REVIEW CPD

The efficacy and safety of use for the prevention of skin cancer

Megan Sander MD, Michael Sander DMD, Toni Burbidge MD, Jennifer Beecker MD

n Cite as: CMAJ 2020 December 14;192:E1802-8. doi: 10.1503/cmaj.201085

n Canada, more than 80 000 cases of skin cancer are diagnosed every year.1 Because exposure to radiation is esti- KEY POINTS mated to be associated with 80%–90% of skin cancers, the use • Several well-conducted randomized controlled trials with long Iof sunscreen — which blocks ultraviolet radiation — is promoted as follow-up showed that sunscreen use reduces the risk of an important means of preventing skin cancers,2,3 as well as - squamous cell and melanoma skin cancers. burn and skin photoaging (see definitions in Appendix 1, available • Commercial protect against the skin-damaging at www.cmaj.ca/lookup/doi/10.1503/cmaj.201085/tab-related​ effects of ultraviolet radiation through either chemical or -content). Use of sunscreen has been shown to reduce the inci- physical ingredients. dence of both melanoma and nonmelanoma skin cancers.4,5 Both • The Canadian Dermatology Association recommends the use of the Canadian Dermatology Association and the American Academy an adequate dose of a broad-spectrum sunscreen with a sun protection factor of at least 30 for most children and adults, as of Dermatology recommend the use of sunscreen for the preven- part of a comprehensive strategy. tion of skin cancer.6,7 Yet, since the development of the first com- • Emerging evidence suggests that some chemical sunscreen mercial sunscreen in 1928, questions regarding the safety and effi- ingredients are systemically absorbed, but the clinical cacy of sunscreen have been raised, and more recently, the impact importance of this remains unclear; further research is required of sunscreens on the environment has become a cause for concern. to establish whether this results in harm. We summarize evidence related to the effectiveness and harms of • Ultraviolet filters found within chemical sunscreens may be sunscreen to help physicians counsel their patients (Box 1). harmful to the environment.

How do sunscreens work? high-intensity ultraviolet radiation, resulting in excitation to higher Sunscreens contain chemical (organic) or physical (inorganic) energy states. When these molecules return to their ground states, compounds that act to block ultraviolet radiation, which is light the result is conversion of the absorbed energy into lower-energy with wavelengths shorter than visible light (subdivided into ultra- wavelengths, such as infrared radiation (i.e., heat).8 violet A [UVA]1, UVA2, ultraviolet B [UVB] and ultraviolet C [UVC]), Physical sunscreen filters, such as and zinc as shown in Figure 1. Generally, the shorter the wavelength, the oxide, reflect or refract ultraviolet radiation away from the skin; greater the potential for light radiation to cause biological dam- however, experimental studies have shown that when particle age. Sunscreen filters are active against UVA1, UVA2 and UVB radi- sizes are very small, as in micronized sunscreens, the mechanism ation. Chemical filters, such as , , octo- of action is similar to that of chemical filters. More specifically, crylene and , are aromatic compounds that absorb micronized and titanium dioxide behave as semicon- ductor metals, which absorb ultraviolet light throughout most of the electromagnetic spectrum.9 The sunscreen ingredients that Box 1: Evidence used in this review are currently approved by Health Canada are listed in Table 1.10 We conducted a targeted search of MEDLINE using a combination of the search terms “sunscreen,” “skin cancer,” “melanoma,” What is the effectiveness of sunscreens in “squamous cell carcinoma,” “basal cell carcinoma,” “photoaging,” preventing photoaging and skin cancer? “safety” and “environment” to identify studies published from 1984 to 2020. We particularly sought randomized controlled trials, Evidence from observational studies,11 a large randomized con- systematic reviews and meta-analyses relevant to this article’s 12 clinical questions. We also identified relevant review articles, basic trolled trial (RCT) and smaller, nonrandomized experimental 13–15 science publications and institutional guidelines. We studies support the effectiveness of sunscreens in preventing supplemented our search with literature from our own collections. the signs of photoaging, including wrinkles, telangiectasia and pig- mentary alterations induced by ultraviolet radiation.11–15 Despite

E1802 CMAJ | DECEMBER 14, 2020 | VOLUME 192 | ISSUE 50 © 2020 Joule Inc. or its licensors REVIEW - Over- E1803 21 Another large 12

UVC 19 unts for less co 100–280 nm Ac than 1% of UVR that reaches the Earth’s surface Not absorbed deeply into the skin Absorbed by the atmosphere and ozone layer Germicidal • • • • Recent meta-analyses haveRecent 20 However, these meta-analyses However, these meta-analyses

d

21,22 window aging and UVB unts for 5% of co 280–315 nm Ac UVR that reaches the Earth’s surface with varied intensity that peaks around midday Partially absorbe by the ozone and clouds, does not penetrate glass Not absorbed as deeply into the skin as UVA Primarily responsible for tanning and burning, less so photo carcinogenesis ISSUE 50 ISSUE | Ultraviolet light Ultraviolet • • • • In organ transplant recipients, a population at high risk of of risk high at population a recipients, transplant organ In

