Photoprotection

Part II. Sunscreen: Development, efcacy, 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 CME INSTRUCTIONS
The following is a journal-based CME activity presented by the American Academy of Dermatology and is made up of four phases: 1. Reading of the CME Information (delineated below) 2. Reading of the Source Article 3. Achievement of a 70% or higher on the online Case-based Post Test 4. Completion of the Journal CME Evaluation CME INFORMATION AND DISCLOSURES Statement of Need: The American Academy of Dermatology bases its CME activities on the Academys core curriculum, identified professional practice gaps, the educational needs which underlie these gaps, and emerging clinical research findings. Learners should reflect upon clinical and scientific information presented in the article and determine the need for further study. Target Audience: Dermatologists and others involved in the delivery of dermatologic care. Accreditation The American Academy of Dermatology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA PRA Credit Designation The American Academy of Dermatology designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity. AAD Recognized Credit This journal-based CME activity is recognized by the American Academy of Dermatology for 1 AAD Credit and may be used toward the American Academy of Dermatologys Continuing Medical Education Award. Disclaimer: The American Academy of Dermatology is not responsible for statements made by the author(s). Statements or opinions expressed in this activity reect the views of the author(s) and do not reect the ofcial policy of the American Academy of Dermatology. The information provided in this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to the diagnostic, management and treatment options of a specic patients medical condition. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of this journal-based CME activity have reported no relevant nancial relationships with commercial interest(s). 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 LOreal. Drs Burnett and Jansen have no conicts of interest to declare. Planners The planners involved with this journal-based CME activity have reported no relevant nancial relationships with commercial interest(s). The editorial and education staff involved with this journal-based CME activity have reported no relevant nancial relationships with commercial interest(s). Resolution of Conflicts of Interest In accordance with the ACCME Standards for Commercial Support of CME, the American Academy of Dermatology has implemented mechanisms, prior to the planning and implementation of this Journal-based CME activity, to identify and mitigate conicts of interest for all individuals in a position to control the content of this Journal-based CME activity. Learning Objectives 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 Technical requirements: American Academy of Dermatology: d Supported browsers: FireFox (3 and higher), Google Chrome (5 and higher), Internet Explorer (7 and higher), Safari (5 and higher), Opera (10 and higher). d JavaScript needs to be enabled. Elsevier: Technical Requirements This website can be viewed on a PC or Mac. We recommend a minimum of: d PC: Windows NT, Windows 2000, Windows ME, or Windows XP d Mac: OS X d 128MB RAM d Processor speed of 500MHz or higher d 800x600 color monitor d Video or graphics card d Sound card and speakers Provider Contact Information: American Academy of Dermatology Phone: Toll-free: (866) 503-SKIN (7546); International: (847) 240-1280 Fax: (847) 240-1859 Mail: P.O. Box 4014; Schaumburg, IL 60168 Confidentiality Statement: American Academy of Dermatology: POLICY ON PRIVACY AND CONFIDENTIALITY Privacy Policy - The American Academy of Dermatology (the Academy) is committed to maintaining the privacy of the personal information of visitors to its sites. Our policies are designed to disclose the information collected and how it will be used. This policy applies solely to the information provided while visiting this website. The terms of the privacy policy do not govern personal information furnished through any means other than this website (such as by telephone or mail). E-mail Addresses and Other Personal Information - Personal information such as postal and e-mail address may be used internally for maintaining member records, marketing purposes, and alerting customers or members of additional services available. Phone numbers may also be used by the Academy when questions about products or services ordered arise. The Academy will not reveal any information about an individual user to third parties except to comply with applicable laws or valid legal processes. Cookies - A cookie is a small file stored on the site users computer or Web server and is used to aid Web navigation. Session cookies are temporary files created when a user signs in on the website or uses the personalized features (such as keeping track of items in the shopping cart). Session cookies are removed when a user logs off or when the browser is closed. Persistent cookies are permanent files and must be deleted manually. Tracking or other information collected from persistent cookies or any session cookie is used strictly for the users efficient navigation of the site. Links - This site may contain links to other sites. The Academy is not responsible for the privacy practices or the content of such websites. Children - This website is not designed or intended to attract children under the age of 13. The Academy does not collect personal information from anyone it knows is under the age of 13. Elsevier: http://www.elsevier.com/wps/find/privacypolicy.cws_home/ privacypolicy

867.e1

867.e2 Jansen et al

J AM ACAD DERMATOL

DECEMBER 2013

In addition to the naturally occurring, physical, and systemic photoprotective agents reviewed in part I, topical ultraviolet radiation lters are an important cornerstone of photoprotection. Sunscreen development, efcacy, testing, and controversies are reviewed in part II of this continuing medical education article. ( J Am Acad Dermatol 2013;69:867.e1-14.) Key words: oxybenzone; photoprotection; photostability; Sun Protection Factor; sunscreen; sunscreen controversies; ultraviolet lter.

SUNSCREENS: TOPICAL PHOTOPROTECTIVE AGENTS Key points

d

CAPSULE SUMMARY
d

Ideal sunscreens provide uniform protection against ultraviolet A and ultraviolet B light. Ideal sunscreens have aesthetically pleasing compositions that enhance compliance.

Ideal sunscreens provide uniform protection across the ultraviolet B and ultraviolet A light range while maintaining sensory and tactile features that enhance the users experience. Sunscreen efficacy depends on ultraviolet filter type (organic or inorganic), photostability, and the addition of Sun Protection Factoreboosting agents.

