Part II. : Development, efficacy, and controversies

Rebecca Jansen, MD,a UliOsterwalder,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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After completing this learning activity, participants should be able to describe the evolution of sunscreen technology; summarize new photoprotective technologies; Elsevier: http://www.elsevier.com/wps/find/privacypolicy.cws_home/ and discuss and explain current sunscreen controversies. privacypolicy

867.e1 867.e2 Jansen et al JAM ACAD DERMATOL DECEMBER 2013

In addition to the naturally occurring, physical, and systemic photoprotective agents reviewed in part I, topical radiation filters are an important cornerstone of photoprotection. Sunscreen develop- ment, efficacy, 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: ; photoprotection; photostability; Sun Protection Factor; sunscreen; sunscreen controversies; ultraviolet filter.

SUNSCREENS: Ultraviolet filters TOPICAL CAPSULE SUMMARY Principles of ultraviolet PHOTOPROTECTIVE radiation absorption AGENTS d Ideal provide uniform by organic ultraviolet Key points protection across the ultraviolet B and filters. In order to absorb d Ideal sunscreens pro- ultraviolet A light range while ultraviolet radiation (UVR), vide uniform protection maintaining sensory and tactile features an organic ultraviolet (UV) against ultraviolet A and that enhance the user’s experience. light filter must contain a

ultraviolet B light. d Sunscreen efficacy depends on suitable chromophore that d p Ideal sunscreens have ultraviolet filter type (organic or has conjugated -electron aesthetically pleasing inorganic), photostability, and the systems. Increasing the num- compositions that en- addition of Sun Protection ber of conjugated double hance compliance. Factoreboosting agents. bonds in the molecule shifts the absorption maximum to d New US Food and Drug Administration The notion of the ‘‘ideal longer wavelengths and also regulations regarding sunscreen testing sunscreen’’ gives rise to a larger absorp- and labeling aim to improve the clarity Since the first commercial tion cross section and, there- of photoprotection of sunscreens. sunscreen was introduced in fore, stronger absorption. In 1928, the use of sunscreens d While there are controversies involving general, the larger the mo- as an integral part of photo- sunscreen ingredients, formulations, and lecular weight of the chro- protection strategy has ex- side effects, based on current data, the mophore, the more the panded worldwide. Table I riskebenefit ratio indicates that it is absorption maximum will highlights the historical de- appropriate to include the use of 1-4 be shifted towards longer velopment of sunscreens. sunscreen as an important component wavelengths. This is the rea- Two factors must be ad- of photoprotection strategy. son that UVB light filters have dressed to produce an 5 smaller molecular weights ‘‘ideal’’ sunscreen. It compared to UVA light or should provide uniform protection across the broad-spectrum filters. range of ultraviolet B light (UVB) and ultraviolet Currently, all organic UV absorbers used in sun- A light (UVA), a property referred to as ‘‘spectral screens are aromatic compounds, each containing homeostasis,’’ which assures that the natural spec- multiple conjugated p-electron systems (Tables II trum of is attenuated in a uniform manner 8 6 and III). The type of substituents and their position (Fig 1). This is particularly useful for protection at the aromatic ring are important for the UV spec- against immunosuppression, which has a broad 7 troscopic properties. Especially advantageous are action spectrum. 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 paraposi- enhance the user’s compliance. tion (so-called pushepull systems). Fig 2 shows a

From the Department of Dermatology,a Henry Ford Hospital, time employee of BASF. Dr Wang has served on the advisory Detroit; BASF Personal Care and Nutrition GmbH,b Monheim; board of L’Oreal. Drs Burnett and Jansen have no conflicts of and the Division of Dermatology,c Memorial Sloan Kettering interest to declare. Cancer Center, New York. Reprint requests: Henry W. Lim, MD, Department of Dermatology, Funding sources: None. Henry Ford Medical Center e New Center One, 3031 W Grand Dr Lim has served as consultant for Ferndale, La Roche-Posay, Blvd, Ste 800, Detroit, MI 48202. E-mail: [email protected]. Pierre Fabre, Uriage, and Palatin. He has received research 0190-9622/$36.00 grants from Clinuvel and Estee Lauder. Mr Osterwalder is a full JAM ACAD DERMATOL Jansen et al 867.e3 VOLUME 69, NUMBER 6