VOLUME 192 VOLUME included studies with retrospective designs with methodological inconsistencies among studies, and 1 included studies that used only UVB filters (rather than broad-spectrum sunscreens). not supported the findings of these RCTs, finding no significant not supported the findings of these RCTs, finding no significant or melanoma either preventing for sunscreen of effectiveness nonmelanoma skin cancers. morbidity and death from skin cancer, a prospective single-centre study of 120 matched patients showed that the use of sun protec- tion factor (SPF) 50 sunscreen over 24 months reduced the devel- opment of actinic keratoses, squamous cell carcinomas and, to a cell carcinomas. basal extent, lesser arrest signs of skin aging caused by photodamage. pared with controls who used a nonactive base cream over 1 sum- mer season (rate ratio 0.62, 95% CI 0.54 to –0.71). Australian RCT showed a significantly reduced rate of developmentAustralian RCT showed a significantly reduced of actinic keratoses (a precursor to squamous cell carcinoma) com sunscreen, of use regular to randomized participants among all, the highest-quality evidence available suggests that sun- screens do prevent skin cancer. |

UVA unts for toaging and Acco 95% of UVR that reaches the Earth’s surface with fairly constant intensity over the course of the day Penetrates the ozone, clouds, and window glass Penetrates human skin more deeply Responsible for pho carcinogenesis, less so tanning and burning UVA1: 300–400 nm UVA1: 300–400 nm UVA2: 315–340 • • • • DECEMBER 14, 2020 | CMAJ Almost 15 years after the completion Almost 18 A well-conducted community-based 4.5- A predefined subgroup analysis in this trial 5 Visible light 16,17 Dermis Epidermis However, the incidence of basal cell carcinomas was not 4,18 Experimental studies from the 1980s and 1990s showed that of the study, participants who used sunscreen daily throughout the 4.5-year study period showed a significantly reduced risk of invasive melanoma (hazard ratio [HR] 0.27, 95% CI 0.08 to –0.97), although very few invasive melanomas were noted, given the long lead time for this type of tumour. confirmed that regular use of sunscreen over a 4.5-year period can significantly reduced, possibly owing to the protracted pathogen­ carcinomas. of basal cell esis

the challenges of studying skin cancer, owing to its multifactorialthe challenges of studying skin cancer, owing evidence supportspathogenesis and long lead time, the following the use of sunscreen in the prevention of skin cancer. sunscreens protect against cell damage consistent with carcinogen- esis in animal models. Schematic representation of the electromagnetic spectrum of light, emphasizing ultraviolet radiation (UVR) frequencies and their effect on Figure 1: Schematic representation of the electromagnetic of radiation, the greater the potential for biological damage. Note: UVA = ultraviolet A, UVB = human skin. Generally, the shorter the wavelength are active against UVA1, UVA2 and UVB radiation. ultraviolet B, UVC = ultraviolet C. Sunscreen filters year RCT of 1621 adult Australians, with follow-up for more than a carcinomascell squamous of incidence lower 40% a found decade, among participants randomized to recommended daily sunscreen compared with participants assigned to use sunscreen on a discre- 0.46 to[CI] interval 0.61, 95% confidence (rate ratio tionary basis 0.81). REVIEW than people with darker skin. although skin cancers are far more prevalent in White individuals E1804 screen usewithanSPFof30orhigherforpeopleallskintypes, The American AcademyofDermatology recommends regular sun- Who shouldusesunscreen? sunscreens withanSPFof30orgreater. Dermatology Association recommends the use of broad-spectrum risk ofskincancersamongpeoplewhoarenotWhite. assess the effectiveness ofregular sunscreen use in reducing the salicylate Diethanolamine-methoxycinnamate Terephthalylidene dicamphor sulfonic acid Padimate-O Oxybenzone Octisalate Octinoxate Meradimate Avobenzone Para-aminobenzoic acid Note: PABA =para-aminobenzoic acid,UVA =ultraviolet A,UVB =ultraviolet B. Zinc oxide Medical ingredient Table 1:Sunscreen ingredients approved by Health Canada Titanium dioxide For children older than 6 months, as well as adults, the Canadian For childrenolderthan6months,aswelladults,theCanadian 24 There have been no studies to CMAJ 7 Split-face studies have Split-facestudieshave methanone (2-Hydroxy-4-methoxyphenyl)(2-hydroxyphenyl) -8 None 2-Ethoxyethyl 3-(4-methoxyphenyl) propenoate Ecamsule hept-1-yl methanesulfonic acid) bis(7,7- Dimethyl-2-oxobicyclo[2.2.1] 3,3¢-(1,4- Phenylenedimethylidene) SX Mexoryl σ-PABA Octyl dimethyl PABA 4-Methylbenzylidene camphor Mexoryl XL Mexoryl Benzophenone-4 2-Hydroxy-4-methoxybenzophenone Benzophenone-3 2-Ethylhexyl 2-cyano-3,3-diphenylacrylate 2-Ethylhexyl salicylate 2-Ethylhexyl methoxycinnamate Menthyl 2-aminobenzoate Homomenthylsalicylate 2-Phenylbenzimidazole-5-sulfonic acid Parsol 1789 Butyl methoxydibenzoylmethane None None Other names None | DECEMBER 14,2020 10 23