New US Food and Drug Administration The notion of the ideal regulations regarding sunscreen testing sunscreen and labeling aim to improve the clarity Since the rst commercial of photoprotection of sunscreens. sunscreen was introduced in 1928, the use of sunscreens While there are controversies involving as an integral part of photosunscreen ingredients, formulations, and protection strategy has exside effects, based on current data, the panded worldwide. Table I riskebenefit ratio indicates that it is highlights the historical deappropriate to include the use of velopment of sunscreens.1-4 sunscreen as an important component Two factors must be adof photoprotection strategy. dressed to produce an It ideal sunscreen.5 should provide uniform protection across the broad-spectrum lters. range of ultraviolet B light (UVB) and ultraviolet Currently, all organic UV absorbers used in sunA light (UVA), a property referred to as spectral screens are aromatic compounds, each containing homeostasis, which assures that the natural specmultiple conjugated p-electron systems (Tables II trum of sunlight is attenuated in a uniform manner and III).8 The type of substituents and their position (Fig 1).6 This is particularly useful for protection at the aromatic ring are important for the UV specagainst immunosuppression, which has a broad troscopic properties. Especially advantageous are action spectrum.7 An ideal sunscreen should also disubstituted systems with an electron-donor (1M-) have pleasing sensory and tactile profiles that and an electron-acceptor (M-) group in paraposienhance the users compliance. tion (so-called pushepull systems). Fig 2 shows a
d d

Ultraviolet lters Principles of ultraviolet radiation absorption by organic ultraviolet lters. In order to absorb ultraviolet radiation (UVR), an organic ultraviolet (UV) light lter must contain a suitable chromophore that has conjugated p-electron systems. Increasing the number of conjugated double bonds in the molecule shifts the absorption maximum to longer wavelengths and also gives rise to a larger absorption cross section and, therefore, stronger absorption. In general, the larger the molecular weight of the chromophore, the more the absorption maximum will be shifted towards longer wavelengths. This is the reason that UVB light lters have smaller molecular weights compared to UVA light or

From the Department of Dermatology,a Henry Ford Hospital, Detroit; BASF Personal Care and Nutrition GmbH,b Monheim; and the Division of Dermatology,c Memorial Sloan Kettering Cancer Center, New York. Funding sources: None. 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 LOreal. Drs Burnett and Jansen have no conflicts of interest to declare. Reprint requests: Henry W. Lim, MD, Department of Dermatology, Henry Ford Medical Center e New Center One, 3031 W Grand Blvd, Ste 800, Detroit, MI 48202. E-mail: [email protected]. 0190-9622/$36.00

J AM ACAD DERMATOL
VOLUME 69, NUMBER 6

Jansen et al 867.e3

Abbreviations used: AAP: AO: AVO: BEMT: CW: E1,1: EU: FDA: ISO: MED: PPD: ROS: SPF: TiO2: UK: USAN: UV: UVA: UVB: UVR: ZnO: American Academy of Pediatrics antioxidant avobenzone bemotrizinol critical wavelength extinction at 1 cm path length and 1% concentration European Union Food and Drug Administration International Organization for Standardization minimal erythema dose persistent pigment darkening reactive oxygen species Sun Protection Factor titanium dixoxide United Kingdom United States Adopted Name ultraviolet light ultraviolet A light ultraviolet B light ultraviolet radiation zinc oxide

comparison of the absorption spectra of ethylhexyldimethyl paraaminobenzoate (United States Adopted Name [USAN], padimate O), with substituents in a paraposition, and a UV absorber with similar groups but in orthoposition, menthyl anthranilate (USAN, meradimate). Because of the substituents in paraposition, padimate O is a more efficient UV filter than meradimate. Photostability. Absorption of a UV photon transfers the UV absorber molecule into an excited electronic state. If the absorbed energy is not sufciently and speedily dissipated into heat, chemical bonds of the UV absorber may break, resulting in degradation of the UV lter. A reversible isomerization (tautomerism) in the excited state can stabilize an UV absorber.9,10 This principle is realized, for instance, in the menthyl anthranilate molecule because of the orthoamino group (Fig 2), resulting in excellent photostability. In others, this is realized via an orthohydroxy group forming hydrogen bonds (eg, bemotrizinol and bisoctrizole). Most of the UV absorbers used in sunscreens are photostable under the conditions of use. Two exceptions are avobenzone (AVO) and octinoxate.11 AVO undergoes rapid photodegradation, which can be stabilized by UV filters octocrylene and bemotrizinol. The latter is not yet available in the United States (Fig 3). In addition, AVO and octinoxate enhance the photodegradation of each other. For this reason, these 2 filters should not be used in combination.12-14 Principles of ultraviolet protection with inorganic ultraviolet lters. Micronized inorganic oxides used in sunscreens (TiO2 and ZnO) attenuate

