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The safety of nanosized particles in titanium dioxideeand zinc oxideebased sunscreens

Marissa D. Newman, MD, Mira Stotland, MD, and Jeffrey I. Ellis, MDBrooklyn, New York

Given the increasing incidence and prevalence of skin cancer, dermatologists are more frequentlyrecommending sunscreens to their patients. However, the safety of titanium dioxide and zinc oxidenanosized particles in the majority of sunscreens has come under scrutiny from governments and thegeneral public. We sought to characterize the use, safety, and regulatory state of nanosized particles intitanium dioxide and zinc oxide in sunscreens based on studies and position statements from 1980 to2008. Although we found no evidence of significant penetration of titanium dioxide and zinc oxidenanosized particles beyond the stratum corneum, further studies must be done to simulate real-worldconditions particularly in sunburned skin and under ultraviolet exposure. ( J Am Acad Dermatol2009;61:685-92.)

Key words:nanoparticles; nanosized particles; percutaneous absorption; reactive oxygen species;sunscreen; titanium dioxide, toxicity; zinc oxide.

INTRODUCTION TO NANOTECHNOLOGYNanotechnology, which refers to the precise

manipulation of matter at the nanometer scale, hasrevolutionized the commercial application of pro-ducts in the fields of medicine, engineering,manufacturing, and information and environmentaltechnology to name a few.1 Nanomaterials are ultra-fine single particleswith a diameter less than 100nm.1

They are commonly found in electronics, rubbertires, sporting equipment, foods, preservatives, andpharmaceuticals. Such small particles allow for tai-lored product formulations that meet the specificdesires of the consumer. The distinctive properties ofnanoparticles are of particular interest to the skin careindustry. Using nanosized particles in cosmeticsgenerates products with improved texture, morevibrant color, and greater skin penetration. Althoughnanoparticles have quickly expanded many indus-tries with profits projected at $1 trillion within 20years, the benefits of using nanoparticles must be

weighed against their potential risks.1 In 1999 the

Food andDrug Administration (FDA) allowed theuseof nanoparticles in sunscreens. Since that time, therehas been controversy regarding the safety of theiruse. Given the frequency with which dermatologistsrecommend these sunscreens, we sought to reviewthe literature on nanosized particles in sunscreensand discuss the relevant safety considerations.

THE USE OF NANOSIZED PARTICLES INSUNSCREENS

Traditional sunscreens before the use of nanosized

particles were thick formulations that did not blendwell into the skin and were cosmetically unappealing.This was a result of the two most common ingredientsin sunscreens, titanium dioxide (TiO2) and zinc oxide(ZnO). TiO2and ZnO have traditionally been used insunscreens because of their ability to filter ultraviolet(UV) A and UVB light. In recent years, manufacturershave started using the nanosized forms of TiO2 andZnO in place of their bulk forms. This new formula-tion has resolved the problem of the unsightly whitefilm of traditional sunscreens and created a vehiclethat is more transparent, less viscous, and blends into

the skin more easily.

Abbreviations used:

FDA: Food and Drug AdministrationROS: reactive oxygen speciesTiO2: titanium dioxideUV: ultravioletZnO: zinc oxide

From the Department of Dermatology, State University of New

York Downstate Medical Center.

Funding sources: None.

Conflicts of interest: None declared.

Reprint requests: Jeffrey I. Ellis, MD, Department of Dermatology,

State University of New York Downstate Medical Center, 450

Clarkson Ave, Brooklyn, NY 11203. E-mail:[email protected].

Published online August 3, 2009.

0190-9622/$36.00

2009 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2009.02.051

685
mailto:[email protected]:[email protected]

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HOW COMMON ARE NANOSIZEDPARTICLES IN SUNSCREENS?

