Supplement to the April 2011

A supplement to Skin&A G IN G & Aging

Sun Care

www.the-dermatologist.com

February 2011

SPECIAL REPORT:

The importance of photoprotection and sunscreen in your patients.

Sun Care
Neutrogena
April 2011

Heather Woolery-Lloyd, MD
Director of Ethnic Skin Care Department of Dermatology and Cutaneous Surgery University of Miami, Miami, FL
Co-Supported by

and

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The Importance of Photoprotection/Sunscreen

Heather Woolery-Lloyd, MD Miami, FL

unscreens are essential for preventing and managing many dermatological conditions. Although originally developed more than 70 years ago to prevent sunburns, sunscreens are now also used to prevent skin cancer, photoaging, pigmentary disorders and a myriad of other dermatoses exacerbated by ultraviolet (UV) exposure.

UV Radiation: Characteristics, and Acute and Long-Term Effects

UV Radiation Characteristics The solar wavelengths include UV radiation, visible light and infrared light. UV radiation can be categorized into UVA, UVB and UVC radiation. UVC does not reach the Earths surface, so UVA and UVB are the ultraviolet rays that play a role in skin disease and are clinically significant. UVA comprises 96.5% of UV radiation, and UVB comprises 3.5%.1 While UVA makes up the vast majority of UV radiation in everyday exposure, UVB is also important as it is considered a major cause of DNA damage in the skin. Table 1 summarizes key characteristics of the solar wavelengths. Acute Effects of UV Radiation UV light affects skin immediately and long-term. The immediate effects include direct DNA damage, immunosuppression and sunburn. Cyclobutane pyrimidine dimers are the most common type of DNA damage in the skin after UV exposure; however, the effects of UV radiation on DNA

is actually more complex. After UV exposure, p53 mutations and pyrimidine-pyrimidone 6-4 photoproducts are observed. In addition, oxidative stress and an inf lammatory response are noted. 24 Human skin has complex repair mechanisms to combat acute UV-induced DNA damage via photolyase, nucleotide excision repair enzymes and an antioxidant network.5 Melanin synthesis after UV exposure is another mechanism to combat UV damage. The melanin observed after UV exposure and the melanin observed in darkly pigmented individuals is most apparent in the apical portion of the keratinocytes. This melanin blocks UV and scatters UV radiation to prevent damage of the DNA contents of the cells.6 Its not surprising that the tumor suppressor gene p53 has recently been implicated as the gene responsible for melanogenesis after UV exposure.7 Immunosuppression is another immediate adverse effect of UV radiation. Immunosuppression after UV radiation is characterized by diminished antigen-presenting cell function, induction of immunosuppressive cytokines and modulation of contact and delayed-type hypersensitivity reactions.8 The role of UVinduced immunosuppression and its relation to skin cancer has not been fully elucidated. Systemic immunosuppression is clearly associated with an increased risk of skin cancer. This is especially evident in the renal transplant population.911 Among these transplant recipients, theres a linear increase in basal cell carcinoma (BCC) risk and an exponential increase in squamous cell carcinoma (SCC) risk.9,10

Table 1. Summary of Solar Wavelengths

Wavelength (nm)
UVC UVB UVA Visible Infrared 200 to 290 290 to 320 320 to 400 400 to 800 800 nm to 300 micrometers