UV mainly by absorption and some scattering.15 Abbreviations used: Depending on particle size, these materials are AAP: American Academy of Pediatrics semiconductors that absorb photons at different AO: antioxidant wavelengths. The smaller the primary particles, the AVO: 16 BEMT: shorter its peak absorption spectrum. The primary CW: critical wavelength particle sizes of TiO2 used in sunscreens are between E1,1: extinction at 1 cm path length and 1% concentration 10 and 30 nm. However, in dispersion, the particles EU: European Union form aggregates with sizes usually around 100 nm. FDA: Food and Drug Administration With ZnO, primary particle sizes from 10 to 200 nm ISO: International Organization for Standardization are available, but mainly the grades with larger MED: minimal erythema dose particles are used. Because of the photocatalytic PPD: persistent pigment darkening effect, TiO2 for sunscreen applications is coated with ROS: SPF: Sun Protection Factor aluminum oxide or silica in order to prevent oxygen TiO2: titanium dixoxide formation. In addition, the rutile crystal form UK: United Kingdom is used in most cases. Rutile is the most common USAN: United States Adopted Name UV: ultraviolet light form of TiO2, has a high refractive index, and can UVA: ultraviolet A light absorb UVR. Although the anatase form of TiO2 has UVB: ultraviolet B light many of the same properties as the rutile form, it has UVR: ultraviolet radiation ZnO: lower UVR absorption and higher tendency for photocatalysis. Particulate organic ultraviolet filters. Sun- comparison of the absorption spectra of ethylhex- screens, especially those with a high Sun Protection yldimethyl paraaminobenzoate (United States Factor (SPF), contain a considerable amount of UV Adopted Name [USAN], ), with substitu- filters. Therefore, solubility of the active substance ents in a paraposition, and a UVabsorber with similar can be a significant problem.17 For this reason, groups but in orthoposition, particulate organic UV filters were developed that (USAN, meradimate). Because of the substituents in allow high SPF products to be developed with paraposition, padimate O is a more efficient UV filter relatively lower concentrations of UV filters. than meradimate. Examples of these UV filters include methylene bis- Photostability. Absorption of a UV photon benzotrazolyl tetramethylbutylphenol (biscotrizole) transfers the UV absorber molecule into an excited and tris-biphenyl triazine. These filters have ex- electronic state. If the absorbed energy is not suffi- tremely low solubility in oil and in water, but can ciently and speedily dissipated into heat, chemical be micronized in an aqueous phase.17,18 Particulate bonds of the UV absorber may break, resulting in biscotrizole shows a broad absorption up to 380 nm. degradation of the UV filter. A reversible isomeriza- Regulations of ultraviolet filters. The safety of tion (tautomerism) in the excited state can stabilize UV filters has to be shown in an extensive program of an UV absorber.9,10 This principle is realized, for toxicologic studies. In Europe and Japan, UV ab- instance, in the menthyl anthranilate molecule be- sorbers are regulated as cosmetics, in the United cause of the orthoamino group (Fig 2), resulting in States as over the counter drugs and in Australia as excellent photostability. In others, this is realized via therapeutic drugs.19 An overview of common UV an orthohydroxy group forming hydrogen bonds filters in sunscreen is shown in Table II. Australia and (eg, bemotrizinol and ). Europe have the most UV filters for sunscreen Most of the UV absorbers used in sunscreens are formulation. By contrast, the United States has the photostable under the conditions of use. Two ex- least number of UV filters available. ceptions are avobenzone (AVO) and octinoxate.11 Limitations of available ultraviolet filters in AVO undergoes rapid photodegradation, which can United States. While sufficient filters are available be stabilized by UV filters and bemo- in the UVB and UVA2 range, only 4 UVA1 (340-400 trizinol. The latter is not yet available in the United nm) filters, all with limitations, are approved in the States (Fig 3). In addition, AVO and octinoxate United States (Figs 4 and 5). AVO is the most efficient enhance the photodegradation of each other. For UVA1 filter, but it is not photostable. In the United this reason, these 2 filters should not be used in States, the maximal concentration is 3%, and it is not 12-14 combination. approved for combination with TiO2 because en- Principles of ultraviolet protection with in- hanced photodegradation of AVO is observed in the organic ultraviolet filters. Micronized inorganic presence of TiO2. AVO is also not approved in oxides used in sunscreens (TiO2 and ZnO) attenuate combination with ZnO for lack of data to show the 867.e4 Jansen et al JAM ACAD DERMATOL DECEMBER 2013

