Brazilian Consensus on Photoprotection

Brazil is a country of continental dimensions with a large heterogeneity of climates and massive mixing of the population. Almost the entire national territory is located between the Equator and the Tropic of Capricorn, and the Earth axial tilt to the south certainly makes Brazil one of the countries of the world with greater extent of land in proximity to the sun. The Brazilian coastline, where most of its population lives, is more than 8,500 km long. Due to geographic characteristics and cultural trends, Brazilians are among the peoples with the highest annual exposure to the sun. Epidemiological data show a continuing increase in the incidence of non-melanoma and melanoma skin cancers. Photoprotection can be understood as a set of measures aimed at reducing sun exposure and at preventing the development of acute and chronic actinic damage. Due to the peculiarities of Brazilian territory and culture, it would not be advisable to replicate the concepts of photoprotection from other developed countries, places with completely different climates and populations. Thus the Brazilian Society of Dermatology has developed the Brazilian Consensus on Photoprotection, the first official document on photoprotection developed in Brazil for Brazilians, with recommendations on matters involving photoprotection.

It is important to emphasize that the superficial UVR levels depend on a group of meteorological, geographic and temporal factors. Therefore, we cannot evaluate the influence of each of these environmental factors separately, but only as a group of elements that may depend on and influence each other. Ozone Ozone, the main absorber of UVR, is produced for the most part in the terrestrial stratosphere of the equatorial region of the planet. However, due to the transportation mechanisms existing in the high atmosphere, a great part of the produced ozone is transported to higher latitudes. Therefore, the equatorial region of the planet has smaller quantities of ozone than higher latitude regions and the poles. Ozone layer is the name given to the region with high concentration of this gas in the Earth's atmosphere, located at a height between 15 and 30 km. This layer contains between 80 and 90% of the total ozone in the terrestrial atmosphere and is responsible for the intensive absorption of UVB radiation and part of the extinction of UVC radiation. The rest of the ozone is mostly found in regions close to the terrestrial surface. During the 1980 decade, scientists observed that the ozone layer was strongly diminished in high latitude regions, especially in the poles. It was found that this drastic reduction, that may reduce by 80 to 90% the total concentration of the gas in the atmosphere, is mainly produced by the free chlorine released by chlorofluorocarbons (CFC), gases created by man and intensively used as manufacturing propellents and refrigerating fluids in the entire planet. The presence of chlorine (or bromine) in great quantities in the atmosphere unbalances the ozone formation and destruction chain, accelerating its destruction process. With less ozone, there is less absorption of UVR and, therefore, increased presence of superficial radiation. Comparisons of ozone contents measured between 1964-1980 and 2002-2005 show an average decrease of 3.5% in the ozone content of the Earth's atmosphere, more intensively in high latitudes and less representative in the tropics. 4 With the objective of slowing down this process of ozone destruction, in 1987 the Montreal Protocol (http://www.protocolodemontreal.org.br/) was established to forbid the production and consumption of CFCs and other gases that destroy the ozone layer. Adhesion of the nations to the Protocol was massive and the elimination of CFC consumption has allowed a recovery of ozone levels in the entire planet. It is foreseen that by the middle of this century the ozone layer will be completely recovered to levels existing prior to production of CFCs. 5 A study by UK Chemistry and Aerosols shows that the Montreal Protocol will prevent the onset of two million new skin cancer cases until the year 2030. 6

In a clear sky situation, the "higher" the Sun is in the sky, the higher the levels of UV radiation are. This means that the farther the Sun is from the horizon, the shorter the optical pathway the radiation has to cross in the atmosphere. Under these conditions, UVR undergoes less interaction with gases and particulates and, consequently, is less attenuated. Therefore, at times close to solar noon, UVR reaches its highest daytime values. The same reasoning may be used to evaluate the variation of UVR fluxes in relation to the season of the year. In the summer, the Sun reaches higher positions in relation to the horizon than in the winter and, consequently, the UVR flux is more intense. The differences between the seasons of the year become more relevant as the latitude becomes higher. That is, in the tropics there is little difference between the position of the Sun in the summer and in the winter, while in higher latitudes this difference is quite significant.

Solid or liquid particles found in the atmosphere are called aerosols. Soot emitted by automobiles, motorcycles and trucks or burning biomass, suspended soil dust or even sea salt from evaporated ocean water are examples of atmospheric aerosols. These particles interact with UVR, most often reflecting the radiation to other directions. However, some types of aerosols are also able to absorb part of the incident UVR. Thus, polluted environments or those with suspended dust may show UVR attenuation in relation to clear sky situations. Some studies demonstrate that polluted locations, such as São Paulo(SP) 8 or Mexico City, 9 may present situations with around 20% of the incident UVR. Nevertheless, such decrease of UVR is observed in periods of intense pollution and aerosols should not be considered as protective agents concerning sun exposure.

The ultraviolet index (UVI) is a scale of values recommended by WHO (World Health Organization), related to the intensity of UV radiation that induces the onset of erythema in human skin. 11 This scale has the purpose of simplifying information of UVR levels to the lay public according to a table of whole values, where zero is the smallest value while the largest value is usually represented by the symbol 11+. However, it is important to emphasize that there is no upper limit. The higher the value, the greater is the potential of solar damage to skin and eyes. The variables that influence the calculation or measurement of UVI are those introduced in the previous subchapter. That is, the total ozone content of the atmosphere is taken into account, as well as the geographic position of the location (the closer it is to the Equator line, the higher the UVI); the altitude of the surface (at high altitudes, higher UVI are observed); the time of day (most of the UVR reaches the surface at times close to solar noon); season of the year (the UVI escalates in the summer and diminishes in the winter); atmospheric conditions (the UVI are generally higher in days of cloudless skies); and type of surface. The use of this scale is an important tool to orient the population regarding the risks of excessive solar exposure. It is especially useful for those groups that are more vulnerable to the damaging effects of UVR, like people with low phototypes (I and II), children, the elderly and tourists, people with history of great cumulative solar exposure and/or skin cancer, etc. The UVI scale and WHO general recommendations for photoprotection are shown in figure 1 . FIGURE 1 The ultraviolet index and WHO recommendations The category designated "low UVI" usually happens at times close to dawn and sunset, in addition to moments when a great mass of dense clouds covers the sky. However, it is always very important to be extremely careful in evaluating UVI when there are clouds, since nebulosity may not significantly attenuate UVR or even intensify radiation levels in short periods of time. It should be remembered that WHO recommends sun protection measures when UVI values are over 3.

A significant set of data collected in the last few years in several regions of Brazil allows us to trace the behavior of ultraviolet solar radiation in Brazilian soil more accurately. We will see that these data show a great need to better educate our population regarding the risks of solar exposure without adequate protection. In Brazil, there is generous offer of ultraviolet radiation. UVR roughly presents higher values for smaller geographic latitudes, but other factors like altitude, season of the year, time of day and meteorologic characteristics such as presence of clouds and atmospheric pollution also influence the intensity of solar radiation. Despite these variations, UVR levels in clear sky conditions are always very high in every season of the year and in almost the entire Brazilian territory. 19 Taking into account geographic position, the North and Northeast regions present the highest cumulative doses of ultraviolet radiation. This means that, in those regions, UVR levels are high and vary little during the entire year. On the other hand, in the South and Southeast regions the effect of the seasons of the year is quite perceptible, so that UVR levels show great variability between winter and summer. 20 It is important to highlight the fact that, in the summer, the Southeast region presents record UVR intensity observed in the country, with levels even higher than in the Northeast region. This occurs due to the geographic position of the Brazilian Southeast region. The city of São Paulo (SP), for example, is at 23º latitude south and this angle coincides with the angle of inclination of the planet in relation to the sun. Therefore, in the summer, the sun reaches its highest point at noon and, consequently, in a clear sky day, UVR levels are more intense. The UV radiation distribution here presented considered only the geographic positions of Brazilian regions. However, it is important to take into account also the meteorologic factors, such as the occurrence of rainy seasons, with the presence of deep clouds that significantly attenuate UV radiation. The Central region of Brazil, for example, may receive great incidence of solar radiation during the dry seasons (autumn and winter), as there is less rainfall and an even larger number of clear sky days. This daytime UVR variability due to the presence or absence of clouds influences the cumulative radiation dose to which an individual is exposed. According to WHO, the recommended daily dose of UV radiation a person should be exposed to is 108 J/m 2 . UVR readings collected in São Paulo (SP), Ilhéus (BA) and Itajubá (MG) between 2005 and 2009, demonstrated that the daily means of UV radiation are similar, around 3300 and 3800 J/m 2 , with smaller variation in value amplitude in the Northeast when compared to the Southeast region. In the summer, the daily means are still larger and may reach values over 7000 J/m 2 . It is a reason for concern to observe that, even in the winter, a person exposed without protection in the period between 8:00 a.m. and 5:00 p.m., may receive a UVR dose higher than recommended. This is a reality for many Brazilian workers. 20 In our country, the cultural trend of solar exposure on beaches is still very popular. Most of the tourists visit Brazilian beaches in the period of greater incidence of UVR, being subject to large UVR quantities and their related hazards. An experiment carried out at the Ponta Negra beach, in Natal (RN), is a clear example of the high UV radiation levels to which an individual may be exposed. In readings taken in the morning, the cumulative dose registered between 9:40 a.m. and noon was 5250 J/m 2 , that is, over 50 times the maximum daily dose recommended by WHO and almost 12 times the necessary dose to trigger erythema in an individual of phototype IV. 20 However, it is important to point out that this kind of dose is not observed only at seaside resorts, but also in urban centers. Awareness of this UVR incidence pattern, as well as the cumulative daily dose Brazilians are apt to receive, are fundamental tools to define skin care policies. In Brazil, the UVI observed in cloudless days and at solar noon is frequently found at extreme levels during the summer in all of the country. In winter, the North and Northeast regions may present UVI at these same extreme levels, while in the South and Southeast mean UVI levels may be observed. 19 , 21 - 23 Figure 2 shows the distribution of maximum UVI in the country on a day in August 2013. Daily UVI data are available at the site of the Center for Weather Forecast and Climatic Studies of the National Institute for Space Research. 24 FIGURE 2 Example of ultraviolet index (UVI) for South America: forecast for clear sky conditions Satellites and Environmental Systems Division – Center for Weather Forecasts and Climate Studies of the National Institute for Space Research. Available at: http://satelite.cptec.inpe.br/uv/ Figure 3 presents mean ultraviolet ind

EFFECTS OF SOLAR RADIATION ON THE SKIN (ULTRAVIOLET RADIATION, VISIBLE LIGHT AND INFRARED RADIATION) INTRODUCTION The reactions caused by sunlight on the skin are many and may be both positive and negative. They depend, among other factors, on radiation intensity and wavelength, as well as on the type of skin of each individual. Moreover, it is a known fact that the dose of energy depends on the time of exposure, the proximity to the sun and radiation wavelength (the longer it is, the greater the penetration of light in the skin). The effects of ultraviolet radiation (UVR) on the skin may be considered immediate (acute) and delayed (chronic). The immediate ones are erythema, increased skin temperature, skin thickening, immediate pigmentation, persistent pigmentation, delayed tanning and vitamin D production, 27 , 28 while the delayed ones are photoaging and skin cancer. 29 - 31 In addition, visible light (VL, 400-780 nm) and infrared radiation (IR, 780 - 1 mm) also exert both acute and chronic effects over the skin, which have also been intensively studied. 32

It is a group of symptoms that may occur after intense exposure to sunlight, resulting in excessive escalation of body temperature, which could be fatal. Usually the body is cooled by sweat, but in some situations this mechanism is not sufficient. In these cases, the body temperature of an individual may rise rapidly and damage vital organs. There are environmental variations that also interfere in the ability of the body to cool itself in high temperature environments, such as, for example, the presence of increased air humidity. In addition, other factors interfere in the body temperature regulation ability, such as age (it is smaller in children and the elderly), obesity, fever and dehydration. The main sunstroke symptoms are: abnormally high body temperature, erythematous skin, tachycardia, cephalea, dyspnea, vertigo, nausea, vomit, dehydration, confusion and loss of consciousness. 38 - 40