| protective clothing. The mainstaysofsunsafetyininfantsincludeavoidanceand ing physicalsunscreensoverchemicalvarieties. tions, inbothabeachsetting with anSPFof50forpreventingsunburnsunderactualusecondi- shown thatsunscreens with an SPF of 100aresuperiorto sunscreens gest washingitoffassoonisnolongerneeded, higher bodysurface-to-volumeratiosandthinnerepidermis. increased absorptionofsunscreeningredientsasaresult children youngerthan6monthsbecauseofthetheoreticalrisk VOLUME 192 Health Canada does not recommend the use of sunscreen for | ISSUE 50 28 Ifsunscreenisusedininfants,expertssug- UV protection 25 andahigh-altitudeskiingsetting. UVA 2 UVA UVA 2 UVA 2 UVA 2 UVA UVA 1 UVA UVA 1 UVA UVA 2 UVA UVB UVB UVB UVB UVB UVB UVB UVB UVB UVB UVB UVB UVB UVA UVA UVA UVA ingredient, % Medical 29 ≤ 7.5 ≤ 12 ≤ 10 ≤ 10 ≤ 15 ≤ 10 ≤ 10 ≤ 15 ≤ 15 ≤ 25 ≤ 25 ≤ 3 ≤ 8 ≤ 6 ≤ 5 ≤ 6 ≤ 5 ≤ 4 ≤ 3 andfavour- ≤ 3 26 27

REVIEW

- - 47 E1805 Physical Physical 48 When swim- 39–41 Aerosolized sun Aerosolized 42 43 44 Moreover, the investiga- 45 When applied under maxi- 45 suggesting that historical advice to to that historical advice suggesting 35–38 A follow-up study confirmed these findings. 46 40 ISSUE 50 ISSUE | Recent experimental studies have shown that sunscreen sunscreen shown that have studies experimental Recent Spray-on sunscreens are less desirable than cream-based cream-based than desirable less are sunscreens Spray-on In contrast to chemical sunscreen ingredients, physical In contrast to chemical sunscreen ingredients, physical VOLUME 192 VOLUME remains on the skin at the desired SPF for as long as 8 hours as 8 hours SPF for as long the skin at the desired remains on application, after a single reapply sunscreen every 2–3 hours need not be followed even even need not be followed every 2–3 hours reapply sunscreen is active. However, reapplication are physically when individuals been of sunscreen having when the likelihood suggested - as after sweating, water immersion, fric removed is high, such exfoliation from sand. tion from clothing and ones, for several reasons. Wind can disperse the sunscreen, Wind can disperse the sunscreen, ones, for several reasons. application. Moreover, because spray-on resulting in inadequate vis­ fast drying, and sometimes not clearly sunscreens are often to determine difficult is it skin, the onto sprayed once ible homogeneous. was application whether ming or sweating are anticipated, water-resistant sunscreens anticipated, water-resistant sunscreens ming or sweating are should be used. What are the key safety concerns? Skin reactions to sunscreens The most common reported adverse reactions and burning) without a include subjective irritation (e.g., stinging Rarely, rash, irritant contact dermatitis and comedogenicity. cause allergic contact chemical sunscreen ingredients may also most the with dermatitis, contact photoallergic and dermatitis octocrylene, ingredients being commonly implicated allergenic oxybenzone and octyl methoxycinnamate. Absorption of sunscreen the by sponsored participants, 24 with RCT small a 2019, In showed systemic United States Food and Drug Administration, avoben oxybenzone, ingredients: sunscreen 4 of absorption zone, octocrylene and ecamsule. mal use conditions, over 4 consecutive days, blood levels for for levels blood days, consecutive 4 over conditions, use mal these compounds exceeded those recommended by US Food and Drug Administration guidelines. tors noted long half-lives for each of these ingredients, sug- gesting that regular sunscreen use may lead to accumulation within the body. However, most people use far less than this volume of sun- screen and, despite their findings, the study investigators encouraged the use of sunscreen given its known protective effects, as the clinical importance of absorption of these ingre- dients is not yet known. Further research is needed to deter- mine whether there are any potential health sequelae from absorption of sunscreen ingredients. sunscreens are not systemically absorbed. An in-vitro study penetrated nanoparticles zinc of 0.03% than less that found the uppermost layer of the stratum corneum, and no particles corneum. stratum lower the in detected were - combus of incidences several and flammable, also are screens exposure to open tion on the skin have been reported after allowed to dry. Finally, flames, even after the sunscreen has been of aerosolized sun- the potential risks associated with inhalation screens have not been adequately studied. | in a 34 Each arm and neck However, using using However, Whole body DECEMBER 14, 2020 | 30–32 Face CMAJ Therefore, it may be pru- Figure 2 offers a rough esti- Figure 2 offers a rough 35 33 Visual aid to guide the correct application of sunscreen for a a for sunscreen of application correct the guide to aid Visual For example, when a sunscreen with an SPF of 50 is a sunscreen with an SPF of 50 is For example, when Each leg 26 APPLYING SUNSCREEN A visual guide A 2015 Canadian consensus meeting agreed that the wording A 2015 Canadian consensus Although product labelling often suggests that sunscreens often suggests that sunscreens Although product labelling Torso