The use of nanosized particles in sunscreens is nottheoretical or simply planned for the future. TheAustralian government recently estimated that 70%of titanium sunscreens and 30% of zincsunscreenswere formulated with nanoingredients.2

In the United States thereare no current regulationswith regard to labeling sun-screens for the inclusion ofnanoparticles, thus no offi-cial data are yet available toquantify the use of these par-ticles. However, ConsumerReportsrecently tested 8 sun-screens and found titaniumand zinc nanosized particlesin each one, whether or notthey contained a label to in-dicate theuse of the ultrafineparticles.3

POTENTIAL RISKS OFNANOSIZEDPARTICLES

The majority of toxicolo-gists believe that the risks of nanoparticles comefrom their inhalation via pollution, candle combus-

tion, or heating foods and subsequent depositionand respiratory tract inflammation.1,4 However, thepotential harm from epidermal application of nano-particles in sunscreens must be reviewed. The po-tential toxicity concerns of nanosized particles insunscreens are a result of their size, their ability toevade immunologic defense mechanisms, their abil-ity to form complexes with proteins, and mostimportantly, their ability to induce the formation offree radicals. In addition to the potential dermalabsorption of nanosized particles in sunscreens, it isimportant to consider the oral absorption of nano-

sized particles in sunscreens for lips and respiratorytract absorption in aerosolized sunscreens.Respiratory tract absorption is also a concern forpowder makeup containing TiO2- and ZnO-basedsunscreens.

The penetration of materials into the stratumcorneum is limited by molecular size. The intercel-lular space between the cells composing the stratumcorneum measures approximately 100 nm3 and maybe widened with topical application of variousproducts.5,6 This raises the question of whether theparticles used in TiO2- and ZnO-based sunscreens

have the potential to penetrate the stratum corneum.

Furthermore, developments in alternative drugdelivery systems at the nanoscale level have intro-duced the concept of a nanoemulsion. This prepara-tion, which includes oil, surfactant, and water,improvesthe bioavailabilityof hydrophobic materials.

Because of their diminutive size, nanoparticlescarry several inherent properties. First, ultrafine

particles have larger surfaceareas per unit mass.7,8

Second, particle toxicity isdetermined by surface reac-tivity. Thus, given their struc-ture, nanoparticles willexhibit greater harm com-pared with larger particlesbecause of their proportion-ally increased surface area.

In addition to their size

and surface reactivity, nano-particles may evade the hu-man bodys natural clearancemodalities and immune de-fenses through a variety ofmechanisms. Some productscontaining nanoparticles areintentionally engineered toescape rapid clearance andimmune surveillance to

achieve the desired therapeutic action. These prop-erties include prolonged half-lives in circulation,

controlled and sustained release, penetration of theblood-brain barrier, and preference for collecting inspecific organs.9

The large surface area of ultrafine particlesprovides a distinctive interface for catalytic reac-tions of surface-located mediators with biologicaltargets such as proteins. When nanoparticles bindproteins, they form complexes with biological andchemical properties different from the originalparticle. Nanoparticle protein complexes may bemore portable than protein complexes formedwith larger particles. When these complexes un-

dergo protein metabolism, they may be trans-located to tissues to which noncomplexednanoparticles or large particles may not have hadprior access. Furthermore, protein metabolism andsubsequent modification occurs at the proportion-ally increased surface area of these nanoparticleprotein complexes.10,11 These surface modifica-tions may enable nanoparticles to escape detectionfrom phagocytosis and immune surveillance.Changes at the surface may also cause the particlesto act as haptens and change their function orrender them antigenic. This antigenicity has impli-

cations for autoimmune disease.

12

CAPSULE SUMMARY

d The US Food and Drug Administration,

international regulatory agencies,

physicians, and the general public are

scrutinizing the safety of nanosized

particles in sunscreens.

d To date, in vivo and in vitro studies have

not demonstrated percutaneous

penetration of nanosized particles intitanium dioxide and zinc oxide

sunscreens.

d Although the weight of evidence

suggests these sunscreens are safe,

future studies must examine these

sunscreens under ultraviolet light and on

broken skin.