The immunosuppression caused by UVR has been more frequently described since 1970, when Kripke demonstrated the absence of tumor rejection by mice previously irradiated with UVR. 41 Furthermore, UVR causes suppression of the immune response of the skin to several antigens, like microorganisms, protein complexes or even haptens. Information on UVR action over immune response is obtained mainly by means of studies with animals. Immunosuppression caused by UVR may affect the skin, internal organs, lymphatic and blood tissues. The immune function may be diminished, depending on UVR wavelength, on UVB, UVA2 (315 - 340 nm) and UVA1(340 - 400 nm), energy dose (erythematous or suberythematous), frequency of URV exposure and area of irradiation. UVB alters Langerhans cells in number, morphology and their main function, which is antigen presentation. These alterations have also been described regarding exposure to UVA. Immunosupression by UVR is mainly modulated by IL-1β, TNF-α, IL-10 and IL-12. The modification in antigen presentation by Langerhans cells, particularly influenced by IL-10, activates Th2 lymphocytes, to the detriment of Th1. This unbalance leads to more IL-10 and IL-4 production. 42 IL-12 seems to have the tendency to neutralize IL-10 action, inhibiting UVR-induced immunosuppression. Immunosuppression or tolerance induced by UVR seems to be conducted by suppressor/regulatory cells, particularly CD4 + CD25 + and Tr-1. 43 It is believed that the urocanic acid, undergoing photoisomerization from the form trans to the form cis when exposed to UVR, may increase IL-10 production, becoming, therefore, a photoimmunosuppression agent. The immunosuppression triggered by UVR leads to alterations of cell response to allergenic and infectious antigens, while allowing the promotion of skin carcinogenesis, which turns UVR into a complete carcinogen (induction/promotion). 41

Photocarcinogenesis consists in the development of skin cancers induced by UVR. 32 UVR produces radical complexes, such as hydroxyl, aqueous electrons, hydrogen radicals and superoxide. These products, in their great majority, are produced by direct and indirect photosensitive reactions inducing DNA breakdown and base damage, being therefore lethal and mutagenic. In the skin, melanin is an important chromophore, which acts as a filter in the absorption of UVA, UVB and VL radiation. Melanin strongly absorbs visible radiation, helping to transform this energy in heat and dispersing it among hairs and blood vessels (capillaries). It also helps to eliminate radicals, such as hydroxyl and oxygen molecules, preserving the DNA against formation of pyrimidine bases. 30 , 53 The sensitivity of somatic cells to UVR is due to defects in pyrimidine dimer reparation induced by UVR. It is noteworthy that exposure to UVB leads to formation of cyclobutane - pyrimidine dimers and pyrimidine-pyridone photoproducts, as the main lesions to DNA. The incorrect repair of these products leads to mutations. Furthermore, the UVR may also produce non dimer photoproducts, like cytosine photohydrates, purine photoproducts and single-stranded DNA breakdown. 54 - 56 As regards UVA radiation, its exact role in carcinogenesis is still unkmown. In this sense, although the photons in the UVA spectrum are less energetic than UVB ones, it is believed that they can still produce mutations and cancer. As the DNA can absorb little of the UVA energy, the lesions typical of UVB, like pyrimidine dimers, are not important in carcinogenesis caused by UVA. It is assumed that UVA genotoxicity would be induced by indirect mechanisms, where free oxygen radicals are generated after the photons are absorbed by still unidentified photosensitizers. 57 When these mutations affect the function of oncogenes and of tumor suppressor genes, such as TP53, PTCH1, BRM and RAS, there is a loss of cellular cycle control, with possible keratinocyte and melanocyte transformation and the onset of tumors. 58 The photoexposed skin is susceptible both to non-melanoma skin cancers, such as basal cell cancer and squamous cell cancer, and to melanoma. The non-melanoma skin cancers have been strongly linked to UV radiation exposure, since both UVA and UVB cause DNA damage and immunosuppression. 59 As to melanoma, a direct relationship has been demonstrated between UVR exposure and the risk to develop this type of tumor. However, there seems to be an association with acute and intense exposure. 60

Infrared radiation (IR) consists in wavelengths longer than 780 nm and up to 1 mm, representing approximately 50% of the solar radiation that reaches the Earth. It has been divided into IR-A (780-1400 nm), IR-B (1400-3000 nm) and IR-C (3000 to 1 mm). IR-A and IR-B can penetrate the epidermis, the dermis and the subcutaneous tissue, while IR-C is almost completely absorbed by the epidermis due to the presence of water. IR exposure is noticed by human beings through heat sensation. 65 Studies have revealed that IR can cause temporary erythema, probably secondary to vasodilation by thermal effect. 66 , 67 Another important observation is that infrared radiation, especially IR-A, contributes to photoaging. The mechanisms involved in this process have been investigated. It is assumed that they include: metalloproteinase-1 induction without induction of its inhibitor, the tissue inhibitor of metalloproteinase-1, which results in collagen breakdown, 68 disorder in electron flow of the mitochondrial electron transport chain, leading to an inadequate production of energy by dermal fibroblasts; 69 angiogenesis stimulation and increased number of mastocytes. 70 Finally, there was evidence that the IR-A seems to be associated with oxidative stress. Darvin et al . proposed that free radical formation would be influenced by the increased temperature occurring during IR radiation. 71 Jung et al. examined the heat effects on the association between IR and free radical formation in in vitro model of human fibroblast. They demonstrated that IR exposure at a temperature of 37ºC did not induce free radicals; however, at temperatures of 39ºC or higher, free radicals were produced. 72

Studies that can better assess the characteristics of the Brazilian population regarding the effects of solar radiation should be encouraged, especially the search for more adequate skin type classification methods when compared to Fitzpatrick's Classification. As regards public health, the escalation of skin neoplasm incidence in the Brazilian population and the importance of solar radiation in the development of such diseases justify the concern about implementation of photoprotection actions. SBD recommends the development of investigations that can better clarify the effect of non-ultraviolet radiation on the skin.

PHOTOEDUCATION INTRODUCTION The term "photoeducation" was introduced in 1988 to integrate the basic photoprotection concepts, determining why, where and how important protection against harmful effects of UV radiation (UVR) is. Over time the photoeducation concept was expanded, with emphasis on the positive and negative effects of sun exposure. 74 , 75 The consequences of excessive photoexposure depend on genetic, behavioral and geographic situation factors, as well as on the influence of external agents, such as concomitant diseases, transplants and use of medications. Among the negative effects of the mentioned photoexposure above the acceptable levels are premature aging, influence on the immunological status and mainly the onset of skin cancers. Skin cancer is the neoplasm with the highest incidence in several countries in the world, including Brazil, with increased morbidity and mortality deriving from its progression. Multiple factors seem to be related to these findings, among them the change of habits of the population regarding solar exposure, estethical valuation of skin tanning and especially the increased exposure to ultraviolet radiation (UVR). 76 , 77 There are estimates that, in the whole world, 45% of the cancers that may be prevented are cutaneous and that most of the deaths caused by melanoma could be avoided. 77 - 79 In this sense, several studies have emphasized the need for educational photoprotection measures for the population. 80 , 81 Even patients who have already been diagnosed with cutaneous neoplasms have diverse behaviors regarding careful awareness of sun exposure and they do not always change their routine, including tanning habits. 82

There are few randomized clinical studies that assess photoeducation interventions in adults. 85 Most of them are based on computer models to generate orientation, which varied from 15 minute sessions to counseling given by professionals in person, in writing or by telephone. 104 - 108 The behavior differences in relation to sun exposure after the interventions, although statistically significant, were small and it is still not clear if they are clinically representative. 85 As regards young adults, studies conducted with college students focused the issue of attempting to change standards based on the appearance, that is, highlighted the harmful effects of ultraviolet radiation in photoaging, rather than messages related to skin cancer prevention. 109 - 112 The interventions varied from fact sheets to 30-minute videos. When groups that used artificial tanning were evaluated after the intervention there was a 35% decrease; however, the follow-up period of these studies was short. 109 , 111 , 112 Most of the interventions that were effective in promoting behavior modifications regarding photo-protection incorporated the use of computers. All of the studies with young adults focused the concern with the appearance, emphasizing the harmful effects of sun regarding premature aging. There is evidence that this argument makes this population group more sensitive to guidance, especially the women. It is interesting to highlight that interventions regarding photoeducation should vary in accordance with gender and age. 85 Another group of people who are particularly susceptible to the risk of excessive sun exposure are workers who are engaged in outdoor activities; data show the increase of pre-neoplastic lesions and nonmelanocytic neoplasms. 113 These individuals are traditionally more resistant to change of habits and wearing photoprotection because they believe it is a waste of time or it is uncomfortable. The perception of attitudes taken by the hiring company, like the implementation of programs, is a strong factor of change for its employees, more marked in those with lighter phototypes, in women, in those with a better educational level and those that always work in open areas. 114 , 115 Results of other countries cannot always be extrapolated to Brazil, but we know that our problems are similar, the climate may be very adverse in several regions of the country and that some companies already include photoprotection among their occupational safety requirements. The result of these initiatives may bring relevant data to the upcoming campaigns and health policies. A questionnaire was recently proposed and validated to estimate the current and past characteristics of photoexposure, as well as photoprotection practices ( Sun Exposure and Behaviour Inventory - SEBI ). 116 This instrument may become very useful in studies about the incidence of skin cancer and risk modifications, as it will allow data comparison, currently very difficult due to the different methods and evaluations used in the studies.

Actions targeted at photoeducation should be divided into four large groups: Children and Adolescents, Adults, Outdoor Workers and Media Actions. Actions for the public composed of Children and Adolescents: The school should participate in this type of education and it is the easiest way to reach children and adolescents. Actions targeted at children younger that 8 years of age should have a different focus than those targeted at preadolescents and adolescents. Incorporate into the school curriculum a space for education regarding photoprotection and photoeducation. Adolescents should receive orientation about the harmful effects of tanning. Establish a long-term photoeducation program combining SBD and governmental initiatives, as well as third sector non-governmental institutions. Actions for the adult population: When targeted at young adults, the harmful effects of ultraviolet radiation in photoaging should be emphasized more than messages related to skin cancer prevention. The participation of public figures increases adherence to and visibility of campaigns, which was confirmed in our National Skin Cancer Campaign. Nevertheless, such participations should be continued. Keep photoprotection guidance as part of the permanent campaign of SBD. Include Photobiology and Photoprotection classes in the Undergraduate Medical curriculum. SBD could contribute with the preparation of the plan and minimum content of this presentation. Actions for outdoor workers Develop education projects on photoprotection to be presented at the companies that employ workers who are engaged in outdoor activities. Develop projects to better assess methods able to measure the level of solar radiation to which outdoor workers are exposed. Offer continuous training to doctors of companies with the above described profile. Promote efforts, together with governmental authorities, to create specific legislation about sunscreen transformation and photoprotective measures like wearing Personal Protective Equipment (PPE) for outdoor workers. Media Actions: Offer training programs to specialized media about the effects of solar radiation and prevention mechanisms. Develop within the roll of SBD members, through the department of photobiology, a group of dermatologists especially prepared to respond to media requests and give interviews or clarification as SBD spokespersons. Prepare and keep available to members the norms of conduct and posture before the media, as well as detailed instructions regarding the position of SBD on photoprotection issues, so that the message is clear and uniform.