UV mainly by absorption and some scattering.15 Depending on particle size, these materials are semiconductors that absorb photons at different wavelengths. The smaller the primary particles, the shorter its peak absorption spectrum.16 The primary particle sizes of TiO2 used in sunscreens are between 10 and 30 nm. However, in dispersion, the particles form aggregates with sizes usually around 100 nm. With ZnO, primary particle sizes from 10 to 200 nm are available, but mainly the grades with larger particles are used. Because of the photocatalytic effect, TiO2 for sunscreen applications is coated with aluminum oxide or silica in order to prevent oxygen radical formation. In addition, the rutile crystal form is used in most cases. Rutile is the most common form of TiO2, has a high refractive index, and can absorb UVR. Although the anatase form of TiO2 has many of the same properties as the rutile form, it has lower UVR absorption and higher tendency for photocatalysis. Particulate organic ultraviolet lters. Sunscreens, especially those with a high Sun Protection Factor (SPF), contain a considerable amount of UV lters. Therefore, solubility of the active substance can be a signicant problem.17 For this reason, particulate organic UV filters were developed that allow high SPF products to be developed with relatively lower concentrations of UV filters. Examples of these UV filters include methylene bisbenzotrazolyl tetramethylbutylphenol (biscotrizole) and tris-biphenyl triazine. These filters have extremely low solubility in oil and in water, but can be micronized in an aqueous phase.17,18 Particulate biscotrizole shows a broad absorption up to 380 nm. Regulations of ultraviolet lters. The safety of UV lters has to be shown in an extensive program of toxicologic studies. In Europe and Japan, UV absorbers are regulated as cosmetics, in the United States as over the counter drugs and in Australia as therapeutic drugs.19 An overview of common UV filters in sunscreen is shown in Table II. Australia and Europe have the most UV filters for sunscreen formulation. By contrast, the United States has the least number of UV filters available. Limitations of available ultraviolet lters in United States. While sufcient lters are available in the UVB and UVA2 range, only 4 UVA1 (340-400 nm) lters, all with limitations, are approved in the United States (Figs 4 and 5). AVO is the most efficient UVA1 filter, but it is not photostable. In the United States, the maximal concentration is 3%, and it is not approved for combination with TiO2 because enhanced photodegradation of AVO is observed in the presence of TiO2. AVO is also not approved in combination with ZnO for lack of data to show the

867.e4 Jansen et al

J AM ACAD DERMATOL

DECEMBER 2013

Table I. Historical development of sunscreen

Year(s) Development

1928 1933 1936 1938 1943 1950s 1956 1970s

1980s 1990s-2000s 2000s-2010s

First commercial use of sunscreen in the United States: emulsion containing benzyl salicylate and benzyl cinnamate1 An ointment containing benzylimidazole sulfonic acid becomes the first commercial sunscreen available in Germany1 The future founder of LOreal, Eug ene Schueller, markets the first commercial sunscreen available in France, an oil preparation containing benzyl salicylate1 Franz Greiter, the founder of Piz Buin Company, develops an effective sunscreen in Austria, Gletscher cr eme; he later improves upon and popularizes the concept of SPF (1974)1 p-Amino benzoic acid is patented2 Higher incomes and expanding travel options spur emergence of the sunscreen market3 Schulze invents the SPF, enabling the evaluation of sunscreen performance4 Introduction of oxybenzone as a broad spectrum UVB/UVA filter; broad introduction of SPF on sunscreen packaging revolutionizes marker, and products are now comparable on a quantitative basis Avobenzone, a long-wave UVA filter, is approved by the US FDA (1988; approved in Europe in 1978) Attitude of consumers toward sun exposure changes as the public becomes increasingly aware of the potential harm from solar radiation 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.

Fig 1. Evolution of sunscreens from predominant protection against UVB light toward spectral homeostasis (E1,1, extinction at 1-cm path length and 1% concentration as a measure for UV light lter efcacy at every wavelength in the UVR range). UV, Ultraviolet; UVB, ultraviolet B; UVR, ultraviolet radiation.

enhancement of UVA protection potential of ZnO in the presence of AVO.20 Ecamsule, the most recent UV filter approved in the United States (2006), is available only for the sponsor of the new drug application (ie, it can only be used in certain products). The third organic UVA1 filter, meradimate (Fig 2), is rather weak and limited to use at concentrations \5%. The fourth UVA1 filter is ZnO, which has low E1,1 value. While it can be used in concentrations of # 25%, in practice, cosmetic limitations exist at such high concentrations. Sun Protection Factoreboosting agents. Better lm forming of sunscreen on the skin leads to a more uniform distribution and therefore to a higher SPF. The use of organic UV lters to stabilize inherently unstable UV lters, such as AVO, leads to a higher SPF and/or better UVA protection. It

should be noted that some of the emollients, photostabilizers, and other ingredients in sunscreen products are also UV absorbers, although they do not appear on the actives list on the drug fact sheet (Table III). Ultraviolet lters not yet available in the United States. In the UVB/UVA2 range, 2 UV lters are frequently used outside of the United States: octyl triazone and diethylhexyl butamido triazone. As seen in Figs 6 and 7, they are the most efficient UVB filters, with a maximal E1,1 value [1400. Less frequently used is amiloxate, a homologue of octinoxate with isopentyl instead of the ethyl-hexyl group. A unique UV filter is polysilicon-15. It has a low E1,1 value of just [150. However, because it has a polymeric structure, it spreads extremely well on the surface of the skin, contributing significantly to the SPF. All new UV lters that reach into the UVA1 range are photostable and shown in Table II. The most efficient broad-spectrum UV filter is bemotrizinol.21,22 Bisoctrizole is a particulate organic UV filter with especially broad UVB and UVA absorbance. The inclusion of only a few percent of bisoctrizole boosts the critical wavelength (CW) to [370 nm.