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The ultimate concern with the use of nanosizedparticles in sunscreens is the formation of freeradicals. TiO2 and ZnO are known photocatalyststhat are used to generate electricity in photovoltaiccells. When exposed to UV light, they emit electrons.These electrons, in turn, induce the formation ofperoxides, free radicals, and other reactive oxygenspecies (ROS). ZnO emits a greater amount ofelectrons than TiO2 and the anatase form emitsmore than rutile form.13 The obvious concern isthat the ROS formed by UV-exposed TiO2and ZnOhave the potential to damage proteins, lipids, andDNA they contact. Of note, mineral sunscreenslacking nanoingredients have been marketed andused under UV exposure for years, but there are nostudies demonstrating the production of potentiallyharmful free radicals with these traditional sun-screens. If these studies were to be undertaken, the

larger particles in mineral sunscreens would haveless surface area to react with UV light and thus, beless likely to form such ROS. Several studies havebeen conducted to address the concern of freeradicaleinduced DNA damage and we have sum-marized their findings below.

DNA DAMAGE BY FREE RADICALPRODUCED IN SUNSCREENS

In 1997, Dunford et al14 demonstrated that whenplasmid DNA was exposed to stimulated sunlight,UVA and UVB rays, in the presence of TiO2particles,

the hydroxyl radicals accelerated the breakage ofDNA strands. It was concluded a health hazard mightexist if TiO2can enter viable living cells after pene-trating the stratum corneum. The authors describedsystems studies as in vitro and in vivo, however,none were actually studied in vivo because culturedhuman fibroblasts were used. Whether this protocoltruly used nanosized particles is unclear because thesize of the particles in the sunscreens was notrevealed.

Serpone et al15 also described the deleteriouseffects of micronized TiO2on DNA. They purported

to have tested for the formation of hydroxyl radicalsproduced on irradiation of TiO2 extracted fromsunscreen in both in vitro and in vivo studies. Theauthors verified TiO2 as an initiator of harmfulreactions including DNA strand breaks throughgeneration of free radicals. However, the methodol-ogy of the study was not described, and thus theresults could not be reproduced or analyzed.

In 2002, Uchino et al16 examined the generation ofhydroxyl radicals by UVA in different forms of TiO2.They found that UVA irradiation of the anatase formof TiO2 generated hydroxyl radicals in a dose-

/exposure-related manner, whereas the rutile form

was significantly less effective at generating hydroxylradicals. Cytotoxicity of the hydroxyl radical wasthen tested using Chinese hamster ovarian cells.These ovarian cells were found to be sensitive tothe amount of hydroxyl radical formed from the firstexperiment.

Recently Hidaka et al17 studied damage to DNAby TiO2 and ZnO after UV exposure. The authorsobserved an increase in nicks on supercoiled DNAplasmids forming a relaxed and ultimately linearDNA conformation as a result of hydroxyl radicalsgenerated by UV irradiated by TiO2 and ZnO.The mechanism of the reaction includes the hydroxylradical attacking the ribose, deoxyadenosine, gua-nosine, and cytidine nucleotides within 30 minutesof irradiation. This reaction results in the rapiddegeneration of DNA constituent nucleotidesdeoxyadenosine-5-monophosphate, guanosine

monophosphate, and cytidine monophosphate inthe presence ofUV irradiated TiO2and ZnO.

Dufour et al18 published a study in 2006 that isoften cited by proponents of nanotechnology. In thisstudy, the investigators applied ZnO to Chinesehamster ovarian cells under 3 conditions: in thedark, under simultaneous irradiation with UV light,or preirradiated with UV light, followed by treat-ment with ZnO in the dark. Interestingly, thenature, incidence, and severity of chromosomeaberrations in preirradiated and simultaneouslyirradiated cells were nearly identical with regard

to cytotoxicity. Given that Chinese hamster ovar-ian cells preirradiated in the absence of ZnOshowed the same increase in the incidence andtype of chromosomal aberrations as Chinese ham-ster ovarian cells receiving simultaneous ZnOtreatment, the authors concluded that chromosomeaberrations were a result of a UV-mediated, en-hanced susceptibility of the mammalian cells toZnO. The authors thus concluded that ZnO isnonphotogenotoxic.