Table I. Historical development of sunscreen

Year(s) Development 1928 First commercial use of sunscreen in the United States: emulsion containing benzyl salicylate and benzyl cinnamate1 1933 An ointment containing benzylimidazole sulfonic acid becomes the first commercial sunscreen available in Germany1 1936 The future founder of L’Oreal, Eugene Schueller, markets the first commercial sunscreen available in France, an oil preparation containing benzyl salicylate1 1938 Franz Greiter, the founder of Piz Buin Company, develops an effective sunscreen in Austria, Gletscher creme; 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 on sunscreen packaging revolutionizes marker, and products are now comparable on a quantitative basis 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 radiation 2000s-2010s Role of topical sunscreens expands from mere protection against to include health prophylaxis

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

should be noted that some of the emollients, photo- stabilizers, and other ingredients in sunscreen pro- ducts are also UV absorbers, although they do not appear on the actives list on the drug fact sheet (Table III). Ultraviolet filters not yet available in the United States. In the UVB/UVA2 range, 2 UV filters are frequently used outside of the United States: octyl Fig 1. Evolution of sunscreens from predominant protec- triazone and diethylhexyl butamido triazone. As tion against UVB light toward spectral homeostasis (E1,1, seen in Figs 6 and 7, they are the most efficient extinction at 1-cm path length and 1% concentration as a UVB filters, with a maximal E1,1 value [1400. Less measure for UV light filter efficacy at every wavelength in frequently used is , a homologue of octi- the UVR range). UV, Ultraviolet; UVB, ultraviolet B; UVR, noxate with isopentyl instead of the ethyl-hexyl ultraviolet radiation. group. A unique UV filter is polysilicon-15. It has a low E1,1 value of just[150. However, because it has enhancement of UVA protection potential of ZnO in a polymeric structure, it spreads extremely well on the presence of AVO.20 , the most recent UV the surface of the skin, contributing significantly to filter approved in the United States (2006), is avail- the SPF. able only for the sponsor of the new drug application All new UV filters that reach into the UVA1 range (ie, it can only be used in certain products). The third are photostable and shown in Table II. The most organic UVA1 filter, meradimate (Fig 2), is rather efficient broad-spectrum UV filter is bemotrizi- weak and limited to use at concentrations \5%. The nol.21,22 Bisoctrizole is a particulate organic UV filter fourth UVA1 filter is ZnO, which has low E1,1 value. with especially broad UVB and UVA absorbance. The While it can be used in concentrations of # 25%, in inclusion of only a few percent of bisoctrizole boosts practice, cosmetic limitations exist at such high the critical wavelength (CW) to [370 nm. concentrations. Sun Protection Factoreboosting agents. Better film forming of sunscreen on the skin leads to a SUNSCREEN USE more uniform distribution and therefore to a higher Key points SPF. The use of organic UV filters to stabilize inher- d The SPF value primarily measures the level ently unstable UV filters, such as AVO, leads to of protection against UVB and UVA2, and is a higher SPF and/or better UVA protection. It based on the ratio of MED on sunscreen- JAM ACAD DERMATOL Jansen et al 867.e5 VOLUME 69, NUMBER 6