- compensate for underapplica with higher SPFs may sunscreens tion. applied under real-world conditions, the sunscreen may provide sunscreen the under real-world conditions, applied an SPF of only 25. - was most appropriate, given differ “apply sunscreen generously” of the public. ences in body habitus person of average height and body habitus, based on advice from the person of average height and body habitus, based on advice from the Canadian Cancer Society and the American Academy of Dermatology. Figure 2: Figure Observational studies have shown that consumers typically typically that consumers studies have shown Observational 20% use ranging between sunscreen, with standard underapply application. the recommended and 50% of How should sunscreen be applied? be sunscreen should How dent to wait 15 to 30 minutes if water resistance is required. dent to wait 15 to 30 minutes if water resistance recent study, immediate protection against ultraviolet radiation recent study, immediate protection against protection after occurred after sunscreen application, although water exposure was not examined. - of sunscreen that should be applied by a per mate of the quantities and build, based on advice from the Canadianson of average height American Academy of Dermatology.Cancer Society and the to 30 minutes before going outdoors, should be applied 15 iStock.com/losw; VectorPocket; fatcat21 VectorPocket; iStock.com/losw; REVIEW study findings. However, highheterogeneitylimitedtheusefulnessof neonates anddecreasedbirthweightinfemaleneonates. nancy were associated with decreased gestational age in male ies, found that high levels of oxybenzone exposure during preg- systemic review,whichevaluatedbothanimalandhumanstud- mulation andbiomagnification. tissues of various fish species, raising the possibility of bioaccu- tional recentconcernisthedetectionofsunscreenfiltersin E1806 tember inCanada). the ultravioletindexisabove3(usually11am–3pm,ApriltoSep - with ultravioletradiationprotection)andseekingshadewhen brimmed hats,eyeprotection(e.g.,“wrap-around”sunglasses for avoidingultravioletradiation,includingtheuseofwide- strategy. Itisimportanttocounselpatientsregardingbehaviours Sunscreen isonlyonepartofacomprehensivephotoprotection may beused? What additionalphotoprotectivemeasures ingredients aredetectableinvariouswatersources Some recentstudieshavereportedthatchemicalsunscreen How dosunscreensaffecttheenvironment? uninformative. marized literaturewasnonuniformandtheresultstherefore associated withreproductiveadverseeffectsinfish,thesum- Although a recent meta-analysis found that oxybenzone is genic andantiandrogeniceffectsofchemicalsunscreens. Low-quality evidencehasledtoconcernsaboutpossibleestro- Endocrine effects sunscreens. filters hasledtomorecosmeticallyacceptablephysical formulation and micronization of physical ultraviolet radiation potentially leadingtounderapplication.Advancesin chemical sunscreens,leavingawhiteresidueontheskin, sunscreens historicallywerelesscosmeticallyappealingthan the findingscouldbeexplainedbystudyconfounding. exposed tobenzophenone-2and4-hydroxybenzophenone,but spective studynotedreducedfecunditywhenmenwere some jurisdictions. have promptedthebanningofoxybenzoneandoctinoxatein persist despitewaste-watertreatmentprocessing. become lessphotoprotective ifitiswetorstretched. associated withglobalwarming. variables includeincreasedoceansalinityandtemperature cated incoralreefbleaching.However,possibleconfounding an ultravioletprotectionfactor (UPF)upto50. that oxybenzoneaffectscoralreeflarvae rent focus of scientific investigation. In-vitro studies have shown tection. tane (i.e.,Spandex,Lycra)—and darkercoloursoffergreaterpro- weave fabrics — such as polyester and cotton, or nylon and elas- The effectsofsunscreeningredientsoncoralreefsareacur- 58,59 Clothinghasbeendesignedfor sunprotectionwith 49 50 50 Amonghumanresearchparticipants,apro- 57 33 Typically,thickerclothingwith tighter 55 55 Thesepreliminarystudies CMAJ 56 andmaybeimpli- | DECEMBER 14,2020 28 Allclothingwill 59 52,53 54 Anaddi- and may 51 One 50