FORMULATION OF TOPICAL SUNSCREEN UV FILTERS Ultraviolet filters are the elements present in photoprotector formulas that interfere directly with the incident solar radiation through absorption, reflection or dispersion of energy. 123 From the structural viewpoint, ultraviolet filters may be organic or inorganic compounds. The organic actives (or chemical filters) absorb UVR photons, promoting an alteration in their molecular structure. The inorganic actives (or physical filters) have a mineral origin and promote the reflection of UVR to the external part of the tissue. 125 Organic filters are conjugated aromatic compounds that operate through a molecular mechanism of UVR absorption and return of this energy to the environment by means of emission of longer and less energetic wavelengths, such as visible light and infrared radiation. 125 Compared to inorganic filters, they present a greater potential of sensitization, greater risk of percutaneous absorption and smaller photostability, strongly dependent on its chemical structure and combination of actives in the formula. 125 More recently, a new generation of organic filters was presented, with larger photostability and lower potential of dermal permeation, substantially reducing the risk for development of sensitization. 125 Depending on their molecular structure, the organic filters may better absorb UVB or UVA radiation. Some more recent molecules are able to produce peaks of UVA and UVB absorption and, for that reason, are called broad spectrum filters. 125 Inorganic filters present a minimum potential for allergic sensitization and high photostability. However, their reflective properties may cause excessive shine and a whitish aspect, limiting their exclusive use to formulas due to the low cosmetic acceptance. 126 Inorganic filters like zinc oxide and titanium dioxide act on the surface of the skin, reflecting incident radiation; nevertheless, when micronized, they may permeate the corneal layer and in addition to reflection, act by diffraction and dispersion. The size of the particles of the inorganic filters is, therefore, a factor that determines their effect. The smaller the particle, the better the skin coverage and, consequently, reflection; but refraction is worse. Therefore, reflection and refraction are inversely related. The efficiency of inorganic filters is related to the size and dispersion of their particles. 126 When micronized, these filters diminish the whitish appearance of the skin and favor the stability of the emulsion. They may be coated with silicone, silica, aluminum oxide, estearic acid, aluminum estearate, among others, improving the dispersion of the filter, avoiding agglomeration of particles and altering the rheology of the emulsion. Titanium dioxide, for example, can only be associated with avobenzone when coated with silica and dimeticone. On the other hand, only some inorganic filters with particle sizes larger than 200 nm are able to reflect in the visible light range, therefore offering protection. 126 The different photoprotector actives also present curves characteristic of UVR absorbance. Usually, commercial sunscreen use a composition of physical and chemical filters to expand the photoprotection spectrum (UVA and UVB), explore synergistic properties and minimize the adverse effects linked to a specific active. In Brazil, sunscreen are categorized by the Brazilian Health Surveillance Agency (ANVISA) as cosmetics (risk degree: 2), which waives the need for a medical prescription to be sold. However, there are regulations concerning the UV filters permitted and the need for studies to be carried out to ascertain their safety and efficacy. 127 , 128 Chart 2 lists 33 actives regulated by ANVISA for commercial use in Brazil. In addition to protection against ultraviolet radiation, there has been interest about actives able to interfere with visible light and infrared radiation. CHART 2 List of actives and maximum concentrations allowed in Brazil FILTER (COMMON OR COMMERCIAL NAME) OTHER NAMES/INCI * COVERAGE ANVISA * PABA 4-Aminobenzoic acid UVB 15 Padimate O Ethylhexyl dimethyl PABA (EHDP) UVB 8 Ethoxylated Ethyl PEG-25 PABA UVB 10 -4-Aminobenzoate Mexoryl SO Camphor benzalkonium UVB 6 methosulfate Mexoryl SD 3-Benzylidene camphor UVB 2 Eusolex 6300 4-methylbenzydilidene camphor (MBC) UVB 4 Mexoryl SW Polyacryamidomethyl benzylidene camphor UVB 6 Mexoryl SL Benzylidene Camphor Sulfonic Acid UVB 6% (expres- sed as acid) Cinoxate Cinoxate UVB 3 Neoheliopan E1000 Isoamyl p-methoxycinnamate UVB 10 Parsol MCX Ethylhexyl methoxycinnamate (OMC ou EHMC) UVB 10 Neo Heliopan OS Ethylhexyl salicilate (EHS) UVB 5 Eusolex HMS Homosalate UVB 15 Neo Heliopan TES Triethanolamine salicylate TEA salicilato UVB 12 Parsol SLX Polysilicone-15 UVB 10 Eusolex OCR Octocrylene (OCR) UVB 10 (of acid) Neo Heliopan Hydro Eusolex 232 Phenylbenzimidazole Sulfonic acid (PBSA) UVB 8 (as acid) Uvasorb HEB Diethylhexyl butamido triazone (DBT) UVB 10 Uvi

One of the issues involved is adherence of the user to daily and routine wearing of sunscreen. 135 Many times, sunscreens are perceived as sticky or uncomfortable products to wear. At the same time, the patients do not perceive the benefits derived from their use, since prevention of photo damage and skin cancer occur mainly on a long term basis. 136 In this regard, sunscreen containing other actives in the same formula have been developed by the pharmaceutical industry with the intention of offering, in addition to photoprotective properties, benefits that may be felt in the short term, thus encouraging frequent use and guaranteeing better protection against the sun. Moisturizers in sunscreen Topical moisturizers are substances designed to improve and maintain the cutaneous barrier. 137 They are used to restore the barrier function of the epidermis, cover small cutaneous microfissures, provide a soft protective film and increase the amount of water in the epidermis, while improving the appearance and tactile properties of the skin. 138 Occlusive substances like dimethicone and petrolatum, as well as moisturizers, such as glycerol and propylene glycol, among others, may be used for this purpose. Studies demonstrate that products containing moisturizers and sunscreens in the same formulation are able to provide effective photoprotection against actinic damage. 139 At the same time, they may be useful in helping to maintain and restore the epidermal barrier. Such characteristics encourage acceptance and adherence of the user, favoring routine application of the product.

According to ANVISA, repellents are classified as cosmetics and follow a specific legislation 150 which determines the allowed ingredients and concentrations, while demanding safety and effectiveness studies. As happens with sunscreen, ANVISA also determines that repellent labels should include certain mandatory information. The best known repellent active is diethyltoluamide (DEET), which presents toxicity and effectiveness against several mosquito species like Anopheles, Phlebotomus, Aedes, Culicidae, ticks and fleas. 151 , 152 Regarding the addition of solar protection actives in repellents, although the ingredients may be used in a formula, there are a few details to be considered: the ability of the sunscreen to filter ultraviolet radiation may be diminished by repellents such as DEET, which is the most common, while the toxicity of the repellent is increased by the sunscreen, especially in children. 153 , 154 The problem is exacerbated by the application instructions, which are a paradox: while sunscreen should be generously and frequently applied (every two hours or more often, if necessary), insect repellents (DEET) should be applied no more frequently than every two to six hours, depending on the concentration. 151 , 155 There are other repellent actives, like essences and icaridin, but their benefits when associated with sunscreen have not been defined yet.

EVALUATION OF SAFETY AND EFFICACY OF SUNSCREEN Necessary safety requirements for ultraviolet filters Brazil has an official list of ingredients classified as ultraviolet filters, which are allowed for use in formulations. 127 This list has as reference the European list of allowed ingredients for sunscreens. For a molecule to be approved for topical use in a photoprotector, a safety dossier must be presented to ANVISA containing standardized topical and systemic toxicological studies, besides evaluation of cutaneous permeation, whose absence makes systemic effects impossible. Follows Chart 4 , with the required studies for safety evaluation of raw material to be used in sunscreens. 156 CHART 4 Toxicological studies required for safety evaluation of a cosmetic ingredient 1. Acute toxicity 2. Subchronic toxicity 3. Percutaneous absorption 4. Irritatio of mucous membranes or skin 5. Sensitization 6. Photoirritation, photosensitization 7. Mutagenicity 8. Photomutagenicity Source: National Agency for Sanitary Vigilance (Agencia Nacional de VigilSncia Sanitaria - ANVISA), 2003. 156 Any of the effects cited above may be demonstrated by toxicological tests. According to calculations, data base and complementary toxicological tests, dose/concentration and route of administration are then established. 156 Thus the importance of toxicological studies of a cosmetic raw material before its use in formulations. All of the substances on ANVISA's list of ingredients for sunscreens are free from systemic toxicity and carcinogenesis when used topically and in the recommended concentrations.

Sunscreens are considered cosmetic according to Brazilian law (risk degree: 2), that is, with greater risk of interaction with human skin. 127 Every product categorized as solar filter must obey a specific law that regulates labeling, FPS and UVA protection determination method. 128 When a manufacturer applies for registration with ANVISA, he should send the studies and a draft of the product label for evaluation. Therefore, any product, regardless of the manufacturer or country of origin, must adapt itself to the norm of the law. If the product has any additional allegation (example: protection against invisible light, hypoallergenic, for oily skin, etc.) it must present evidence for that allegation. 128 , 156 ANVISA recommends that some safety studies be developed to ensure greater safety for the consumer, like studies on photoirritation and photosensitization. 156 The ingredients in sunscreens are developed seeking to reduce adverse reactions to a minimum, and when these occur, they must not be systemic but occur on the application site. According to Schauder and Ippen, 159 the typical patients with adverse reaction to sunscreens are women with history of photodermatosis, such as polymorphous light eruption, for they are continuous users and on skin already inflamed, with altered cutaneous barrier. The most common type of described reaction is photosensitization. 160

The benefits of wearing sunscreens in the prevention and treatment of different conditions or dermatological diseases are already well established in the literature. Its most immediate and evident benefit is the prevention of sunburn, which, by the way, was the motivation behind the researchers in the beginning of the twentieth century to develop products capable of avoiding it, particularly for aquatic and leisure activities. 163 As regards public health, on the other hand, the main benefit of the correct use of sunscreens is the prevention of cutaneous cancer. Studies show that the continuous use of sunscreens is capable of preventing the development of non-melanoma skin cancer and cutaneous melanoma. 164 - 166 The quantification of the efficacy of a sunscreen is essential to determine its effectiveness in the prevention of solar damage, that is, what is its ability to protect the skin from deleterious effects of the sun. To choose a method capable of determining its efficacy, one must have in mind the desired marker ( end point ). In other words, which damage are we considering when measuring sunscreen efficacy? We can didactically divide photoprotecting methods into three broad categories: In vivo methods: Methods that use the evaluation of a biological end point triggered by solar radiation, verifying the capability of the product to suppress or reduce the event. It may be considered an ideal method, as long as it is a relevant marker, of easy observation, rapid onset and measurable by a method with reproducibility and repeatability. Spectrophotometric Methods: Due to the ability of sunscreens to reflect or absorb radiation, readings that use spectrophotometry may be particularly useful, especially in the development of formulations or in conditions in which in vivo readings do not meet the minimum methodological requirements. In vitro Methods: By means of cell cultures or specific reagents, in vitro methods are an alternative, in specific conditions, for evaluating molecular or cellular alterations triggered by solar radiation, and when the protection ability afforded by a photoprotector cannot be evaluated by in vivo methods. Even though, as said above, the main benefit from using a sunscreen is the prevention of skin cancer, a disease that develops slowly and insidiously, the in vivo model does not represent the best method for quantification of its efficacy. The first method developed and validated for evaluating the efficacy of a sunscreen was the Solar Protection Factor (SPF), which quantifies the protection against solar erythema (sunburn), considering (MED) the minimal erythemal dose. MED is the necessary amount of UVR to produce a minimal erythema on the skin. In 1978, a study for determination of the SPF was standardized for the first time by the American agency Food and Drugs Administration (FDA) as being the numerical ratio between the MED of skin photoprotected by sunscreen (applied in the quantity of 2mg/cm 2) and the MED of non-photoprotected skin. 123 , 167 SPF = MED (protected skin)/MED (non-protected skin) The proposed study was performed using a group of 20 volunteers with phototypes I-III (Fitzpatrick Scale), submitted to increasing doses of UVR through an artificial source of light called "solar simulator". The radiation is applied to skin areas photoprotected with solar filter (2 mg/cm 2) and to unprotected areas. After an exposure period of 16 to 24 hours, a MED reading is performed for both areas and its ratio is calculated. The average values found in the group of volunteers is the SPF of the tested product. 123 After the proposed method was published by the FDA, different international regulatory agencies and other institutions proposed their methods for calculating the efficacy of a sunscreen. We highlight, among them, the method described in 1994 by the European Union through the Comité de Liaison des Associations Européennes de l'Industrie de la Parfumerie - COLIPA, which received, in 2005, its last update and the name International Sun Protection Factor Test Method (ISPF). 123 Despite their differences, FDA and COLIPA/Internacional methods produce similar results and, in practice, we can say they generate equivalent SPF values. 123 Since then the methodologies described by the North Americans (FDA) and Europeans (COLIPA) became references in determining SPF in several countries, being internationally accepted. The FDA (used in USA) and COLIPA (used in Europe and in other countries) methods were updated in 2011 168 and 2006, 169 respectively. In Brazil, through Resolution RDC 30 published by ANVISA in 2012, 128 all products named solar filters must present studies that prove their efficacy through at least one of the two international methodologies or their current updates, FDA 2011 or COLIPA 2006. 123 In addition to the SPF test, the water resistance test evaluates if a sunscreen is capable of maintaining its efficacy (SPF) even after periods of immersion in water. This ev

