REVIEWS

Sunscreens: An overview and update

Divya R. Sambandan, BA,a and Desiree Ratner, MDb New York, New York
Sunscreens are an important aspect of photoprotection. Their efcacy in reducing photocarcinogenesis and photoaging is widely documented. Although there are concerns regarding long-term sunscreen safety, the advantages of sunscreen use are far more compelling. In addition, novel technologies and ultraviolet lters are improving the aesthetics and efcacy of modern products. ( J Am Acad Dermatol 2011;64:748-58.)

BACKGROUND
Sunscreen ingredients are found in many types of skin care products. Initially developed to prevent sunburn, sunscreens have evolved to protect against other harmful effects of ultraviolet radiation (UVR). UVB (280-320 nm) typically induces erythema and direct DNA damage via pyrimidine dimer formation, whereas UVA (320-400 nm) is associated with tanning and photoaging.1-3 UVA also generates excess reactive oxygen species which indirectly damage DNA.4,5 Although skin cells possess antioxidants, DNA repair enzymes, and stress signaling to minimize such damage, excessive UV exposure can still lead to mutations and genetic instability. UVA exposure has also been shown to increase dermal inflammatory cell numbers, while decreasing human epidermal antigenpresenting cell activity and Langerhans cell numbers.6,7 This UV-induced immunosuppression likely plays an indirect, permissive role in photocarcinogenesis, whereas long-term sun exposure likely plays a more direct role in non-melanoma skin cancer (NMSC) development, as shown in animal models using experimental UVR.8,9 Sunscreens have been available since 1928 and today play a major role in skin cancer prevention and sun protection. The sunscreen industry initially focused on increasing the sun protection factor (SPF)

Abbreviations used: AAD: AK: FDA: MED: MPD: NMSC: PABA: SPF: UVR: American Academy of Dermatology actinic keratosis Food and Drug Administration minimal erythemal dose minimal pigmenting dose non-melanoma skin cancer para-aminobenzoic acid sun protection factor ultraviolet radiation

From Columbia University College of Physicians and Surgeonsa and Department of Dermatology, Columbia University Medical Center.b Funding sources: None. Conflicts of interest: None declared. Reprint requests: Divya Sambandan, BA, Columbia University College of Physicians and Surgeons, 630 West 168th St, Box 120, New York, NY 10032. E-mail: drs2142@columbia.edu. Published online February 4, 2011. 0190-9622/$36.00 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.01.005

and UVB protection of its products by formulating novel lter combinations and developing newer ingredients, such as para-aminobenzoic acid (PABA). Patented in 1943, PABA, an effective UVB filter, became one of the first active ingredients to be widely used in commercial sunscreens, although its staining properties and high rate of contact allergies limit its use today. The Food and Drug Administration currently regulates sunscreens as over-the-counter drugs to maintain acceptable safety standards.10 Recent research and the 2007 FDA sunscreen labeling proposal have placed stronger emphasis on UVA protection.11 At sea level, UVA comprises approximately 95% of the UV energy reaching the earths surface, whereas UVB comprises the remaining 5%.12 While UVB protection and high SPF are imperative, UVA protection is now recognized to be equally essential and has become a target for enhanced sunscreen efficacy.13 This review provides an update regarding the revised FDA sunscreen labeling guidelines, current active ingredients, the efcacy of sunscreens in preventing photocarcinogenesis and photoaging, and the safety and implications of sunscreen use.

SUNSCREEN LABELING AND CURRENT FDA REGULATIONS

The FDA proposed an amendment on August 27, 2007 to update sunscreen-labeling regulations. The

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major points presented included limiting SPF labeling to 501 for products with SPF values of 60 and above, addition of a 4-star UVA protection rating system, approval of new combinations of sunscreen ingredients, and improved usage directions placed on approved products.11