| cancers overa12-monthperiod. development ofboth actinic keratoses and nonmelanoma skin twicedailywasassociatedwithadecreasedrateof 500 mg IIIRCT,whichhasnotbeenreplicated,nicotinamide one phase did occurtendedtobehigh-grademalignancies. little tonoactualantioxidantactivity. established thatsunscreensclaimantioxidantactivityhave screen formulationstoremainbiologicallyactive.Studieshave protection. Antioxidantscannotyetbestabilizedwithinsun- emerging aspotentialagentsoftopicalandnontopicalphoto- nium andpolyphenols found within green tea extracts) are Topical photolyases and antioxidants (vitamin C, vitamin E, sele- Potential newsunscreentechnologies References of establishedsunscreensandnovelagentsisongoing. sunscreens asanalternative.Researchonthesafetyandefficacy damage; peoplewhoareconcernedmayconsiderusingphysical temically absorbed and may be contributing to environmental has shownthatsomechemicalsunscreeningredientsaresys - older than6months,forphotoprotection.Low-qualityevidence broad-spectrum sunscreenwithanSPFofatleast30forpeople Canadian DermatologyAssociationrecommendstheuseofa sunscreen ifsunexposurecannotbeavoided.Presently,the seeking shade and wearing protective clothing, as well as using on photoprotection strategies, including avoiding midday sun, noma skincancer.Therefore,physiciansshouldcounselpatients reduces theriskofdevelopingbothmelanomaandnonmela- mon inCanada.High-qualityevidencehasshownthatsunscreen associated withthedevelopmentofskincancers,whicharecom- Exposure toultravioletradiationisdirectlyharmfulandhasbeen Conclusion cyclobutene pyrimidine dimers in human keratocytes. studies toenhance DNArepair anddecrease the formationof cause cutaneousflushing.Nicotinamidehasbeenshowninearly form ofniacin(vitaminB3).However,unlikeniacin,itdoesnot as polymorphouslighteruptionandsolarurticaria. for dermatologicdiseasesinducedbyultravioletradiation,such sun exposurewithoutsignificantadverseeffects,andishelpful P. leucotomosextractincreasestheminimalerythemadoseof vention ofphotodamage.ThereisevidencefromsmallRCTsthat native toCentralandSouthAmerica,areusedasagentsforpre- Polypodium leucotomos VOLUME 192 1. 3. 2. Nicotinamide, also known as niacinamide, is the active amide Photoprotective agentstakenorally,suchasniacinamideand radiation exposurein theUKin2010.BrJCancer2011;105(Suppl2):S66-9. Parkin DM,MesherD,SasieniP.13.Cancers attributabletosolar(ultraviolet) melanoma andskincancer.Currentstatus. ArchDermatol1996;132:436-43. Koh HK,GellerAC,MillerDR,etal.Prevention andearlydetectionstrategiesfor /Canadian-Cancer-Statistics-2014-EN.pdf (accessed2020Mar.15). media/cancer.ca/CW/cancer information/cancer 101/Canadiancancer statistics Toronto: CanadianCancerSociety;2014;1-132. Available:www.cancer.ca/~/ cancer statistics2014:specialtopic:skincancers.CanadianCancerStatistics. Canadian CancerSociety’sAdvisoryCommitteeonStatistics. | ISSUE 50 extract, which is derived from a fern 66 However,theskincancersthat 60–62 63–65 62 In In ​ REVIEW ​ ​