ORAL PHOTOPROTECTION Solar exposure is capable of causing damage to the skin. Clinically, these alterations can be seen in photoexposed areas (deep wrinkles, increased skin fragility, solar melanoses, sagging) when compared to photoprotected skin areas. 181 Ultraviolet radiation (UVR) is responsible for acute and chronic cutaneous alterations. Acute alterations result from direct impact of UVR on biological chromophores such as DNA, leading to structural damage and release of proinflammatory cytokines, enzymes and immunosuppressive factors. 182 - 184 Chronic alterations result from cumulative damage and cellular inability to repair, leading to photoaging and cancer. All these effects may be induced either by exposure to ultraviolet A (UVA) or ultraviolet B (UVB) radiation, due to direct modifications of cell structures or by generating reactive oxygen species (ROS). 185 - 186 It is estimated that approximately 50% of the damage induced by UVR results from production of ROS, leading to molecular and cellular damage which will interfere with solar erythema, pigmentation and photodermatoses, in the short-term, and in the long-term with photocarcinogenesis and photoaging. 187 Recent studies demonstrate that photoprotective measures are capable of preventing biological damage generated by suberythematogenic doses of UVR and deterioration of dermal tissues. 188 According to Gilaberte and Gonzáles, the main current innovations in photoprotection are divided into two categories: 1) the introduction of new ingredients to traditional topical sunscreen, and 2) the use of oral formulations capable of delivering systemic photoprotection. 189 According to reports in the literature, the following products listed in chart 6 may exert systemic photoprotection activity. 189 CHART 6 Main actives with systemic photoprotective action Vitamins (vitamin C and vitamin E) Carotenoids (betacarotene, astaxanthin, lycopene, lutein) Polyphenols (flavonoids, resveratrol, pycnogenol) Probiotics Fatty acids: eicosapentaenoic acid and omega 3 Polypodium leucotomos Association of antioxidants Other substances: chocolate, caffeine, acetyl salicylic acid, ibuprofen, indomethacin, antimalarials, corticosteroids The role of nutrition in the skin appearance has always been a topic of interest for scientists and physicians worldwide over the centuries. The skin is able to reflect the general state of health and show evidence of aging. The powerful antioxidant action of vitamins, carotenoids, tocopherols, flavonoids and a great variety of vegetable extracts, which have been used extensively by the industry in topical agents as well as in oral supplements, with the goal of extending youth and enhancing skin appearance, has been demonstrated. The main strategy of prevention against free radicals comes down to a healthy lifestyle (calorie restriction, body care and performing regular physical exercises) associated with conditions of low stress, balanced nutritional diet and food rich in antioxidants. 190 There is evidence that some substances, when administered orally, could exert a preventative action against UVR-induced cutaneous damage without causing adverse effects. The action mechanism is varied, acting in different phases of signalization, resulting in antioxidant, anti-inflammatory and immunomodulating action. 189 Several substances of botanical origin, used as topical sunscreen, seem to present similar effectiveness when administered orally. Within this group alcaloids would be included, such as caffeine, Polypodium leucotomos extract, polyphenols and carotenoids. 189 Oral photoprotection is a term used to designate the isolated use or a combination of several active ingredients which have demonstrated the capability of minimizing the damage caused by solar radiation in the skin. Next, we will cover the main substances described in the literature which could present evidences of exerting oral photoprotecting activity. It is important to emphasize that none of the substances that will be described can claim to replace the use of topical sunscreen, since none of them has the capability of preventing UVR penetration in the skin. To this day they are capable of acting, in some way, as coadjuvants in the photoprotection process.

The vitamin E complex corresponds to a group of 8 compounds called tocopherols. Tocopherol is a liposoluble antioxidant which links itself to membranes and is a scavenger of highly reactive oxygen species. Like vitamin C, it is a natural antioxidant, non-enzymatic and endogenous. Vitamin E acts synergically with vitamin C. When molecules activated by UVR oxidize cellular components, an induction of lipid peroxidation chain reaction in polyunsaturated fatty acid-rich membranes occurs. The antioxidant Dalpha-tocopherol is oxidized to tocoferoxyl radical, a process that can be regenerated by vitamin C. 195 , 196 Besides ascorbic acid, glutathione and coenzyme Q10 can also recycle tocopherol. Great amounts of tocopherol are available in vegetables, vegetable oils, such as wheat germ oil, sunflower oil, safflower oil and seed, corn, and in some kinds of meat. Natural ingestion of vitamin E helps against collagen cross linking and lipid peroxidation, which are related with cutaneous aging. By means of the process described above, D-alpha-tocopherol is involved in the stabilization of cell membranes by oxidation inhibition of polyunsaturated fatty acids, like arachidonic acid of phospholipidic membranes. 190 Topical application of vitamin E is described as a way to reduce erythema, sunburn cells, induced UVB cutaneous damage and photocarcinogenesis in most published studies. 192 There are several clinical studies which tested the effects of tocopherol. Data may seem controversial, however high doses of oral vitamin E seem to affect the response to UVB in humans. 197 Mireles-Rocha et al., in their study, compared the oral use of 1200 IU/day of alpha-tocopherol (group 1), 2g/day of vitamin C (group 2) and the combination of both (group 3) for one week. The results demonstrated an elevation of minimal erythemal dose of 60 to 65 mJ/cm 2 in group 1 and 50 to 70 mJ/cm 2 in group 3. There was no difference in group 3. 198 In a 3-month-long study, Placzek et al. observed the effects of combination of ascorbic acid (vitamin C - 2g/day) with D-tocopherol (vitamin E - 1000 IU/day) administered orally to human volunteers with epidermal damage induced by UVB. The treatment was well tolerated and could be used in the prevention of deleterious effects of UVB radiation (formation of thymine dimers) and skin cancer, according to the authors. 199 The treatment with oral combination of vitamin C and E enhances the photoprotecting effects if compared with monotherapy. The authors recommend that this synergistic interchange of several antioxidants must be considered in future research on cutaneous photoprotection. 200

Astaxanthin can be foind in microalgae, yeast, salmon, trout, shrimp, crayfish and crustaceans. It is biosynthesized by microalgae and phytoplanktons, which are eaten by zooplankton and crustaceans. They accumulate astaxanthin and are ingested by fish that obtain astaxanthin in the food chain. 213 Astaxanthin has considerable potential and promising applications in human health and nutrition. A protecting potential against several diseases has been attributed to it. 214 The UV protecting action of algae extracts containing 14% of astaxanthins compared to synthetic astaxanthin was investigated. The authors report that pre-incubation with synthetic astaxanthin or with algae extract could prevent UVA induced alterations in activity of cellular superoxide dismutase and a decrease in the amount of glutathione in the cells. 215 In the study carried out by Câmera et al., the damage modulation related to UVA by astaxanthin, canthaxanthin and beta-carotene for photoprotection in human dermal fibroblasts was compared. 216 Astaxanthin demonstrated a significant photoprotecting effect in fighting UVA-induced alterations in broad areas. Uptake of astaxanthin by fibroblasts was greater than by canthaxanthin and beta-carotene, leading to the belief that the effect of astaxanthin in photooxidative alterations was greater than that of other substances. A recent study of Suganuma et al. demonstrated that astaxanthin could interfere with the expression of elastase/neutral endopeptidase of cutaneous fibroblasts and with type 1 UVA-induced matrix metalloproteinases. 217 Both studies suggest that the effects of UVA radiation, such as skin sagging and formation of creases can be prevented or at least minimized by oral or topical administration of astaxanthins. 217

Lutein is a xanthophyllic carotenoid with potent antioxidant activity. In an animal model, oral supplementation of lutein was able to accumulate in the skin, diminishing the generation of free radicals after ultraviolet exposure. 219 In 2007, a comparative study on the use of lutein associated with zeaxanthin in topical, oral or both forms was conducted, demonstrating that all groups presented an improvement of cutaneous elasticity; however, the group which combined oral and topical treatment presented a synergistic effect with higher degree of antioxidant action and enhancement of cutaneous hydration. Studies have been conducted aiming at demonstrating other possible cutaneous effects of lutein, such as: cell proliferation reduction, anti-inflammatory and immunosuppressing activity and inhibition of photocarcinogenesis. 220

The term probiotics is defined as "live microorganisms which, when consumed in adequate amounts, confer a beneficial health effect on the host". 233 The main probiotics used by humans and animals are enterococci, lactobacilli and bifidobacteria, which are part of the natural flora of the intestinal tract. Prebiotics are nonviable food components, which confer healthy benefits to hosts, associated with microbiota modulation. Clinical studies using bacterial probiotics ( Lactobacillus johnsonii NCC 533) to modulate homeostasis of the cutaneous immune system, altered due to UV exposure by solar simulator in humans, suggest that certain probiotics may help in preserving cutaneous homeostasis by modulating the skin immune system. 234 - 236 This specific strain of Lactobacillus johnsonii associated with carotenoids ( β -carotene: 4.8 mg/day; lycopene: 2 mg) was able to prevent the reduction in density of UV-induced Langerhans cells in human volunteers. 181

Essential fatty acids are long-chain polyunsaturated fatty acids derived from linolenic (omega-3), linoleic (omega-6) and oleic acids. They are not produced by the human body and must be consumed in the daily diet. They are present in foods such as fish, linseed, hemp oil, soybean oil, canola oil, chia seed, sunflower seed, salmon and tuna. 190 In a study which evaluated fish oil action over UV-induced prostaglandin metabolism, 13 patients with polymorphous light eruption received supplementation for 3 months. The authors demonstrated the reduction of UV-induced inflammation, possibly due to decreasing levels of prostaglandin E. 241 Oral administration of an antioxidant group containing vitamin C, vitamin E, pycnogenol and primrose oil inhibited significantly the formation of wrinkles caused by chronic UVB irradiation through inhibition of UVB-induced metalloproteinases. 239 POLYPODIUM LEUCOTOMOS Polypodium leucotomos is a botanic extract, originated from a tropical fern which grows in areas of Central and South America, more frequently in altitudes from 700 to 1,300 meters. It has been described by botanical expeditions since the 18 th century and was used by the natives in infusions due to its antiphlogistic and antitumoral action. 242 - 244 As of the 90's, studies with the P. leucotomos extract began to appear, conducted by Harvard teachers Fitzpatrick, Phatak e Gonzáles. It contains several pharmacological markers, among them phenolic derivatives, such as chlorogenic acid, vanillic acid, caffeic acid and ferulic acid. 244 , 245 Since then, a series of scientific studies was published in the literature, demonstrating the several action mechanisms of this phytoextract: antioxidant action, immunoprotecting action, DNA protection and reorganization of skin architecture. 244 - 249 In 1996, the antioxidant action of Polypodium leucotomos could be demonstrated through its capability of reduction of superoxide anion (55%), lipid per-oxidation (50%) and singlet oxygen (10%). More recently, the ability of caffeic acid and ferulic acid to inhibit the lipid peroxidation chain was demonstrated. Ferulic acid was also shown to be a potent UV photons absorber. 242 - 244 In 2004, a study with 10 volunteers demonstrated that the presence of Polypodium leucotomos was capable of decreasing the depletion of Langerhans cells. Its inhibiting action in the photoisomerization of urocanic acid was also evaluated, demonstrating its immunomodulatory action. 246 , 247 The capability of inhibiting the formation of sunburn cells and the formation of thymine dimers revealed the DNA protection potential exerted by Polypodium leucotomos . A study done with a culture of fibroplasts and keratinocytes suggested that Polypodium leucotomos would have a protecting effect over fibroblasts. 249 Based on the action mechanisms described, several clinical indications have been employed for its utilization, such as reduction of solar erythema, phototherapy erythema and polymorphous light eruption. It has also been indicated as a coadjuvant treatment for diseases like vitiligo, psoriasis and melasma. 244 , 250 , 251 Its plasma peak is 2 hours and its half-life 6 hours, with its greatest effect happening between 2 to 4 hours after ingestion. Its dose varies from 1 to 5 tablets (250 mg), depending on skin involvement and degree of solar exposure.