Distribution of light at the Earths surface

Stratospheric only 0.5% 9.5% 40% 50%

Ability to penetrate glass

N/A No Yes Yes Yes

Level of skin penetration

N/A Epidermis Dermis Hypodermis Hypodermis

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Sunburn, another acute effect of excessive sun exposure, is due to UVB radiation. A sunburn is the inf lammator y process resulting from UV exposure that initiates a process (apoptosis) that removes the irreversibly damaged keratinocytes after excessive UV radiation. Its a mechanism of programmed cell death in severely damaged keratinocytes.12 Long-Term Effects of UV Radiation Long-term effects of UV radiation on the skin include the visible signs of photoaging, epidermal thickening, skin cancers and pigmentary disorders. Photoaging is caused by UVA and UVB radiation. UVB is absorbed in the epidermis and induces c-Jun; it combines with c-Fos, is naturally abundant and produces activator protein-1(AP-1). This transcription factor induces matrix metalloproteinases. In contrast to UVB, UVA reaches the dermis and is absorbed by f ibroblasts. UVA induces reactive oxygen species. This leads to the induction of matrix metalloproteinases and mitochondrial DNA mutations. MMP-1, known as interstitial collagenase, cleaves collagen I, II and III. MMP-9, known as gelatinase, cleaves collagen IV, V and gelatin. In photoaged skin, these cumulative effects result in reduction of collagens I, III and VII, increase in elastotic material in the reticular dermis, and marked reduction in f ibrillin.13 Clinically, this long-term damage to the dermis is characterized by f ine lines, wrinkling and skin laxity. Skin cancers are also long-term effects of chronic UV radiation. Studies suggest that intense, acute exposures result-

due to the long-term effects of chronic sun exposure. Melasma is exacerbated by acute and chronic UV radiation. Postinf lammatory hyperpigmentation can be observed with acute UV radiation after acne, burns or any injury to the skin. This is especially prominent in darker skinned patients. In addition, darkly pigmented individuals often complain of progressive darkening and uneven pigmentation of facial skin with advancing age. This progressive facial darkening is also most likely due to chronic UV exposure. For all disorders of hyperpigmentation, and especially with melasma, sun protection is an absolutely essential therapeutic component. Effects of UV Radiation From Artificial Tanning Beds Twenty-eight million Americans use artificial UV tanning each year.17 Tanning-bed bulbs emit mostly UVA radiation and approximately 5% UVB radiation.18 Many studies have linked artificial tanning bed usage to melanoma.1820 Tanning bed use also increases the risk of non-melanoma skin cancers.21 Counseling is essential to educate patients especially teenage patients about the significant skin cancer risks associated with artificial tanning beds and lamps.

Photoprotection

Melanin: A Natural Photoprotectant The photoprotection conferred by melanin in darkly pigmented skin greatly inf luences the UV-induced differences observed in black and white skin. Epidermal architecture in black and white subjects supports this notion. One study demonstrated an intact, compact stratum lucidum in sun-exposed black skin, in contrast to a swollen, cellular In addition, darkly pigmented individuals often stratum lucidum in sun-exposed white skin. complain of progressive darkening and uneven Black skin rarely exhibited atrophy, while white skin had numerous focal areas of atpigmentation of facial skin with advancing age. rophy, necrosis, vacuoles and dyskeratosis. 22 This progressive facial darkening is also most Melanin clearly protects against UV light. likely due to chronic UV exposure. It acts as a neutral density f ilter to equally reduce penetration of all wavelengths of light. 23 In a study using skin samples from blacks and whites, investigators found that f ive times as ing in sunburns are associated with melanoma, and chronic much UV light reached the upper dermis of white skin when UV exposure is associated with SCC.14,15 In addition, a recent compared to black skin. The authors determined that the main study suggests that regular sunscreen use can prevent mela- site of UV f iltration in white patients was the stratum cornenomas. In this prospective study, 1621 participants were as- um, compared to the malpighian layer in black patients. The signed to two groups daily sunscreen to the face and arms average protection offered by melanin in black skin was calcucombined with 30 mg beta carotene, and discretionary use lated to be equivalent to a sun protective factor (SPF) of 13.4 of sunscreen combined with a placebo pill. The participants compared to 3.4 for white skin. The photoprotection observed participated in the study for 5 years, then were followed for in black skin is due to both increased melanin content and the 10 years after study completion. Invasive melanoma was re- unique distribution of melanosomes in dark skin. 23 duced 73% in the daily sunscreen group.16 Pigmentary disorders, such as solar lentigos, melasma and Sunscreen Agents post-inf lammatory hyperpigmentation, are frequently obVarious topical agents provide sun protection and prevent the served with acute and long-term UV radiation. Solar lentigos deleterious effects of acute and chronic sun exposure. Broadand mottled pigmentation characteristic of photoaged skin are spectrum sun protection is most desirable. For this reason, most