Despite the studies that suggest nanoparticulateTiO2 and ZnO are potentially toxic to DNA via the

formation of ROS, many researchers believe thisshould only be viewed as a legitimate toxicity con-cern if there were evidence to suggest that nano-particulate TiO2and ZnO are capable of penetratingthe epidermis. If the nanosized particles in sun-screens applied to the skin penetrate the dermis,there is a concern for systemic absorption of theseparticles that have potential inflammatory and carci-nogenic effects. Several authors have proposed thattopically applied nanoparticles may reach the dermisand ultimately incorporate systemically.19,20 We willexamine the in vivo and in vitro studies of nano-

particulate TiO2and ZnO penetration in intact skin.

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These studies involve both human and animal sub-jects. Of note, the permeability of animal skin differswidely for certain materials. Penetration of rabbit

skin is greater than rodent skin, which is greater thanpig skin, which is greater than human skin.21

PERCUTANEOUS PENETRATION OFTOPICALLYAPPLIED TIO2 SUNSCREENS

See Table I.22-29 In a larger study, Lademann et al23

investigated the penetration of TiO2 microparticlesinto the horny layer and the orifice of the hair folliclein human skin. The distribution of the microparticlesin the horny layer was analyzed using the method oftape stripping in combination with spectroscopicmeasurements. The penetration of TiO2 was inves-

tigated in histologic skin sections. Deeper layers of

the stratum corneum were devoid of TiO2. Biopsyspecimens were taken from areas where the hornylayer had been removed by tape stripping. In

isolated areas, a penetration of coated TiO2 wasobserved in the orifice of the follicle. The amount ofTiO2found in any given follicle was less than 1% ofthe applied total amount of sunscreen. Penetration ofmicroparticles into the viable skin tissue was notdetected.

Mavon et al29 assessed the penetration of TiO2,a mineral sunscreen into human skin in vivo,using the tape stripping method, and in vitro,using a compartmental approach. TiO2 and meth-ylene bis-benzotriazoyl tetramethylbutylphenolwere quantified using colorimetric assay and

high performance liquid chromatography analysis,

Table I. Titanium dioxide skin penetration studies

TiO2 studies

Study Material 1coating Particle size Design Results

Tan et al,22 1996 TiO2 Not specified Human skin, in vitro No penetration into

skinNo coating specified

Lademann et al,23

1999

TiO2 150-170 nm Human skin biopsy Penetration into upper

layers of stratum

corneum; ;1% of

particles in ostium of

follicle

Al2O3, stearic acid

coated

European Union,24

2000

TiO2 14 nm-200m Human skin, tape

stripping or biopsy;

pig skin, in vitro

Penetration limited to

stratum corneumAnatase and rutile

coating

Pflucker et al,25 2001 TiO2 10-100 nm Human skin, in vitro Penetration into upper

layers of stratum

corneum

SiO2, Al2O3, SiO2 1

Al2O3 coating

Schulz et al,26 2002 TiO2 10-100 nm Human skin biopsy Particles in and on

upper layers of

stratum corneumSiO2 6 Al2O3 coating

Gottbrath andMuller-

Goymann,27 2003

TiO2 Not specified Human skin, tape

stripping

Particles in and on

upper layers of

stratum corneum

No coating information

Menzel et al,28 2004 TiO2 45-150 nm Pig skin, in vitro Particles in stratum

corneum; minimal

penetration into

stratum granulosum


Mavon et al,29 2007 TiO2 20 nm Human skin, in vitro Penetration in upper

layers of stratum

corneum

SiO2 coated

Adapted with permission from Nohynek et al.37



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respectively. Transmission electron microscopyand particle-induced radiographic emission tech-niques localized the TiO2 in skin sections. Greaterthan 90% of TiO2 was recovered in the first 15tape strippings. The remaining 10% did not pen-etrate the viable tissue, but was localized in thefurrows and in the opened infundibulum. No TiO2was detected in the follicle, viable epidermis, ordermis. Similar to the conclusions of the above-

reviewed studies, the in vivo and in vitro studies

showed an absence of TiO2 penetration into theviable skin layers through either transcorneal ortransfollicular pathways.