New systemic substances that enhance photoprotection measures have been studied and melanin stimulators stand out in this field. Tanning is the main physiological photoprotecting response of the skin. Tanned skin promotes SPF between 2 and 4, reducing photoinduced DNA damage. Thus it is believed that melanin stimulation without solar exposure may reduce this damage. 189 The analogues of the alpha-melanocyte stimulating hormone (α-MSH) can be used for stimulation of melanogenesis. Three fragments (melanotan I, II and III) demonstrated in vitro agonist action to melanocortin-1 receptor and the capability of stimulating melanogenesis. 257 Melanotan I, administered in the dose of 20 mg, twice daily, for 60 days, demonstrated an increase in tolerance to solar exposure and a reduction of adverse effects in patients who carry erythropoietic protoporphyria. 258

MECHANICAL OR OTHER PHOTOPROTECTION MEANS The use of photoprotective measures capable of offering a physical or mechanical barrier to solar radiation, avoiding its incidence on the skin, may be named mechanical photoprotection. Among the mechanical photoprotection measures, we can include the use of clothing, hats, sunglasses, natural or artificial coverage and glass, as we will see in the next items. Photoprotection through the use of clothing Photoprotection by means of clothing and hats is the oldest, most common and easiest way to be achieved and should be divulged as excellent protection against UVR (ultraviolet radiation). 259 - 261 The use of clothing as a sun barrier is secular knowledge and may be proven by merely observing drawings from the time of old Egyptian and Medo-Persian civilizations, in which socially privileged people wisely covered themselves with clothing and head ornaments, which protected them from UVR and conferred them status. These habits lasted until the industrial revolution and the beginning of the 20 th century, when the cult of tanned skin as a symbol of health and beauty was established and ever larger skin areas were exposed to the sun. 259 The use of clothes and hats as UVR protection factors should be considered a first-line choice for protection against UVA and especially UVB. 262 Among the advantages of the use of clothes, safety and the certainty of uniformity and continuity of offered protection should be emphasized. It starts immediately upon wearing them, without the need for a period of solar pre-exposure, and continues if one remains dressed, as opposed to solar filters, which require some waiting time and reapplications. Clothing is practical in several moments and situations. Another interesting factor is the low economic investment required, when compared with other forms of protection. The disadvantage is that only the area covered by cloth is protected, and this fact becomes relevant in a country where people tend to diminish the size of clothes during summer, mainly in recreational and sports activities performed outdoors, like in Brazilian beaches. 263 In recent years, interest has grown over the importance of clothes as a protective barrier against UVR in scientific circles, mainly in special situations, such as during childhood, when early protection is paramount in the prevention of cancer. This viewpoint was reinforced by some studies, like one carried out with children from nurseries in Germany, who presented reduction of melanocytic lesions proportionally to greater use of clothes. 264 - 266 In countries such as Australia, where educational campaigns about children wearing more clothes have been promoted for several years, the search for adequate clothing for outdoor activities by the parents has become very popular, especially on beaches. 265 In several countries advances have already been made for normatization of adequate uniforms for workers in risk situations, like those who exert their activities outdoors (construction workers, healthcare agents, postmen, etc.) or those exposed to artificial radiation sources (welders). 267 - 270 The tendency of these campaigns is to extend and emphasize the importance of wearing adequate clothes, especially in moments of leisure, and increase the concern about the issue for the group of patients with photosensitivity disorders. 259 , 262 , 271 Clothes block UVR in different degrees, depending on the material they are made of, in addition to factors related to their use. Among the factors that increase the protection offered by clothes is the composition of synthetic fabrics (polyester and nylon) and weave density. The thicker, more closely knit and compacted the weave is, the greater the photoprotection will be, which is the most important aspect to determine a high SPF. In practice, this idea is applied when choosing closely knit, heavy and dense fabrics for outdoor workers' uniforms, usually made of denim, that in spite of having cotton in its composition, provides good protection due to its very dense weave. Dark colors, such as black, dark blue, dark red and dark green, have high concentration of dyes and absorb more UVR than light tones, like white, beige and pastel colors, even with the same fabric weave and composition. Some fabrics, like cotton and linen, when washed for the first time may shrink and close the spaces between their threads, which would increase protection. However, clothes that are washed and worn too often are prone to protect less, for the weave becomes loose and open. Factors that may diminish the protective capability against UVR are open and thin weave, very frequent with natural fibers like cotton, natural silks and wool; we also have, as a factor that decreases protection, humidity and stretching of products because fabrics that are moistened and submitted to tension offer poorer protection. Chart 7 presents the main factors that interfere with the protective capability of fabrics

Studies show that solar radiation can be potentially dangerous for ocular structures, especially cornea, lens and retina. 279 After solar exposure, photochemical reactions may happen in these structures, leading to acute and chronic damage. 261 , 279 , 280 Acute lesions are: photokeratitis (by UVC and UVB radiation) and solar retinitis (by direct exposure to visible light). Chronic damage include cataract, pterygium, macular degeneration and skin cancer. 261 , 279 Different ocular tissues absorb different wavelengths of UV radiation. The cornea absorbs mainly UVR with wavelengths below 295 nm. Excessive exposure to UVB radiation may cause conjunctivitis and permanent damage to the cornea. Wavelengths between 295 and 400 nm penetrate deeper and may cause damage to the lens, such as cataract. 261 , 279 Visible and infrared light cause damage to the retina. The main photoprotective measure to prevent damage by solar radiation to the eyes is wearing sunglasses. The efficacy of sun glasses against UVR depends on size, radiation absorbing materials (which are incorporated into the lens) and posterior surface reflection of the lens. 261 Australia published the first norm for sunglasses in 1971. In 1997, the last Australian normative project (AS1067) was modified and largely revised to reflect the European norm in effect (EN 1836:1997). 279 The first norm in the United States was published in 1972 by the American National Standards Institute (ANSIZ80.3:1972). In 2001, the most recent version was published. The ANSI Z80.3 is voluntary and not followed by all manufacturers. 279 The International Organization for Standardization is preparing an international norm. 261 , 279 In order to promote adequate ocular protection, it is recommended, by the main eye health organizations of the United States, to wear sun glasses which absorb 99% to 100% of all UV spectrum (up to 400nm), and additional protection for the retina must be provided by lenses that reduce transmission of blue and violet light. 261 There is no standard for the color of the lens. Sunglasses with too dark lenses may cause pupil dilation and increase opening of the eyelid, resulting in greater lens exposure to UV radiation. 279 Glasses should ideally protect all the area around the eye, widening ocular and eyebrow protection. 279 Only the Australian norm AS1067 recommends in its publication measures related to the size of lens. 279 Expensive sun glasses do not necessarily provide better UV protection. 261 , 279 There is no adequate regulation for the manufacture and labeling of sunglasses in Brazil yet.

Glass panels are ceramic materials and therefore part of a wide class of materials, with diverse applications, from civil construction to biological implants - the bioactive glasses. 282 We are interested in glasses used in civil construction (windows and glass panels), in automobiles and in eye glasses, for they represent the interface between the skin and sun radiation, and for that reason, it is imperative to know the capability of these glasses to block solar radiation, especially UV. 279 Some characteristics of the glass material may exert influence over UV radiation protection properties, such as: type, color, layers and coating of the glass. 279 Types of glass Some of the main types of glass used in windows are: Clear glass: it is transparent and colorless. Its main characteristic is the capability of providing protection against the elements while allowing transmission of visible light inside. Depending on its thickness, clear glass transmits more than 90% of visible light (between 400-780 nm) and up to 83% of solar heat. 279 Printed glass: obtained through continuous pouring of glass mass, the surface is engraved with the most varied textures by means of metal rollers. 283 Laminated glass: it is produced by associating two layers of glass to a plastic layer (PVB - polyvinyl butyral ), under heat and pressure. Once glass and plastic are fused together, the result is a glass which acts as a single unit, usually very similar to the common clear glass. The benefit of the laminated glass is that, if broken, its fragments remain adhered to the PVB layer instead of being scattered, reducing the risk of accidents. PVB filters approximately 99% of ultraviolet radiation without diminishing transmission of visible light. 284 Tempered glass: it is obtained through gradual heating and sudden cooling in a tempering oven (vertical or horizontal) and essentially is a safety glass. In case of breakage, it is fragmented in mildly sharp and very small pieces. 284 Some studies have reported the importance of glasses in blocking UVB radiation and certain range of the UVA band. 279 Other investigations have corroborated the importance of glass as a photoprotecting agent against undesired biological effects. 284 Duarte et al. 285 , in a study published in 2008, demonstrated that all types of glass reduced UVA transmission. Laminated glass was the most efficient in totally blocking ultraviolet A radiation, which could be explained by its production characteristics: association of two glass sheets and one sheet of plastic (PVB - polyvinyl butyral ), which turns it into an effective barrier against UVA. 284 Colors present great influence in radiation transmission. The green glass sample totally blocks UVA radiation, and the yellow glass one allows only 1.3% through. 285 In glass manufacturing, additives may be used for dying. Fe3+ confers a brownish-yellow coloring, whereas the mixture of Fe3+ and Fe2+ results in green. Other dyes may be added to obtain other colors. The Fe2+ ion absorbs light in the infrared region, whereas Fe3+ absorbs light in the ultraviolet egion. This way, samples containing Fe3+ in paint pigments are more efficient in diminishing UVA transmission. 286 , 287 Regarding glass thickness, UVA radiation transmission diminishes when the former increases, but is of little significance when compared with other analyzed variables. Plastic films with 35% and 20% visibility (visible light transmission) filter UVA below 370 and 380 nm, respectively. 284 UVB radiation is totally blocked by all glass samples used, at any distance from the emitting source, for its penetrance power is smaller than UVA's. 279 , 284 , 285 Besides, the distance of the glass from the light emitting source influences in a significant way the amount of basal radiation, and the greater the distance, the smaller the irradiation and, therefore, the smaller the transmission of UV by the glasses. This fact can be explained by the great dissipation of energy that occurs at greater distances in environmental conditions. 284 Applying the results above to an everyday situation, the UVB radiation on an individual inside a car with closed windows is null. Even in the case of UVA radiation, the transmission is insufficient to produce actinic damage since besides the glass blocking an important portion of radiation, small alterations in the distance to the light source already diminish the irradiation significantly. In view of these considerations, internal environments with glass can be considered safe for photoprotection, an important finding in the field of occupational medicine, where the use of glass cabins in professional vehicles, for example, would be a preventative health measure for workers.

PRACTICAL ASPECTS OF PHOTOPROTECTION ORIENTATION CHAPTER 7A - GENERAL MEASURES The prescription of sunscreen, as well as all the orientation about photoprotective measures, are part of the routine of dermatologists in their assistance activities. The correct orientation provided to patients will ensure more efficient results of the dermatological treatment prescribed. There are different conditions in which the dermatologist must guide his patients concerning photoprotection; the most important are listed below: 288 - 290 Treatment and prevention of cutaneous neoplasms in predisposed patients. Treatment and prevention of photoaging within a more complete cosmiatric program. Treatment and prevention of photodermatoses or photo-induced dermatoses. Prevent development of photoirritation or photosensitization arising from other dermatological treatments proposed, such as the use of topical retinoids, psoralens and photodynamic therapy. Prevention of post-inflammatory hyperchromia in cosmiatric treatments, particularly ablative ones. Orientation within a more complete photoprotection program, for either a child or adult population, for outdoor recreational or sport activities. Orientation for prevention of actinic damage in workers whose activities are partially outdoors. In all of the situations described, there will be particularities when selecting the most adequate sunscreen, in relation to product use and other photoprotective measures offered, which will be tackled in the following chapters. In general, however, the selection of the most adequate photoprotector and guidance regarding its correct use is always up to the dermatologist. Selecting Sunscreens As stated in previous chapters, every sunscreen sold in Brazil is registered by ANVISA, based on a technical dossier, for corroboration the safety and efficacy of the product. This way, one should always assume that every product registered in the country has the safety and efficacy profile minimally required. 128 With the wide range of products available in the Brazilian market, the adequate selection of a sunscreen by the prescribing dermatologist in each specific case must be based on two sources of information: - Formulation of product (active ingredients, vehicle ingredients, presence of antioxidants or other secondary actives or yet the galenic form of the product), including the cosmeticity of the product. - Product labeling attributes and additional studies performed.

Besides the SPF value, a very important fact when choosing a sunscreen is UVA protection. As mentioned before, the new Brazilian photoprotection legislation determines that a product, in order to declare UVA protection or broad spectrum protection, must present a UVA-PF value greater than a third of the SPF value and a critical wavelength greater than 370 nm. 128 , 288 These considerations are based on different studies that point to an equilibrium in UVB and UVA protection when these measures are met. 288 , 297 It is for the dermatologist, therefore, to select products that meet this demand, requesting additional data from the manufacturer.

Determining stability is not yet a requirement for registering sunscreens in Brazil. However, we know that products advertised for intense or extensive sun exposure, like for outdoor activities, must have their photostability evaluated in order to assure consumers they are safe for use in these conditions. 288 , 296 , 297 It is recommended that the dermatologist request photostability data from the manufacturer.