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Figure 1. Sunscreen with standard zinc oxide on lateral half of hand (left) vs sunscreen with transparent zinc oxide on lateral half of hand (right). The white/grey hue is more obvious with a standard zinc oxide formulation(left).

formulations contain combinations of various UVB and UVA blockers to provide broad-spectrum coverage. Physical Sunscreens The physical blockers include zinc oxide, titanium dioxide and iron oxide. Zinc oxide and titanium dioxide are most frequently used and are typically combined together or with chemical blockers to achieve the widest range of coverage. Zinc oxides coverage is in the range of 290 nm to 370 nm. Titanium dioxides coverage is in the range of 290 nm to 400 nm, depending on the particle size. These agents can absorb some UV photons similar to chemical filters,24 but mainly scatter and physically block sunlight from entering the skin. Most formulations leave a grey or white tint on the skin, which can be problematic in darker-skinned patients. Micronized formulations have been developed to address this issue. Although micronized formulations have improved the aesthetics of physical sunscreens in patients with skin of color, even these formulations are still somewhat visible on darkly pigmented individuals (see Figure 1). Micronized zinc oxide contains nanoparticles of zinc (< 100 nm), which has raised concerns regarding systemic absorption. At this size, there is concern that nanoparticles could interact with biomolecules, and penetrate cell walls and the

blood-brain barrier. 25 However, many in vitro and animal in vivo studies examining absorption of micronized zinc oxide have shown no measurable absorption. 2629 Chemical Sunscreens In contrast to physical sunscreens, chemical sunscreens absorb UV light. Chemical sunscreens provide immediate protection, but typically need to be applied up to 20 minutes before sun exposure to provide adequate water resistance. Chemical sunscreen agents are rarely used alone and need to be combined to achieve broad-spectrum coverage. The various sunscreen agents are summarized in Table 2. Chemical sunscreens may cause contact dermatitis and, it should be noted, they may also (rarely) cause photocontact allergy. Because most sunscreen formulations contain several agents, if contact dermatitis is a concern, patch testing of individual chemicals is necessary. Oxybenzone is the most common cause of photocontact dermatitis due to sunscreen. 30 This agent is found in up to 30% of commercially available sunscreens and should be considered f irst in patients with sunscreen allergies. 31 Other common causes of contact dermatitis include PABA (now rarely used), cinna-

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Table 2. Overview of Sunscreen Agents

UVB Physical Blockers UVA

Other Sunscreen Controversies: Retinyl Palmitate and Vitamin D

Another more recent concern was over the use of retinyl palmitate (RP) in sunscreens. Based on analysis of the data from the National Toxicology Program, media reports suggested that sunscreens containing RP, a storage form of vitamin A, may slightly increase the risk of skin cancer. The claim of photocarcinogenic potential by the media was based on observed reactive-oxygen-species production in mice treated with RP and exposed to UVA. 37 However, several studies dating to 1977 have failed to conclusively find a photocarcinogenic effect associated with the combination of retinoic acid and UV exposure. 3843 A review of the existing evidence concluded that, based on currently available data from in vitro, animal and human studies, theres no convincing evidence to support the notion that RP in sunscreens is photocarcinogenic. In fact, decades of clinical use suggest that retinoids are helpful in skin cancer chemoprevention. 37 The role of sunscreen and photoprotection in Vitamin D def iciency remains a controversial topic. As mentioned previously, evidence suggests that regular sunscreen use can prevent photodamage, SCC and melanoma. The main issues are still whether regular sunscreen use increases the risk of vitamin D def iciency, and how we address this topic with patients. Clearly, in patients with signif icant risk factors for melanoma, regular sunscreen use is preventative and desirable. In darker-skinned patients with lower risks for cutaneous malignancies and higher risk of vitamin D def iciency, sunscreen recommendations should be more conservative. In these patents, daily sunscreen applied to all exposed areas is not necessary. Based on a critical review of the scientif ic literature, the American Academy of Dermatology recommends in an updated position statement that the public obtain vitamin D from a healthy diet that includes food naturally rich in vitamin D, foods and beverages fortif ied with vitamin D, and/or dietary supplements.44

