SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 264 CLINICAL MANAGEMENT RECOMMENDATIONS Oxybenzone and Sunscreens: A Critical Review of the Evidence and a Plan for Discussion with Patients Rachel S Mirsky BAa, Giselle Prado MDb, Ryan M Svoboda MD, MSc, Darrell S Rigel MD, MSd aAlbert Einstein College of Medicine, Bronx, NY bNational Society for Cutaneous Medicine, New York, NY cDuke University School of Medicine, Durham, NC dDepartment of Dermatology, NYU School of Medicine, New York, NY There has been recent extensive controversy concerning potential environmental and health hazards of oxybenzone (also known as benzophenone-3 and Eusolex 4360). In July 2018, the Hawaii Governor signed a law prohibiting sale and distribution of sunscreens containing oxybenzone.1 The ban will go into effect in January 2021 and is intended to alleviate possible negative environmental effects of sunscreen chemicals on nearby coral reefs. Although there has been widespread related media attention, there is little definitive scientific research supporting the associated concerns.1 In addition, some advocacy groups have raised worries regarding potential human health hazards of oxybenzone. Given these controversies, it is critical that dermatologists have a clear understanding of the underlying issues related to oxybenzone in order to effectively counsel their patients. The purpose of this paper is to provide dermatologists with a framework for presenting this issue to patients. In-vitro experiments have found oxybenzone can cause coral bleaching at concentrations of 33-50 parts per million (ppm).2 However, these experiments created artificial conditions not reflective of actual marine reef ecosystems. Additionally, they raised oxybenzone concentrations to levels much greater than those found in the ocean. To put this into perspective, water sampled off the coasts of Hawaii and the US Virgin Islands have shown maximum oxybenzone concentrations of 0.019 and 1.4 ppm respectively – materially less than those noted in the in-vitro study and therefore unlikely to cause harm.3 Environmental changes such as global warming are a more likely culprit in coral bleaching. In Hawaii, water temperature more strongly correlates geographically with coral bleaching than visitor density and associated oxybenzone levels.4 The increased water temperatures promote viral infection of an important algae, Zooxanthellae, that lives symbiotically on coral.2 The algae are necessary for coral to perform photosynthesis. Scientists believe that coral bleaching on the Great Barrier Reef has occurred as a direct result of increased water temperatures from global warming.5 Additionally, the locations where maximal coral bleaching has occurred IS OXYBENZONE THE REASON FOR CORAL BLEACHING? SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 265 do not correlate with where humans populate.6 There are no in-vivo studies that have shown oxybenzone to be directly causative in coral bleaching. Oxybenzone has the ability to penetrate the skin, and its metabolic breakdown products are excreted in the urine. Systemic absorption has been observed at a rate of 1% to 2% after topical application.7 However, the concentrations achieved by cutaneous penetration are too low to cause toxicity.8 Very high levels of oxybenzone were associated with estrogenic effects in rats.9 In that study, immature rats were given extreme doses of oxybenzone orally and found to have increased uterine weights. To reach equivalent systemic concentrations of oxybenzone in humans, one would need to apply sunscreen at the FDA recommended density of 2 mg/cm2 to 100% body surface area daily for 35 years.10 Researchers also measured plasma concentrations of oxybenzone and reproductive hormones in men and women after application of 10% oxybenzone, finding no biologically significant differences in hormone levels.11 Oxybenzone has also been suggested as a contact allergen. However, a meta-analysis of 64 studies measuring oxybenzone rates of sensitization and irritation found only 0.07% of 19,570 patients had true contact dermatitis to oxybenzone when undergoing patch testing.12 Another study of 23,908 patients found only 0.9% had a patch-test-proven sunscreen allergy.13 To date, there have been no clinically significant negative effects of oxybenzone in humans. Since 1978, oxybenzone has been