protected skin compared to unprotected method as the assessment of the UVA protection. For skin. example, a sunscreen with a SPF of 30 must have a d Methods for assessment of UVA protection. UVA protection factor of at least 10.27 In the UK, the vary by country; in the US critical wave- ratio of UVA absorbance to mean UVB absorbance is length method is used. measured in vitro; a star rating system is used.28 Evaluation of efficacy Australia adopted the in vitro test procedure The SPF and the UVA protection profile are the 2 ISO 24443:2012 for determining broad-spectrum common indices used to quantify the efficacy of performance, which is similar to the European sunscreens. The measurement of SPF depends on assessment.29 The adoption of this UVA testing minimal erythema dose (MED), which is defined as method, which determines the spectral absorbance ‘‘the smallest UV dose that produces perceptible characteristics of UVA protection in a reproducible redness of the skin (erythema) with clearly defined manner, has led to the development of sunscreens borders at 16 to 24 hours after UV exposure.’’23 with 10 to 20 times the protection against UVA SPF measurement is performed in vivo using a radiation when compared to sunscreens complying panel of paid volunteers with Fitzpatrick type I, II, or with the old standard.29 III skin.23,24 Sunscreen is applied to the protected test In 2011, the US Food and Drug Administration sites at a density of 2 mg/cm2, which allows for even (FDA) mandated the use of in vitro CW for testing of and reproducible application of the sunscreen. SPF is UVA protection.30,31 Briefly, the CW test is conducted then calculated as the ratio of MED on sunscreen- by applying the test product to 3 different polyme- protected skin to that on unprotected skin. There are thylmethacrylate plates at a density of 0.75 mg/cm2. a number of factors that can affect SPF measurement To take into account the photostability of the pro- results: variation in the emission spectrum and total duct, a preirradiation dose of 800 J/m2 (ie, 80 mJ/ irradiance of light sources used in different labora- cm2, the equivalent of 4 times the MED of Fitzpatrick tories; the duration, force, and uniformity of appli- skin phototype II) is delivered to the test product. UV cation of sunscreen; and subjectivity of visual transmittances are then measured from 290 to 400 assessment of the MED. These are the reasons for nm. CW is defined as the wavelength at which 90% of the required incorporation of a standard sunscreen the total area under the absorbance curve occurs for all SPF testing to ensure agreement of results (Fig 8). Sunscreens that have a CW of $ 370 nm are among different laboratories. It should be noted that then allowed to claim broad-spectrum status. high intensity solar simulators are needed to permit Immune protection factor. Photoimmuno- testing of high SPF sunscreens within practical time suppression by UVR is an in vivo parameter forming limits; therefore, exposure to UV in SPF tests does not the basis for the index of protection known as accurately simulate exposure to sunlight during daily immune protection factor. Immune protection factor activity. can be assessed by measuring the UVR-induced Ultraviolet A light testing. The SPF value suppression of either the induction or elicitation mainly measures the level of protection against arms of the delayed-type or contact hypersensitivity erythemogenic spectra of UV light (ie, UVB and responses.7 However, standardization of both the UVA2).23 Improved understanding of the deleterious definition and the method for determination of effects of UVA radiation has underpinned the devel- immune protection factor has yet to be established. opment of better UVA filters and testing standards for measuring UVA protection. Factors affecting sunscreen efficacy Methods for testing UVA protection have been Knowledge and behavioral barriers. Sun- adopted by regulatory bodies in Japan, the European screen should always be used in conjunction with Union (EU), United Kingdom (UK), Australia, and other photoprotective measures (Table IV). Many the United States. However, the methodologies vary consumers lack a fundamental understanding of the by country.25 Japan uses persistent pigment darken- relationship between UVA/UVB and sunscreen pro- ing (PPD) as a clinical endpoint. PPD measures the tection ratios.32 In practice, most people often apply minimal UVA radiation dose required to induce the only 25% to 50% of the amount used for SPF testing.32 first perceptible pigmentation changes (ie, minimal This results in an effective SPF that is # 33% of pigmenting dose) in sunscreen-protected skin com- the labeled SPF. Recently, a modification of the pared to unprotected skin. Sunscreen products are ‘‘teaspoon rule’’ for sunscreen application has been then rated as PA1,PA11,PA111,orPA1111 proposed.33 Namely, to achieve 2 mg/cm2 of density, (where PA indicates the protection grade from the following should be done: 1 teaspoon of sun- UVA).26 The EU requires UVA protection factor to screen to the face/head/neck, 1 teaspoon to each be at least one-third of the labeled SPF, with PPD 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 867.e6