Amount to be applied The recommended amount of sunscreen in order to evenly coat the skin, considering its irregularities, is 2 mg/cm 2 . Different studies show that with this amount it is possible to achieve a 1mm coating on the whole skin surface. 39 For an average adult of 70 kg and 170 cm tall, the necessary amount to coat the whole body would be 35 to 40 grams. 290 On the other hand, as mentioned earlier, in practice users apply much smaller amounts of sunscreen, with expressive decrease of the real protection achieved. 5 Consequently, according to scientific publications and as a recommendation of regulatory agencies, users should be encouraged to apply larger amounts of sunscreen. One of the recommended strategies is using the "teaspoon rule", in which we consider the application of 1 teaspoon on the cephalic segment and on each of the upper limbs, as well as 2 teaspoons on trunk/back and on each of the lower limbs, as depicted in Figure 5 . 298 FIGURE 5 Teaspoon rule: ideal amount for photoprotector application Adapted source: Isedeh P, et al. 2013. 298 Another proposed strategy is recommending the application of a photoprotector in two layers, one after the other, doubling the amount applied, getting closer to the amount of 2 mg/cm 2 .

Reapplication of a sunscreen is very relevant as it is known that there is a decline in the protecting effect with time, sun exposure and due to environmental factors (clothes, towels, wind, water among others). 290 , 295 This decrease in protection may vary widely, depending on protector formulation and activities exerted by the user. Because it is something difficult to assess, it is understood that the 2-hour time interval be suggested as a general recommendation to the population, even acknowledging that, for some products and in some situations, the interval for reapplication could be wider. 288 , 290 , 295

ORIENTATION ABOUT PHOTOPROTECTION FOR SPECIFIC GROUPS OR AREAS INTRODUCTION Specific groups require special consideration when we speak of photoprotection. The type of sun exposure, skin characteristics and individual habits, as well as the diversity of photoprotective measures, demand individualized assessment in choosing ideal measures to be recommended. It is up to the dermatologist to consider all the particularities at the time of guiding patients regarding photoprotective measures. In terms of public health and photoeducation, we must also consider population groups when engaging in action for photoprotection. Guidance on photoprotection for different population groups and also for specific skin areas, which need special care, are presented below. Pregnancy Pregnancy constitutes a scenario of changing hormonal levels and predisposes the occurrence of physiological or pathological modifications of the skin, like melasma. It is assumed that one of the causes for this predisposition would be the high levels of melanocyte-stimulating hormone in this period. 300 In fact, it is estimated that half of pregnant women suffer from melasma. 299 Whereas general prevalence of melasma in Latinamerican women is around 1.5% to 33%, among pregnant ones this rate rises to 50% or even 80%. 299 - 302 Even if it seems an obvious choice, solar protection as a measure to avoid the onset or worsening of melasma during pregnancy is not frequently investigated. A study performed in Chile at a prenatal clinic evaluated melasma incidence in pregnant women, wearing an SPF 10 sunscreen or placebo. The frequency of melasma onset in the two groups was statistically similar, but considering only women who applied the filter correctly, there was significant difference. 303 In a cohort clinical study, without a control group, a team of researchers from a pharmaceutical sunscreen manufacturer laboratory oriented the use of the product by 185 pregnant women every two hours for six months, with 12 of them having a history of melasma. At six months, 2 new cases of melasma occurred, and 8 of the 12 who already had melasma saw improvement. At six months, 1 more case of melasma occurred, totaling 1.6%. At the end of pregnancy, there were 5 cases (2.7%), which the authors 299 considered much lower than the rate found in pregnant women in another study performed in the same region (53%), but without sunscreen. 304 However, the study did not use a comparison control group. It is possible that guidance for solar protection during pregnancy is being neglected by health professionals. In a study with 109 puerperal women in southern Brazil, it was verified that most of them used to get exposed to the sun at noon for approximately one hour. More than 70% of them did not wear sunscreen and only one woman applied it more than once per day. In an interview, they said the reason for not wearing sun screen was lack of habit. Around 15% of them used other forms of protection, mostly sunglasses. The ones with lighter skin protected themselves more from the midday sun and used more sun screen. Only 35% of the women reported receiving information about risks of sun exposure during prenatal care and none received prescription for sunscreen. Of the 25 patients with melasma, 20 (80%) developed lesions during pregnancy, most of them with a habit of one to two-hour daily sun exposure, and only six used solar filters. 300 Concern about safety for pregnant women to wear solar filters has been considered by researchers. Substances approved by the different international regulatory agencies and by ANVISA were exhaustively evaluated as to their toxicological risk, including the risk of teratogenicity, and are considered safe for use during pregnancy. An additional preoccupation is the recent introduction of nanoparticulate ingredients for use in sunscreens. Different articles 305 - 308 have already been published about the safety of nanoparticles in sunscreen, but there are no studies yet specifically related to nanoparticles in photoprotetors for use during pregnancy.

Photoprotection in Childhood Photoprotection of the pediatric population is fundamental and should be part of well-child care, as well as be oriented by a dermatologist. Three age groups are considered for photoprotection recommendations: Breastfed babies younger than 6 months. should not be directly exposed to the sun. when necessary, it is recommended they wear clothes and hats that cover the skin. wearing sunscreen is not recommended for this age group; it may be prescribed and oriented by the dermatologist in exceptional situations. Children older than 6 months - general measures should not be directly exposed to the sun in the period between 10:00 a.m. and 3:00 p.m. use the "shadow rule": if the shadow of its body is smaller than its height, the child should not be exposed to the sun. the use of mechanical photoprotection measures, like wearing clothes, hats and staying in the shade are essential in a photoprotection program for this age group. photoprotection should always be recommended when necessary. Always recommend sunscreens with SPF above 30 and UVA protection. Whenever possible, opt for products indicated for the pediatric population. Children from 6 months to 2 years of age: preference for products composed totally or for the most part of inorganic filters. Products in the form of cream and sticks are particularly recommended. Children older than 2 years of age: wear products with an adequate balance of organic and inorganic filters, high substantivity (water resistance), easy application and spreadability. Creamy lotions and aerosol products are better accepted. Particular attention should be paid to adequate application of aerosols. Sunscreens should be applied wearing the least quantity of clothes possible, 15 to 30 minutes before sun exposure and reapplied every 2 hours or after immersion in water. Recommend application of a generous quantity of sun protector or application in two consecutive layers, as already explained, to reach a quantity close to 2 mg/cm 2 .

Photoprotective measures, including wearing sunscreen, should be recommended for individuals of any skin color, including those of African descent ethnicity. The dermatologist should pay special attention to skin photoprotection of African descent ethnicity patients, for the greater risk of onset of pigmentary dermatoses as well as the risk, although reduced, for the onset of cutaneous neoplasms. Sport activities Athletes who practice outdoor activities receive a considerable dose of UVR. Adequate photoprotective measures should be taken for this group in view of the high degree of exposure associated with intense sudoresis. 330 Sudoresis induced by heat and by the physical activity may contribute significantly to skin damage caused by UVR, since it increases sensitivity and risk for sunburn. This is probably due to hydration of the stratum corneum with decrease of reflection and dispersion. 331 A study with 290 college athletes showed that, although 96% of them agreed that sunscreen decreased skin cancer rates, over 50% of them had never worn sunscreen and 75% of those who did wore it less than 3 times per week. The most frequent justification for not wearing it (39%) was the desire to have tanned skin. 332 Due to reapplication difficulties and the long time of exposure, wearing clothes made of fabrics with ultraviolet protection and adequate caps or hats, in addition to sunglasses, which protect not only the eyes but the periorbital and malar regions as well, are essential. 330 When we talk about sunscreen, the ideal for those who practice sports is one that provides greater adherence, due to constant sweating and water activities. The spray form is often preferred because it dries easily and is quickly applied, in spite of not having the same adhesion of a filter with greater substantivity; it is reserved for subsequent reapplications. As regards the burning sensation in the eyes, inorganic filters are believed to be less irritating and thicker vehicles used as base or a stick keep the product on the place of application and are favorites for this specific region. 135 The athletes who practice water sports are more affected by UVR, as a consequence of little protection provided by clothes, constant contact with the water and reflection of sunlight on the surface of the water. Some products use inverse emulsion (oils in the external emulsion phase) to increase the resistance of the product to the water. Inverse emulsions and those based on insoluble particles may not be cosmetically satisfactory like the traditional emulsions of organic filters, but they may provide more protection. 333 In a Danish study with 24 volunteers submitted to physical activity and submersion in a bathtub, the SPF of the inorganic and organic sunscreen was reduced by 38% and 41%, respectively, after 4 hours, and 55% and 58% after 8 hours. 334 ANVISA, in RDC 30/2012, requests that allegations concerning water resistance be ascertained by specific methodologies defined in this new regulation. The manufacturers may indicate on their labels the expressions: "Water Resistant", "Very Water Resistant", "Water/Sweat Resistant" or "Water/Perspiration Resistant", as long as this characteristic is ascertained. 128 For a patient with this profile, the ideal is to wear adequate clothing with UV protection. Portable UVA/UVB meters have been sold in the last few years targeted to the practice of sports. In 1976, the first polysulfone-based adhesives were used; however, their use was restricted to research due to the need for a spectrophotometer to assess their absorbance and capture only between 280-315nm (UVB). 335 Currently, bracelets made of encapsulated benzyl-viologen, that changes color according to exposure to ultraviolet radiation are being sold in Europe and are calibrated to assess in real time if the patient with phototype II has reached the maximum recommended UV dose. 336 In 2004, the use of electronic meters that store UVA and UVB readings at pre-established intervals was started for research purposes, allowing reuse and discharge of data to a computer for analysis. 337 Recently, this equipment began to be sold in New Zealand for personal use. 338

Photoprotection is fundamental in the treatment and prevention of melasma. The dermatologist should use all possible strategies to improve adherence of patients with melasma to protective measures, beginning with non exposure to the sun. Clarification regarding the best times to be in the sun are essential, as well as the duration of protection and the consequent need for reapplication. The use of mechanical measures like hats is a recommendation that extends protection and should always be part of the prescription. In case of melasma, the sun protector should have the following characteristics: High SPF, preferably above 50. UVA protection proportionately elevated. If possible, offer colored sunscreen, in the a form of makeup foundation ot compact cream. Use products that protect in the visible light range. Orientation regarding application and reapplication of the product for melasma patients is the same offered as general orientation. The use of oral photoprotective agents with proven effectiveness in prevention and treatment of melasma may be recommended as adjuvant measure. Sensitive skin Ever since sunscreen began to be sold, many actives have been introduced alone or combined in their formulations. With the dissemination of knowledge about the effects of UV radiation and awareness campaigns for prevention of skin cancer, there was great consumption escalation, and new forms of presentation were introduced in the market. Special situations like filters for daily use, makeup with filters, protectors resistant to water and sand, photostable and with better cosmetic acceptability led to greater adherence. However, new and numerous actives appeared in pharmaceutical forms, enhancing the allergenic potential of products. 353 Sensitive skin is understood by some authors as the cutaneous manifestation with more exuberant symptomatology than signs, which includes the burning or stinging sensation on the face after application of a single or a group of facial products, without presence of frankly established erythema, thus differing from clinical pictures of contact dermatitis irritation. 354 Many patients perceive themselves as having "sensitive skin" without in fact presenting the clinical picture related to this dermatosis. Furthermore, nearly 20% of contact allergies attributed to cosmetics cite sunscreens, requiring a differential etiological diagnosis. Adult women with actinic damage present more allergies, while they are more rare in children. 355 Among the substances, minerals such as titanium dioxide are rarely allergenic, but there is evidence that others, such as PABA (paraminobenzoic acid), may be very allergenic. 356 The "Guide for Safety Evaluation of Cosmetic Products (Guia para Avaliação de Segurança de Produtos Cosméticos)" of the National Agency for Sanitary Vigilance (Agência Nacional de Vigilância Sanitária - Anvisa) defines the characteristics and the necessary safety tests (cumulative irritability, sensitization, phototoxicity, cutaneous photoallergy and safety trials using it in sensitive skin populations) that the cosmetic should present to have an "Indicated for sensitive skin" label. 156

