Current challenges in photoprotection HenryW.Lim,MD,a Maria-Ivonne Arellano-Mendoza, MD,b and Fernando Stengel, MDc Detroit, Michigan; Mexico City, Mexico; and Buenos Aires, Argentina Electromagnetic radiation in the ultraviolet, visible, and infrared ranges all produce biologic effects. Ultraviolet filters are the most well-studied photoprotective measure for the adverse effects of ultraviolet radiation. Because of the reported endocrinologic effects of oxybenzone in animal studies, its effects on coral reefs, and its photocontact allergy potential, its use has been minimized in many countries worldwide. New developments in topical antioxidants and oral and subcutaneous agents (eg, Polypodium leucotomos extract, afamelanotide, nicotinamide) with photoprotective and antiphoto- carcinogenic properties could potentially provide addition modalities for protection against the effects of visible light and infrared radiation. ( J Am Acad Dermatol 2017;76:S91-9.) Key words: afamelanotide; antioxidant; nicotinamide; oxybenzone; photoprotection; Polypodium leucotomos extract; sunscreen. lthough the need to prevent acute (ery- thema) and chronic (skin cancer and photo- Abbreviations used: aging) skin damage resulting from exposure 25(OH)D: 25-hydroxyvitamin D A CPD: cyclobutane pyrimidine dimer to ultraviolet (UV) radiation (UVR) (UVB and UVA) is EPP: erythropoietic protoporphyria well understood, the safest and most effective way to FDA: Food and Drug Administration achieve this still presents a number of challenges, MMP: matrix metalloproteinase ROS: reactive oxygen species specifically, in the practical implementation of sun- SPF: sun-protection factor protective measures. These include concerns about UV: ultraviolet the safety of some currently available UV filters, UVR: ultraviolet radiation whether sunscreens detrimentally affect serum vitamin-D levels, whether new nontopical agents can offer significant additional sun protection, and SUNSCREEN SAFETY AND EFFICACY how to protect against recently identified harmful Oxybenzone effects of radiation at frequencies outside the UV Oxybenzone (benzophenone-3) is an organic range of the solar spectrum. filter that absorbs both UVB and short-range UVA It should be emphasized that although sunscreen (UVA2). Because few other organic UVA filters have products are excellent means of photoprotection, been approved by the US Food and Drug they should always be part of the total photo- Administration (FDA), oxybenzone is widely used protection package, which includes seeking shade, in the United States. Concerns were expressed about wearing protective clothing and a wide-brimmed the safety of oxybenzone after reports of cases of hat, and using sunglasses. allergic and photoallergic contact dermatitis and From the Department of Dermatology, Henry Ford Hospital, served as a consultant for La Roche-Posay, Roche, Vichy, and a Detroit ; Department of Dermatology, Hospital General de Pierre Fabre Dermo-Cosmetique/Av ene. b Mexico Dr Eduardo Liceaga ; and Fundacion del Cancer de Accepted for publication September 18, 2016. c Piel, Buenos Aires. Reprint requests: Henry W. Lim, MD, Henry Ford Medical Center, Publication of this supplement is supported by Laboratoires New Center One, 3031 W Grand Blvd, Suite 800, Detroit, MI Dermatologiques Avene. 48202. E-mail: [email protected]. Disclosure: Dr Lim has served as a consultant for Pierre Fabre Published online December 27, 2016. Dermo-Cosmetique/Avene and received research grants from 0190-9622/$36.00 Estee Lauder, Ferndale, and Allergan. Dr Arellano has served as Ó 2016 by the American Academy of Dermatology, Inc. a consultant for Galderma, Bioderma, Sanfer, Pierre Fabre http://dx.doi.org/10.1016/j.jaad.2016.09.040 Dermo-Cosmetique/Av ene, and Leo Pharma. Dr Stengel has S91 S92 Lim, Arellano-Mendoza, and Stengel JAM ACAD DERMATOL MARCH 2017 because of its potential for endocrine disruption andIndianoceans,19 and presenting a hazard to reported in an animal model. Oxybenzone is the the viability of the reefs. most common photoallergen among all the UV Outside the United States oxybenzone has been filters.1 A 10-year retrospective analysis found that replaced in many sunscreens by other UV filters. 