​ E1807 Skin Pharmacol Physiol Pharmacol Skin ISSUE 50 ISSUE | Inhal Toxicol 2019;31:357-67. Photodermatol Photoimmunol Photomed 2012;28:127-32. Matta MK, Florian J, Zusterzeel R, et al. Effect of sunscreen application on Matta MK, Florian J, Zusterzeel R, et al. Effect of sunscreen application on plasma concentration of sunscreen active ingredients: a randomized clinical trial. JAMA 2020;323:256-67. Filipe P, Silva JN, Silva R, et al. Stratum corneum is an effective barrier to TiO2 absorption. percutaneous nanoparticle ZnO and 2077–9. Califf RM, Shinkai K. Filling in the evidence about sunscreen. JAMA 2019;321: Petersen B, Datta P, Philipsen PA, et al. Sunscreen use and failures–on site PA, et al. Sunscreen use and failures–on site Petersen B, Datta P, Philipsen Photochem Photobiol Sci 2013;12:190-6. observations on a sun-holiday. Application patterns among participants randomizedNeale R, Williams G, Green A. a skin cancer prevention trial. Arch Dermatol to daily sunscreen use in 2002;138:1319-25. J, et al. An update to the recommended core Marrett LD, Chu MBH, Atkinson for public education in Canada: a consensus content for sun safety messages report. Can J Public Health 2016;107:e473-9. testing: sunscreen drug products for over-the-coun- Labeling and effectiveness Spring (MD): US Food ter human use — small entity compliance guide. Silver and Drug Administration; 2012. Available: www.fda.gov/regulatory-information /search-fda-guidance-documents/labeling-and-effectiveness-testing-sunscreen (accessed 2020 Mar. 16).-drug-products-over-counter-human-use-small-entity for a standard sun- de Gálvez MV, Aguilera J, Buendía EA, et al. Time required UV photography study. J screen to become effective following application: a Eur Acad Dermatol Venereol 2018;32:e123-4. sunscreen in human skinBodekær M, Akerström U, Wulf HC. Accumulation of ultraviolet radiationafter daily applications: a study of sunscreens with different filters. factor persistence Beyer DM, Faurschou A, Philipsen PA, et al. Sun protection or ultraviolet exposure. on human skin during a day without physical activity Photodermatol Photoimmunol Photomed 2010;26:22-7. factor persistence Bodekaer M, Faurschou A, Philipsen PA, et al. Sun protection during a day with physical activity and bathing. Photodermatol Photoimmunol Photomed 2008;24:296-300. the sand/rub resistanceStokes RP, Diffey BL. A novel ex vivo technique to assess of sunscreen products. Int J Cosmet Sci 2000;22:329-34. and day-care products. Stokes RP, Diffey BL. The water resistance of sunscreen Br J Dermatol 1999;140:259-63. Diffey BL. When should sunscreen be reapplied? J Am Acad Dermatol 2001;​45:882-5. Barr J. Spray-on sunscreens need a good rub. J Am Acad Dermatol 2005; ​52:180-1. of an aerosol gener- Pearce K, Goldsmith WT, Greenwald R, et al. Characterization nano-enabled consumeration system to assess inhalation risks of aerosolized products. Matta MK, Zusterzeel R, Pilli NR, et al. Effect of sunscreen application under maximal use conditions on plasma concentration of sunscreen active ingredi- ents: a randomized clinical trial. JAMA 2019;321:2082-91. Autier P, Boniol M, Severi G, et al.; European Organization for Research and G, et al.; European Organization for Research and Autier P, Boniol M, Severi Co-operative Group. Quantity of sunscreen Treatment of Cancer Melanoma Br J Dermatol 2001;144:288-91. used by European students. Rodríguez E, Valbuena MC, Rey M, et al. Causal agents of photoallergic contact dermatitis diagnosed in the national institute of dermatology of Colombia. Photodermatol Photoimmunol Photomed 2006;22:189-92. Recalls and safety alerts: important sunscreen safety tips for Canadians. Canadians. for tips safety sunscreen important alerts: safety and Recalls https://healthycanadians.gc.ca/ Canada; 2018. Available: Ottawa: Health Mar. 15). (accessed 2020 recall-alert-rappel-avis/hc-sc/2018/66966a-eng.php sun pro- application, safety, and S, Dawson A, et al. Sunscreen Li H, Colantonio J Cutan Med Surg 2019;23:357-69. tection: the evidence. peopleand children populations: specific in Photoprotection K. Buster T, Cestari 2017;76:S110-21. of color. J Am Acad Dermatol Ghazipura M, McGowan R, Arslan A, et al. Exposure to benzophenone-3 and Ghazipura M, McGowan R, Arslan A, et al. Exposure to benzophenone-3 and reproductive toxicity: a systematic review of human and animal studies. Reprod Toxicol 2017;73:175-83. 2009;22:266-75. Rai R, Shanmuga SC, Srinivas C. Update on photoprotection. Indian J Dermatol 2012;57:335-42.

