Photoprotection

Part II. Sunscreen: Development, efficacy, and controversies

Rebecca Jansen, MD,a Uli Osterwalder, MS,b Steven Q. Wang, MD,c Mark Burnett, MD,c and Henry W. Lim, MDa

Detroit, Michigan; Monheim, Germany; and New York, New York

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core curriculum, identified professional practice gaps, the educational needs which

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The editors involved with this CME activity and all content validation/peer reviewers

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Authors

Dr Lim has served as consultant for Ferndale, La Roche-Posay, Pierre Fabre, Uriage,

and Palatin. He has received research grants from Clinuvel and Estee Lauder. Mr

Osterwalder is a full time employee of BASF. Dr Wang has served on the advisory

board of L’Oreal. Drs Burnett and Jansen have no conflicts of interest to declare.

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After completing this learning activity, participants should be able to describe the

evolution of sunscreen technology; summarize new photoprotective technologies;

and discuss and explain current sunscreen controversies.

Date of release: December 2013

Expiration date: December 2016

� 2013 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2013.08.022

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privacypolicy

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J AM ACAD DERMATOL

DECEMBER 2013867.e2 Jansen et al

In addition to the naturally occurring, physical, and systemic photoprotective agents reviewed in part I,topical ultraviolet radiation filters are an important cornerstone of photoprotection. Sunscreen develop-ment, efficacy, testing, and controversies are reviewed in part II of this continuing medical educationarticle. ( J Am Acad Dermatol 2013;69:867.e1-14.)

Key words: oxybenzone; photoprotection; photostability; Sun Protection Factor; sunscreen; sunscreencontroversies; ultraviolet filter.

CAPSULE SUMMARY

d Ideal sunscreens provide uniformprotection across the ultraviolet B andultraviolet A light range whilemaintaining sensory and tactile featuresthat enhance the user’s experience.

d Sunscreen efficacy depends onultraviolet filter type (organic orinorganic), photostability, and theaddition of Sun ProtectionFactoreboosting agents.

d New US Food and Drug Administrationregulations regarding sunscreen testingand labeling aim to improve the clarityof photoprotection of sunscreens.

d While there are controversies involvingsunscreen ingredients, formulations, andside effects, based on current data, theriskebenefit ratio indicates that it isappropriate to include the use ofsunscreen as an important componentof photoprotection strategy.

SUNSCREENS:TOPICALPHOTOPROTECTIVEAGENTSKey pointsd Ideal sunscreens pro-vide uniformprotectionagainst ultraviolet A andultraviolet B light.

d Ideal sunscreens haveaesthetically pleasingcompositions that en-hance compliance.

The notion of the ‘‘idealsunscreen’’

Since the first commercialsunscreen was introduced in1928, the use of sunscreensas an integral part of photo-protection strategy has ex-panded worldwide. Table Ihighlights the historical de-velopment of sunscreens.1-4

Two factors must be ad-dressed to produce an‘‘ideal’’ sunscreen.5 It

should provide uniform protection across therange of ultraviolet B light (UVB) and ultravioletA light (UVA), a property referred to as ‘‘spectralhomeostasis,’’ which assures that the natural spec-trum of sunlight is attenuated in a uniform manner(Fig 1).6 This is particularly useful for protectionagainst immunosuppression, which has a broadaction spectrum.7 An ‘‘ideal’’ sunscreen should alsohave pleasing sensory and tactile profiles thatenhance the user’s compliance.

the Department of Dermatology,a Henry Ford Hospital,

etroit; BASF Personal Care and Nutrition GmbH,b Monheim;

d the Division of Dermatology,c Memorial Sloan Kettering

ancer Center, New York.

ing sources: None.

im has served as consultant for Ferndale, La Roche-Posay,

erre Fabre, Uriage, and Palatin. He has received research

ants from Clinuvel and Estee Lauder. Mr Osterwalder is a full

time employee of BASF. D

board of L’Oreal. Drs Burn

interest to declare.

Reprint requests: Henry W. L

Henry Ford Medical Cente

Blvd, Ste 800, Detroit, MI

0190-9622/$36.00

Ultraviolet filtersPrinciples of ultraviolet

radiation absorptionby organic ultravioletfilters. In order to absorbultraviolet radiation (UVR),an organic ultraviolet (UV)light filter must contain asuitable chromophore thathas conjugated p-electronsystems. Increasing the num-ber of conjugated doublebonds in the molecule shiftsthe absorption maximum tolonger wavelengths and alsogives rise to a larger absorp-tion cross section and, there-fore, stronger absorption. Ingeneral, the larger the mo-lecular weight of the chro-mophore, the more theabsorption maximum willbe shifted towards longerwavelengths. This is the rea-son that UVB light filters havesmaller molecular weightscompared to UVA light or

broad-spectrum filters.Currently, all organic UV absorbers used in sun-

screens are aromatic compounds, each containingmultiple conjugated p-electron systems (Tables IIand III).8 The type of substituents and their positionat the aromatic ring are important for the UV spec-troscopic properties. Especially advantageous aredisubstituted systems with an electron-donor (1M-)and an electron-acceptor (�M-) group in paraposi-tion (so-called pushepull systems). Fig 2 shows a

r Wang has served on the advisory

ett and Jansen have no conflicts of

im, MD, Department of Dermatology,

r e New Center One, 3031 W Grand

48202. E-mail: hlim1@hfhs.org.

Abbreviations used:

AAP: American Academy of PediatricsAO: antioxidantAVO: avobenzoneBEMT: bemotrizinolCW: critical wavelengthE1,1: extinction at 1 cm path length and 1%

concentrationEU: European UnionFDA: Food and Drug AdministrationISO: International Organization for

StandardizationMED: minimal erythema dosePPD: persistent pigment darkeningROS: reactive oxygen speciesSPF: Sun Protection FactorTiO2: titanium dixoxideUK: United KingdomUSAN: United States Adopted NameUV: ultraviolet lightUVA: ultraviolet A lightUVB: ultraviolet B lightUVR: ultraviolet radiationZnO: zinc oxide

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VOLUME 69, NUMBER 6Jansen et al 867.e3

comparison of the absorption spectra of ethylhex-yldimethyl paraaminobenzoate (United StatesAdopted Name [USAN], padimate O), with substitu-ents in a paraposition, and a UVabsorber with similargroups but in orthoposition, menthyl anthranilate(USAN, meradimate). Because of the substituents inparaposition, padimate O is a more efficient UV filterthan meradimate.

Photostability. Absorption of a UV photontransfers the UV absorber molecule into an excitedelectronic state. If the absorbed energy is not suffi-ciently and speedily dissipated into heat, chemicalbonds of the UV absorber may break, resulting indegradation of the UV filter. A reversible isomeriza-tion (tautomerism) in the excited state can stabilizean UV absorber.9,10 This principle is realized, forinstance, in the menthyl anthranilate molecule be-cause of the orthoamino group (Fig 2), resulting inexcellent photostability. In others, this is realized viaan orthohydroxy group forming hydrogen bonds(eg, bemotrizinol and bisoctrizole).