an FDA approved sunscreen agent. Although there are some restrictions and labeling requirements for use in Europe, it is widely used in sunscreens and other consumer products in the US.14 It has broad-spectrum coverage, successfully filtering UVA (320- 440 nm) and UVB (290-320 nm) rays. Oxybenzone has many advantages over inorganic ingredients (TiO2 and ZnO). It is photostable, inexpensive, and easily spread on skin. Consumers often prefer sunscreen formulations with organic sunscreening agents due to greater cosmetic acceptability. Although inorganic sunscreens have a relatively flat UV protection spectrum, they have significant disadvantages, including minimal water-resistance, clumping, need for more frequent reapplication, and inability to achieve high SPFs without being cosmetically unacceptable due to deposition of a white cast on the skin. The highest SPF sunscreens often require a combination of both organic and inorganic filters to optimize UV-protection. Regular sunscreen usage reduces skin cancer risk.15 Hawaii has one of the highest rates of skin cancer in the US making it surprising that this state chose to implement this law. As such, the Hawaii Medical Association, many expert dermatologists, and sunscreen manufacturers all opposed the law.1 Other states may follow Hawaii’s lead in banning oxybenzone. IS THERE DATA TO SUGEST THAT OXYBENZONE IS HARMFUL TO HUMANS? WHY IS OXYBENZONE USED IN THE MAJORITY OF U.S. SUNSCREENS? ARE THERE OTHER POTENTIAL PROBLEMS WITH OXYBENZONE RESTRICTIONS? SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 266 Only 30% of sunscreens will be available to the population in Hawaii leading to a potential increased future skin cancer risk in both residents and visitors.1 Spray formulations of sunscreen are rapidly becoming the most popular choice of sunscreen users16 and creating oxybenzone-free versions of these products is difficult due to the inherent physical properties of inorganic sunscreen agents. Patients are ill informed about sunscreen, including gaps in understanding of concepts such as “sun protection factor”, “broad spectrum”, and proper techniques of sunscreen application.17,18 Additionally, little research has been done on patient knowledge of sunscreen composition. Due to this knowledge gap, the most worrisome outcome is that consumers may decide to forgo sunscreen based on unfounded fears that “sunscreen is bad” and thus increase their skin cancer risk. The current state of science does not appear to justify instituting an outright ban on oxybenzone. Misinformation and misinterpretation of studies that were not done in humans (such as those done on rats, in vitro, and in artificial marine ecosystems) led to this law.2,3,9 As dermatologists and physicians, we should strive to be patient centric and continue our focus on lowering skin cancer incidence and mortality. This is not to say that dermatologists are not sensitive to possible negative effects on the environment. While we encourage further research, we believe that the potential risks to patients by curtailing access to effective sunscreening agents must be seriously considered. A recently published review of the environmental effects of sunscreen ingredients concluded that potential environmental concerns alone should not detract dermatologists from continuing to educate their patients on the importance of sun protection.19 Weighing a theoretical risk of coral damage versus a clear benefit from sunscreen usage and then prohibiting patients from obtaining over 70% of sunscreens is not in their benefit. Given this, we suggest the following approach when discussing these issues with patients: 1) There is strong data to support sunscreen usage lowers skin cancer risk. 2) There is laboratory evidence to suggest oxybenzone has negative environmental effects, but these experiments were not representative of real-world conditions and thus results are inconclusive. 3) If a patient is concerned about possible environmental effects, they may use inorganic sunscreens, but they should be counseled about the associated disadvantages. 4) Sunscreens are one part of a total sun-protection package that includes avoiding the midday sun and using sun-protective clothing. 