SUNSCREEN USE Key points

d

The SPF value primarily measures the level of protection against UVB and UVA2, and is based on the ratio of MED on sunscreen-

J AM ACAD DERMATOL
VOLUME 69, NUMBER 6

Jansen et al 867.e5

protected skin compared to unprotected skin. d Methods for assessment of UVA protection. vary by country; in the US critical wavelength method is used. Evaluation of efcacy The SPF and the UVA protection prole are the 2 common indices used to quantify the efcacy of sunscreens. The measurement of SPF depends on minimal erythema dose (MED), which is dened as the smallest UV dose that produces perceptible redness of the skin (erythema) with clearly dened borders at 16 to 24 hours after UV exposure.23 SPF measurement is performed in vivo using a panel of paid volunteers with Fitzpatrick type I, II, or III skin.23,24 Sunscreen is applied to the protected test sites at a density of 2 mg/cm2, which allows for even and reproducible application of the sunscreen. SPF is then calculated as the ratio of MED on sunscreenprotected skin to that on unprotected skin. There are a number of factors that can affect SPF measurement results: variation in the emission spectrum and total irradiance of light sources used in different laboratories; the duration, force, and uniformity of application of sunscreen; and subjectivity of visual assessment of the MED. These are the reasons for the required incorporation of a standard sunscreen for all SPF testing to ensure agreement of results among different laboratories. It should be noted that high intensity solar simulators are needed to permit testing of high SPF sunscreens within practical time limits; therefore, exposure to UV in SPF tests does not accurately simulate exposure to sunlight during daily activity. Ultraviolet A light testing. The SPF value mainly measures the level of protection against erythemogenic spectra of UV light (ie, UVB and UVA2).23 Improved understanding of the deleterious effects of UVA radiation has underpinned the development of better UVA filters and testing standards for measuring UVA protection. Methods for testing UVA protection have been adopted by regulatory bodies in Japan, the European Union (EU), United Kingdom (UK), Australia, and the United States. However, the methodologies vary by country.25 Japan uses persistent pigment darkening (PPD) as a clinical endpoint. PPD measures the minimal UVA radiation dose required to induce the first perceptible pigmentation changes (ie, minimal pigmenting dose) in sunscreen-protected skin compared to unprotected skin. Sunscreen products are then rated as PA1, PA11, PA111, or PA1111 (where PA indicates the protection grade from UVA).26 The EU requires UVA protection factor to be at least one-third of the labeled SPF, with PPD

method as the assessment of the UVA protection. For example, a sunscreen with a SPF of 30 must have a UVA protection factor of at least 10.27 In the UK, the ratio of UVA absorbance to mean UVB absorbance is measured in vitro; a star rating system is used.28 Australia adopted the in vitro test procedure ISO 24443:2012 for determining broad-spectrum performance, which is similar to the European assessment.29 The adoption of this UVA testing method, which determines the spectral absorbance characteristics of UVA protection in a reproducible manner, has led to the development of sunscreens with 10 to 20 times the protection against UVA radiation when compared to sunscreens complying with the old standard.29 In 2011, the US Food and Drug Administration (FDA) mandated the use of in vitro CW for testing of UVA protection.30,31 Briefly, the CW test is conducted by applying the test product to 3 different polymethylmethacrylate plates at a density of 0.75 mg/cm2. To take into account the photostability of the product, a preirradiation dose of 800 J/m2 (ie, 80 mJ/ cm2, the equivalent of 4 times the MED of Fitzpatrick skin phototype II) is delivered to the test product. UV transmittances are then measured from 290 to 400 nm. CW is defined as the wavelength at which 90% of the total area under the absorbance curve occurs (Fig 8). Sunscreens that have a CW of $ 370 nm are then allowed to claim broad-spectrum status. Immune protection factor. Photoimmunosuppression by UVR is an in vivo parameter forming the basis for the index of protection known as immune protection factor. Immune protection factor can be assessed by measuring the UVR-induced suppression of either the induction or elicitation arms of the delayed-type or contact hypersensitivity responses.7 However, standardization of both the definition and the method for determination of immune protection factor has yet to be established. Factors affecting sunscreen efcacy Knowledge and behavioral barriers. Sunscreen should always be used in conjunction with other photoprotective measures (Table IV). Many consumers lack a fundamental understanding of the relationship between UVA/UVB and sunscreen protection ratios.32 In practice, most people often apply only 25% to 50% of the amount used for SPF testing.32 This results in an effective SPF that is # 33% of the labeled SPF. Recently, a modification of the teaspoon rule for sunscreen application has been proposed.33 Namely, to achieve 2 mg/cm2 of density, the following should be done: 1 teaspoon of sunscreen to the face/head/neck, 1 teaspoon to each upper extremity, a total of 2 teaspoons to the front

Table II. Common ultraviolet light filters approved in Australia, Europe, Japan, and the United States
Concentration limits in sunscreen (%) INCI CE no.* USAN Trade name*y INCI abbreviation AUS EU JP US
z