Concentration limits in sunscreen (%) INCI CE no.* USAN Trade name*y INCI abbreviation AUS EU JP US asne al et Jansen Broad-spectrum and UVAI (340-400 nm) z Bis-ethylhexyloxyphenol S 81 Bemotrizinol Tinosorb S BEMT 10 10 3 mmethoxyphenyl triazine Butyl methoxydibenzoylmethane S 66 Avobenzone Parsol 1789 BMBM 5 5 10 3 Diethylamino hydroxybenzoyl S 83 Uvinul A Plus DHHB 10 10 10 — hexyl benzoate Disodium phenyl dibenzimidazole S 80 Bisdisulizole Neo Heliopan DPDT 10 10 — — tetrasulfonate disodium AP z S 73 — Mexoryl XL DTS 15 15 — Menthyl anthranilate — Meradimate MA 5 5 z Methylene bis-benzotriazolyl S 79 Bisoctrizole Tinosorb M MBBT 10 10 10 tetramethylbutylphenol (active) zx Terephthalylidene dicamphor S 71 Ecamsule Mexoryl SX TDSA 10 10 10 sulfonic acid k Zinc oxide S 76 Zinc oxide ZnO (Nanox) ZnO No limit No limit 25 UVB (290-320 nm) and UVAII (320-340 nm) z 4-Methylbenzylidene camphor S 60 Eusolex 6300 MBC 4 4 — -3 S 38 Oxybenzone BP3 10 10 5 6 Benzophenone-4 S 40 Uvinul MS40 BP4 10 5 10 10 Polysilicone-15 S 74 — Parsol SLX PS15 10 10 10 — z Diethylhexyl butamido triazone S 78 — Uvasorb HEB DBT — 10 — { Ethylhexyl rimethyl PABA S 08 Padimate O Eusolex 6007 EHDP 8 8 10 8 Ethylhexyl methoxycinnamate S 28 Octinoxate Uvinul MC 80 EHMC 10 10 20 7.5 Ethylhexyl salicylate S 13 Octisalate Neo Heliopan EHS 5 5 10 5 OS z S 69 Octyltriazone Uvinul T 150 EHT 5 5 3 Homomenthyl salicylate S 12 Eusolex HMS HMS 15 10 10 15 z Isoamyl p-methoxycinnamate S 27 Amiloxate Neo Heliopan IMC 10 10 — E1000 Octocrylene S 32 Octocrylene Uvinul N 539 T OCR 10 10 10 10 JA M A CAD D ECEMBER D ERMATOL 2013 JAM ACAD DERMATOL Jansen et al 867.e7 VOLUME 69, NUMBER 6

and back torso, and 2 teaspoons to each lower

4 extremity. Studies have shown the incorrect application and reapplication of sunscreen by the lay public and the , United States need for avoidance of unnecessary sun exposure 32,34

USAN after its application. It is clear that a sustained 3 effort in public education is still needed.

Initiatives to enhance clarity and consistency of sunscreen use , United States; 8 US 25 No limit 25 Updating the 2011 US Food and Drug Admin- istration regulations. Effective December 2012, sunscreens that have an SPF $ 15 and CW $ 370 nm lter development. can display the claim that ‘‘if used as directed with other sun protection measures, decrease the risk of 4 ### # 25 skin cancer and early skin aging caused by the sun.’’30,31 For sunscreens that are not broad-

, p-Amino benzoic acid; spectrum (ie, CW \370 nm) or are broad-spectrum but with an SPF \15, these above claims will not be PABA allowed on the label. In addition, the terms ‘‘sunblock,’’ ‘‘water proof,’’ , Japan;