Most of the UV absorbers used in sunscreens arephotostable under the conditions of use. Two ex-ceptions are avobenzone (AVO) and octinoxate.11

AVO undergoes rapid photodegradation, which canbe stabilized by UV filters octocrylene and bemo-trizinol. The latter is not yet available in the UnitedStates (Fig 3). In addition, AVO and octinoxateenhance the photodegradation of each other. Forthis reason, these 2 filters should not be used incombination.12-14

Principles of ultraviolet protection with in-organic ultraviolet filters. Micronized inorganicoxides used in sunscreens (TiO2 and ZnO) attenuate

UV mainly by absorption and some scattering.15

Depending on particle size, these materials aresemiconductors that absorb photons at differentwavelengths. The smaller the primary particles, theshorter its peak absorption spectrum.16 The primaryparticle sizes of TiO2 used in sunscreens are between10 and 30 nm. However, in dispersion, the particlesform aggregates with sizes usually around 100 nm.With ZnO, primary particle sizes from 10 to 200 nmare available, but mainly the grades with largerparticles are used. Because of the photocatalyticeffect, TiO2 for sunscreen applications is coated withaluminum oxide or silica in order to prevent oxygenradical formation. In addition, the rutile crystal formis used in most cases. Rutile is the most commonform of TiO2, has a high refractive index, and canabsorb UVR. Although the anatase form of TiO2 hasmany of the same properties as the rutile form, it haslower UVR absorption and higher tendency forphotocatalysis.

Particulate organic ultraviolet filters. Sun-screens, especially those with a high Sun ProtectionFactor (SPF), contain a considerable amount of UVfilters. Therefore, solubility of the active substancecan be a significant problem.17 For this reason,particulate organic UV filters were developed thatallow high SPF products to be developed withrelatively lower concentrations of UV filters.Examples of these UV filters include methylene bis-benzotrazolyl tetramethylbutylphenol (biscotrizole)and tris-biphenyl triazine. These filters have ex-tremely low solubility in oil and in water, but canbe micronized in an aqueous phase.17,18 Particulatebiscotrizole shows a broad absorption up to 380 nm.

Regulations of ultraviolet filters. The safety ofUV filters has to be shown in an extensive program oftoxicologic studies. In Europe and Japan, UV ab-sorbers are regulated as cosmetics, in the UnitedStates as over the counter drugs and in Australia astherapeutic drugs.19 An overview of common UVfilters in sunscreen is shown in Table II. Australia andEurope have the most UV filters for sunscreenformulation. By contrast, the United States has theleast number of UV filters available.

Limitations of available ultraviolet filters inUnited States. While sufficient filters are availablein the UVB and UVA2 range, only 4 UVA1 (340-400nm) filters, all with limitations, are approved in theUnited States (Figs 4 and 5). AVO is the most efficientUVA1 filter, but it is not photostable. In the UnitedStates, the maximal concentration is 3%, and it is notapproved for combination with TiO2 because en-hanced photodegradation of AVO is observed in thepresence of TiO2. AVO is also not approved incombination with ZnO for lack of data to show the

Fig 1. Evolution of sunscreens from predominant protec-tion against UVB light toward spectral homeostasis (E1,1,extinction at 1-cm path length and 1% concentration as ameasure for UV light filter efficacy at every wavelength inthe UVR range). UV, Ultraviolet; UVB, ultraviolet B; UVR,ultraviolet radiation.

Table I. Historical development of sunscreen

Year(s) Development

1928 First commercial use of sunscreen in the United States: emulsion containing benzyl salicylate andbenzyl cinnamate1

1933 An ointment containing benzylimidazole sulfonic acid becomes the first commercial sunscreenavailable in Germany1

1936 The future founder of L’Oreal, Eug�ene Schueller, markets the first commercial sunscreen available inFrance, an oil preparation containing benzyl salicylate1

1938 Franz Greiter, the founder of Piz Buin Company, develops an effective sunscreen in Austria, Gletschercr�eme; he later improves upon and popularizes the concept of SPF (1974)1

1943 p-Amino benzoic acid is patented2

1950s Higher incomes and expanding travel options spur emergence of the sunscreen market3

1956 Schulze invents the SPF, enabling the evaluation of sunscreen performance4

1970s Introduction of oxybenzone as a broad spectrum UVB/UVA filter; broad introduction of SPF onsunscreen packaging revolutionizes marker, and products are now comparable on a quantitativebasis

1980s Avobenzone, a long-wave UVA filter, is approved by the US FDA (1988; approved in Europe in 1978)1990s-2000s Attitude of consumers toward sun exposure changes as the public becomes increasingly aware of the

potential harm from solar radiation2000s-2010s Role of topical sunscreens expands from mere protection against sunburn to include health

prophylaxis

FDA, Food and Drug Administration; SPF, Sun Protection Factor; UVA, ultraviolet A light; UVB, ultraviolet B light.

J AM ACAD DERMATOL

DECEMBER 2013867.e4 Jansen et al

enhancement of UVA protection potential of ZnO inthe presence of AVO.20 Ecamsule, themost recent UVfilter approved in the United States (2006), is avail-able only for the sponsor of the new drug application(ie, it can only be used in certain products). The thirdorganic UVA1 filter, meradimate (Fig 2), is ratherweak and limited to use at concentrations\5%. Thefourth UVA1 filter is ZnO, which has low E1,1 value.While it can be used in concentrations of # 25%, inpractice, cosmetic limitations exist at such highconcentrations.

SunProtectionFactoreboostingagents. Betterfilm forming of sunscreen on the skin leads to amore uniform distribution and therefore to a higherSPF. The use of organic UV filters to stabilize inher-ently unstable UV filters, such as AVO, leads toa higher SPF and/or better UVA protection. It

should be noted that some of the emollients, photo-stabilizers, and other ingredients in sunscreen pro-ducts are also UV absorbers, although they do notappear on the actives list on the drug fact sheet(Table III).

Ultraviolet filters not yet available in theUnited States. In the UVB/UVA2 range, 2 UV filtersare frequently used outside of the United States: octyltriazone and diethylhexyl butamido triazone. Asseen in Figs 6 and 7, they are the most efficientUVB filters, with a maximal E1,1 value[1400. Lessfrequently used is amiloxate, a homologue of octi-noxate with isopentyl instead of the ethyl-hexylgroup. A unique UV filter is polysilicon-15. It has alow E1,1 value of just[150. However, because it hasa polymeric structure, it spreads extremely well onthe surface of the skin, contributing significantly tothe SPF.

All new UV filters that reach into the UVA1 rangeare photostable and shown in Table II. The mostefficient broad-spectrum UV filter is bemotrizi-nol.21,22 Bisoctrizole is a particulate organic UV filterwith especially broad UVB and UVA absorbance. Theinclusion of only a few percent of bisoctrizole booststhe critical wavelength (CW) to[370 nm.

SUNSCREEN USEKey pointsd The SPF value primarily measures the levelof protection against UVB and UVA2, and isbased on the ratio of MED on sunscreen-

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VOLUME 69, NUMBER 6Jansen et al 867.e5

protected skin compared to unprotectedskin.

d Methods for assessment of UVA protection.vary by country; in the US critical wave-length method is used.

Evaluation of efficacyThe SPF and the UVA protection profile are the 2

common indices used to quantify the efficacy ofsunscreens. The measurement of SPF depends onminimal erythema dose (MED), which is defined as‘‘the smallest UV dose that produces perceptibleredness of the skin (erythema) with clearly definedborders at 16 to 24 hours after UV exposure.’’23

SPF measurement is performed in vivo using apanel of paid volunteers with Fitzpatrick type I, II, orIII skin.23,24 Sunscreen is applied to the protected testsites at a density of 2 mg/cm2, which allows for evenand reproducible application of the sunscreen. SPF isthen calculated as the ratio of MED on sunscreen-protected skin to that on unprotected skin. There area number of factors that can affect SPF measurementresults: variation in the emission spectrum and totalirradiance of light sources used in different labora-tories; the duration, force, and uniformity of appli-cation of sunscreen; and subjectivity of visualassessment of the MED. These are the reasons forthe required incorporation of a standard sunscreenfor all SPF testing to ensure agreement of resultsamong different laboratories. It should be noted thathigh intensity solar simulators are needed to permittesting of high SPF sunscreens within practical timelimits; therefore, exposure to UV in SPF tests does notaccurately simulate exposure to sunlight during dailyactivity.