867.e6 Jansen et al

Broad-spectrum and UVAI (340-400 nm) Bis-ethylhexyloxyphenol S mmethoxyphenyl triazine Butyl methoxydibenzoylmethane S Diethylamino hydroxybenzoyl S hexyl benzoate Disodium phenyl dibenzimidazole S tetrasulfonate Drometrizole trisiloxane S Menthyl anthranilate Methylene bis-benzotriazolyl S tetramethylbutylphenol Terephthalylidene dicamphor S sulfonic acid Zinc oxide S UVB (290-320 nm) and UVAII (320-340 nm) 4-Methylbenzylidene camphor S Benzophenone-3 S Benzophenone-4 S Polysilicone-15 S Diethylhexyl butamido triazone S Ethylhexyl rimethyl PABA{ S Ethylhexyl methoxycinnamate S Ethylhexyl salicylate S Ethylhexyl triazone Homomenthyl salicylate Isoamyl p-methoxycinnamate Octocrylene

81 66 83 80 73 79 71 76 60 38 40 74 78 08 28 13

Bemotrizinol Avobenzone

Tinosorb S Parsol 1789 Uvinul A Plus Neo Heliopan AP Mexoryl XL Tinosorb M (active) Mexoryl SX ZnO (Nanox) Eusolex 6300 Uvinul MS40 Parsol SLX Uvasorb HEB Eusolex 6007 Uvinul MC 80 Neo Heliopan OS Uvinul T 150 Eusolex HMS Neo Heliopan E1000 Uvinul N 539 T

BEMT BMBM DHHB DPDT DTS MA MBBT TDSA ZnO MBC BP3 BP4 PS15 DBT EHDP EHMC EHS EHT HMS IMC OCR

10 5 10 10 15 5 10 10 No limit 4 10 10 10 8 10 5 5 15 10 10

10 5 10 10 15 10 10
k

3 10 10 10 10 No limit 5 10 10 10 20 10 3 10 10

3
z

Bisdisulizole disodium Meradimate Bisoctrizole Ecamsule Zinc oxide Enzacamene Oxybenzone Sulisobenzone Padimate O Octinoxate Octisalate Octyltriazone Homosalate Amiloxate Octocrylene

zx

25
z

4 10 5 10 10 8 10 5 5 10 10 10

6 10
z

8 7.5 5
z

S 69 S 12 S 27 S 32

15

10
J AM ACAD DERMATOL

DECEMBER 2013

J AM ACAD DERMATOL
VOLUME 69, NUMBER 6

Jansen et al 867.e7

AU, Australia; CE, Cosmetics Europe; EU, European Union; INCI, International Nomenclature for Cosmetic Ingredients; JP, Japan; PABA, p-Amino benzoic acid; US, United States; USAN, United States Adopted Name; UVA, ultraviolet A; UVB, ultraviolet B. *Cosmetics Europe (formerly the European Cosmetic, Toiletry, and Perfumery Association) order number reflects chronology of ultraviolet light filter development. y Trade names are property of their respective manufacturers. z Submitted for US Food and Drug Administration approval through Time and Extent Application. x Approved in certain formulations up to 3% via the new drug application. k Currently under EU-review by Scientific Committee on Consumer Safety, opinion on nonenano grade positive. { Not being supported in the EU and may be delisted. # Not yet approved in the EU or anywhere else but positive opinion by Scientific Committee on Consumer Safety.8

No limit

and back torso, and 2 teaspoons to each lower extremity. Studies have shown the incorrect application and reapplication of sunscreen by the lay public and the need for avoidance of unnecessary sun exposure after its application.32,34 It is clear that a sustained effort in public education is still needed. Initiatives to enhance clarity and consistency of sunscreen use Updating the 2011 US Food and Drug Administration regulations. Effective December 2012, sunscreens that have an SPF $ 15 and CW $ 370 nm can display the claim that if used as directed with other sun protection measures, decrease the risk of skin cancer and early skin aging caused by the sun.30,31 For sunscreens that are not broadspectrum (ie, CW \370 nm) or are broad-spectrum but with an SPF \15, these above claims will not be allowed on the label. In addition, the terms sunblock, water proof, sweat proof, or all day protection are not allowed. Going forward, labels may only contain the statement water resistant (40 minutes) or water resistant (80 minutes), reecting the actual water resistant testing wherein test subjects are immersed in a whirlpool twice for 20 minutes or 4 times for 20 minutes, followed by measurement of the SPF. Lastly, as of this writing, the US FDA has yet to make the nal determination on the following proposed items: SPF capped at 50, sunscreens in the form of oils, lotions, creams, gels, butter, pastes, and ointment as eligible dosage forms, sunscreens in the form of wipes, towelettes, powders, body wash, and shampoo are not eligible, and safety of sprays.

25 25 25 Eusolex T2000 TiO2

PBSA

Ensulizole

Titanium dioxide

Tinosorb A2B

Eusolex 232

TBPT

SUNSCREEN CONTROVERSIES
Oxybenzone Key points d Oxybenzone has been shown to have estrogenic effect, both in vitro and in an in vivo animal model. d It has been used in the United States since the 1970s, and no untoward cause and effect relationship in humans has been reported. The potential hormonal disruption effect of oxybenzone, an organic UV lter with an absorption prole ranging from 270 to 350 nm, has been discussed in the past few years. It has been used in the US since the 1970s, and prevalence of exposure to the compound among the US population is estimated to be 96%.35 In vitro experiments using human breast cancer cells suggest that oxybenzone can exert both

S 45

Phenylbenzimidazole sulfonic acid Titanium dioxide

S 75

Tris biphenyl triazine

S 84

867.e8 Jansen et al

J AM ACAD DERMATOL

DECEMBER 2013

Table III. Emollients and photostabilizers (boosters) with ultraviolet lighteabsorbing properties
UV light absorption Name Trade name* Max (E1,1) Max (nm)

Butyloctyl salicylate Benzotriazolyl dodecyl p-cresol Ethylhexyl methoxycrylene Polyester-8 Diethylhexyl syringylidenemalonate Diethylhexyl 2,6-naphthalate

Hallbrite BHB Tinogard TL Solastay S1 Polycrylene Oxynex ST Corapan TQ

140 350/380 320 160 370 310/60

306 304/337 340 306 338 295/350

E1,1, Extinction at 1-cm pathlength and 1% concentration; UV, ultraviolet. *Trade names are the property of their respective manufacturers.