Rating UVB protection SPF is largely a measure of CAPSULE SUMMARY UVB protection. An SPF15 ACTIVE SUNSCREEN sunscreen lters about 94% INGREDIENTS A detailed understanding of available UV of UVB rays, whereas SPF30 There are 17 active sunfilters will assist in counseling individual blocks about 97%.14 The screen ingredients currently patients regarding appropriate minimal erythemal dose approved by the FDA (Table sunscreen use. (MED) of UVR is the minimal II), compared with at least 34 The fundamental component of a good dose that produces sunburn. in Australia and 28 in the sunscreen is broad-spectrum (UVA/UVB) SPF is defined as the MED European Union (EU).22,23 coverage. ratio of protected to unproThis gap arises from the tected skin. In theory, appliUnited States handling of While regular sunscreen use reduces cation of a product with SPF5 these ingredients as over-thephotocarcinogenesis and photoaging, it provides sunburn protection counter drugs rather than cosmay also have adverse effects on vitamin for five times longer than metic products, necessitating D levels. unprotected skin. However, a more rigorous and extensive this is not entirely accuapproval process. Sunscreen rate.15,16 The FDA standard for SPF testing requires ingredients are generally divided into inorganic and application of 2 mg/cm2 to protected skin. True organic agents, previously termed physical blockers application thickness is estimated to be closer to 0.5 and chemical absorbers, respectively. Each ingredient to 1.0 mg/cm2, which lowers the effective SPF.17-20 has several names, including trade, US-adopted, and chemical International Nomenclature Cosmetic Ingredient names.21 Rating UVA protection UVA2 is the major contributor to persistent pigInorganic agents ment darkening.21 Under the new FDA regulations, sunscreen products will be required to designate Inorganic sunscreen ingredients act by reecting UVA protection properties based on a 4-star rating or scattering visible, UV, and infrared radiation over a system, which will be derived from in vivo and in broad-spectrum. The major inorganic agents used vitro testing.11 The former test determines the UVA today are zinc oxide and titanium dioxide (see Table protection factor (UVA-PF), which measures a sunII), which are photostable and require a thick appliscreens ability to prevent tanning, defined as the cation to achieve adequate reflection.24 Zinc oxide offers better UVA protection, whereas titanium dioxminimal pigmenting dose (MPD) ratio of protected ide provides superior UVB protection and has a to unprotected skin. The UVA-PF predominantly whiter tone because of its higher refractive index.25 gauges UVA2 (340-400 nm) protection. Analogous The reddish hue of iron oxide, another physical to MED, the MPD is the amount of UVA required to blocker, is closer to natural skin color and is often produce the first observable pigment darkening. added to sunscreens to mask the opacity of titanium The in vitro test calculates the UVA1/UV ratio and dioxide and zinc oxide.14 Because of aesthetic conmore closely approximates the UVA1 (320-340 nm) cerns, inorganic agents were unpopular until reprotection afforded by sunscreens. This ratio ascently, when particulate forms were introduced. sesses the amount of UVA1 penetrating a roughened Microsized titanium dioxide and zinc oxide (10-50 optical-grade quartz plate before and after sunscreen nm) decrease visible light scattering and improve application. To account for the varying photostability cosmetic acceptability more than their 200- to 500of different sunscreens, a UVR dose proportional to nm nonmicrosized, opaque forms.14 They can also the SPF of the product under analysis is delivered absorb UVR, but the absorption range of the particbefore obtaining measurements. ulate form shifts toward shorter wavelengths, away The testing procedures described above allow for from the UVA zone. Microfine particles also tend to sunscreen stratication into low, medium, high, and aggregate, leading to decreased efficacy. To prevent highest protection, which determines their nal UVA
d d d

ratings (Table I). If in vivo and in vitro testing produce divergent results, the UVA grade displayed will be the lower of the previously determined UVAPF or UVA1/UV categories. If a one-star, low grade is not attained in both tests, the sunscreen cannot claim to offer UVA protection. This labeling system aims to educate consumers regarding the quality of available sunscreens.

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Table I. Four-star UVA protection rating system11

Category UVA-PF* (in vivo) UVA1/UV (in vitro)