5) The optimal sunscreen is one that patients will use consistently, keeping in mind cost and cosmetic acceptability. With the media attention given to this topic, public awareness and questions from our patients will continue to increase in magnitude. Using this framework, dermatologists will be more prepared to answer patient questions, dispel HOW SHOULD DERMATOLOGISTS RECONCILE THE SCIENCE TO ADVOCATE FOR PATIENTS? WHAT IS A REASONABLE APPROACH TO DISCUSS THIS ISSUE WITH PATIENTS? SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 267 misconceptions, and optimize sunscreen selection. Conflict of Interest Disclosures: Dr. Rigel has been an investigator for Neutrogena in the past. Ms. Mirsky, Dr. Prado, and Dr. Svoboda have no conflicts to disclose. Funding: None. Corresponding Author: Giselle Prado, MD National Society for Cutaneous Medicine New York, NY 10016 drgiselleprado@gmail.com References: 1. Bever L. Hawaii just banned your favorite sunscreen to protect its coral reefs. Washington Post. Jul 6, 2018. https://www.washingtonpost.com/ne ws/energy- environment/wp/2018/07/02/hawaii -is-about-to-ban-your-favorite- sunscreen-to-protect-its-coral- reefs/?noredirect=on&utm_term=.d3a 78b2ef2b1. Accessed Jul 11, 2018. 2. Danovaro R, Bongiorni L, Corinaldesi C, et al. Sunscreens cause coral bleaching by promoting viral infections. Environ Health Perspect. 2008;116(4):441-7. 3. Downs CA, Kramarsky-winter E, Segal R, et al. Toxicopathological Effects of the Sunscreen UV Filter, Oxybenzone (Benzophenone-3), on Coral Planulae and Cultured Primary Cells and Its Environmental Contamination in Hawaii and the U.S. Virgin Islands. Arch Environ Contam Toxicol. 2016;70(2):265-88. 4. Rodgers KS, Bahr KD, Jokiel PL, Richards donà A. Patterns of bleaching and mortality following widespread warming events in 2014 and 2015 at the Hanauma Bay Nature Preserve, Hawai'i. PeerJ. 2017;5:e3355. 5. Hughes TP, Kerry JT, Baird AH, et al. Global warming transforms coral reef assemblages. Nature. 2018;556(7702):492-496. 6. Bruno JF, Valdivia A. Coral reef degradation is not correlated with local human population density. Sci Rep. 2016;6:29778. 7. Hayden CG, Roberts MS, Benson HA. Systemic absorption of sunscreen after topical application. Lancet. 1997;350(9081):863-4. 8. Hayden CG, Cross SE, Anderson C, Saunders NA, Roberts MS. Sunscreen penetration of human skin and related keratinocyte toxicity after topical application. Skin Pharmacol Physiol. 2005;18(4):170-4. 9. Schlumpf M, Cotton B, Conscience M, Haller V, Steinmann B, Lichtensteiger W. In vitro and in vivo estrogenicity of UV screens. Environ Health Perspect. 2001;109(3):239-44. 10. Wang SQ, Burnett ME, Lim HW. Safety of oxybenzone: putting numbers into perspective. Arch Dermatol. 2011;147(7):865-6. 11. Janjua NR, Mogensen B, Andersson AM, et al. Systemic absorption of the sunscreens benzophenone-3, octyl- methoxycinnamate, and 3-(4-methyl- benzylidene) camphor after whole- body topical application and reproductive hormone levels in humans. J Invest Dermatol. 2004;123(1):57-61. 12. Agin PP, Ruble K, Hermansky SJ, Mccarthy TJ. Rates of allergic sensitization and irritation to oxybenzone-containing sunscreen products: a quantitative meta-analysis of 64 exaggerated use studies. Photodermatol Photoimmunol Photomed. 2008;24(4):211-7. mailto:drgiselleprado@gmail.com SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 268 13. Warshaw EM, Wang MZ, Maibach HI, et al. Patch test reactions associated with sunscreen products and the importance of testing to an expanded series: retrospective analysis of North American Contact Dermatitis Group data, 2001 to 2010. Dermatitis. 2013;24(4):176-82. 14. Mancuso JB, Maruthi R, Wang SQ, Lim HW. Sunscreens: An Update. Am J Clin Dermatol. 2017;18(5):643-50. 15. Ghiasvand R, Weiderpass E, Green AC, Lund E, Veierød MB. Sunscreen Use and Subsequent Melanoma Risk: A Population-Based Cohort Study. J Clin Oncol. 2016;34(33):3976-3983. 16. Teplitz RW, Glazer AM, Svoboda RM, Rigel DS. Trends in US sunscreen formulations: Impact of increasing spray usage. J Am Acad Dermatol. 2018;78(1):187-18 17. Kong BY, Sheu SL, Kundu RV. Assessment of Consumer Knowledge of New Sunscreen Labels. JAMA Dermatol. 2015;151(9):1028-30. 18. Glazer AM, Svoboda RM, Teplitz RW, et al. Overcoming Consumer Challenges in Sunscreen Selection. SKIN – J Cutan Med. 2018;2(3):168-171. 19. Schneider SL, Lim HW. Review of environmental effects of oxybenzone and other sunscreen active ingredients. J Am Acad Dermatol. 2018;