Fig 4. UVB and UVA2 light lters commonly used in the United States. UVA, Ultraviolet A; UVB, ultraviolet B. Fig 2. Ultraviolet light absorption spectra of ethylhexyldimethyl p-amino benzoate (padimate O) and menthyl anthranilate (meradimate). E1,1, Specific extinction.

Fig 5. UVA1 and broad-spectrum UV light lters commonly used in the United States. UV, Ultraviolet; UVA, ultraviolet A. Fig 3. Photostability of avobenzone, alone and in presence of octocrylene and bemotrizinol.

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

application of sunscreens with 6% oxybenzone to attain the same level of exposure in humans. In humans, in a single-blinded, short-term clinical study, exposure to oxybenzone did not produce clinically relevant effects on hormonal homeostasis.42 Oxybenzone was detected in urine of studied subjects 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% of human milk samples in a study conducted in

J AM ACAD DERMATOL
VOLUME 69, NUMBER 6

Jansen et al 867.e9

Fig 6. UVB light lters not yet available in the United States. UVB, Ultraviolet B.

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

Table IV. Complete photoprotection package

Shade Protective clothing Wide-brimmed hat Sunglasses Sunscreen

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

Switzerland, and high oxybenzone levels in mothers urine were associated with decreased birth weight in girls and increased birth weight and head circumference in boys.44 While no cause and effect relationship was established in the above studies, continued careful observation is warranted. Retinyl palmitate Key points d Concerns have been raised regarding the photocarcinogenic potential of retinyl palmitate. d Analysis of results of animal studies, and experience on its use in humans, failed to indicate any compelling evidence of photocarcinogenesis of retinyl palmitate. Vitamin A is an essential nutrient that plays a major role in a number of important physiologic functions.45 As the storage form of vitamin A, retinyl palmitate (RP) has been approved for use by the FDA in foods as a fortifier, over the counter and prescription drugs, cosmetic products, and sunscreens as an antioxidant (AO). However, the use of RP in sunscreens has raised concerns regarding the potential photocarcinogenic effect of the compound.

An in-depth review of this topic has been conducted by Wang et al.46 Briefly, 8 in vitro studies were conducted to evaluate the photocarcinogenicity of RP between 2002 and 2009. Of these, 4 showed the formation of free radicals by RP after exposure to UVA radiation.47-49 The FDA National Toxicology Program subsequently conducted a large scale in vivo study using SKH-1 hairless mice, which have a thin epidermis and a predisposition to developing skin cancer. RP cream (0.1% and 0.5%) was applied, and mice were then exposed to UVR (6.75 mJ/cm2 or 13.7 mJ/cm2).50 Only mice that received 0.5% RP and that were exposed to low-dose UVR revealed a statistically significant increase in the rate of cancerous lesion formation. Therefore, no clear evidence on photocarcinogenesis could be established based on this study. In addition, the medical community has a longstanding history of safely using a number of oral and topical forms of vitamin A derivatives. Therefore, conclusive evidence is lacking that RP increases the risk of cutaneous carcinogenesis in humans.

Ultraviolet lters and inammation Key point d Ultraviolet filters may have antiinflammatory properties.

867.e10 Jansen et al

J AM ACAD DERMATOL

DECEMBER 2013

A study on the antiinammatory properties of UV lters was performed in a mouse model, using ear inammation induced by topical phorbol-myristateacetate application.51 The authors concluded that many of the common UV filters have significant antiinflammatory properties. If confirmed in UV-induced inflammation in humans, this finding could contribute to the understanding on the assessment of the SPF values and biologic effects of sunscreens. It should be emphasized that the protective property of sunscreens against acute and chronic effects of UV has now been well established. Nanoparticles Key points d Concerns have been raised on the ability of metal oxide nanoparticles to generate cytotoxic reactive oxygen species and the penetration of these particles through the epidermis. d Published evidence indicates that as used in cosmetic products, including sunscreens, micro- and nanosized ZnO and TiO2 do not pose 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 toxicity to animal and human cells have yielded conflicting results.53-64 In view of the potential toxicity, manufacturers have coated the nanosized ZnO and TiO2 with compounds such as aluminum oxide and SiO2, both to minimize the formation of ROS65 and to reduce cytotoxicity by preventing adherence of nanoparticles to cells.66 It is also important to remember that the endogenous AO systems in the skin can neutralize ROS generated by these metal oxides. Concern also exists regarding the percutaneous penetration of nanoparticles. To date, numerous in vitro and in vivo studies, conducted in both animal and human skin, have shown that nanoparticles are conned to the level of the stratum corneum after topical application, even in skin where the barrier function has been altered.67-72 The shedding and turnover of stratum corneum further prevents accumulation of nanoparticles.73 Along the same mechanism, the outward direction of hair shaft growth and flow of sebum push nanoparticles out of the hair follicle.74 Based on current evidence, the EUs Scientic Committee on Emerging and Newly Identied Health Risks concluded that the topical use of TiO275 and ZnO76 in cosmetic products does not pose a risk to humans. However, until more data are available, their use at sites with severely impaired barrier function should be minimized.