JP ‘‘sweat proof,’’ or ‘‘all day protection’’ are not 8 2 allowed. Going forward, labels may only contain the statement ‘‘water resistant (40 minutes)’’ or ‘‘wa- ter resistant (80 minutes),’’ reflecting 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,

nano grade positive. as of this writing, the US FDA has yet to make the e final determination on the following proposed items: Tinosorb A2B TBPT Eusolex T2000 TiO 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 sham- poo are not eligible, and safety of sprays. — dioxide SUNSCREEN CONTROVERSIES , International Nomenclature for Cosmetic Ingredients; Oxybenzone INCI Key points d Oxybenzone has been shown to have estro- S 45 Eusolex 232 PBSA S 84 S 75 Titanium genic effect, both in vitro and in an in vivo animal model. d It has been used in the United States since , ultraviolet B. , European Union; the 1970s, and no untoward cause and effect EU UVB relationship in humans has been reported. The potential hormonal disruption effect of oxy- benzone, an organic UV filter with an absorption

, ultraviolet A; profile ranging from 270 to 350 nm, has been discussed in the past few years. It has been used in UVA , Cosmetics Europe;

CE the US since the 1970s, and prevalence of exposure to the compound among the US population is estimated to be 96%.35 acid In vitro experiments using human breast cancer , Australia; Phenylbenzimidazole sulfonic Tris biphenyl triazine Trade names are propertySubmitted of for their US respective Food manufacturers. and Drug Administration approval through Time and ExtentNot Application. being supported in the EU and may be delisted. Currently under EU-review by Scientific Committee on ConsumerNot Safety, yet opinion approved on in non the EU or anywhere else but positive opinion by Scientific Committee on Consumer Safety. Approved in certain formulations up to 3% via the new drug application. Adopted Name; *Cosmetics Europe (formerly the European Cosmetic, Toiletry, and Perfumery Association) order number reflects chronology of ultraviolet light fi AU y z x k { # cells suggest that oxybenzone can exert both 867.e8 Jansen et al JAM 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 Hallbrite BHB 140 306 Benzotriazolyl dodecyl p-cresol Tinogard TL 350/380 304/337 Ethylhexyl methoxycrylene Solastay S1 320 340 Polyester-8 Polycrylene 160 306 Diethylhexyl syringylidenemalonate Oxynex ST 370 338 Diethylhexyl 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 4. UVB and UVA2 light filters commonly used in the United States. UVA, Ultraviolet A; UVB, ultraviolet B.

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

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

Fig 3. Photostability of avobenzone, alone and in pres- application of sunscreens with 6% oxybenzone to ence of octocrylene and bemotrizinol. attain the same level of exposure in humans. In humans, in a single-blinded, short-term clinical estrogenic36-39 and antiandrogenic39,40 effects. In an study, exposure to oxybenzone did not produce in vivo study, Schlumpf et al38 found that the weight clinically relevant effects on hormonal homeosta- of the uteri in 21-day-old rats fed with oxybenzone sis.42 Oxybenzone was detected in urine of studied ([1500 mg/kg/day) was 23% greater than uteri of the subjects in the United States and Denmark; however, control group. However, the dosage of oxybenzone it was not correlated with the use of sunscreens.35,43 used in this study was exceedingly high, and Wang One or more UV filters were detected in 85% of et al41 estimated that it would take 277 years of daily human milk samples in a study conducted in JAM ACAD DERMATOL Jansen et al 867.e9 VOLUME 69, NUMBER 6