Zinc oxide

Titanium dioxide

Chemical Blockers

Cinnamates-octyl methoxycinnamate

Phenylbenzimidazole sulfonic acid

Salicylates-octyl salicylate, homosalate

PABA Dibenzoylmethanes-avobenzone/Parsol 1789, Eusolex 8020 Benzophenones-oxybenzone, Eusolex 4360, methanone, Uvinal M40, diphenylketone Ecamsule

X X Primarily UVA X

X X Primarily UVB

Octocrylene

Measuring Photoprotection: SPF, PFA and Water Resistance

In all sunscreen formulations, the SPF refers primarily to UVB protection. Sunscreens with SPFs of 15, 30 and 45 block 93%, 96.5% and 98% of UVB radiation, respectively. SPF compares the time of UVB exposure necessary to induce erythema in the absence of product with the time needed to induce the same erythema in the presence of product. This ratio (protected/unprotected) is the SPF.45 Until recently, there was no objective measure available for consumers to quantify the amount of UVA protection provided by a given sunscreen formulation. Consumers knew only if a sunscreen formulation contained UVA blockers, but the degree of UVA protection could vary widely. The UVA protection of a sunscreen agent can be measured by various techniques. The FDA has recognized the protection factor of UVA (PFA) as an acceptable method of measuring UVA coverage.

mates and methoxydibenzoyl methane. 30,32,33 Physical blockers are rarely associated with contact dermatitis and should be used in patients with sensitivity to chemical sunscreens. Other concerns with chemical sunscreens focus on oxybenzone. This ingredient has raised concerns due to studies that demonstrated systemic absorption in healthy children and adults. 34,35 For this reason, oxybenzone is no longer used as a sunscreen agent in some countries; however there are data showing topically applied oxybenzone does not exhibit reproductively toxic potential. 36 Oxybenzone remains commonly used in the United States. One reason is that there are no equivalent alternatives available in the United States. Further studies are necessary to determine the clinical signif icance of systemically absorbed oxybenzone.

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Figure 2. The quantity of sunscreen necessary to cover the face at a dose of 2 mg/cm2 (left) versus the quantity of sunscreen in two pumps from a standard facial sunscreen bottle (right)

PFA measures induced pigmentation on unsensitized skin af- sunscreen for the body is 2 mg/cm 2 . To achieve this quantity, ter UVA exposure. PFA compares the time of UVA exposure patients would have to apply 30 ml to cover the body.45 Siminecessary to induce pigmentation in the absence of product larly, for facial application, approximately 1.2 gm of sunscreen with the time needed to induce the same pigmentation in the is required to achieve the 2 mg/cm 2 dose.44 Most women use presence of product. This ratio (protected/unprotected) is the significantly less than 1.2 gm during routine facial sunscreen PFA.45 The PFA grading system of UVA protection will soon application (see Figure 2). One study found that most users probably achieve an SPF of be required by the FDA for all products that claim UVA coverage. The PFA score will be quantif ied on a four-point scale between 20% and 50% of the expected SPF because inadequate of 1* to 4* and will let consumers compare UVA coverage sunscreen quantities are applied.47 Realistically, patients are not between formulations. likely to change the quantity of sunscreen application in everyWaterproof is no longer used to describe sunscreen, as no day use. For most patients 2 mg/cm 2 of sunscreen for daily use sunscreen is truly waterproof. Instead the term water resis- may be perceived to be too much and not cosmetically accepttant is used. A water-resistant product maintains the SPF lev- able. Increasing the SPF from 15 to 30 for a product used daily el after 40 minutes of water immersion. To measure this, patients apply sunscreen, swim for 20 minutes, air dry, then swim again for Topical antioxidants increase the skins natural 20 minutes. A very water-resistant (formerly antioxidant reservoir and augment photoprotection by waterproof ) product maintains the SPF level after 80 minutes of water immersion (four preventing free-radical damage induced by UV radiation. 20-minute cycles).45

Correct Sunscreen Application

Correct application of sunscreen is essential to achieve the desired SPF and PFA. Studies show that most people do not apply sufficient sunscreen.46,47 One European study showed students applied one-fifth the recommended sunscreen quantity.46 To obtain the labeled SPF protection, the necessary quantity of is one possible solution to address this problem. High-SPF sunscreens have been shown to help compensate for this common underapplication.48 For extensive sun exposure such as at the beach and other outdoor events, generous sunscreen application should be encouraged.