PERCUTANEOUS PENETRATION OFTOPICALLYAPPLIED ZnO SUNSCREENS

SeeTable II.30-32 Cross et al32 determined humanepidermal penetration of a transparent nanoparticulateZnO sunscreen formulation using diffusion cells,

24-hour exposure, and electron microscopy to

Table II. Zinc oxide skin penetration studies

ZnO studies

Study Material 1 coating Particle size Design Results

Pirot et al,30 1996 ZnO Not specified Human skin, in vitro 0.36% Penetration in 72 h


EuropeanUnion,31 2003

ZnO Not specified Human nonpsoriatic andpsoriatic skin; pig skin,

in vitro

No change in plasma zinclevels; in vitro,

penetration\1% of

dose; most ZnO

recovered from stratum

corneum

Cross et al,32 2007 ZnO 15-30 nm Human skin, in vitro No penetration in

epidermis or dermis;

\0.03% of applied Zn

recovered in

No coating information stratum corneum


Table III. Combined titanium dioxide and zinc oxide skin penetration studies

TiO2 and ZnO combined studies

Study Material 1 coating Particle size Design Results

Lansdown and Taylor,33

1997

TiO2, ZnO \2-20 m Rabbit, in vivo Penetration into stratum

corneum and outer

hair follicle


Dussert and Gooris,34

1997

TiO2, ZnO TiO2: 50-100 nm Human skin,

in vitro

Penetration into upper

layers of stratum

corneum


ZnO: 20-200 nm

Gontier et al,35

2004 TiO2, ZnO Not specified Human, pig, mouseskin, in vitro

TiO2 found inintercellular space

between corneocytes

of upper layers of

stratum corneum

Al2O3

Gamer et al,36 2006 TiO2 TiO2: 30-60 nm Pig skin, in vitro Penetration in upper

layers stratum

corneum; 0.8%-1.4% of

applied dose

recovered

SiO2, dimethicone

coated

ZnO: \160 nm

ZnO uncoated




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locate the nanoparticles in the exposed skinlayers. Less than 0.03% of the applied zinc contentpenetrated the epidermis, which was not signifi-cantly different from the penetration of theplacebo. No particles were detected in the lowerstratum corneum or viable epidermis by electronmicroscopy as was similar to the above-reviewedinvestigations.

PERCUTANEOUS PENETRATION OFTOPICALLY APPLIED TiO2AND ZnOSUNSCREENS

SeeTable III.33-36 Gamer et al36 investigated the invitro absorption of microfine TiO2 and ZnO in pigskin. The mean total titanium recovery was 86% to100% depending on the formulation applied. Nearlyall of the titanium applied was removed from the skinsurface by washing. Titanium was never detected in

the receptor fluid. The mean total recovery of zincwas 102% to 107% of the total zinc applied. Theamount of zinc found in the skin membrane andreceptor fluid was comparable in untreated, vehicle-treated, or test-treated subjects. The authors con-cluded that neither the TiO2 nor ZnO penetratedfurther than the stratum corneum.

THE REGULATORY STATE OF NANOSIZEDPARTICLES

In addition to dermatologists and sunscreen con-sumers, governing bodies are also concerned about

these reviewed experiments. The European Unionand Australian cosmetic regulatory bodies havereviewed the toxicity of titanium and zinc nanoing-redients in sunscreens. In 2006 the Australian Thera-peutic Goods Administration conducted a review ofscientific literature in relation to the use of titaniumand zinc nanosized particles. They concluded thatthere is evidence from isolated cell experiments thatzinc oxide and titanium dioxide can induce freeradical formation in the presence of light and thatthis maydamage these cells. However, this would onlybe of concern in people using sunscreens if the zinc

and titanium penetrated into viable skin cells. Theweight of current evidence is that they remain on theskin surface and in the outer dead layer.