Ultraviolet A light testing. The SPF valuemainly measures the level of protection againsterythemogenic spectra of UV light (ie, UVB andUVA2).23 Improved understanding of the deleteriouseffects of UVA radiation has underpinned the devel-opment of better UVA filters and testing standards formeasuring UVA protection.

Methods for testing UVA protection have beenadopted by regulatory bodies in Japan, the EuropeanUnion (EU), United Kingdom (UK), Australia, andthe United States. However, the methodologies varyby country.25 Japan uses persistent pigment darken-ing (PPD) as a clinical endpoint. PPD measures theminimal UVA radiation dose required to induce thefirst perceptible pigmentation changes (ie, minimalpigmenting dose) in sunscreen-protected skin com-pared to unprotected skin. Sunscreen products arethen rated as PA1, PA11, PA111, or PA1111(where PA indicates the protection grade fromUVA).26 The EU requires UVA protection factor tobe at least one-third of the labeled SPF, with PPD

method as the assessment of the UVA protection. Forexample, a sunscreen with a SPF of 30 must have aUVA protection factor of at least 10.27 In the UK, theratio of UVA absorbance to mean UVB absorbance ismeasured in vitro; a star rating system is used.28

Australia adopted the in vitro test procedureISO 24443:2012 for determining broad-spectrumperformance, which is similar to the Europeanassessment.29 The adoption of this UVA testingmethod, which determines the spectral absorbancecharacteristics of UVA protection in a reproduciblemanner, has led to the development of sunscreenswith 10 to 20 times the protection against UVAradiation when compared to sunscreens complyingwith the old standard.29

In 2011, the US Food and Drug Administration(FDA) mandated the use of in vitro CW for testing ofUVA protection.30,31 Briefly, the CW test is conductedby applying the test product to 3 different polyme-thylmethacrylate plates at a density of 0.75 mg/cm2.To take into account the photostability of the pro-duct, a preirradiation dose of 800 J/m2 (ie, 80 mJ/cm2, the equivalent of 4 times the MED of Fitzpatrickskin phototype II) is delivered to the test product. UVtransmittances are then measured from 290 to 400nm. CW is defined as the wavelength at which 90% ofthe total area under the absorbance curve occurs(Fig 8). Sunscreens that have a CW of $ 370 nm arethen allowed to claim broad-spectrum status.

Immune protection factor. Photoimmuno-suppression by UVR is an in vivo parameter formingthe basis for the index of protection known asimmune protection factor. Immune protection factorcan be assessed by measuring the UVR-inducedsuppression of either the induction or elicitationarms of the delayed-type or contact hypersensitivityresponses.7 However, standardization of both thedefinition and the method for determination ofimmune protection factor has yet to be established.

Factors affecting sunscreen efficacyKnowledge and behavioral barriers. Sun-

screen should always be used in conjunction withother photoprotective measures (Table IV). Manyconsumers lack a fundamental understanding of therelationship between UVA/UVB and sunscreen pro-tection ratios.32 In practice, most people often applyonly 25% to 50% of the amount used for SPF testing.32

This results in an effective SPF that is # 33% ofthe labeled SPF. Recently, a modification of the‘‘teaspoon rule’’ for sunscreen application has beenproposed.33 Namely, to achieve 2mg/cm2 of density,the following should be done: 1 teaspoon of sun-screen to the face/head/neck, 1 teaspoon to eachupper extremity, a total of 2 teaspoons to the front

Table II. Common ultraviolet light filters approved in Australia, Europe, Japan, and the United States

INCI CE no.* USAN Trade name*y INCI abbreviation

Concentration limits in sunscreen (%)

AUS EU JP US

Broad-spectrum and UVAI (340-400 nm)Bis-ethylhexyloxyphenolmmethoxyphenyl triazine

S 81 Bemotrizinol Tinosorb S BEMT 10 10 3 z

Butyl methoxydibenzoylmethane S 66 Avobenzone Parsol 1789 BMBM 5 5 10 3Diethylamino hydroxybenzoylhexyl benzoate

S 83 Uvinul A Plus DHHB 10 10 10 —

Disodium phenyl dibenzimidazoletetrasulfonate

S 80 Bisdisulizoledisodium

Neo HeliopanAP

DPDT 10 10 — —

Drometrizole trisiloxane S 73 — Mexoryl XL DTS 15 15 — z

Menthyl anthranilate — Meradimate MA 5 5Methylene bis-benzotriazolyltetramethylbutylphenol

S 79 Bisoctrizole Tinosorb M(active)

MBBT 10 10 10 z

Terephthalylidene dicamphorsulfonic acid

S 71 Ecamsule Mexoryl SX TDSA 10 10 10 zx

Zinc oxide S 76 Zinc oxide ZnO (Nanox) ZnO No limit k No limit 25UVB (290-320 nm) and UVAII (320-340 nm)4-Methylbenzylidene camphor S 60 Enzacamene Eusolex 6300 MBC 4 4 — z

Benzophenone-3 S 38 Oxybenzone BP3 10 10 5 6Benzophenone-4 S 40 Sulisobenzone Uvinul MS40 BP4 10 5 10 10Polysilicone-15 S 74 — Parsol SLX PS15 10 10 10 —Diethylhexyl butamido triazone S 78 — Uvasorb HEB DBT — 10 — z

Ethylhexyl rimethyl PABA{ S 08 Padimate O Eusolex 6007 EHDP 8 8 10 8Ethylhexyl methoxycinnamate S 28 Octinoxate Uvinul MC 80 EHMC 10 10 20 7.5Ethylhexyl salicylate S 13 Octisalate Neo Heliopan

OSEHS 5 5 10 5

Ethylhexyl triazone S 69 Octyltriazone Uvinul T 150 EHT 5 5 3 z

Homomenthyl salicylate S 12 Homosalate Eusolex HMS HMS 15 10 10 15Isoamyl p-methoxycinnamate S 27 Amiloxate Neo Heliopan

E1000IMC 10 10 — z

Octocrylene S 32 Octocrylene Uvinul N 539 T OCR 10 10 10 10

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J AM ACAD DERMATOL

VOLUME 69, NUMBER 6Jansen et al 867.e7

and back torso, and 2 teaspoons to each lowerextremity.

Studies have shown the incorrect application andreapplication of sunscreen by the lay public and theneed for avoidance of unnecessary sun exposureafter its application.32,34 It is clear that a sustainedeffort in public education is still needed.

Initiatives to enhance clarity and consistencyof sunscreen use

Updating the 2011 US Food and Drug Admin-istration regulations. Effective December 2012,sunscreens that have an SPF $ 15 and CW $ 370 nmcan display the claim that ‘‘if used as directed withother sun protection measures, decrease the risk ofskin cancer and early skin aging caused by thesun.’’30,31 For sunscreens that are not broad-spectrum (ie, CW\370 nm) or are broad-spectrumbut with an SPF\15, these above claims will not beallowed on the label.

In addition, the terms ‘‘sunblock,’’ ‘‘water proof,’’‘‘sweat proof,’’ or ‘‘all day protection’’ are notallowed. Going forward, labels may only containthe statement ‘‘water resistant (40 minutes)’’ or ‘‘wa-ter resistant (80 minutes),’’ reflecting the actual waterresistant testing wherein test subjects are immersedin a whirlpool twice for 20 minutes or 4 times for 20minutes, followed bymeasurement of the SPF. Lastly,as of this writing, the US FDA has yet to make thefinal determination on the following proposed items:SPF capped at 50, sunscreens in the form of oils,lotions, creams, gels, butter, pastes, and ointment aseligible dosage forms, sunscreens in the form ofwipes, towelettes, powders, body wash, and sham-poo are not eligible, and safety of sprays.