Antioxidants Key points d Antioxidants incorporated into sunscreens have the potential of added protection against the effects of ultraviolet radiation. d A 2011 study concluded that all tested sunscreens had no or minimal antioxidant properties. AOs have been incorporated into many sunscreen products to neutralize the cytotoxic effects of ROS generated by UV exposure.77,78 In human studies, after UVR exposure, it has been shown that subjects who applied sunscreen that contained meticulously stabilized AOs had greater reduction in matrix metalloproteinase-1 levels and less pigment induction and epidermal proliferation when compared to controls.79,80 However, Wang et al81 found that many sunscreen products in the United States that claimed to contain AO ingredients actually had no or negligible AO capability, most likely because of the lack of stability of AOs. Vitamin D synthesis Key points d Rigorous photoprotection, including the use of sunscreens, is associated with vitamin D insufficiency. d However, because of inadequate application, serum 25-hydroxyvitamin D levels are not affected with normal usage of sunscreens. A growing body of evidence has shown an important role for vitamin D in human health. In 2011, the Institute of Medicine concluded that the available data supported only the benets of vitamin D in skeletal health, while no conclusive evidence was available to support the extraskeletal health benets.82 The Institute of Medicine report issued guidelines defining vitamin D deficiency at a serum 25-hydroxyvitamin D (25[OH]D) level of 12 ng/mL. The guidelines also stated that most normal individuals are considered to have sufficient vitamin D at a serum 25(OH)D level of 20 ng/mL. The committee recommended daily requirements of 400 IU for infants \1 year of age, 600 IU vitamin D for adults \70 years if age, and 800 IU/d for those [70 years of age. Three sources of vitamin D exist: vitamin Derich food, dietary supplements, and cutaneous synthesis after exposure to UVB. Currently available data indicate that dietary or supplemental vitamin D should be the preferred modern-day method of maintaining normal serum levels.83 In controlled laboratory settings, and in patients with photosensitive lupus erythematosus and

J AM ACAD DERMATOL
VOLUME 69, NUMBER 6

Jansen et al 867.e11

erythropoietic protoporphyria, sunscreens and photoprotection have been shown to be associated with low 25(OH)D levels.84-88 However, Norval et al89 concluded through a review of the literature that normal usage of sunscreen does not generally result in vitamin D insufficiency. Similarly, Linos et al90 found that in whites, seeking shade and wearing long sleeves were associated with low 25(OH)D levels, while frequent sunscreen use had no effect on 25(OH)D levels.90 The most likely explanation for these findings is that most individuals do not adequately apply sunscreens (ie, \2 mg/cm2). Photoallergic dermatitis and allergic contact dermatitis. While UV lters can cause both allergic and photoallergic contact dermatitis,91 the latter condition occurs more frequently. It should be emphasized that considering the widespread use of sunscreens, contact and photocontact dermatitis is uncommon. Photoallergic dermatitis from sunscreens is from organic UV filters, with benzophenone-3 (also known as oxybenzone) being the most common cause.92-94 Use in pediatric populations Key points d In children, as in adults, broad-spectrum sunscreens should be used only as adjunct to other photoprotective measures. d For those \2 years of age, if needed, sunscreens containing inorganic UV filters could be used on exposed areas. Epidemiologic data have shown that childhood sun exposure increases the risk of cutaneous carcinogenesis in adulthood.95-99 The latest FDA sunscreen final monograph, published in 1999, indicated that physicians should be consulted for the use of sunscreens in infants \6 months of age.20 More recent guidelines issued by the American Academy of Pediatrics (AAP; 2011)100 and Centers for Disease Control and Prevention (CDC; 2003)101 both recommend that UVR exposure in children be reduced or prevented as a first-line strategy against solar UVR damage, with sunscreen used as a complementary measure. Specifically, the AAP does permit the use of sunscreen on small areas of skin when other photoprotective measures are not possible.99 Contrary to these recommendations, in practice, sunscreens remain the primary method of photoprotection used in children.102,103 Given the long-term risks of UVR exposure, proper photoprotective practice in the pediatric population, similar to adults, should include providing shade, wearing protective clothing, wide brim hat, sunglasses and, only on the uncovered areas, the use of broad-spectrum sunscreen.

The increasingly widespread use of sunscreens among the pediatric population has generated concern regarding their safety. Compared to adults, the higher body surface areaevolume ratio of children and unique microstructure of immature skin suggest that children, especially infants, may absorb a greater fraction of topically applied substances.104,105 In addition, the capacity to metabolize and excrete absorbed substances may not yet be fully mature in young children and infants, putting them at risk for side effects and toxicities not seen in adults. Although firm data are lacking, because of the controversy on the systemic absorption of UV filters, especially benzophenones,44 and the evidence from numerous studies showing the lack of percutaneous penetration of inorganic UV filters,67-72 it is a prudent clinical practice to recommend the use of sunscreens with only inorganic UV filters in children \2 years old.
The authors thank Ms Stephanie Stebens, MLIS, librarian, Henry Ford Hospital, for her assistance with manuscript preparation.
REFERENCES 1. Roelandts R. History of photoprotection. In: Lim HW, Draelos ZD, editors. Clinical guide to sunscreens and photoprotection. 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 development. 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 sunscreenwhere 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 Publication 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 December 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 methane UVA filters: Part 1. J Photochem Photobiol B 1995;28: 229-34.