No UVA protection +*** ++** +++* ++++

None Low Medium High Highest

\2 2 to 4 4 to 8 8 to 12 $ 12

\0.20 0.20 to 0.39 0.40 to 0.69 0.70 to 0.95 [0.95

Octocrylene is a weak UVB absorber. Although octocrylene improves photostability, it is costly and difcult to integrate into sunscreen products.26 Ensulizole is a water-soluble UVB filter, which provides a lighter, less oily consistency than most other sunscreen ingredients and is often found in daily moisturizers. Organic UVA agents Benzophenones provide broad-spectrum UVB and UVA protection. However, they are photolabile and their oxidation can interrupt the antioxidant system. The FDA has approved 3 benzophenones: oxybenzone, sulisobenzone, and dioxybenzone. Oxybenzone is most commonly used, but has the highest incidence of photoallergic contact dermatitis.26 Meradimate is a weaker filter used to enhance UVA2 protection.30 Avobenzone (butyl methoxydibenzoylmethane, Parsol 1789), a potent UVA lter, was the rst FDAapproved organic agent to effectively lter UVA1. However, it is highly photolabile; 1 hour of sun exposure decreases its photoprotective properties by 50%to 60%.31 Avobenzone can also affect the stability of other active sunscreen ingredients.32 Much effort has therefore been invested in developing avobenzone stabilizing formulations with agents such as octocrylene and Tinosorb S.33,34 Helioplex stabilizing technology, patented by Neutrogena, combines avobenzone, oxybenzone, and diethylhexyl 2,6naphthalate and is designed to prevent avobenzone photodegradation.35 Approved by the FDA in 2006, ecamsule (terephthalydene dicamphor sulfonic acid; Mexoryl SX; LOreal, Paris, France) is the newest broad-spectrum agent. Ecamsule has been shown to prevent or reduce UV-induced pigmentation, pyrimidine dimer formation, p53 protein accumulation, alteration of Langerhans cell density, and photodermatoses.36 In the United States, ecamsule is now exclusively found in Anthelios products, combined with avobenzone and octocrylene. Broad-spectrum products Most sunscreen agents provide protection in a particular UV range and offer insufcient photoprotection when used alone. Cinnamates and salicylates are often mixed with other UVB absorbers to augment SPF. Broad-spectrum (UVB/UVA) products are produced by combining lters with varying UV absorption spectra. For example, avobenzone, a superior UVA blocker, can be combined with homosalate and octisalate, UVB lters, to yield broad-spectrum coverage. Because of the increased photolability of benzophenones and avobenzone, octocrylene is

UVA-PF, UVA protection factor. *UVA-PF is defined as the minimal pigmenting dose ratio of protected skin to unprotected skin.

this, they are coated with dimethicone or silica, thereby reducing free radical formation and increasing photostability.24 Because of their photostability, inorganic agents are preferred for children and sunscreen-allergic individuals.26 Inorganic, opaque sunscreens may also protect against visible lighte induced photosensitivity diseases.27 Organic UVB agents Organic sunscreen ingredients, many of which specically lter UVB, act by absorbing UVR and converting it to heat energy (see Table II). PABA is the most potent UVB agent, whose ability to bind keratinocytes increases skin staining, but allows it to withstand water immersion and perspiration.26 Many reports of contact allergies to PABA exist, and it has therefore been largely replaced by less effective PABA derivatives, such as padimate O, which have better safety profiles and rarely stain skin.14,28 Padimate O is generally used in combination with other UV filters to increase overall SPF. Cinnamates, including octinoxate and cinoxate, are currently the most popular UVB lters in the United States because they do not stain and rarely cause irritation.14,26 Since they are one order of magnitude less potent than padimate O and have reduced water resistance, cinnamate-based sunscreens require frequent reapplication. Although encapsulation techniques have improved their photostability, they can degrade after sunlight exposure, which decreases their efficacy.29 Salicylates, the weakest organic UVB agents, include octisalate, homosalate, and trolamine salicylate. These agents possess favorable safety proles and are added to sunscreens in relatively high concentrations to augment UVB protection. Octisalate and homosalate are highly photostable agents used to reduce photodegradation of other active sunscreen ingredients. They are also hydrophobic and can serve as solvents for other sunscreen agents.26 In contrast, trolamine salicylate is water soluble and is often found in hair products.

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Table II. FDA-approved active sunscreen ingredients

Maximum FDA-approved concentration (%) Peak absorption wavelength (nm) Range of protection (nm) Protection provided (UVB/UVA)

FDA-approved*active sunscreen ingredient

Inorganic Titanium dioxide Zinc oxide Organic UVB PABA Padimate O Octinoxate (octyl methoxycinnamates) Cinoxate Octisalate (octyl salicylate) Homosalate Trolamine salicylate Octylocrylene Ensulizole (phenylbenzimidazole sulfonic acid) Organic UVA Oxybenzone Sulisobenzone Dioxybenzone Meradimate (menthyl anthranilate) Avobenzone Ecamsule (terephthalydene dicamphor sulfonic acid [Mexoryl SX])
*FDA approved as of Dec. 7, 2009.