SUNSCREEN CONTROVERSIESOxybenzoneKey pointsd Oxybenzone has been shown to have estro-genic effect, both in vitro and in an in vivoanimal model.

d It has been used in the United States sincethe 1970s, and no untoward cause and effectrelationship in humans has been reported.

The potential hormonal disruption effect of oxy-benzone, an organic UV filter with an absorptionprofile ranging from 270 to 350 nm, has beendiscussed in the past few years. It has been used inthe US since the 1970s, and prevalence of exposureto the compound among the US population isestimated to be 96%.35

In vitro experiments using human breast cancercells suggest that oxybenzone can exert both

Table III. Emollients and photostabilizers (‘‘boosters’’) with ultraviolet lighteabsorbing properties

Name Trade name*

UV light absorption

Max (E1,1) Max (nm)

Butyloctyl salicylate Hallbrite BHB 140 306Benzotriazolyl dodecyl p-cresol Tinogard TL 350/380 304/337Ethylhexyl methoxycrylene Solastay S1 320 340Polyester-8 Polycrylene 160 306Diethylhexyl syringylidenemalonate Oxynex ST 370 338Diethylhexyl 2,6-naphthalate Corapan TQ 310/60 295/350

E1,1, Extinction at 1-cm pathlength and 1% concentration; UV, ultraviolet.

*Trade names are the property of their respective manufacturers.

Fig 2. Ultraviolet light absorption spectra of ethylhexyl-dimethyl p-amino benzoate (padimate O) and menthylanthranilate (meradimate). E1,1, Specific extinction.

Fig 3. Photostability of avobenzone, alone and in pres-ence of octocrylene and bemotrizinol.

Fig 4. UVB and UVA2 light filters commonly used in theUnited States. UVA, Ultraviolet A; UVB, ultraviolet B.

Fig 5. UVA1 and broad-spectrum UV light filters com-monly used in the United States. UV, Ultraviolet; UVA,ultraviolet A.

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DECEMBER 2013867.e8 Jansen et al

estrogenic36-39 and antiandrogenic39,40 effects. In anin vivo study, Schlumpf et al38 found that the weightof the uteri in 21-day-old rats fed with oxybenzone([1500mg/kg/day) was 23% greater than uteri of thecontrol group. However, the dosage of oxybenzoneused in this study was exceedingly high, and Wanget al41 estimated that it would take 277 years of daily

application of sunscreens with 6% oxybenzone toattain the same level of exposure in humans.

In humans, in a single-blinded, short-term clinicalstudy, exposure to oxybenzone did not produceclinically relevant effects on hormonal homeosta-sis.42 Oxybenzone was detected in urine of studiedsubjects in the United States and Denmark; however,it was not correlated with the use of sunscreens.35,43

One or more UV filters were detected in 85% ofhuman milk samples in a study conducted in

Fig 6. UVB light filters not yet available in the UnitedStates. UVB, Ultraviolet B.

Fig 7. UVA1 and broad-spectrum UV filters not yet avail-able in United States. UV, Ultraviolet; UVA, ultraviolet A.

Fig 8. CW testing of sunscreen products. Sunscreen 1 hasa CWof 357 nm, and cannot claim to be a broad-spectrumproduct. Sunscreen 2 has a CWof 378 nm; therefore, it is abroad-spectrum sunscreen. CW, Critical wavelength.

Table IV. Complete photoprotection package

Shade

Protective clothingWide-brimmed hatSunglassesSunscreen

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Switzerland, and high oxybenzone levels in mother’surine were associated with decreased birth weight ingirls and increased birth weight and head circumfer-ence in boys.44 While no cause and effect relation-ship was established in the above studies, continuedcareful observation is warranted.

Retinyl palmitateKey pointsd Concerns have been raised regarding thephotocarcinogenic potential of retinylpalmitate.

d Analysis of results of animal studies, andexperience on its use in humans, failed toindicate any compelling evidence of photo-carcinogenesis of retinyl palmitate.

Vitamin A is an essential nutrient that plays amajor role in a number of important physiologicfunctions.45 As the storage form of vitamin A, retinylpalmitate (RP) has been approved for use by the FDAin foods as a fortifier, over the counter and prescrip-tion drugs, cosmetic products, and sunscreens as anantioxidant (AO). However, the use of RP in sun-screens has raised concerns regarding the potentialphotocarcinogenic effect of the compound.

An in-depth review of this topic has been con-ducted byWang et al.46 Briefly, 8 in vitro studies wereconducted to evaluate the photocarcinogenicity ofRP between 2002 and 2009. Of these, 4 showed theformation of free radicals by RP after exposure toUVA radiation.47-49 The FDA National ToxicologyProgram subsequently conducted a large scalein vivo study using SKH-1 hairless mice, whichhave a thin epidermis and a predisposition to devel-oping skin cancer. RP cream (0.1% and 0.5%) wasapplied, and mice were then exposed to UVR (6.75mJ/cm2 or 13.7 mJ/cm2).50 Only mice that received0.5% RP and that were exposed to low-dose UVRrevealed a statistically significant increase in the rateof cancerous lesion formation. Therefore, no clearevidence on photocarcinogenesis could be estab-lished based on this study.

In addition, the medical community has a long-standing history of safely using a number of oral andtopical forms of vitamin A derivatives. Therefore,conclusive evidence is lacking that RP increases therisk of cutaneous carcinogenesis in humans.

Ultraviolet filters and inflammationKey pointd Ultraviolet filters may have antiinflamma-tory properties.

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A study on the antiinflammatory properties of UVfilters was performed in a mouse model, using earinflammation induced by topical phorbol-myristate-acetate application.51 The authors concluded thatmany of the common UV filters have significantantiinflammatory properties. If confirmed inUV-induced inflammation in humans, this findingcould contribute to the understanding on the assess-ment of the SPF values and biologic effects ofsunscreens. It should be emphasized that the pro-tective property of sunscreens against acute andchronic effects of UV has now been well established.

NanoparticlesKey pointsd Concerns have been raised on the ability ofmetal oxide nanoparticles to generate cyto-toxic reactive oxygen species and the pene-tration of these particles through theepidermis.

d Published evidence indicates that as used incosmetic products, including sunscreens,micro- and nanosized ZnO and TiO2 do notpose a risk to humans.

Micro- and nanosized ZnO and TiO2 (diameter\100 nm) can generate reactive oxygen species(ROS) upon UV exposure.52 Studies on the toxicityto animal and human cells have yielded conflictingresults.53-64 In view of the potential toxicity, manu-facturers have coated the nanosized ZnO and TiO2

with compounds such as aluminum oxide and SiO2,both to minimize the formation of ROS65 and toreduce cytotoxicity by preventing adherence ofnanoparticles to cells.66 It is also important to re-member that the endogenous AO systems in the skincan neutralize ROS generated by these metal oxides.

Concern also exists regarding the percutaneouspenetration of nanoparticles. To date, numerousin vitro and in vivo studies, conducted in both animaland human skin, have shown that nanoparticles areconfined to the level of the stratum corneum aftertopical application, even in skin where the barrierfunction has been altered.67-72 The shedding andturnover of stratum corneum further prevents accumu-lation of nanoparticles.73 Along the same mechanism,the outward direction of hair shaft growth and flow ofsebum push nanoparticles out of the hair follicle.74

Based on current evidence, the EU’s ScientificCommittee on Emerging and Newly IdentifiedHealth Risks concluded that the topical use ofTiO2

75 and ZnO76 in cosmetic products does notpose a risk to humans. However, until more data areavailable, their use at sites with severely impairedbarrier function should be minimized.