Photoprotection for patients with history of contact dermatitis caused by sunscreens should be preferably achieved with products that contain only inorganic filters and without fragrance. Contact tests may be recommended for adequate investigation. Rosacea Rosacea is a chronic disorder, characterized by erythema, papules, pustules and telangiectasias; it predominates in the central face and varies from mild to exuberant forms, such as the rhinophyma, more frequent in men. It predominates in women in the 30 to 50 years old age group and it is estimated that from 1.5 to 10 % of the population is affected with this disorder. 358 Although its pathogenesis is not completely defined, genetic and environmental factors have an impact in the exacerbation of the clinical picture. Foods like chocolate, coffee, some seasonings, tea, alcohol, systemic medications, such as cholinergic agents, vasodilators, rifampicin, emotional factors, physical exercises and solar radiation, among others, are factors associated with worsening of symptoms. 358 Therapy includes from topical medication to surgical procedures. In every form, patients are oriented regarding triggering factors and the importance of wearing the adequate sun protector. Products that associate specific actives for topical treatment and sunscreens can and should be used; evidence shows better outcomes with this association. 359 Due to greater sensitivity and alterations in the cutaneous barrier function, patients with rosacea may present sensitivity to cosmetic and makeup products; however, makeup with sun protector may be used, always giving preference to those that are non alcoholic. Makeup with greenish tones is important to reduce the appearance of facial erythema. The National Rosacea Society, in the USA, recommends wearing makeup that includes UV radition protection, formulations without perfume, hypoallergenic and alcohol-free. 360

Photoprotection for patients with oily or acneic skin should be achieved with products especially developed for this purpose and that demonstrate the promised effect, like control or reduction of skin oiliness, through specific studies. Vehicles in the form of gel, cream gel or fluid are the most recommended for this group of patients. Vitiligo Patients with vitiligo have a diminished risk of developing skin cancer, both melanoma and non melanoma, during their lifetime, and although there are isolated reports stating the contrary, apparently phototherapy does not increase the risk, as demonstrated in epidemiological study. 363 A possible explanation for this would be that patients with vitiligo tend to protect themselves more with clothes exactly because they know that the skin in the regions with lesions is more sensitive to the sun and is easily severely burned, generating actinic damage. 364 Vitiligo treatment has as principle the activation and migration of melanocytes from the borders of the depigmented lesion, penetrating 2 to 3 mm into the lesion; the larger reserves of melanocytes are close to hair follicles; therefore hairless areas (palms, soles of feet) respond poorly to the treatment. 365 , 366 The guidelines of the American Academy of Dermatology are that a broad spectrum photoprotector be applied after the therapy session with psoralene and phototherapy, before the patient leaves the office, since inadvertent and unprotected sun exposure, six to eight hours after the session, may cause phototoxicity and blisters. 366 Due to the sensitivity of depigmented skin, both to UVA and UVB rays, the broad spectrum photoprotector is mandatory for patients with vitiligo, to prevent sunburns. However, all the exposed skin, and not only the lesions, should be protected. 366 Sunscreen protection brings with it another benefit: one of the complaints of patients having phototherapy is the increased contrast between the area of the lesion and normal skin, which tans under radiation. Thus, when irradiating the lesion, the treatment would darken the normal skin as well. By diminishing tanning of the normal skin, this contrast is less marked. The protection factor has to be at least 15 for skins type I or II, and wearing protective clothes and hats is recommended. 365 Camouflage of lesions with products containing pigments may be used. 365 , 366 Some patients with very large lesions may opt for depigmentation of the skin without lesion. In such cases, photoprotection, including wearing sunscreen and avoiding outdoor activities, are measures to be taken for a whole lifetime 86 and the patient should be made aware of this fact.

The ears are the fifth most common location affected by non melanoma skin cancers of the cephalic segment, responsible for around 5% of cases, according to recent study with more than 600 patients at the University of Cornell. 371 The proportion regarding gender in these cases was 17.6 men to 1 woman, due to the natural protection of hair. The most affected areas were the helix and antihelix regions, with little higher prevalence of squamous cell than basal cell (1:0.7) carcinomas.

The lower lip is a frequent site of neoplastic and preneoplastic actinic lesions. In a study with 362 beach workers from Rio Grande do Norte, around 27.1% had lip lesions. 376 Use of lip protector is paramount for patients under intense sun exposure, particularly those that present a more protruding lower lip. It was demonstrated that the regular use of lipsticks with sunscreen reduce the frequency of lip cancer. These lipsticks must meet criteria such as broad spectrum protection and photostability. 377 As to the safety of lip protectors, there are experimental in vivo studies which show that the concentration of octyl methoxycinnamate - one of the most common components of lip sunscreen - necessary to cause fertility problems in rats was 450 mg/kg, demonstrating its low toxicity potential. 378 Notwithstanding, in vitro studies evaluating the safety of ingesting inorganic protectors demonstrate that repeated mucosa exposures to low concentrations of zinc oxide result in persistent DNA damage, 379 and the exposure of intestinal cells to titanium dioxide result in loss of villi, which could lead to malnutrition and malabsorption. 380

SUN AND VITAMIN D INTRODUCTION Vitamin D is obtained by human beings from sunlight, diet (mainly fish and fortified milk) and supplements. Its action as a hormone and its regulation involving parathyroid hormone (PTH), calcium and phosphorus has many important physiological consequences, especially concerning skeletal health. However, vitamin D receptors were evident in the majority of body cells and enzymes capable of converting circulating 25-hydroxyvitamin D (25 (OH) D) to its active form 1.25 dihydroxyvitamin D (1.25 (OH) D), leading to endless new findings about its function. 381 Besides its protecting role against bone fractures, rickets, osteomalacia and osteoporosis, vitamin D is now proposed as a reducer of a spectrum of chronic diseases, including internal cancers, cardiovascular diseases, autoimmune diseases, metabolic disorders and mental diseases. 382 , 383 Its importance was demonstrated in immunology and infectious diseases, and its deficiency associated with, for example, the increase of tuberculosis rates. 384 , 385 A recent study reported that incidence of flu in winter decreases when the adequate status of vitamin D is maintained. 386 At the same time that numerous indications of vitamin D for prevention and/or therapy of diseases appeared, its minimum value, considered as normal by researchers, led to an alarming insufficiency epidemic. 387 , 388 It is assumed that public health campaigns about solar protection and changes in lifestyle may play a role in this reduction. Important aspects of ambient sunlight, photoprotection and status of vitamin D will be analyzed here. Metabolism More than 90% of vitamin D is obtained by skin production through sunlight. 389 When a photon of ultraviolet B light (UVB) (290-315 nm) reaches the skin, it photoisomerizes the 7-dehydrocholesterol (7-DHC) in the cell's membrane to precholecalciferol (previtamin D3), which is rapidly converted, through heat-isomerization, in cholecalciferol (vitamin D3). Peak blood levels of vitamin D3 occur after one day and is stored in body fat later on for release when necessary. Vitamin D2 (ergosterol), originating from yeast and plants is obtained in the diet and follows the same metabolic pathway of vitamin D3. Vitamin D3 enters the circulation via vitamin D binding protein, is hydroxylated in the liver to calcidiol (25 (OH) D), and again hydroxylated, mainly in the kidneys, to its active form, calcitriol (1.25 (OH) D). 390 However, both previtamin D3 and vitamin D3 are sensitive to UV radiation, and continuous exposure to UVB causes its photodegradation in the skin to inactive products. 391 Vitamin D3 maximum cutaneous synthesis is limited to 15-20% of the initial 7-DHC concentration, with less than one minimal erythema dose (MED) production plateau. 390 , 392 Serum concentration of 25 (OH) D is the value used to determine the status of vitamin D, as well as 1.25 (OH) D, which is under rigorous endocrine system control. The minimum recommended level of 25 (OH) D is currently controversial and under discussion. The implications of vitamin D deficiency remain uncertain and many suppositions are still uncorroborated. The American Academy of Pediatrics and the American Society of Endocrinology consider the concentration of 20 ng/mL as the cutoff point for deficiency; on the other hand the American Institute of Medicine proposes that 16 ng/mL is the appropriate minimum level. The Society of Endocrinology recommends an additional classification of 21 to 29 ng/mL as insufficiency of vitamin D. 393 These values were associated with lower risk of fractures and suppression of PTH elevation, a deficiency marker which stimulates the production of 1.25 (OH) D for maintenance of intestinal calcium absorption. 394 A level below 30 ng/mL (75 nmol/L) is considered "insufficient" by most specialists, and less than 20 ng/mL (50 nmol/L) is considered "deficient". 395 , 396 Intoxication by vitamin D, associated with hypercalcemia and hyperphosphatemia, is extremely rare and may be caused by doses greater than 50,000 UI per day and a level of (25 (OH) D) above 150 ng/mL. 381 Photodegradation of vitamin D3 produced by the skin avoids intoxication by vitamin D through sun exposure. With the whole body exposed to a single minimal erythema dose, the equivalent to about 10,000 IU to 20,000 IU of oral ingestion is produced. 381 , 397 Estimates vary, but around half of MED of direct sunlight on arms and legs can produce the equivalent to around 3,000 IU of vitamin D3. 381 Midday sun exposure twice a week, for 5-30 minutes, was suggested as sufficient for adequate production of vitamin D in white populations. Notwithstanding, as we will discuss, the need for exposure time suffers diverse influences and may be variable. 381 Coincidentally, cutaneous synthesis of vitamin D3, as well as erythema (sunburn) occurs at its maximum approximately in the same wavelength of 296 nm of UVB, even though the action spectrum of erythema is extended to the UVA spect

Higher altitudes result in shorter distances and less dense atmosphere, favoring the passage of UVB radiation. There is a 4% increase of the amount that reaches exposed skin for each 300m increase in altitude. 406 Even though it is not a perfect reading of UVB radiation or the capability of synthesizing vitamin D, the UV index is a non-tridimensional representation of erythemal action of the weighted irradiance spectrum. The greater values of UV index (20-25) were detected in Mauna Loa Observatory, in Hawaii (altitude 11,155 feet, latitude 21 º N) and in the area of Peruvian Altiplano (altitude 12,800 feet, latitude 15 º N). 399 Although the vitamin D synthesis potential may be better in higher altitudes, a study demonstrated that adult Tibetans, who live in relatively low latitudes and high altitudes (altitude over 12 thousand feet, latitude 29-32 º N), had low levels of 25 (OH) D, with 40-100% below 30 ng/mL, depending on the population. 407 Nomads presented the lowest levels, all of them below 30 ng/mL and 80% below 12 ng/mL, while farmers presented the most elevated levels, 40% below 30 ng/mL and none below 12 ng/mL. Tibetan diet is extremely poor in vitamin D and the cold weather makes covering most of the skin mandatory. According to the authors' conclusion, these factors are responsible for low levels of vitamin D, even though they see five times more yearly UVB radiation than Norwegians, who live farther north and in very low altitudes. 407

Skin pigmentation The degree of skin pigmentation and age influence vitamin D production. The onset of rickets and vitamin D deficiency among dark-skinned and Indian populations, immigrants of latitude north cities in the United States and United Kingdom, while similar populations in their countries of origin did not have this problem led to speculation that the increase of skin pigmentation could predispose dark-skinned individuals to vitamin D deficiency. 412 - 415 Although diet has been many times a confusing factor, an investigation was proposed to elucidate the role of melanin concentration in photoproduction of vitamin D. Melanin absorbs UV radiation in the epidermis, which limits the number of available photons to convert 7-DHC molecules in previtamin D3. Fitzpatrick phototype is commonly used to classify the type of skin, describing the melanin content in the epidermis and cutaneous reaction (tanning or burning) to UV radiation after a prolonged non-exposure period. 416 These phototypes also indicate propensity to solar damage and vitamin D production. Phototypes I and II present light skin, which burns easily and rarely tans, whereas phototype III presents light skin, however with more ability to tan, and, therefore, will have less UV radiation damage later. Phototypes IV-VI present darker skin, with a larger amount of melanin, that tans easily and rarely burns. In theory, higher phototypes tend to diminish in the population as the distance from the Equator increases, with greater prevalence of light skin in higher latitudes, where UVB must be maximized for vitamin D production and dark skin in equatorial regions, where UV radiation is widely available during the whole year. 415 Consequently, the risk of sunburns and skin cancer is greater when light-skinned individuals travel to lower latitudes, and deficiency of vitamin D, as mentioned above, is more prevalent in polar regions. An initial study by Clemens et al., in 1982, exposed several black and white patients to a single dose of ultraviolet radiation. 417 In white individuals, serum levels of 25 (OH) D increased 30% to 50% compared to basal levels within 24 to 48 hours after exposure, whereas in black individuals it did not have any effect. After an UV radiation exposure six times greater than the one white patients received, only one of the black patients presented an increase of 25 (OH) D 24 hours later, although smaller than in all of the white individuals with the initial dose only. This was the first time that skin pigmentation limitation of in vivo vitamin D production capacity was corroborated. The same group divulged data revealing that pigmented skin ( ex vivo? ) requires longer UV radiation exposure periods to produce similar levels of previtamin D3 in comparison with light skin. 418 Relatively less Vitamin D3 is produced per exposure unit to UV radiation, however, after repeated UV doses, high concentrations of melanin do not prevent vitamin D levels from reaching values considered sufficient. This was confirmed by Lo et al., who determined MED in six Pakistani and Indian immigrants (phototypes III-V) and four white controls (phototypes II-III) in the United Kingdom, and next irradiated the whole body of each individual with 1.5 MED of UV radiation. 419 Both groups had similar increases in vitamin D levels on the following day and there were no significant differences in serum concentrations of vitamin D between the two groups. Even though greater total exposure to UV radiation was necessary for higher phototypes (MED for the darkest patient was five times larger than the smallest control), the total capacity for vitamin D production was not affected by skin type and it is similar in response to equivalent MED. Age The decreasing levels of vitamin D in the elderly is well known, with multiple factors involved, including lack of sun exposure, malnutrition and malabsorption. 420 , 421 The reduction of efficiency in synthesizing vitamin D with age was analyzed in several studies, showing that, even with abundant sun exposure, serum levels of 25 (OH) D are smaller in healthy older people when compared to younger controls. Seasonal variations also diminish or even disappear with advancing age. 421 , 422 The capability for synthesizing vitamin D is based on the availability of 7-DHC. MacLaughlin and Holick demonstrated that, with aging, there is a reduction in quantity of 7-DHC in the epidermis; likewise, the potential for vitamin D3 production. 420 The authors obtained skin samples of six patients, all phototype III, with identical surface areas, and measured the quantity of 7-DHC, which decreased approximately in half from age 21 to 88. Next, the specimens were exposed to equal amounts of UV radiation and the resultant synthesis of previtamin D3 was quantified. By using as a reference a skin sample from an 8-year-old patient, an 18-year-old man produced 80% of previtamin D3 amount, a 77-year-old patient 37% and another 82-year-old patie