70.2% of almost 24,000 patients patch-tested with UV These include broad-spectrum filters such as bemo- filters between 2001 and 2010 had positive reactions trizinol and bisoctrizole, which are not currently to oxybenzone.2 In 2014, oxybenzone was largely available in the United States, and ecamsule, which is responsible for the naming of available in the United States benzophenones as contact only in products approved CAPSULE SUMMARY allergen of the year by the though the New Drug American Contact Dermatitis Application process. In 2015 d In addition to application of sunscreen, Society.3 Potential endocrine the FDA announced that proper photoprotection consists of effects of oxybenzone ecamsule, bemotrizinol, bi- seeking shade, wearing photoprotective were identified in several soctrizole, and 5 other sun- clothing and hat, and using sunglasses. in vitro studies4-6 and an screen ingredients that had in vivo study showed dose- d Ultraviolet filters have been well been awaiting approval in dependent estrogenic activ- established to be effective against the the United States through ity in 21-day-old rats adverse effects of ultraviolet radiation. the Time and Extent fed doses of oxybenzone d With increased understanding of the Application process were 7 ($1500 mg/kg/d). It should effect of visible light and infrared not generally recognized as be noted that the doses of radiation, studies on antioxidants and safe and effective, despite oxybenzone used in the an- oral and subcutaneous topical forms of approval by regulatory imal study were very high photoprotection are ongoing. agencies in many parts of and the estrogenic potency the world.20 detected was 1 million-fold less than the estradiol control.8,9 Short-term studies Antioxidants that looked at topical application of UV filters Traditional sunscreens provide effective protec- including oxybenzone in human beings found that tion against erythema but not similarly effective there were no significant UV filtererelated alter- protection against the generation of reactive oxygen ations on the endocrinologic effects on either repro- species (ROS) in the skin after exposure to UVR, ductive hormones10 or thyroid function.11 especially UVA.21 Therefore, antioxidants are incor- Mathematic modeling indicated that it would take porated in many sunscreen products because of their 277 years using a sunscreen containing 6% oxy- ability to scavenge and reduce levels of ROS, benzone used at 2 mg/cm2 (the dose recommended the primary mediator of oxidative damage to the for sun-protection factor [SPF] testing by the FDA) skin.22-24 Compared with sunscreen alone, the addi- or 1 mg/cm2 (reported real-life use) to achieve the tion of antioxidants has been shown to suppress ROS systemic levels of oxybenzone achieved in the formation by an additional 1.7-fold for SPF 4, and study in rats.12 Oxybenzone has been in use in the 2.4-fold for SPF 15 and 50 formulas, respectively.25 United States since at least the early 1970s with no Sunscreen with added antioxidant has been shown clinical report of estrogenic side effects. Thus, all to be more efficient than sunscreen alone in sup- current data indicate that oxybenzone is safe. pressing other changes in the skin known to be Nonetheless, in the European Union the label of induced to exposure to UVR such as development of a sunscreen containing oxybenzone must include pigmentation, depletion of Langerhans cells, and a cautionary statement (‘‘contains benzophenone- induction of matrix metalloproteinase (MMP)-9.22-24 3’’) if the concentration is over 0.5%.13 These and other data indicate that addition of Oxybenzone has also emerged as a potential antioxidants to sunscreens represents a potentially hazardous environmental contaminant. Water sam- effective strategy to minimize UV damage. The pling studies have shown that it is not fully antioxidants that have been studied include vitamins eliminated during waste water treatment,14,15 and A (retinol), C (ascorbic acid), and E (a-tocopherol), oxybenzone and its metabolites have been and (e)-epigallocatechin-3-gallate, a polyphenol detected in fish, with antiandrogenic and anties- component of green tea. Antioxidants are inherently trogenic effects.16,17 A genotoxic effect of oxy- unstable compounds, however, so are difficult to benzone on coral was recently reported in a formulate in an acceptable, stable, and biologically laboratory study,18 supporting earlier evidence of active composition for sunscreen products. A 2011 bleaching effects on coral in the Atlantic, Pacific, analysis of 12 commercially available US sunscreens JAM ACAD DERMATOL Lim, Arellano-Mendoza, and Stengel S93 VOLUME 76, NUMBER 3 with added antioxidants listed in their labels indi- studies reported low serum 25(OH)D levels associ- cated that 10 had no antioxidant power at all ated with sunscreen application.37-39 However, a (measured as the compound’s capacity to remove a 2009 review of the available evidence concluded certain number of free radicals in certain time that although sunscreens can significantly reduce the 26 intervals) and the other 2 had only low power. production of UVB-induced previtamin D3 when applied under strictly controlled conditions, in real Nanoparticles life, normal use does not generally result in vitamin- The safety of sunscreens containing inorganic