AntioxidantsKey pointsd Antioxidants incorporated into sunscreenshave the potential of added protectionagainst the effects of ultraviolet radiation.

d A 2011 study concluded that all tested sun-screens had no or minimal antioxidantproperties.

AOs have been incorporated into many sunscreenproducts to neutralize the cytotoxic effects of ROSgenerated by UV exposure.77,78 In human studies,after UVR exposure, it has been shown that subjectswho applied sunscreen that contained meticulouslystabilized AOs had greater reduction in matrixmetalloproteinase-1 levels and less pigment induc-tion and epidermal proliferation when compared tocontrols.79,80 However, Wang et al81 found that manysunscreen products in the United States that claimedto contain AO ingredients actually had no or negli-gible AO capability, most likely because of the lackof stability of AOs.

Vitamin D synthesisKey pointsd Rigorous photoprotection, including the useof sunscreens, is associated with vitamin Dinsufficiency.

d However, because of inadequate application,serum 25-hydroxyvitamin D levels are notaffected with normal usage of sunscreens.

A growing body of evidence has shown animportant role for vitamin D in human health. In2011, the Institute of Medicine concluded that theavailable data supported only the benefits of vitaminD in skeletal health, while no conclusive evidencewas available to support the extraskeletal healthbenefits.82 The Institute of Medicine report issuedguidelines defining vitamin D deficiency at a serum25-hydroxyvitamin D (25[OH]D) level of 12 ng/mL.The guidelines also stated that most normal individ-uals are considered to have sufficient vitamin D at aserum 25(OH)D level of 20 ng/mL. The committeerecommended daily requirements of 400 IU forinfants\1 year of age, 600 IU vitamin D for adults\70 years if age, and 800 IU/d for those[70 years ofage. Three sources of vitamin D exist: vitaminDerich food, dietary supplements, and cutaneoussynthesis after exposure to UVB. Currently availabledata indicate that dietary or supplemental vitamin Dshould be the preferred modern-day method ofmaintaining normal serum levels.83

In controlled laboratory settings, and in patientswith photosensitive lupus erythematosus and

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erythropoietic protoporphyria, sunscreens and pho-toprotection have been shown to be associated withlow 25(OH)D levels.84-88 However, Norval et al89

concluded through a review of the literature thatnormal usage of sunscreen does not generally resultin vitamin D insufficiency. Similarly, Linos et al90

found that in whites, seeking shade and wearinglong sleeves were associated with low 25(OH)Dlevels, while frequent sunscreen use had no effect on25(OH)D levels.90 The most likely explanation forthese findings is that most individuals do not ade-quately apply sunscreens (ie,\2 mg/cm2).

Photoallergic dermatitis and allergic contactdermatitis. While UV filters can cause both allergicand photoallergic contact dermatitis,91 the latter con-ditionoccursmore frequently. It shouldbeemphasizedthat considering the widespread use of sunscreens,contact and photocontact dermatitis is uncommon.Photoallergic dermatitis from sunscreens is from or-ganic UV filters, with benzophenone-3 (also known asoxybenzone) being the most common cause.92-94

Use in pediatric populationsKey pointsd In children, as in adults, broad-spectrumsunscreens should be used only as adjunctto other photoprotective measures.

d For those \2 years of age, if needed, sun-screens containing inorganic UV filters couldbe used on exposed areas.

Epidemiologic data have shown that childhoodsun exposure increases the risk of cutaneous carci-nogenesis in adulthood.95-99 The latest FDA sun-screen final monograph, published in 1999,indicated that physicians should be consulted forthe use of sunscreens in infants\6 months of age.20

More recent guidelines issued by the AmericanAcademy of Pediatrics (AAP; 2011)100 and Centersfor Disease Control and Prevention (CDC; 2003)101

both recommend that UVR exposure in children bereduced or prevented as a first-line strategy againstsolar UVR damage, with sunscreen used as a com-plementary measure. Specifically, the AAP doespermit the use of sunscreen on small areas of skinwhen other photoprotective measures are not pos-sible.99 Contrary to these recommendations, in prac-tice, sunscreens remain the primary method ofphotoprotection used in children.102,103 Given thelong-term risks of UVR exposure, proper photo-protective practice in the pediatric population, sim-ilar to adults, should include providing shade,wearing protective clothing, wide brim hat, sun-glasses and, only on the uncovered areas, the use ofbroad-spectrum sunscreen.

The increasingly widespread use of sunscreensamong the pediatric population has generated con-cern regarding their safety. Compared to adults, thehigher body surface areaevolume ratio of childrenand unique microstructure of immature skin suggestthat children, especially infants, may absorb a greaterfraction of topically applied substances.104,105 Inaddition, the capacity to metabolize and excreteabsorbed substances may not yet be fully mature inyoung children and infants, putting them at risk forside effects and toxicities not seen in adults.Although firm data are lacking, because of thecontroversy on the systemic absorption of UV filters,especially benzophenones,44 and the evidence fromnumerous studies showing the lack of percutaneouspenetration of inorganic UV filters,67-72 it is a prudentclinical practice to recommend the use of sunscreenswith only inorganic UV filters in children \2 yearsold.

The authors thank Ms Stephanie Stebens, MLIS, librar-ian, Henry Ford Hospital, for her assistance with manu-script preparation.

REFERENCES

1. Roelandts R. History of photoprotection. In: Lim HW, Draelos

ZD, editors. Clinical guide to sunscreens and photoprotec-

tion. New York: Informa Healthcare USA; 2009. pp. 1-10.

2. Gasparro FP, Mitchnick M, Nash JF. A review of sunscreen

safety and efficacy. Photochem Photobiol 1998;68:243-56.

3. Giacomini P. Sunprotection: historical perspective. In: Shaath

NA, editor. Sunscreens: regulations and commercial devel-

opment. 3rd ed. Boca Raton (FL): Taylor & Francis; 2005. pp.

71-84.

4. Schulze R. Some tests and remarks regarding the problem of

sunscreens that are found on the market [in German]. Parfum

Kosmet 1956;37:310-6.

5. Osterwalder U, Herzog B. The long way towards the ideal

sunscreen—where we stand and what still needs to be done.

Photochem Photobiol Sci 2010;9:470-81.

6. Diffey B. The need for sunscreens with broad spectrum

protection. In: Urbach F, editor. Biological responses to

ultraviolet a radiation. Overland Park (KS): Valdenmar Publi-

cation Co; 1992. pp. 321-8.

7. Fourtanier A, Moyal D, Maccario J, Compan D, Wolf P,

Quehenberger F, et al. Measurement of sunscreen immune

protection factors in humans: a consensus paper. J Invest

Dermatol 2005;125:403-9.

8. Scientific Committee on Consumer Safety. Opinion on

1,3,5-Triazine, 2,4,6-tris[1,1’-bipheny]-4-yl- [Revision of De-

cember 2011]. Adopted by the 12th plenary session of the

SCCS of 20 September 2011. Brussels: European Commission;

2011.

9. Barltrop JA, Doyle JD. Excited states in organic chemistry.

London: John Wiley & Sons; 1975.

10. Otterstedt JEA. Photostability and molecular structure.

J Chem Phys 1973;58:5716-25.

11. Herzog B, Wehrle M, Quass K. Photostability of UV absorber

systems in sunscreens. Photochem Photobiol 2009;85:869-78.