VOLUME 192 VOLUME 48. 47. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 46. 31. 44. 45. 28. 29. 30. 27. 49. 50. |

​ ​ DECEMBER 14, 2020 | CMAJ N Engl J Med 1993;329:1147-51. 1997;3:510-4. prevention of squamousvan der Pols JC, Williams GM, Pandeya N, et al. Prolonged Biomarkerscell carcinoma of the skin by regular sunscreen use. Cancer Epidemiol Prev 2006;15:2546-8. by regular sunscreenThompson SC, Jolley D, Marks R. Reduction of solar keratoses use. 2006;55:741-60. of SPF 100+ sunscreenGreater efficacy al. Williams JD, et CL, Kohli I, Nicholson compared with SPF 50+ in prevention during 5 consecutive days of sun- Dermatol Acad Am light exposure: A randomized, double-blind clinical trial. J 2020;82:869-77. Williams JD, Maitra P, Atillasoy E, et al. SPF 100+ sunscreen is more protective against sunburn than SPF 50+ in actual use: results of a randomized, double- blind, split-face, natural sunlight exposure clinical trial. J Am Acad Dermatol 2018;78:902-910.e2. Ulrich C, Jürgensen JS, Degen A, et al. Prevention of non-melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, pro- spective, case-control study. Br J Dermatol 2009;161(Suppl 3):78-84. Silva ES, Tavares R, Paulitsch F da S, et al. Use of sunscreen and risk of mela- noma and non-melanoma skin cancer: a systematic review and meta-analysis. Eur J Dermatol 2018;28:186-201. sunscreen- the assessing in Challenges al. et M, Egger JS, Stenehjem Rueegg CS, melanoma association. Int J Cancer 2019;144:2651-68. Sunscreen FAQs. Des Plaines (IL): American Academy of Dermatology Association; 2020. Available: www.aad.org/media/stats-sunscreen (accessed 2020 Aug. 16). Gloster HM, Neal K. Skin cancer in skin of color. Vol. 55. J Am Acad Dermatol -sunscreen-monograph-consultation-document.html -document​-sunscreen-monograph-consultation-document.html (accessed 2020 Mar. 10). chronic sunscreen use on Boyd AS, Naylor M, Cameron GS, et al. The effects of 1995;33:941-6. the histologic changes of dermatoheliosis. J Am Acad Dermatol and prevention of skin Hughes MCB, Williams GM, Baker P, et al. Sunscreen aging: a randomized trial. Ann Intern Med 2013;158:781-90. intermittent sunscreenPhillips TJ, Bhawan J, Yaar M, et al. Effect of daily versus skin response in humans.application on solar simulated UV radiation-induced J Am Acad Dermatol 2000;43:610-8. moisturizer effectively Seité S, Reinhold K, Jaenicke T, et al. Broad-spectrum prevents molecular reactions to UVA radiation. Cutis 2012;90:321-6. on skin cancer and Iannacone MR, Hughes MCB, Green AC. Effects of sunscreen 2014;30:55-61. photoaging. Photodermatol Photoimmunol Photomed to determine sunscreenSambuco CP, Forbes PD, Davies RE, et al. An animal model Acad cell damage. J Am protectiveness against both vascular injury and epidermal Dermatol 1984;10:737-43. skin cancer: inhibitionAnanthaswamy HN, Loughlin SM, Cox P, et al. Sunlight and Nat Med sunscreens. by skin mouse UV-irradiated in mutations p53 of Green A, Williams G, Neale R, et al. Daily sunscreen application and betacarotene application Daily sunscreen Neale R, et al. Williams G, Green A, of and squamous-cell carcinomas in prevention of basal-cell supplementation 1999;354:723-9. controlled trial. Lancet the skin: a randomised sunscreen melanoma after regular GM, Logan V, et al. Reduced Green AC, Williams 2011;29:257-63. trial follow-up. J Clin Oncol use: randomized American Academy of Dermatology; cancer. Schaumburg (IL): Prevent skin www.aad.org/public/diseases/skin-cancer/prevent/how 2016:1. Available: (accessed 2020 Mar. 15). position statement sun protection and sun- Canadian Dermatology Association https:// 2020. Available: Association; Canadian Dermatology Ottawa: use. screen dermatology.ca/wp-content/uploads/2020/02/Sun-Protection-and-Sunscreen (accessed 2020 Mar. 15).-Use-Position-Statement-EN.pdf efficacy. and safety sunscreen of review A JF. Nash M, Mitchnick FP, Gasparro Photochem Photobiol 1998;68:243-56. SM. Sunscreen products: rationale for use, formulationGeoffrey K, Mwangi AN, Maru considerations. Saudi Pharm J 2019;27:1009-18. development and regulatory 2012. Canada; Health Ottawa: monograph. sunscreen — document guidance Draft: Available: ​/ www.canada.ca/en/health-canada/services/drugs-health-products public-involvement-consultations/natural-health-products/draft-guidance

6. 8. 9. 4. 7. 5.