25.0 25.0 15.0 8.0 7.5 3.0 5.0 15.0 12.0 10.0 4.0 6.0 10.0 3.0 5.0 3.0 10.0

Varies Varies 283 311 311 290 307 306 260-355 303 310 290, 325 366 352 336 360 345

290-350 290-400 260-313 290-315 280-310 270-328 260-310 290-315 269-320 287-323 290-340 270-350 250-380 206-380 200-380 310-400 295-390

UVB, UVA2 UVB, UVA1

UVB

UVB, UVA2 UVB, UVA2 UVB, UVA2 UVA2 UVA1, UVA2 UVA1, UVA2

often added to improve sunscreen photostability with these agents. Organic and inorganic lters may also act synergistically to increase SPF.37 Inorganic agents scatter UV light, increasing the photons optical pathways and enhancing subsequent absorption by organic agents.37

SUNSCREEN EFFICACY
When applied correctly, sunscreens are efcacious in preventing acute sunburn and tanning. They have also been successful in reducing some chronic effects of UVR irradiation, including immunosuppression, photocarcinogenesis, and photoaging. Vehicle type and application patterns Sunscreen vehicles often determine product efcacy. To maintain the photoprotective properties and photostability of its UV lters, a sunscreen vehicle must minimize interaction of inert and active ingredients. Vehicle type also determines sunscreen durability and water resistance. The FDA designates sunscreens with intact photoprotective properties after two 20-minute exposures to water as waterresistant. The term very water-resistant has replaced water proof and applies to sunscreens remaining effective after four 20-minute periods of water immersion.11 It is important to note, however, that after water exposure in the FDA testing protocol, subjects do not towel test sites, which is not typical in

the real world. In addition, despite their label, even water resistant sunscreens can exhibit a gradual loss in SPF with subsequent water immersions.38 Sunscreen vehicles include lotions/creams, waterbased gels, sticks, sprays, and cosmetics. Lotions and creams, consisting of either oil-in-water or water-inoil emulsions, permit the greatest diversity of formulations and are most commonly used. Gels are easily washed away by swimming and sweat, but are preferred by patients with oily skin or recurrent acne. Sticks are used for protecting small areas like the lips or nose. Sprays are convenient, but are often applied insufciently. Sunscreen agents may also be found in hair care products, such as shampoos and articial dyes, to protect against UV-induced color change and protein damage.39,40 Vehicle type often plays a role in cosmetic acceptability, application patterns, and compliance. The opacity of inorganic sunscreens and the greasiness of organic agents may contribute to inadequate application and subsequent SPF reduction.41 Sunscreen failure can stem from insufficient application and infrequent reapplication.18-20,42 Possible approaches to improving patient compliance include daily textmessage reminders as well as mandatory sunscreen distribution and education on appropriate use at high sun exposure locations.43 Creating single-use products that must be used completely during a day of sun exposure may also counter inadequate sunscreen

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application tendencies. Novel packaging can also improve usage, such as Blue Lizards color-changing bottle that alerts users to the need for sunscreen application at increased ambient UV levels. Photocarcinogenesis Sunscreen use may reduce the risk of developing actinic keratoses (AKs) and NMSC, and regular use of sunscreens has been shown to be cost effective in preventing NMSC and AKs.44-47 The mechanism by which these agents reduce photocarcinogenesis may involve protection against UV-induced reduction in epidermal antigen-presenting cells.7 The association between melanoma and sunscreen use is more ambiguous. It was previously thought that sunscreen use could increase the risk of developing melanoma. However, two separate reviews failed to nd correlations between sunscreen use and melanoma risk.48-50 While sun protection is still recommended, its benefit may vary because of the role of individual genetic factors in melanoma development.51 The multifactorial nature of melanoma may partly explain the inconsistent associations found between sunscreen use and melanoma development. Photoaging Sun exposure accelerates intrinsic skin aging via UV-induced generation of reactive oxygen species. UVB and UVA penetrate deeply into the dermis, producing dystrophic elastin bers and collagen meshwork damage.52,53 Chronically irradiated skin can be metabolically overactive, leading to epidermal hyperplasia, irregular pigmentation, telangiectases, elastosis, reduced collagen, and wrinkles. One 2-year, randomized trial demonstrated that regular use of SPF 29 sunscreen prevented solar elastosis to a greater degree than placebo.54 An additional study showed that daily broad-spectrum sunscreen use prevented changes associated with photoaging, including epidermal thickening and decreased collagen.55