12. Schwack W, Rudolph T. Photochemistry of dibenzoyl meth-

ane UVA filters: Part 1. J Photochem Photobiol B 1995;28:

229-34.

J AM ACAD DERMATOL

DECEMBER 2013867.e12 Jansen et al

13. Stobbe H, Lehfeldt A. Polymerization and depolymerization

by light of different wavelengths. II a and b-trans cinnamic

acids, allo-cinnamic acids and their dimers. Ber Dtsch Chem

Ges 1925;58B:2415-27.

14. Kohnlein M. Studies on the photochemical behavior of the

UV-filter octyl methoxycinnamate in model system, sun-

screen as well as on the skin [dissertation in German].

Stuttgart, Germany: University of Hohenheim; 2000.

15. Schlossmann D, Shao Y. Inorganic ultraviolet filters. In: Shaath

NA, editor. Sunscreens: regulations and commercial devel-

opment. 3rd ed. Boca Raton (FL): Taylor & Francis; 2005. pp.

239-79.

16. van Grieken R, Aguado J, Lopez-Munoz MJ, Marugan J.

Synthesis of size-controlled silica-supported TiO2 photocat-

alysts. J Photochem Photobiol A Chem 2002;148:315-22.

17. Herzog B. Prediction of sun protection factors and UV-A

parameters by calculation of UV transmissions through

sunscreen films of inhomogenous surface structure. In:

Shaath NA, editor. Sunscreens: regulations and commercial

development. 3rd ed. Boca Raton (FL): Taylor & Francis; 2005.

pp. 881-902.

18. Herzog B, Katzenstein A, Quass K, Stehlin A, Luther H.

Physical properties of organic particulate UV-absorbers

used in sunscreens. I. Determination of particle size with

fiber-optic quasi-elastic light scattering (FOQELS), disc cen-

trifugation, and laser diffractometry. J Colloid Interface Sci

2004;271:136-44.

19. Ahmed FK. Worldwide regulation of UV filters: current status

and future trends. In: Lim HW, Draelos ZD, editors. Clinical

guide to sunscreens and photoprotection. New York: Informa

Healthcare; 2009. pp. 65-81.

20. Department of Health and Human Services, Food and

Drug Administration. Sunscreen drug products for

over-the-counter human use. Final rule. Federal Register

1999;64:27666-93.

21. Herzog B, H€uglin D, Borsos E, Stehlin A, Luther H. New UV

absorbers for cosmetic sunscreens: a breakthrough for the

photoprotection of human skin. Chimia (Aarau) 2004;58:

554-9.

22. Herzog B, Hueglin D, Osterwalder U. New sunscreen actives.

In: Shaath NA, editor. Sunscreens: regulations and commer-

cial development. 3rd ed. Boca Raton (FL): Taylor & Francis;

2005. pp. 291-320.

23. International Organization for Standardization, International

Commission on Illumination. Erythema reference action

spectrum and standard erythema dose. Joint ISO/CIE Stan-

dard. ISO 17166 ⁄ CIE S007. Vienna, Austria: CIE Central

Bureau; 1999.

24. The European Cosmetic Toiletry and Perfumery Association,

Cosmetic Toiletry and Fragrance Association of South Africa,

Japan Cosmetic Industry Association. Colipa guidelines:

international sun protection factor (SPF) testing method.

Brussels: Colipa; 2006.

25. Lim HW, Naylor M, H€onigsmann H, Gilchrest BA, Cooper K,

Morison W, et al. American Academy of Dermatology Con-

sensus Conference on UVA protection of sunscreens: sum-

mary and recommendations. Washington, DC, Feb 4, 2000.

J Am Acad Dermatol 2001;44:505-8.

26. Japan Cosmetic Industry Association. JCIA measurement

standard for UVA protection efficacy. Toranomon 2-chome,

Minato-Ku Tokyo: JCIA; 1995. p. 105.

27. The European Cosmetic Toiletry and Perfumery Association

In Vitro Photoprotection Method Task Force. Colipa guide-

lines: method for in vitro determination of UVA protection.

Brussels: Colipa; 2011.

28. Measurement of UVA: UVB ratio according to the Boots

star rating system 2008 revision ed. Nottingham: Boots UK

Limited; 2008.

29. International Organization for Standardization web site. ISO

24443:2012. Determination of sunscreen UVA photoprotec-

tion in vitro. Available at: http://www.iso.org/iso/

catalogue_detail?csnumber=46522. Accessed August 30,

2013.

30. United States Department of Health and Human Services,

Food and Drug Administration. Labeling and effectiveness

testing; sunscreen drug products for over-the-counter hu-

man use. Final rule. Federal Register 2011;76:35620-65.

31. Wang SQ, Lim HW. Current status of the sunscreen regulation

in the United States: 2011 Food and Drug Administration’s

final rule on labeling and effectiveness testing. J Am Acad

Dermatol 2011;65:863-9.

32. Wang SQ, Dusza SW. Assessment of sunscreen knowledge: a

pilot survey. Br J Dermatol 2009;161(Suppl 3):28-32.

33. Isedeh P, Osterwalder U, Lim HW. Teaspoon rule revisited:

proper amount of sunscreen application. Photodermatol

Photoimmunol Photomed 2013;29:55-6.

34. Thieden E, Philipsen PA, Sandby-Moller J, Wulf HC. Sunscreen

use related to UV exposure, age, sex, and occupation based

on personal dosimeter readings and sun-exposure behavior

diaries. Arch Dermatol 2005;141:967-73.

35. Calafat AM, Wong LY, Ye X, Reidy JA, Needham LL. Concen-

trations of the sunscreen agent benzophenone-3 in residents

of the United States: National Health and Nutrition Exami-

nation Survey 2003-2004. Environ Health Perspect 2008;116:

893-7.

36. Nakagawa Y, Suzuki T. Metabolism of 2-hydroxy-

4-methoxybenzophenone in isolated rat hepatocytes and

xenoestrogenic effects of its metabolites on MCF-7 human

breast cancer cells. Chem Biol Interact 2002;139:115-28.

37. Heneweer M, Muusse M, van den Berg M, Sanderson JT.

Additive estrogenic effects of mixtures of frequently used UV

filters on pS2-gene transcription in MCF-7 cells. Toxicol Appl

Pharmacol 2005;208:170-7.

38. Schlumpf M, Cotton B, Conscience M, Haller V, Steinmann B,

Lichtensteiger W. In vitro and in vivo estrogenicity of UV

screens. Environ Health Perspect 2001;109:239-44.

39. Schlumpf M, Schmid P, Durrer S, Conscience M, Maerkel K,

Henseler M, et al. Endocrine activity and developmental

toxicity of cosmetic UV filters—an update. Toxicology 2004;

205:113-22.

40. Ma R, Cotton B, Lichtensteiger W, Schlumpf M. UV filters with

antagonistic action at androgen receptors in the MDA-kb2

cell transcriptional-activation assay. Toxicol Sci 2003;74:

43-50.

41. Wang SQ, Burnett ME, Lim HW. Safety of oxybenzone:

putting numbers into perspective. Arch Dermatol 2011;147:

865-6.

42. Janjua NR, Mogensen B, Andersson AM, Petersen JH,

Henriksen M, Skakkebaek NE, et al. Systemic absorption of

the sunscreens benzophenone-3, octyl-methoxycinnamate,

and 3-(4-methyl-benzylidene) camphor after whole-body

topical application and reproductive hormone levels in

humans. J Invest Dermatol 2004;123:57-61.