Fig 6. UVB light filters not yet available in the United Fig 8. CW testing of sunscreen products. Sunscreen 1 has States. UVB, Ultraviolet B. 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 filters not yet avail- able in United States. UV, Ultraviolet; UVA, ultraviolet A. An in-depth review of this topic has been con- ducted by Wang et al.46 Briefly, 8 in vitro studies were Switzerland, and high oxybenzone levels in mother’s conducted to evaluate the photocarcinogenicity of urine were associated with decreased birth weight in RP between 2002 and 2009. Of these, 4 showed the girls and increased birth weight and head circumfer- formation of free radicals by RP after exposure to ence in boys.44 While no cause and effect relation- UVA radiation.47-49 The FDA National Toxicology ship was established in the above studies, continued Program subsequently conducted a large scale careful observation is warranted. in vivo study using SKH-1 hairless mice, which have a thin epidermis and a predisposition to devel- oping skin cancer. RP cream (0.1% and 0.5%) was Retinyl palmitate applied, and mice were then exposed to UVR (6.75 Key points mJ/cm2 or 13.7 mJ/cm2).50 Only mice that received d Concerns have been raised regarding the 0.5% RP and that were exposed to low-dose UVR photocarcinogenic potential of retinyl revealed a statistically significant increase in the rate palmitate. of cancerous lesion formation. Therefore, no clear d Analysis of results of animal studies, and evidence on photocarcinogenesis could be estab- experience on its use in humans, failed to lished based on this study. indicate any compelling evidence of photo- In addition, the medical community has a long- carcinogenesis of retinyl palmitate. standing history of safely using a number of oral and Vitamin A is an essential nutrient that plays a topical forms of vitamin A derivatives. Therefore, major role in a number of important physiologic conclusive evidence is lacking that RP increases the functions.45 As the storage form of vitamin A, retinyl risk of cutaneous carcinogenesis in humans. palmitate (RP) has been approved for use by the FDA in foods as a fortifier, over the counter and prescrip- tion drugs, cosmetic products, and sunscreens as an Ultraviolet filters and inflammation antioxidant (AO). However, the use of RP in sun- Key point screens has raised concerns regarding the potential d Ultraviolet filters may have antiinflamma- photocarcinogenic effect of the compound. tory properties. 867.e10 Jansen et al JAM ACAD DERMATOL DECEMBER 2013