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Green, white and black teas are all derived from the plant Camellia sinensis. Green and white teas are harvested from the There have been many recent advances in sunscreen formu- earliest leaves of the Camellia sinensis plant, which are rich in lations related to UVA coverage. In the past, long-term UVA polyphenols and possess greater antioxidant properties. The coverage was a challenge because the most commonly used polyphenol EpiGalloCatechin-3-O-Gallate (EGCG) is the UVA agent, avobenzone, is not photostable. Although avoben- main compound in green and white tea responsible for antizone is considered a superior UVA blocker, if not photostabi- oxidant activity.45 The photoprotective properties of tea have lized, the UVA protection declines steadily over time.49 Reap- been extensively studied. In one recent study, both green and plication at 1.5- to 2-hour intervals is required to compensate white tea protected against UV induced effects on cutanefor the photo-instability of avobenzone and to maintain UVA ous immunity as measured by oxidative damage to DNA and coverage. Several photostable UVA blockers have recently been Langerhans cells.60 This augmented photoprotection could introduced to the U.S. market. not be attributed to UV absorption because the topical teas A stable complex of avobenzone, oxybenzone and a photo- had an SPF of 1. Green and white tea offered similar levels of stabilizing ingredient, diethylhexyl 2, 6-naphthalate has been protection.60 Topical green tea polyphenols have also demonintroduced and offers long-term UVA protection. Commer- strated a dose-dependent reduction in UV-induced erythema cially available as Helioplex or Active Photobarrier Complex, and sunburn cells. 53 this stabilized avobenzone complex provides long-term UVA Genistein is an isof lavone derived from soybeans. In vivo protection.45 Ecamsule is another photostable UVA blocker. and in vitro studies have demonstrated that genistein inhibits UV induced oxidative damage and blocks c-Fos and c-Jun proto-oncogene expresResearch on photoprotection continues to grow, and sion. 58,59 Soy derivatives also inhibit UVinduced pigmentation by inhibiting the pronew technologies provide innovative ways to improve tease-activated receptor 2 pathway (PAR-2), protection for our patients. which regulates melanosome transfer. Theres decreased melanosome transfer in the presence of soybean trypsin inhibitor and Bowman Bik Its a water-soluble sun f ilter that is effective against shorter UVA wavelengths. Commercially available as Mexoryl SX, inhibitor. 61 The use of soy derivatives also improves UV-inthis agent was available in Europe before introduction to duced pigmentary changes as demonstrated in a double-blind the United States. Mexoryl XL, an oil-soluble UVA f ilter, is placebo-controlled trial in which objective and subjective available globally, but not yet in the United States.45 measures showed uneven skin tone and mottled pigment improved when compared to vehicle. 62 Antioxidants and Photoprotection The addition of antioxidants to sunscreen formulations Oral Photoprotection represents another signif icant and clinically relevant advanceThe photoprotective effects of antioxidants are not observed ment in sunscreen technology. Newer sunscreen formulations only when applied topically. Oral antioxidants have been deminclude antioxidants to improve protection via a different onstrated to offer significant photoprotection. These include mechanism. Although most sunscreens block between 93% to polypodium leucotomos, ellagic acid, grape seed extract and pine 98% of sunburn-causing rays, UVA still enters the epidermis. tree bark extract.54,56,57,63 UVA radiation induces free-radical formation and inf lammaPolypodium leucotomos is derived from tropical ferns and tion in the skin. Altering UVA induced inf lammation with possesses signif icant antioxidant activity. Its currently marantioxidants is a new concept in sun protection. Antioxidants keted in the United States as a natural sun protection supplein sunscreens act as free-radical scavengers to prevent UVA- ment. Oral polypodium leucotomos demonstrated reduced induced inf lammation. UV-induced pyrimidine dimers, erythema and sunburn Kang et al demonstrated that pretreatment of human skin cells. 54 The benef icial effects of oral polypodium leucotomos with the antioxidants inhibited the induction of collagenase by has also been reported in photodematoses such as polymorUV light.50 Antioxidants naturally present in the skin include phous light eruption and solar urticaria.64 vitamin C (from diet), vitamin E (from diet), glutathione (synAdditionally, several open- and closed-label studies have thesized) and ubiquinone (synthesized).51 Topical antioxidants demonstrated the effects of oral antioxidants as a monotherapy increase the skins natural antioxidant reservoir and augment in the treatment of melasma. These include oral pycnogenol photoprotection by preventing free-radical damage induced by (pine tree-bark extract) and a combination therapy.63,65 The UV radiation. Various antioxidants have been studied for their combination therapy included procyanidin and vitamins A, C photoprotective effects. Some of these include agents vitamin and E. In this double-blind placebo-controlled study of women C, green tea, polypodium leucotomos, reservatrol, grape seed with melasma, monotherapy with the oral antioxidant resulted extract, pomegranate extract and genistein. 5259 in improvement in MASI scores at 8 weeks when compared to