The US FDA is a member agency of the NationalNanotechnology Initiative, a federal research anddevelopment program that promotes the responsibleexpansion of nanotechnology. In the United States,the FDA in 1999 made a decision to allow nanosizedparticle ingredients to be used in sunscreens withoutnew safety assessments based on previous safetyassessments of larger particles. However, in 2006, acoalition of public interest organizations led by the

International Center for Technology Assessment and

including Friends of the Earth filed the first US legalaction on the potential human health and environ-mental risks of nanotechnology. The legal petitionfiled with the FDA demanded that the FDA compre-hensively amend its regulations to address the humanhealth and environmental risks of nanomaterials inconsumer products, including requiring mandatorynanoingredient product labeling andpremarket nano-specific toxicity testing. The petition also called for therecall of nanosunscreens currently on the market withmanufactured nanosized particles of TiO2.

In 2007 the FDA convened a task force to examinethe scientific and regulatory challenges that accom-pany the growth in nanotechnology. Their reportrecommended: (1) the consideration of guidancethat would clarify what information manufacturersshould give the FDA about products and when theuse of nanoscale ingredients may change the regu-

latory status of products; (2) that manufacturerscontact the FDA early in the product developmentprocess; (3) that the FDA assess data needs forregulated nanotechnology products including bio-logic effects; (4) that the FDA develop their ownbody of inhouse experts to rapidly consider newadvances in nanotechnology; and (5) that the FDAevaluate their current testing approaches to examinethe safety, effectiveness, and quality of nanoscaleproducts. New regulations were also proposed withregard to sunscreen labeling, most notably, a ratingsystem for UVA protection.

CONCLUSIONSThere are legitimate and verified toxicity concerns

with regard to TiO2and ZnO nanosized particles insunscreens resulting from their inherent propertiesand their ability to form ROS when exposed to UVlight. However, these toxicity concerns can only berealized if nanoparticulate TiO2and ZnO are able topenetrate the epidermis. Although the studies re-viewed in this article suggest that titanium and zincnanosized particles do not penetrate the stratumcorneum, they contain several inherent problems

leaving us unable to conclude with certainty thatnanosized particles are safe to use in sunscreens.

To begin with, interpretation of the in vivo skinpenetration studies between different species shouldbe undertaken with caution as the permeability canvary widely depending on the nature of the speciesand of the compound being studied. In general, thepenetration of rabbit skin is greater than rat skin,which is greater than pig skin, which is greater thanhuman skin.37

Second, all reviewed in vitro studies were con-ducted on intact skin. When the stratum corneum

layer is disrupted in skin that is traumatized or



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diseased, might these nanosized particles penetratefurther? The review of Schafer-Korting et al38 suggeststhat although certain skin diseases may affect skinpenetration of topical agents, the majority of theliterature supports that slightly compromised skinhas no greater susceptibility to penetration. In psori-asis, the epidermis is hyperkeratotic and thus, likelyexhibits less penetration of topically appliedmaterials.However, in eczema, where the stratum corneum isoften disrupted, penetration of topicals has beenshown to be greater than in psoriatic skin. Whendiscussing the safety of nanosized particles in sun-screens, we must examine the properties of sun-burned skin, as people often reapply sunscreen afterthey have received substantial sun exposure andpossible burn. Gunther et al39 determined that thepercutaneous absorption and bioavailability of meth-ylprednisolone aceponate lotion applied to UVB-

induced sunburned skin and intact skin was equalor lower for the sunburned skin. Removal of thestratum corneum by tape stripping significantly in-creased penetration of the steroid lotion in both skintypes. The authors concluded that inflamed skinproduces a thickened epidermis that enhances thebarrier function of the skin. Further studies arewarranted to determine whether these principlesapply to TiO2- and ZnO-based sunscreens appliedto damaged skin.

Finally, all of the studies reviewed on skin pene-tration were conducted without control for UV expo-

sure. Therefore, no study has yet simulated the real-life scenario for the application of sunscreens.

Future studies to determine the safety of ZnO andTiO2nanosized particles in sunscreens should repro-duce a human model for the real-world application ofsunscreens including broken skin and accounting forUVexposure. These studies may, in addition, measurethe potential penetration of ROS, formed on thestratum corneum from nanosized particles exposedto UV light into the upper layers of the epidermis.

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