43. Frederiksen H, Aksglaede L, Sorensen K, Nielsen O, Main KM,

Skakkebaek NE, et al. Bisphenol A and other phenols in urine

from Danish children and adolescents analyzed by isotope

diluted TurboFlow-LC-MS/MS. Int J Hyg Environ Health 2013

Mar 11 [Epub ahead of print].

44. Krause M, Klit A, Blomberg Jensen M, Soeborg T, Frederiksen

H, Schlumpf M, et al. Sunscreens: are they beneficial for

J AM ACAD DERMATOL

VOLUME 69, NUMBER 6Jansen et al 867.e13

health? An overview of endocrine disrupting properties of

UV-filters. Int J Androl 2012;35:424-36.

45. Packer L, Obermueller-Jevic U, Kraemer K, Sies H, editors.

Carotenoids and retinoids: molecular aspects and health

issues. Urbana (IL): AOCS Publishing; 2005.

46. Wang SQ, Dusza SW, Lim HW. Safety of retinyl palmitate in

sunscreens: a critical analysis. J Am Acad Dermatol 2010;63:

903-6.

47. Cherng SH, Xia Q, Blankenship LR, Freeman JP, Wamer WG,

Howard PC, et al. Photodecomposition of retinyl palmitate in

ethanol by UVA light-formation of photodecomposition

products, reactive oxygen species, and lipid peroxides.

Chem Res Toxicol 2005;18:129-38.

48. Xia Q, Yin JJ, Cherng SH, Wamer WG, Boudreau M, Howard

PC, et al. UVA photoirradiation of retinyl palmitate—forma-

tion of singlet oxygen and superoxide, and their role in

induction of lipid peroxidation. Toxicol Lett 2006;163:30-43.

49. Yin JJ, Xia Q, Fu PP. UVA photoirradiation of anhydroretinol—

formation of singlet oxygen and superoxide. Toxicol Ind

Health 2007;23:625-31.

50. Department of Health and Human Services, National Toxi-

cology Program web site. TR-568: technical report pathology

tables and curves. Pathology tables: SKH-1/NCTR male

and female mice. Available at: http://ntp.niehs.nih.

gov/?objectid=555571BB-F1F6-975E-76F2BC5E369EB6F7. Ac-

cessed July 21, 2013.

51. Couteau C, Chauvet C, Paparis E, Coiffard L. UV filters,

ingredients with a recognized anti-inflammatory effect. PloS

One 2012;7:e46187.

52. Newman MD, Stotland M, Ellis JI. The safety of nanosized

particles in titanium dioxidee and zinc oxideebased sun-

screens. J Am Acad Dermatol 2009;61:685-92.

53. Wamer WG, Yin JJ, Wei RR. Oxidative damage to nucleic acids

photosensitized by titanium dioxide. Free Radic Biol Med

1997;23:851-8.

54. Hidaka H, Kobayashi H, Koike T, Sato T, Serpone N. DNA

damage photoinduced by cosmetic pigments and sunscreen

agents under solar exposure and artificial UV illumination.

J Oleo Sci 2006;55:249-61.

55. Dunford R, Salinaro A, Cai L, Serpone N, Horikoshi S, Hidaka

H, et al. Chemical oxidation and DNA damage catalysed by

inorganic sunscreen ingredients. FEBS Lett 1997;418:87-90.

56. Uchino T, Tokunaga H, Ando M, Utsumi H. Quantitative

determination of OH radical generation and its cytotoxicity

induced by TiO(2)-UVA treatment. Toxicol In Vitro 2002;16:

629-35.

57. Nakagawa Y, Wakuri S, Sakamoto K, Tanaka N. The photo-

genotoxicity of titanium dioxide particles. Mutat Res 1997;

394:125-32.

58. Sharma V, Singh SK, Anderson D, Tobin DJ, Dhawan A. Zinc

oxide nanoparticle induced genotoxicity in primary human

epidermal keratinocytes. J Nanosci Nanotechnol 2011;11:

3782-8.

59. Hackenberg S, Scherzed A, Kessler M, Froelich K, Ginzkey C,

Koehler C, et al. Zinc oxide nanoparticles induce photo-

catalytic cell death in human head and neck squamous cell

carcinoma cell lines in vitro. Int J Oncol 2010;37:1583-90.

60. Kocbek P, Teskac K, Kreft ME, Kristl J. Toxicological aspects of

long-term treatment of keratinocytes with ZnO and TiO2

nanoparticles. Small 2010;6:1908-17.

61. Dufour EK, Kumaravel T, Nohynek GJ, Kirkland D, Toutain H.

Clastogenicity, photo-clastogenicity or pseudo-

photo-clastogenicity: genotoxic effects of zinc oxide in the

dark, in pre-irradiated or simultaneously irradiated Chinese

hamster ovary cells. Mutat Res 2006;607:215-24.

62. Yin JJ, Liu J, Ehrenshaft M, Roberts JE, Fu PP, Mason RP, et al.

Phototoxicity of nano titanium dioxides in HaCaT keratino-

cytes—generation of reactive oxygen species and cell dam-

age. Toxicol Appl Pharmacol 2012;263:81-8.

63. Hackenberg S, Friehs G, Froelich K, Ginzkey C, Koehler C,

Scherzed A, et al. Intracellular distribution, geno- and cyto-

toxic effects of nanosized titanium dioxide particles in the

anatase crystal phase on human nasal mucosa cells. Toxicol

Lett 2010;195:9-14.

64. Hackenberg S, Friehs G, Kessler M, Froelich K, Ginzkey C,

Koehler C, et al. Nanosized titanium dioxide particles do not

induce DNA damage in human peripheral blood lympho-

cytes. Environ Mol Mutagen 2011;52:264-8.

65. Livraghi S, Corazzari I, Paganini MC, Ceccone G, Giamello E,

Fubini B, et al. Decreasing the oxidative potential of TiO(2)

nanoparticles through modification of the surface with

carbon: a new strategy for the production of safe UV filters.

Chem Commun (Camb) 2010;46:8478-80.

66. Pan Z, Lee W, Slutsky L, Clark RA, Pernodet N, Rafailovich MH.

Adverse effects of titanium dioxide nanoparticles on human

dermal fibroblasts and how to protect cells. Small 2009;5:

511-20.

67. Cross SE, Innes B, Roberts MS, Tsuzuki T, Robertson TA,

McCormick P. Human skin penetration of sunscreen nano-

particles: in-vitro assessment of a novel micronized zinc oxide

formulation. Skin Pharmacol Physiol 2007;20:148-54.

68. Kimura E, Kawano Y, Todo H, Ikarashi Y, Sugibayashi K.

Measurement of skin permeation/penetration of nanopar-

ticles for their safety evaluation. Biol Pharm Bull 2012;35:

1476-86.

69. Miquel-Jeanjean C, Crepel F, Raufast V, Payre B, Datas L,

Bessou-Touya S, et al. Penetration study of formulated

nanosized titanium dioxide in models of damaged and

sun-irradiated skins. Photochem Photobiol 2012;88:1513-21.

70. Sadrieh N, Wokovich AM, Gopee NV, Zheng J, Haines D,

Parmiter D, et al. Lack of significant dermal penetration of

titanium dioxide from sunscreen formulations containing

nano- and submicron-size TiO2 particles. Toxicol Sci 2010;

115:156-66.

71. Monteiro-Riviere NA, Wiench K, Landsiedel R, Schulte S,

Inman AO, Riviere JE. Safety evaluation of sunscreen formu-

lations containing titanium dioxide and zinc oxide nano-

particles in UVB sunburned skin: an in vitro and in vivo study.

Toxicol Sci 2011;123:264-80.