Advances in Sunscreen Technology: New Agents and Antioxidants

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placebo pill.64 The efficacy of oral antioxidants in melasma is presumably due to their photoprotective effects. Oral antioxidants represent a new and growing field in photoprotection and should be considered as adjunctive therapy in patients with severe melasma, solar urticaria, polymorphous light eruption and other photodermatosis.

Sun-Protective Clothing
Sun protective clothing is becoming increasingly popular as a method of sun protection for adults and children. The level of protection in these clothes is designated by the UV protection factor (UPF) and is a measurement guideline that is similar to the SPF. Wide-brimmed hats are also helpful. A 4-inch brim that covers the ears is recommended for the best protection. One study found that a hat alone can provide an SPF of around 5.66 Sun-protective clothing is especially useful for outdoor activities, as it eliminates the need for reapplication of sunscreen on covered areas throughout the day.

Summary
Photoprotection continues to play an essential role in many dermatologic diseases. Currently available agents block, scatter or absorb UV radiation. Although antioxidants, cannot replace conventional sunscreens, their use as an adjunct in sunscreens has presented a new mechanism of protection. Oral photoprotective agents are also an area of increased growth. Research on photoprotection continues to grow, and new technologies provide innovative ways to improve photoprotection for our patients. n Dr. Woolery-Lloyd is the director of ethnic skin Care for the University of Miami Department of Dermatology and Cutaneous Surgery. She also maintains a private practice in Miami Beach and Midtown Miami.