SAFETY AND ADVERSE EFFECTS OF SUNSCREEN

While sunscreens can effectively protect against photocarcinogenesis and photoaging, they may also have adverse effects, including contact sensitivity, risk of vitamin D deciency, and estrogenicity. Sensitivity and toxicity from systemic absorption Although infrequent and subjective, stinging and burning are the most common complaints associated with sunscreens.56 True allergic contact dermatitis is rarely caused by sunscreen ingredients,57 although

its incidence may be underestimated.58 PABA and oxybenzone are the most common contact photoallergens in use today, whereas avobenzone, sulisobenzone, octinoxate, and padimate O have fewer reported reactions.57 Patients with photodermatoses and eczema may be predisposed to developing photoallergy and should be counseled appropriately. Salicylates, ecamsule, and inorganic agents cannot penetrate the stratum corneum, so photosensitivity to these agents is uncommon.26,59 There are mixed reports regarding the penetration and systemic effects of microne inorganic agents. An Australian government review concluded that nanosized zinc oxide and titanium dioxide remain on the skin surface without penetrating the stratum corneum.60 Studies have also demonstrated that nanosized titanium dioxide can pass through cell membranes and impair function of human dermal fibroblast cultures.61 Polymer-coating these particles may prevent cell membrane adhesion, thereby preserving cell function.61 Microfine zinc oxide and titanium dioxide can induce neural stem cell apoptosis, although this toxic effect may be more dose dependent than size dependent.59,62,63 Because nanosized zinc oxide particles do not penetrate stratum corneum, the layers of which have a high turnover rate, significant in vivo safety concerns are unlikely.64-66 Some organic sunscreen agents, including oxybenzone and octinoxate, have been detected in plasma and urine after 4 days of whole-body topical application.67 The concentrations used in this study were the maximum allowed in the EU, 10%, whereas the maximum approved concentrations in the U.S. for oxybenzone and octinoxate are 6% and 7.5%, respectively.67 Despite these concerns, the benefits afforded by proper sunscreen use likely outweigh the toxicity risks. To definitively determine the risk of systemic absorption of sunscreen ingredients, testing appropriate filter concentrations and commercial sunscreen formulations will be helpful, particularly in children and pregnant women. Combination products containing sunscreen ingredients and DEET, an insect repellent, are now readily available.21 Concurrent administration of DEET and oxybenzone may increase absorption of both agents and reduce SPF.68-70 While sunscreen should be reapplied at least every 2 hours, DEET should be applied sparingly and infrequently. This inherent incongruity may predispose patients either to photodamage or to DEET toxicity. Vitamin D Vitamin D synthesis requires exposure to UVB. At least 90% of an individuals vitamin D requirement is estimated to be derived in this manner.71 There is

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ongoing controversy over the effects of sunscreen use on UV-dependent cutaneous synthesis of vitamin D3 (cholecalciferol). Because proper use of SPF-15 sunscreen may reduce vitamin D synthesis by over 98%, some suggest that regular sunscreen application may cause vitamin D insufficiency, whereas others have shown that long-term sunscreen use has little to no effect on vitamin D levels and function.72-76 Possible explanations for these discrepancies include the fact that a significant portion of vitamin D is obtained through diet, limited sun exposure is required to produce adequate vitamin D, most people apply sunscreen insufficiently, and even when applied appropriately some UVR still penetrates the skin. While the American Academy of Dermatology (AAD) once asserted that vitamin D deficiency in healthy individuals was not related to sunscreen application, it recently revised its position, stating that regular sunscreen use may increase the likelihood of developing vitamin D insufficiency, such that some patients could require extra vitamin D via diet or supplements.77 While sunscreen use and photoprotection can effectively reduce skin cancer risk, individuals must be aware of their vitamin D status to avoid other risks. In recent years, the role of vitamin D in calcium homeostasis and bone development has been established, and abnormal vitamin D levels have been implicated in some autoimmune, neurologic, and cardiovascular diseases.78-81 Epidemiologic studies have also linked low vitamin D levels to a greater risk for breast, colorectal, and prostate cancer, and even melanoma.82-86 Despite these concerning results, additional data are required to determine vitamin Ds actual role, if any, in these disease processes. Long-term trials controlling for confounding factors, such as latitude, season, and diet, will be essential. Patients at high risk for vitamin D insufciency include those who are elderly, darker skinned, housebound, photosensitive, or obese, and patients residing in more northern latitudes who regularly use sunscreens and photoprotective clothing.87,88 The AAD recommends counseling these groups regarding the U.S. Department of Agriculture Dietary Guidelines for vitamin D supplementation, which recommends a daily dose of 1000 IU, obtained through the diet or supplements.89 If supplements are used, vitamin D3, produced in the skin, is generally preferred over vitamin D2 (ergocalciferol). The U.S. Food and Nutrition Board has set an upper limit on vitamin D intake at 2000 IU per day for those older than 12 months to avoid toxicity.90 Estrogenicity Several sunscreen agents have been found to have estrogenic effects. One study reported that