A study on the antiinflammatory properties of UV Antioxidants filters was performed in a mouse model, using ear Key points inflammation induced by topical phorbol-myristate- d Antioxidants incorporated into sunscreens acetate application.51 The authors concluded that have the potential of added protection many of the common UV filters have significant against the effects of ultraviolet radiation. antiinflammatory properties. If confirmed in d A 2011 study concluded that all tested sun- UV-induced inflammation in humans, this finding screens had no or minimal antioxidant could contribute to the understanding on the assess- properties. ment of the SPF values and biologic effects of sunscreens. It should be emphasized that the pro- AOs have been incorporated into many sunscreen products to neutralize the cytotoxic effects of ROS tective property of sunscreens against acute and generated by UV exposure.77,78 In human studies, chronic effects of UV has now been well established. after UVR exposure, it has been shown that subjects who applied sunscreen that contained meticulously Nanoparticles stabilized AOs had greater reduction in matrix Key points metalloproteinase-1 levels and less pigment induc- d Concerns have been raised on the ability of tion and epidermal proliferation when compared to metal oxide nanoparticles to generate cyto- controls.79,80 However, Wang et al81 found that many toxic reactive oxygen species and the pene- sunscreen products in the United States that claimed tration of these particles through the to contain AO ingredients actually had no or negli- epidermis. gible AO capability, most likely because of the lack d Published evidence indicates that as used in of stability of AOs. cosmetic products, including sunscreens, micro- and nanosized ZnO and TiO2 do not pose a risk to humans. Vitamin D synthesis Key points Micro- and nanosized ZnO and TiO (diameter 2 d Rigorous photoprotection, including the use \100 nm) can generate reactive oxygen species 52 of sunscreens, is associated with vitamin D (ROS) upon UV exposure. Studies on the toxicity insufficiency. to animal and human cells have yielded conflicting d 53-64 However, because of inadequate application, results. In view of the potential toxicity, manu- serum 25-hydroxyvitamin D levels are not facturers have coated the nanosized ZnO and TiO2 affected with normal usage of sunscreens. with compounds such as aluminum oxide and SiO2, both to minimize the formation of ROS65 and to A growing body of evidence has shown an reduce cytotoxicity by preventing adherence of important role for vitamin D in human health. In nanoparticles to cells.66 It is also important to re- 2011, the Institute of Medicine concluded that the member that the endogenous AO systems in the skin available data supported only the benefits of vitamin can neutralize ROS generated by these metal oxides. D in skeletal health, while no conclusive evidence Concern also exists regarding the percutaneous was available to support the extraskeletal health penetration of nanoparticles. To date, numerous benefits.82 The Institute of Medicine report issued in vitro and in vivo studies, conducted in both animal guidelines defining vitamin D deficiency at a serum and , have shown that nanoparticles are 25-hydroxyvitamin D (25[OH]D) level of 12 ng/mL. confined to the level of the stratum corneum after The guidelines also stated that most normal individ- topical application, even in skin where the barrier uals are considered to have sufficient vitamin D at a function has been altered.67-72 The shedding and serum 25(OH)D level of 20 ng/mL. The committee turnover of stratum corneum further prevents accumu- recommended daily requirements of 400 IU for lation of nanoparticles.73 Along the same mechanism, infants \1 year of age, 600 IU vitamin D for adults the outward direction of hair shaft growth and flow of \70 years if age, and 800 IU/d for those[70 years of sebum push nanoparticles out of the hair follicle.74 age. Three sources of vitamin D exist: vitamin Based on current evidence, the EU’s Scientific Derich food, dietary supplements, and cutaneous Committee on Emerging and Newly Identified synthesis after exposure to UVB. Currently available Health Risks concluded that the topical use of data indicate that dietary or supplemental vitamin D 75 76 TiO2 and ZnO in cosmetic products does not should be the preferred modern-day method of pose a risk to humans. However, until more data are maintaining normal serum levels.83 available, their use at sites with severely impaired In controlled laboratory settings, and in patients barrier function should be minimized. with photosensitive lupus erythematosus and JAM ACAD DERMATOL Jansen et al 867.e11 VOLUME 69, NUMBER 6 erythropoietic protoporphyria, sunscreens and pho- The increasingly widespread use of sunscreens toprotection have been shown to be associated with among the pediatric population has generated con- low 25(OH)D levels.84-88 However, Norval et al89 cern regarding their safety. Compared to adults, the concluded through a review of the literature that higher body surface areaevolume ratio of children normal usage of sunscreen does not generally result and unique microstructure of immature skin suggest in vitamin D insufficiency. Similarly, Linos et al90 that children, especially infants, may absorb a greater found that in whites, seeking shade and wearing fraction of topically applied substances.104,105 In long sleeves were associated with low 25(OH)D addition, the capacity to metabolize and excrete levels, while frequent sunscreen use had no effect on absorbed substances may not yet be fully mature in 25(OH)D levels.90 The most likely explanation for young children and infants, putting them at risk for these findings is that most individuals do not ade- side effects and toxicities not seen in adults. quately apply sunscreens (ie, \2 mg/cm2). Although firm data are lacking, because of the Photoallergic dermatitis and allergic contact controversy on the systemic absorption of UV filters, dermatitis. While UV filters can cause both allergic especially ,44 and the evidence from and photoallergic contact dermatitis,91 the latter con- numerous studies showing the lack of percutaneous dition occurs more frequently. It should be emphasized penetration of inorganic UV filters,67-72 it is a prudent that considering the widespread use of sunscreens, clinical practice to recommend the use of sunscreens contact and photocontact dermatitis is uncommon. with only inorganic UV filters in children \2 years Photoallergic dermatitis from sunscreens is from or- old. ganic UV filters, with benzophenone-3 (also known as The authors thank Ms Stephanie Stebens, MLIS, librar- oxybenzone) being the most common cause.92-94 ian, Henry Ford Hospital, for her assistance with manu- script preparation. Use in pediatric populations Key points REFERENCES 1. Roelandts R. History of photoprotection. In: Lim HW, Draelos d In children, as in adults, broad-spectrum ZD, editors. Clinical guide to sunscreens and photoprotec- sunscreens should be used only as adjunct tion. New York: Informa Healthcare USA; 2009. pp. 1-10. to other photoprotective measures. 2. Gasparro FP, Mitchnick M, Nash JF. 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