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plant Skin Cancer in Renal Transplant Recipients. Br J Dermatol. 2008;158(2):217224. 10. Berg D, Otley CC. Skin Cancer in Organ Transplant Recipients: Epidemiology, Pathogenesis, and Management. J Am Acad Dermatol. 2002;47(1):117 11. Euvrard S, Kanitakis J, Claudy A. Skin Cancers After Organ Transplantation. N Engl J Med. 2003;348(17):16811691. 12. Schwarz A, Bhardwaj R, Aragane Y, et al. Ultraviolet-B-Induced Apoptosis of Keratinocytes: Evidence for Partial Involvement of Tumor Necrosis Factor-Alpha in the Formation of Sunburn Cells. J Investigative Dermatol. 1995;104(6):922927. 13. Fisher GJ, Datta SC, Talwar HS, et al. Molecular Basis of SunInduced Premature Skin Ageing and Retinoid Antagonism. Nature. 1996;379(6563):335339. 14. Kennedy C, Bajdik CD, Willemze R, et al. The Inf luence of Painful Sunburns and Lifetime Sun Exposure on the Risk of Actinic Keratoses, Seborrheic Warts, Melanocytic Nevi, Atypical Nevi, and Skin Cancer. J Invest Dermatol. 2003;120(6):10871093. 15. Westerdahl J, Olsson H, Ingvar C. At What Age Do Sunburn Episodes Play a Crucial Role for the Development of Malignant Melanoma. Eur J Cancer. 1994;30A(11):16471654. 16. Green A, Williams G, Logan V, Strutton G. Reduced Melanoma After Regular Sunscreen Use: Randomized Trial Follow-Up. J Clinical Oncology. 2011;29(3):257263. 17. American Academy of Dermatology. Indoor Tanning Fact Sheet. 2010. Accessed 25 February 2011. Available at http://www.aad.org/media/background/factsheets/fact_indoortanning.html. 18. Ting W, Schultz K, Cac NN, et al. Tanning Bed Exposure Increases the Risk of Malignant Melanoma. Int J Dermatol. 2007;46(12):12531257. 19. Swerdlow AJ, Weinstock MA. Do Tanning Lamps Cause Melanoma? An Epidemiologic Assessment J Am Acad Dermatol. 1998;38(1):8998. 20. Chen YT, Dubrow R, Zheng T, et al. Sunlamp Use and the Risk of Cutaneous Malignant Melanoma: A Population-Based Case-Control Study in Connecticut, USA. Int J Epidemiol. 1998;27(5):758765. 21. Karagas MR, Stannard VA, Mott LA, et al. Use of Tanning Devices and Risk of Basal Cell and Squamous Cell Skin Cancers. J Natl Cancer Inst. 2002;94(3):224226. 22. Montagna W, Carlisle K: The Architecture of Black and White Facial Skin. J Am Acad Dermatol. 1991;24(6 Pt 1):929937. 23. Kaidbey KH, Agin PP, Sayre RM, et al: Photoprotection by Melanin A Comparison of Black and Caucasian Skin. J Am Acad Dermatol. 1979;1(3):249260. 24. Sayre RM, Kollias N, Robers RL, Baqer A. Physical Sunscreens. J Soc Cosmet Chem. 1990;41(2):103109. 25. Osmond MJ, McCall MJ. Zinc Oxide Nanoparticles in Modern Sunscreens: An Analysis of Potential Exposure and Hazard. Nanotoxicology. 2010;4(1):1541. 26. Baroli B, Ennas MG, Loffredo F, et al. Penetration of Metallic Nanoparticles in Human Full-Thickness Skin. J Invest. Dermatol. 2007;127(7):17011712. 27. Inman AO, Landsiedel R, Wiech K, et al. Assessment of UVB-Damaged Skin In Vivo With Sunscreen Formulations Containing Titanium and Zinc Nanoparticles. Toxicologist. Abstract 2067, 2010:439. 28. Monteiro-Riviere NA, Wiech K, Landsiedel R, et al. In vitro Penetration Studies of Four Sunscreen Formulations Containing Titanium and Zinc Nanoparticles in UVB-Damaged Skin. Toxicologist. Abstract 2068, 2010:439.