padimate O, octinoxate, homosalate, and oxybenzone increased in vitro proliferation of MC7 cells, a human mammary tumor cell line. This study also noted a dose-dependent increase in the uterine weight of immature Long-Evans rats when fed octinoxate and oxybenzone, although its experimental methods might have been awed.91-93 Homosalate and oxybenzone exhibit anti-androgen and anti-progesterone activity in vitro.94,95 Other studies suggest that the estrogenic activity of UV filters may be amplified in combined sunscreen formulations, even when the concentrations used did not yield estrogenic activity when tested separately.96,97 In one study, oxybenzone and octinoxate were systemically absorbed after 1 weeks application, although no signicant change in reproductive hormone levels was observed.98 While UV filters should be tested for endocrine activity to ensure long-term safety, no consensus exists regarding their effective estrogenicity or clinical relevance. Longer studies on the endocrine effects of UV agents are therefore warranted.

IMPLICATIONS OF SUNSCREEN USE

Behavioral changes A recent review examined the association between sunscreen use and sun exposure, concluding that sunscreen use increased the duration of intentional sun exposure between 13% and 39%.99 Specifically, use of sunscreens with a higher SPF appeared to lengthen exposure times.100 The anticipated protection from sunscreen likely instills a false sense of safety, but more importantly, higher SPFs raise the threshold for sunburn.101 Increased UV exposure should not be viewed as a side effect of high SPF sunscreens, but rather as an occurrence in specific populations, especially those misusing sunscreens as tanning aids.102,103 Individuals extending their sun exposure in this manner may in fact be at increased risk of skin cancer. Recommended sunscreen use and photoprotection The AAD recommends regular sunscreen use to prevent skin cancer. Selecting a sunscreen with broadspectrum (UVB/UVA) coverage is vital, and daily use of an SPF30 product is recommended. Sunscreens must be applied liberally and uniformly, 15 to 30 minutes before exposure. To remain effective, they must be reapplied often, especially when perspiring or swimming. However, sunscreens are only a single aspect of photoprotection. Adopting sun-protective behaviors is the best way to prevent UV-induced skin damage, such as avoiding the sun between 10 AM and 4 PM, when UVR is at its peak. Seeking shade may help,

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Table III. Unapproved sunscreen agents, non-pharmacological agents, and novel mechanical devices14,21,26
Peak absorption wavelength (nm) Properties

Unapproved sunscreen agents UVB Octyl triazone (ethylhexyl triazone, Uvinul T150) Enzacamene (methyl benzylidene camphor) Amiloxate (isoamyl p-methoxycinnamate) Broad spectrum (UVB/UVA) Mexoryl XL (drometriazole trisiloxane) Tinosorb S (bemotrizinol) Tinosorb M (bisoctrizole) UVAsorb HEB (diethylhexyl butamido triazone) Neo Heliopan AP (bisdisulizole disodium) Uvinul A Plus Non-pharmacological agents Topical antioxidants DNA repair enzymes Novel mechanical devices Sol-Gel Microencapsulation SUNSPHERES
N/A, Not applicable; SPF, sun protection factor.

314 295 308 303, 344 310, 348 303, 358 312 334 354 N/A Flavonoids, resveratrol, green tea extracts T4 endonuclease V, photolyase UV filters loaded into 1-m silica shells SPF boosters that scatter incident light

N/A

but it is estimated that 50% of UVA exposure occurs in the shade.104 Sunglasses, wide-brimmed hats, and sun-protective clothing are alternative ways to shield skin from the effects of UVR.