72. Senzui M, Tamura T, Miura K, Ikarashi Y, Watanabe Y, Fujii M.

Study on penetration of titanium dioxide (TiO2) nanoparticles

into intact and damaged skin in vitro. J Toxicol Sci 2010;35:

107-13.

73. Lademann J, Richter H, Schaefer UF, Blume-Peytavi U, Teich-

mann A, Otberg N, et al. Hair follicles - a long-term reservoir for

drug delivery. Skin Pharmacol Physiol 2006;19:232-6.

74. Lademann J, Knorr F, Richter H, Blume-Peytavi U, Vogt A,

Antoniou C, et al. Hair follicles—an efficient storage and

penetration pathway for topically applied substances. Sum-

mary of recent results obtained at the Center of Experimental

and Applied Cutaneous Physiology, Charite -Universitatsme-

dizin Berlin, Germany. Skin Pharmacol Physiol 2008;21:150-5.

75. Scientific Committee on Cosmetic Products and Non-Food

Products (SCCNFP). Opinion of the Scientific Committee on

Cosmetic Products and Non-Food Products intended for

consumers concerning titanium dioxide. Adopted by the

14th plenary session of SCCNFP of 24 October 2000. Brussels:

Colipa; 2000.

76. Scientific Committee on Cosmetic Products and Non-Food

Products. Opinion of the Scientific Committee on Cosmetic

J AM ACAD DERMATOL

DECEMBER 2013867.e14 Jansen et al

Products and Non-Food Products intended for consumers

concerning zinc oxide. Adopted by the 24th plenary session

of the SCCNFP of 24e25 June 2003. Brussels: Colipa; 2003.

77. Halliwell B, Gutteridge JMC. Free radicals in biology and

medicine. 4th ed. Oxford: Oxford University Press; 2007.

78. Haywood R, Wardman P, Sanders R, Linge C. Sunscreens

inadequately protect against ultraviolet-A-induced free rad-

icals in skin: implications for skin aging and melanoma?

J Invest Dermatol 2003;121:862-8.

79. Matsui MS, Hsia A, Miller JD, Hanneman K, Scull H, Cooper KD,

et al. Non-sunscreen photoprotection: antioxidants add value

to a sunscreen. J Investig Dermatol Symp Proc 2009;14:56-9.

80. Wu Y, Matsui MS, Chen JZ, Jin X, Shu CM, Jin GY, et al.

Antioxidants add protection to a broad-spectrum sunscreen.

Clin Exp Dermatol 2011;36:178-87.

81. Wang SQ, Osterwalder U, Jung K. Ex vivo evaluation of radical

sun protection factor in popular sunscreens with antioxi-

dants. J Am Acad Dermatol 2011;65:525-30.

82. Institute of Medicine Committee to Review Dietary Reference

Intakes for Vitamin D and Calcium. Dietary reference intakes

for calcium and vitamin D. Washington, DC: National Acad-

emy of Sciences; 2011.

83. Vanchinathan V, Lim HW. A dermatologist’s perspective on

vitamin D. Mayo Clin Proc 2012;87:372-80.

84. Matsuoka LY, Wortsman J, Hollis BW. Use of topical sunscreen

for the evaluation of regional synthesis of vitamin D3. J Am

Acad Dermatol 1990;22:772-5.

85. Matsuoka LY, Wortsman J, Hanifan N, Holick MF. Chronic

sunscreen use decreases circulating concentrations of

25-hydroxyvitamin D. A preliminary study. Arch Dermatol

1988;124:1802-4.

86. Matsuoka LY, Ide L, Wortsman J, MacLaughlin JA, Holick MF.

Sunscreens suppress cutaneous vitamin D3 synthesis. J Clin

Endocrinol Metab 1987;64:1165-8.

87. Cusack C, Danby C, Fallon JC, Ho WL, Murray B, Brady J, et al.

Photoprotective behaviour and sunscreen use: impact on

vitamin D levels in cutaneous lupus erythematosus. Photo-

dermatol Photoimmunol Photomed 2008;24:260-7.

88. Holme SA, Anstey AV, Badminton MN, Elder GH. Serum

25-hydroxyvitamin D in erythropoietic protoporphyria. Br J

Dermatol 2008;159:211-3.

89. Norval M, Wulf HC. Does chronic sunscreen use reduce

vitamin D production to insufficient levels? Br J Dermatol

2009;161:732-6.

90. Linos E, Keiser E, Kanzler M, Sainani KL, Lee W, Vittinghoff E,

et al. Sun protective behaviors and vitamin D levels in the US

population: NHANES 2003-2006. Cancer Causes Control 2012;

23:133-40.

91. Fisher AA, Rietschel RL, Fowler JF, Fisher AA. Fisher’s contact

dermatitis. 6th ed. Hamilton (ON): BC Decker Inc.; 2008.

92. European Multicentre Photopatch Test Study (EMCPPTS)

Taskforce. A European multicentre photopatch test study.

Br J Dermatol 2012;166:1002-9.

93. Bryden AM, Moseley H, Ibbotson SH, Chowdhury MM, Beck

MH, Bourke J, et al. Photopatch testing of 1155 patients:

results of the U.K. Multicentre Photopatch Study Group. Br J

Dermatol 2006;155:737-47.

94. Zug KA, Warshaw EM, Fowler JF Jr, Maibach HI, Belsito DL,

Pratt MD, et al. Patch-test results of the North American

Contact Dermatitis Group 2005-2006. Dermatitis 2009;20:

149-60.

95. Whiteman DC, Whiteman CA, Green AC. Childhood sun

exposure as a risk factor for melanoma: a systematic review

of epidemiologic studies. Cancer Causes Control 2001;12:

69-82.

96. Gallagher RP, Hill GB, Bajdik CD, Fincham S, Coldman AJ,

McLean DI, et al. Sunlight exposure, pigmentary factors, and

risk of nonmelanocytic skin cancer: I. Basal cell carcinoma.

Arch Dermatol 1995;131:157-63.

97. Gallagher RP, Hill GB, Bajdik CD, Coldman AJ, Fincham S,

McLean DI, et al. Sunlight exposure, pigmentation factors,

and risk of nonmelanocytic skin cancer: II. Squamous cell

carcinoma. Arch Dermatol 1995;131:164-9.

98. Elwood JM, Jopson J. Melanoma and sun exposure: an

overview of published studies. Int J Cancer 1997;73:

198-203.

99. Whiteman D, Green A. Melanoma and sunburn. Cancer

Causes Control 1994;5:564-72.

100. Council on Environmental Health, Section on Dermatology.

Ultraviolet radiation: a hazard to children and adolescents.

Pediatrics 2011;127:588-97.

101. Centers for Disease Control and Prevention. Preventing skin

cancer: findings of the Task Force on Community Preventive

Services on reducing exposure to ultraviolet light. MMWR

Recomm Rep 2003;52:1-12.

102. Robinson JK, Rigel DS, Amonette RA. Summertime sun

protection used by adults for their children. J Am Acad

Dermatol 2000;42:746-53.

103. Hall HI, Jorgensen CM, McDavid K, Kraft JM, Breslow R.

Protection from sun exposure in US white children ages 6

months to 11 years. Public Health Rep 2001;116:353-61.

104. Stamatas GN, Nikolovski J, Luedtke MA, Kollias N, Wiegand

BC. Infant skin microstructure assessed in vivo differs from

adult skin in organization and at the cellular level. Pediatr

Dermatol 2010;27:125-31.

105. Nikolovski J, Stamatas GN, Kollias N, Wiegand BC. Barrier

function and water-holding and transport properties of

infant stratum corneum are different from adult and con-

tinue to develop through the first year of life. J Invest

Dermatol 2008;128:1728-36.