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29. Ryman-Rasmussen JP, Riviere JE, Monteiro-Riviere NA. Penetration of Intact Skin by Quantum Dots With Diverse Physicochemical Properties. Toxicol Sci. 2006;91(1):159165. 30. Rietchel R, Fowler J, eds. Fischers Contact Dermatitis. 5th Ed. Philadelphia: Lippincott Williams and Wilkins, 2001:403. 31. Emonet S, Asche-Koo F, PerinMinisimi MJ, et al. Anaphylaxis to Oxybenzone, a Frequent Constituent of Sunscreens. J Allergy Clin Immunol. 2001;107(3):556557. 32. Levy SB. Sunscreens for Photoprotection.EMedicine.com. 26 Jan 2011. Accessed 25 February 2011. Available at http://emedicine.medscape.com/article/1119992-overview. 33. Foley P, Nixon R, Marks R, et al. The Frequency of Reactions to Sunscreens: Results of a Longitudinal Population-Based Study on the Regular Use of Sunscreens in Australia. Br J Dermatol.1993;128(5):512518. 34. Hayden CG, Roberts MS, Benson HA. Systemic Absorption of Sunscreen After Topical Application. Lancet. 1997;350(9081):863864. 35. Jiang R, Roberts MS, Collins DM, Benson HA. Absorption of Sunscreens Across Human Skin: An Evaluation of Commercial Products for Children and Adults. Br J Clin Pharmacol. 1999;48(4):635637. 36. Daston GP, Gettings SD, Carlton BD, et al. Assessment of the Reproductive Toxic Potential of Dermally Applied 2-hydroxy-4-methoxybenzophenone to Male B6C3F1 Mice. Fundam Appl Toxicol. 1993;20(1):120124. 37. Wang S, Dusza S, Lim H. Safety of Retinyl Palmitate in Sunscreens: A Critical Analysis. J Am Acad Dermatol. 2010;63(5):903906. 38. Epstein JH. Effects of Beta-Carotene on Ultraviolet Induced Cancer Formation in the Hairless Mouse Skin. Photochem Photobiol. 1977;24(2);211213 39. Epstein JH, Grekin DA. Inhibition of Ultraviolet-Induced Carcinogenesis by All-Trans Retinoic Acid. J Invest Dermatol. 1981;76(3):178180. 40. Forbes PD, Urbach F, Davies RE. Enhancement of Experimental Photocarcinogenesis by Topical Retinoic Acid. Cancer Lett. 1979;7(23):8590. 41. Kligman LH, Kligman AM. Lack of Enhancement of Experimental Photocarcinogenesis by Topical Retinoic Acid. Arch Dermatol Res. 1981;270(4):453462. 42. Connor MJ, Lowe NJ, Breeding JH, Chalet M. Inhibition of Ultraviolet-B Skin Carcinogenesis by All-Trans-Retinoic Acid Regimens That Inhibit Ornithine Decarboxylase Induction. Cancer Res. 1983;43(1);171174. 43. Kligman LH, Crosby MJ. Topical Tretinoin Enhances CorticosteroidInduced Inhibition of Tumorigenesis in Hairless Mice Previously Exposed to Solar Simulating Radiation. Cancer Lett. 1996;107(2):217222. 44. American Academy of Dermatology. Position Statement on Vitamin D. 14 Nov 2009. Accessed 25 Feb 2011. Available at http://www.aad. org/forms/policies/uploads/ps/ps-vitamin%20d.pdf. 45. Baumann L. Cosmetic Dermatology. 2nd Ed. New York: The McGraw Hill Company, 2009:247. 46. Autier P, Boniol M, Severi G, Dore JF, European Organization for Research and Treatment of Cancer Melanoma Co-operative Group. Quantity of Sunscreen Used by European Students. Br J Dermatol. 2001;144(2):288291. 47. Stokes RP, Diffey BL. How Well Are Sunscreen Users Protected? Photodermatol Photoimmunol Photomed. 1997;13(56):186188. 48. Cole C, Hao O, Stanfield J, Appa Y. The Relevance of High-SPF Products: HIgh-SPF Sunscreens Help Compensate Under-Application. Poster presented at the American Academy of Dermatology 69th Annual Meeting, New Orleans, LA: Feb 4-8, 2011. Abstract published in J Am Acad Dermatol Poster Abstracts. 2011;62(2 Suppl):AB139. 49. Def landre A, Lang G. Photostability Assessment of Sunscreens. Benzylidene Camphor and Dibenzoylmethane Derivatives. Intl J Cosmet Sci. 1988;10(2):5362. 50. Kang S, Chung JH, Lee JH, et al. Topical N-Acetyl Cysteine and Genistein Prevent Ultraviolet-Light-Induced Signaling That Leads to Photoaging in Human Skin In Vivo. J Invest Dermatol. 2003;120(5):835841. 51. Pinnell SR. Cutaneous Photodamage, Oxidative Stress, and Topical Antioxidant Protection. J Am Acad Dermatol. 2003;48(1):119. 52. 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Sun protection for skin worshippers

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