FUTURE DIRECTIONS
One approach to enhancing sunscreens is to develop innovative UV lters that are suitable and safe for human use. The safety and efcacy of several new agents are under review for US FDA approval (Table III). Most of these ingredients have been on the market in the EU, Canada, and Australia for years. Octyl triazone (ethylhexyl triazone, Uvinul T150), enzacamene (methyl benzylidene camphor), and amiloxate (isoamyl p-methoxycinnamate) are three UVB filters that will likely be added soon to the FDA sunscreen monograph. The photostable Mexoryl XL (LOreal; drometrizole trisiloxane, silatriazole) lters UVB and UVA2, acting synergistically with ecamsule to increase dramatically overall UVA protection.3 Tinosorb S (bemotrizinol) and Tinosorb M (bisoctrizole) are highly photostable, broad-spectrum agents developed by Ciba Specialty Chemicals, Switzerland. Tinosorb S is oil soluble and stabilizes avobenzone and octinoxate.33 Tinosorb M consists of microfine particles (100-200 nm) dispersed within the aqueous phase of sunscreens and can reflect, scatter, and absorb UVR.14 Because of their relatively large size, Tinosorb filters rarely cause allergic contact dermatitis, systemic absorption, or endocrine-like effects.26,105 Uvasorb HEB (diethylhexyl butamido

triazone) is another UVA agent presently under FDA review. Neo Heliopan AP (bisdisulizole disodium) and Uvinul A Plus are other promising prospects which will likely be considered by the FDA in the future. Neo Heliopan AP is a water-soluble UVA filter, while Uvinul A Plus is the anticipated successor to avobenzone because of its high photostability and similar absorptive properties.21 Ongoing research and positive safety reviews should facilitate FDA approval of these agents. Topical antioxidants and DNA repair stimulants are being explored as options for expanding the photoprotective abilities of sunscreens. Topical antioxidants, including avonoids, resveratrol, and green tea extracts, may diminish UV-related skin damage, although they can be unstable and diffuse poorly into the epidermis.14,106-109 DNA repair enzymes, such as T4 endonuclease V and photolyase, have been shown to decrease DNA damage after UV exposure.110-112 Similarly, application of thymidine dinucleotides to human skin before UV exposure may prime the cellular DNA repair response and diminish subsequent UV-induced damage.113 To overcome the time-consuming FDA approval process, other sunscreen technologies have been investigated. These novel techniques can boost a products SPF without introducing new UV agents. This has contributed to the current SPF escalation in the sunscreen market and has prompted some to question whether costly, high-SPF products are worthwhile, given the minimal incremental protection provided as SPF increases. Despite these concerns, the

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following advances have increased sunscreen potency. Developed by Sol-Gel Technologies, Ltd, the microencapsulation approach loads UV lters into 1-m silica shells.114,115 By means of this technique, products with sunscreen agents that have traditionally been incompatible can be prepared. Because the active ingredients do not directly contact the skin, microencapsulation may help to lower the incidence of contact allergies and systemic sunscreen absorption. Several products currently take advantage of this technique, specifically Eusolex UV Pearls (Merck). SUNSPHERES (Rohm and Haas) are SPF boosters emerging as novel sunscreen vehicles.116 SUNSPHERES are filled with water and made of styrene/acrylate copolymers that do not absorb UVR. Once these products are applied to the skin, the water escapes the SUNSPHERE, and the remaining hollow capsule scatters incident light, increasing the chance that light will contact the UV filters and improving the products effective SPF by 50% to 70%.116 Because SUNSPHERES are inert, they are not regulated in the United States and are used in sunscreens, skin care products, and cosmetics. In summary, the efcacy of sunscreens in reducing photoaging and skin cancers is widely documented. UVA- and UVB-blocking products protect against sunburn as well as more subtle suberythemal skin damage. While there may be concerns over the longterm safety of UV lters, the benets of sunscreens clearly outweigh their potential risks. However, the principal barrier to attaining these benets is patient compliance. Taking advantage of improved technologies and product efcacy may require patient education and public health measures encouraging sunscreen use. New technologies that improve aesthetics may also help to increase compliance, thereby decreasing the incidence of skin cancer and the severity and extent of photoaging.
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