Avoid the sunlight Preventing exposure to UVB radiation may be done in several ways, either by avoiding it completely (staying indoors), covering the skin with clothes or applying a sunscreen. To illustrate the potential effect of complete absence of UVB radiation over vitamin D levels, we mention two studies, in which healthy members from submarine tripulations presented a reduction of 40% in serum concentration of 25 (OH) D after two months under water, independently from food fortification. 436 , 437 In some groups, for example patients with severe reaction to sunlight, the photoprotecting behavior is mandatory. Due to photosensitivity, many patients with cutaneous lupus erythematosus actively avoid sunlight. Cusack et al. interviewed 52 patients with cutaneous lupus erythematosus about several behavioral and physical characteristics, then measured serum levels of 25 (OH) D (end of summer). 438 Serum levels of 25 (OH) below 30 ng/mL were found in 67% of the individuals (average of 25.3 ng/mL), with most significant decrease in patients that physically avoided sunlight (use of hats, protection clothes, avoiding midday sun) (p = 0.004) and a little less in patients that used sunscreen daily (p = 0.042). A study of Kamen et al. demonstrated that, in patients with systemic lupus erythematosus, photosensitivity was the second predictor of critically low 25 (OH) D levels, with an odds ratio of 12.9 (p < 0.01), second only to kidney disease (odds ratio 13.3, p < 0.01). 439 The ones most affected by adverse effects of the sun probably take the greatest precautions to minimize exposure and therefore have the lowest levels of vitamin D. Systemic immunosuppression in patients that received transplant of solid organs has been associated with an increased risk of skin cancer, thus avoiding sunlight is recommended to these patients. 440 Querings et al. measured serum levels of 25 (OH) D at the end of winter in 31 31-year-old kidney transplant patients and in sex-matched controls. 441 All transplanted patients reported practicing solar protection with the use of sunscreens, avoiding the sun and wearing protective clothes. Transplanted patients presented significant lower levels of 25 (OH) D in comparison with controls (average concentration of 10.9 ng/ml vs 20.0 ng/ml, p = 0.007). Nevertheless, the decrease in sun exposure is only one of several potential contributing factors in these patients. The use of glucocorticoids, for example, increases the breaking of 25 (OH) D. Vitamin D deficiency has also been demonstrated in patients who received bone marrow transplant. 442 , 443 A third group of patients who practice strict photoprotection is the one which presents inherent tendency for skin cancer formation, including patients with xeroderma pigmentosum (XP) and basal cell nevus syndrome (BCNS). Querings and Reichrath conducted a small study about three patients with XP and BCNS, finding they had serum levels of 25 (OH) D significantly reduced (average of 9.5 ng/mL). 444 It was again demonstrated that photoprotection is associated with reduced vitamin D serum levels. On the other hand, Sollitto et al. showed that eight patients with XP, who practiced rigorous solar protection measures, were capable of maintaining low levels of 25 (OH) D (average serum concentration of 17.8 ng/ml), without the need for supplementation. 445 At the time the study was published, the 10 to 55 ng/mL range was considered normal. Sollitto et al. stated that adequate levels of vitamin D could be maintained in the absence of any supplementation and/or exposure to UV rays, even though these patients were young (27 years old in average, within the range of 14-49), active and had an estimated daily vitamin D intake of 307 IU. Due to greater recommended concentrations today (20 to 30 ng/mL), these patients would be considered vitamin D deficient. 445 A broad investigation, with more than 1,400 white women, conducted by Glass et al. in the United Kingdom, analyzed the relationship between vitamin D, skin pigmentation and exposure to UV rays. 446 It was noticed that higher phototypes (III and IV) presented higher serum levels of 25 (OH) D (average of 32.9 ng/ml), when compared to low phototypes (types I and II) (average of 28.5 ng/mL, p < 0.0001). Data revealed a behavioral tendency in dark-skinned patients to seek the sun, which was positively correlated with vitamin D status. Malvy et al. conducted a similar study in France, involving 1,191 individuals and also observed that serum levels of 25 (OH) D were lower in light-skinned individuals (p < 0.024). 447 Studies about individuals who work in the sun, such as farmers and lifeguards, revealed high levels of 25 (OH) D, with average concentrations between 54 and 65 ng/mL. 397 In spite of greater sun exposure being related with higher levels of vitamin D, the interesting results from Binkley et al. suggest that abundant exposure may not be sufficient to enhance vitamin D status in all subject

Adequate application of sun screen may avoid damage caused by UV radiation in the skin, but the same blocked UVB is also necessary for vitamin D production. 456 - 459 Although we suspect intuitively that the adequate use of sunscreen precludes sufficient synthesis of vitamin D, there are few studies that analyze this question. 460 , 461 Matsuoka et al. presented in vitro and in vivo evidence that application of para-aminobenzoic acid (PABA), a common ingredient of older sun screens, prevents cutaneous synthesis of vitamin D. 462 Ethanol or ethanol + PABA 5% were applied in pieces of human skin and then exposed to simulated solar radiation. Synthesis of previtamin D3 was completely blocked in pieces treated with solar filter; as for the non-treated pieces, 15% of 7-DHC was converted to previtamin D3 in the basal layer of epidermis. Eight white individuals received separately 1 MED of UV radiation on the whole body. Four subjects applied a PABA-based sunscreen, SPF 8, one hour before exposure. One day after exposure, serum levels of vitamin D3 increased significantly in the four non-treated subjects, but remained unchanged in the individuals who used sunscreen (p < 0.01). Even though there were few patients in the study, the results provide evidence of vitamin D synthesis suppression with the use of PABA-based sunscreens. Matsuoka et al. published another study one year later. 463 The authors compared 20 white-skinned individuals with personal history of skin cancer, who over the past 12 months had applied PABA-based sun screens on all exposed body parts, to controls who lived in the same household or neighborhood and were of the same age. Users of solar filters presented less than half the average 25 (OH) D serum levels compared with controls (16.1 VS 36.6 ng/mL, p < 0.001), in dosage taken in the summer. It is important to emphasize that 25 (OH) levels were not analyzed in the beginning of the study or before the use of sunscreen. The amount of sun exposure was estimated by researchers and direct measurement was not done. The individuals with a history of skin cancer probably put more effort in avoiding sunlight than their partners and neighbors, confusing the results. 464 Matsuoka et al. did a third study, similar to the first one, in which an SPF 15 sunscreen was applied on different skin areas of white patients (phototype III), one hour before receiving slightly less than one MED on the whole body. 465 Once more, they measured vitamin D3 levels (instead of 25 (OH) D) before and 24 hours after sun exposure and found that wearing sunscreen on all the body prevented the synthesis of vitamin D3. Applying sunscreen to all areas, except for the head and neck or arms, caused a slight but statistically insignificant increase in vitamin D3 (p > 0.05). Significant increase of vitamin D3 serum levels occurred only when more than 19% of total body surface was free of solar protection (p < 0.05). Holick et al. estimated that adequate application of an SPF 8 solar filter reduces production of vitamin D by more than 90%, and a reduction of 99% is achieved when SPF 15 is applied. 466 Evidence that the application of a solar filter would make vitamin D synthesis difficult, from research which analyzed individual doses in controlled environments were apparently sound, but the results of larger scale studies were not consistent with these findings. The first double-blind randomized clinical trial on the subject was conducted by Marks et al., in 1995, in Australia, and involved more than 100 patients, to whom SPF 17 sunscreens or placebo were designated. 467 All participants in the study presented a history of at least one solar keratosis and were older than 40 years of age. Serum levels of 25 (OH) D and 1.25 (OH) D were obtained at the beginning of the trial and seven months later, after the Australian summer. The adequate use of sun screen was verified by periodic weighing of packagings. The results showed that the use of solar filter did not prevent seasonal increase of 25 (OH) D. The responses were similar in both groups, independently from distribution by age, gender, sun exposure or skin type. Even so, in the placebo group there was a statistically significant increase of 1.25 (OH) D (p = 0.0009) serum levels, which rose by 4.5 ng/mL, whereas, in the group that used sunscreens, the increase was only 0.5 pg/ ml. Levels of 1.25 (OH) D remained within the reference range (12.5-51.7 pg/mL) in all participants and there was no statistical difference between global levels of 1.25 (OH), either at the start or end of research. Seasonal increase of 1.25 (OH) D was an unexpected finding. 1.25 (OH) D is considered free from personal fluctuations, probably due to rigorous control via feedback. 467 - 469 The authors were not able to offer an explanation for changes in 1.25 (OH) D levels. However, the most important finding shows that the marker for vitamin D deficiency, 25 (OH) D, was not affected due to use of sunscre

Vitamin D benefits The only benefit clearly related to vitamin D is its relationship with bone health through participation in calcium metabolism. Appropriate vitamin D levels are related to rickets and osteoporosis prevention. The evidence that vitamin D reduces the risk for onset of chronic non skeletal diseases is inconsistent, inconclusive and does not meet cause-effect relationship criteria. 479

Ultraviolet radiation type B (UVB), with action peak at 296 nm, acts on vitamin D metabolism, transforming 7-dehydrocholesterol in precholecalciferol (pre-vitamin D3) in the epidermis. From this point, a sequence of metabolic hydroxylation reactions will take place in the liver and kidneys, until the active form of vitamin D (1.25-dihydrocholecalciferol) is produced. The estimated UVB dose required for production of 1000 IU of Vitamin D is 0.25 Mínimal Erythema Dose (MED), when about 25% of total body area is exposed. It is, therefore, considered small if compared to the dose necessary to produce erythema. In a country with high levels of solar insolation, such as Brazil, a few minutes of exposure to the external environment, whatever the weather and only hands and face, would be sufficient for vitamin D production. Therefore we should be more concerned with the risks related to solar exposure than with the risks related to non exposure. As regards the time for sun exposure, we know that the UVB radiation level in the period before 10 o'clock in the morning and after 3 o'clock in the afternoon (daylight saving time not considered) is minimal and does not justify solar exposure during these periods, particularly with the intention to produce vitamin D.

We know that the adequate use of sunscreen significantly reduces the amount of UVB radiation that reaches the cutaneous surface and may theoretically interfere in vitamin D production. However, in practice we know that the regular use of sunscreen does not lead to vitamin D deficiency. The possible justification found would be that, as users do not apply the sunscreen in the proper amount and with the recommended frequency and regularity, a sufficient amount of UVB radiation would reach the skin surface for production of vitamin D. Therefore, wearing sunscreen as customarily done by users could not be considered as a factor predisposing to development of vitamin D deficiency.