867.e12 Jansen et al

J AM ACAD DERMATOL

DECEMBER 2013

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, sunscreen 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 development. 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 photocatalysts. 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 centrifugation, 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. glin D, Borsos E, Stehlin A, Luther H. New UV 21. Herzog B, Hu 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 commercial 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 Standard. 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. nigsmann H, Gilchrest BA, Cooper K, 25. Lim HW, Naylor M, Ho Morison W, et al. American Academy of Dermatology Consensus Conference on UVA protection of sunscreens: summary 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 guidelines: 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 photoprotection 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 human 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 Administrations 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. Concentrations of the sunscreen agent benzophenone-3 in residents of the United States: National Health and Nutrition Examination Survey 2003-2004. Environ Health Perspect 2008;116: 893-7. 36. Nakagawa Y, Suzuki T. Metabolism of 2-hydroxy4-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 filtersan 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 6

Jansen et al 867.e13

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

health? An overview of endocrine disrupting properties of UV-filters. Int J Androl 2012;35:424-36. Packer L, Obermueller-Jevic U, Kraemer K, Sies H, editors. Carotenoids and retinoids: molecular aspects and health issues. Urbana (IL): AOCS Publishing; 2005. Wang SQ, Dusza SW, Lim HW. Safety of retinyl palmitate in sunscreens: a critical analysis. J Am Acad Dermatol 2010;63: 903-6. 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. Xia Q, Yin JJ, Cherng SH, Wamer WG, Boudreau M, Howard PC, et al. UVA photoirradiation of retinyl palmitateformation of singlet oxygen and superoxide, and their role in induction of lipid peroxidation. Toxicol Lett 2006;163:30-43. Yin JJ, Xia Q, Fu PP. UVA photoirradiation of anhydroretinol formation of singlet oxygen and superoxide. Toxicol Ind Health 2007;23:625-31. Department of Health and Human Services, National Toxicology 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. Accessed July 21, 2013. Couteau C, Chauvet C, Paparis E, Coiffard L. UV filters, ingredients with a recognized anti-inflammatory effect. PloS One 2012;7:e46187. Newman MD, Stotland M, Ellis JI. The safety of nanosized particles in titanium dioxidee and zinc oxideebased sunscreens. J Am Acad Dermatol 2009;61:685-92. Wamer WG, Yin JJ, Wei RR. Oxidative damage to nucleic acids photosensitized by titanium dioxide. Free Radic Biol Med 1997;23:851-8. 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. 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. 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. Nakagawa Y, Wakuri S, Sakamoto K, Tanaka N. The photogenotoxicity of titanium dioxide particles. Mutat Res 1997; 394:125-32. 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. Hackenberg S, Scherzed A, Kessler M, Froelich K, Ginzkey C, Koehler C, et al. Zinc oxide nanoparticles induce photocatalytic cell death in human head and neck squamous cell carcinoma cell lines in vitro. Int J Oncol 2010;37:1583-90. 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. Dufour EK, Kumaravel T, Nohynek GJ, Kirkland D, Toutain H. Clastogenicity, photo-clastogenicity or pseudophoto-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 keratinocytesgeneration of reactive oxygen species and cell damage. 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 cytotoxic 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 lymphocytes. 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 nanoparticles: 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 nanoparticles 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 formulations containing titanium dioxide and zinc oxide nanoparticles 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, Teichmann 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 folliclesan efficient storage and penetration pathway for topically applied substances. Summary of recent results obtained at the Center of Experimental and Applied Cutaneous Physiology, Charite -Universitatsmedizin 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

867.e14 Jansen et al

J AM ACAD DERMATOL

DECEMBER 2013

77. 78.

79.

80.

81.

82.

83. 84.

85.

86.

87.

88.

89.

90.

91.

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. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. 4th ed. Oxford: Oxford University Press; 2007. Haywood R, Wardman P, Sanders R, Linge C. Sunscreens inadequately protect against ultraviolet-A-induced free radicals in skin: implications for skin aging and melanoma? J Invest Dermatol 2003;121:862-8. 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. 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. Wang SQ, Osterwalder U, Jung K. Ex vivo evaluation of radical sun protection factor in popular sunscreens with antioxidants. J Am Acad Dermatol 2011;65:525-30. 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 Academy of Sciences; 2011. Vanchinathan V, Lim HW. A dermatologists perspective on vitamin D. Mayo Clin Proc 2012;87:372-80. 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. 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. Matsuoka LY, Ide L, Wortsman J, MacLaughlin JA, Holick MF. Sunscreens suppress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab 1987;64:1165-8. 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. Photodermatol Photoimmunol Photomed 2008;24:260-7. Holme SA, Anstey AV, Badminton MN, Elder GH. Serum 25-hydroxyvitamin D in erythropoietic protoporphyria. Br J Dermatol 2008;159:211-3. Norval M, Wulf HC. Does chronic sunscreen use reduce vitamin D production to insufficient levels? Br J Dermatol 2009;161:732-6. 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. Fisher AA, Rietschel RL, Fowler JF, Fisher AA. Fishers 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 continue to develop through the first year of life. J Invest Dermatol 2008;128:1728-36.