18. 19. 25. 26. 20. 21. 22. 23. 24. 11. 12. 13. 14. 15. 16. 17. 10. REVIEW E1808 57. 56. 55. 54. 53. 52. 51.

and CummingSchoolofMedicine(Michael Sander, Burbidge),SectionofDermatology, Affiliations: DepartmentofMedicine(Megan This articlehasbeenpeerreviewed. other competinginterestsweredeclared. Janssen, Leo Pharmaceuticals and Lilly. No receiving honorariafromAbbVie,Celgene, Competing interests:ToniBurbidgereports Cutan MedSurg2019;23:648-9. en­ oxybenzone oroctinoxatesunscreensbasedontheconfirmedadverse Ouchene L, Litvinov IV, Netchiporouk E. Hawaii and other jurisdictions ban U.S. VirginIslands.ArchEnvironContamToxicol2016;70:265-88. tured primarycellsanditsenvironmentalcontaminationinHawaiithe sunscreen UVfilter,oxybenzone(Benzophenone-3),oncoralplanulaeandcul- Downs CA, Kramarsky-Winter E, Segal R, et al. Toxicopathological effects ofthe other sunscreenactiveingredients.JAmAcadDermatol2019;80:266-71. Schneider SL,LimHW.Reviewofenvironmentaleffectsoxybenzoneand treatment plants.EnvironInt2016;86:24-44. Ramos S,HomemV,AlvesA,etal.AreviewoforganicUV-filters in wastewater 2015;22:19706-15. and drinkingwaterinSãoPauloState(Brazil).EnvironSciPollutResInt da SilvaCP,EmídioES,deMarchiMRR.TheoccurrenceofUVfiltersinnatural 2005;39:953-62. wastewater, insurfacewaters,andfishfromSwissLakes.EnvironSciTechnol Balmer ME,BuserH-R,MüllerMD,etal.OccurrenceofsomeorganicUVfiltersin 2014;180:1168-75. type ultravioletradiationfiltersandcouples’fecundity.Am J Epidemiol Buck LouisGM,KannanK,SapraKJ,etal.Urinaryconcentrationsofbenzophenone- vironmental effectsofsunscreeningredientsonaquaticenvironments.J CMAJ | DECEMBER 14,2020 to the conception and design of the work, Contributors: Alloftheauthorscontributed (Beecker), Ottawa,Ont. The OttawaHospitalResearchinstitute Medicine (Beecker),UniversityofOttawaand of Medicine,TheOttawaHospital;Faculty Division ofDermatology(Beecker),Department Sander), University of Calgary, Calgary, Alta.;

| 58. 65. 64. 63. 62. 61. 60. 59. 66. VOLUME 192

cotomos extractinhealthyadultsubjects.JClinAesthetDermatol2015;8:19-23. Nestor MS,BermanB,SwensonN.Safetyandefficacyoforalpolypodiumleu- in dermatologicdiseases:areviewoftheliterature.JDrugsDermatol2014;13:148-53. Choudhry SZ,BhatiaN,CeilleyR,etal.RoleoforalPolypodiumleucotomosextract tion. JAmAcadDerm2017;76(3S1):S91–9. Lim HW, Arellano-Mendoza M-I, Stengel F. Current challenges in photoprotec- 2011;65:525-30. factor inpopularsunscreenswithantioxidants.J Am Acad Dermatol Wang SQ, Osterwalder U, Jung K. Ex vivo evaluation of sun protection development, efficacy,andcontroversie.JAmAcadDermatol2013;69:867.e1-14. Jansen R,OsterwalderU,WangSQ,etal.Photoprotection:partII.Sunscreen: 2007;23:264-74. Gies P.Photoprotectionbyclothing.PhotodermatolPhotoimmunolPhotomed with naturalcolorants.BMCDermatol2004;4:15. Sarkar AK. An evaluation of UV protection imparted by cotton fabrics dyed for skin-cancerchemoprevention.NEnglJMed2015;373:1618-26. Chen AC,MartinAJ,ChoyB,etal.Aphase3randomizedtrialofnicotinamide Dermatol 2004;51:910-8. mos extractdecreasesultraviolet-induceddamageofhumanskin.J Am Acad Middelkamp-Hup MA,PathakParradoC,etal.OralPolypodiumleucoto- | ISSUE 50 [email protected] [email protected] Correspondence to:MeganSander, accountable forallaspectsofthework. the versiontobepublishedandagreed intellectual content, gave final approval of manuscript, revised it critically for important tion ofdata.Alltheauthorsdrafted and theacquisition,analysisinterpreta-