindium-zinc-oxides21 and zirconium particlesfrom welding fumes22.

A range of data is available on the effectsof nanoparticles, whereby a close correla-tion exists between surface texture and bio-logical effects. In rats and mice, for exam-ple, titanium dioxide (or nickel- and vana-dium dioxide particles) measuring 20 nm ad-ministered directly into the lungs triggeredstronger inflammatory reactions than 250nm particles. These and other results showthat toxicity is influenced more by the sur-

face than by mass12

. Moreover, beyond thesize of the surface, its features (for examplethe presence of reactive groups on the sur-face) determine the toxicity. In a specialmouse model, a recent pilot study shows thatintraperitoneally administered (area of thebody covered by peritoneum), long (ca.20 m), needle-shaped nanotubes can trig-ger chronic inflammation, while short and/orcurved nanotubes induce no such effects.Since their features (form, length and insol-ubility) resemble those of asbestos fibers, acomparable mechanism of action has beendiscussed23.

A key issue is a potential carcinogenic effectof inhaled nanoparticles. The administrationof high doses of granular and biologicallystable nanodust (inert bulk material) in ratswas shown to be correlated with an elevat-ed tumor frequency24. It remains unclear,however, whether this involves a direct geno-toxic effect of the nanoparticles or whetherit reflects secondary reactions such as the re-lease of free radicals, as is the case in chron-ic inflammations. The question of how smallamounts of nanoparticles behave in humansand whether they can induce cancer cannot

be answered at this point. There is also un-certainty about what happens with the ab-

sorbed particles. Some are taken up (inter-nalized) by epithelial cells, as has been de-scribed for nano-scale titanium dioxide,gold, polystyrene and zirconium)22,25. Theunderlying explanatory model states that the

released free radicals possibly trigger so-called oxidative stress and irreparably dam-age the cells (cytotoxicity). Other authors dis-cuss the potential deposition of the nanopar-ticles directly onto the DNA, which can leadto a genotoxic effect20. Absorbed nanopar-ticles can translocate from the lung into theblood10,14,27,28, whereby these results are be-ing hotly debated. There is agreement that,beyond the size of the particles, their surfacetexture and charge or coating can influencethe biological effectivity12,15.

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ConclusionsNanoparticles with a diameter of up to

100 nm, such as carbon or metallic ox-

ide particles, are already present in the en-

vironment. They can induce biological ef-

fects via cell membrane penetration and

are more reactive than larger particles. The

use of nanoparticles, however, can im-

prove the efficiency of cosmetic products

for example, and makes it possible to cre-

ate new coatings (e.g. scratch-proof

paints). Moreover, they are considered as

candidates for new and promising med-

ical applications and therapies. The in-creasing use of nanoparticles, however,

calls for further research in order to be able

to conduct risk assessments. In particular,

it is important to investigate the actual ex-

posure of different groups such as con-

sumers, occupationally exposed persons,

and patients as well as both users and pro-

ducers of nanoparticles. In addition, the

material uptake mechanisms need to be

investigated for a better understanding of

the effects.


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Notes and References

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3 Lademann, J., Richter, H., Schaefer, U. F.,Blume-Peytavi, U., Teichmann, A., Otberg, N.and Sterry, W., 2006, Hair follicles a long-term reservoir for drug delivery, Skin Pharma-col Physiol 19(4), 232-6.

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