Photoprotection

CONTINUING

MEDICAL EDUCATION

Photoprotection Prisana Kullavanijaya, MD, and Henry W. Lim, MD Detroit, Michigan Many agents affect the transmission of ultraviolet light to human skin. These include naturally occurring photoprotective agents (ozone, pollutants, clouds, and fog), naturally occurring biologic agents (epidermal chromophores), physical photoprotective agents (clothing, hats, make-ups, sunglasses, and window glass), and ultraviolet light filters (sunscreen ingredients and sunless tanning agents). In addition, there are agents that can modulate the effects of ultraviolet light on the skin (antioxidants and others). All of the above are reviewed in this article. ( J Am Acad Dermatol 2005;52:937-58.) Learning objective: At the conclusion of this learning activity, participants should be able to provide an overview of all aspects of photoprotection.

U

ltraviolet radiation (UVR) from the sun is divided into UVC (270-290 nm), UVB (290320 nm), and UVA, which is subdivided into UVA2 (320-340 nm) and UVA1 (340-400 nm). UVC emitted by the sun is filtered by ozone in the stratosphere; therefore, it does not reach the earth’s surface. The amount of solar UVB and UVA reaching the earth’s surface is affected by latitude, altitude, season, time of the day, cloudiness, and ozone layer. The highest irradiance is at the equator and higher elevations. On the earth’s surface, the ratio of UVA to UVB is 20:1. UVR is strongest between 10 AM to 4 PM. Because UVA is of longer wavelength compared with UVB, it is less effected by altitude or atmospheric conditions. UVA, compared with UVB, can penetrate deeper through the skin, and is not filtered by window glass. It has been estimated that approximately 50% of exposure to UVA occurs in the shade.1 Acute response of human skin to UVB irradiation includes erythema, edema, and pigment darkening followed by delayed tanning, thickening of the epidermis and dermis, and synthesis of vitamin D; chronic UVB effects are photoaging, immunosuppression, and photocarcinogenesis.2 UVB-induced erythema occurs approximately 4 hours after exposure, peaks around 8 to 24 hours, and fades over a day or so; in fair-skinned and older individuals, UVB erythema may be persistent, sometimes lasting for

From the Department of Dermatology, Henry Ford Hospital. Funding sources: None. Conflicts of interest: None identified. Reprint requests: Henry W. Lim, MD, Department of Dermatology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202. E-mail: [email protected]. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.07.063

weeks.3 The effectiveness of UV to induce erythema declines rapidly with longer wavelength; to produce the same erythemal response, approximately 1000 times more UVA dose is needed compared with UVB.4,5 The time courses for UVA-induced erythema and tanning are biphasic. Erythema is often evidenced immediately at the end of the irradiation period6; it fades in several hours, followed by a delayed erythema starting at 6 hours and reaching its peak at 24 hours.6-9 The action spectrum for UV-induced tanning and erythema are almost identical; however, UVA is more efficient in inducing tanning whereas UVB is more efficient in inducing erythema.10 Immediate pigment darkening (IPD), which occurs within seconds after UVA and visible light exposure and disappears within 2 hours after exposure, is the result of photo-oxidation of existing melanin.11,12 At higher UVA fluences (8-25 J/cm2), IPD is followed by pigmentation that is present between 2 and 24 hours after exposure; this is referred to as persistent pigment darkening (PPD). Similar to IPD, PPD is a result of photo-oxidation of melanin.10 Delayed tanning, which peaks at 72 hours after UV irradiation, is caused by increased tyrosinase activity and formation of new melanin,13 leading to increases in the number of melanocytes, melanosomes, the degree of melanization, and the number of melanosomes transferred to keratinocytes. It should be noted that there is no pigment production after UVB exposure unless there is a preceding erythemal response. UVB-induced delayed tanning has been shown to have a sun protection factor (SPF) of 3, whereas that induced by UVA is not photoprotective.13 After single acute UVB exposure, there is an increase in epidermal, and to lesser extent dermal, mitotic activity, which persists from days to weeks, leading to an approximate two-fold thickening of the 937

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epidermis and dermis.14 Single UVA exposure does not increase epidermal thickness; only repeated exposures may do so, but to a lesser extent than UVB.15 Most of the immunosuppressive effects of UV exposure have been ascribed to UVB. However, more recent studies indicated that UVA radiation is even more immunosuppressive than UVB.16-18 UVA causes DNA damage by oxidative process19; the reactive oxygen species generated induces increased melanin synthesis, leading to delayed tanning response, and cell membrane lipid peroxidation eventuating in cutaneous inflammation. Close correlation between erythema and DNA damage associated with carcinogenesis has been documented. Mutation of p53 gene has been found in greater than 90% of squamous cell carcinoma, 60% of actinic keratosis, and 50% of basal cell carcinoma.20 In addition, deleterious effects have been demonstrated after nonerythemal UV exposure. Several studies have shown that repeated suberythemal UV exposure can induce reactive oxygen species—mediated DNA damage and pyrimidine dimer formation, leading to skin cancer in animal models.21-23 Suberythemal UVR suppresses delayed type hypersensitivity (DTH) in human beings, and alters Langerhans cell number, function, and morphology in mice.24-27 In animal models, photoimmunosuppression has been shown to be mediated through generation of cis-urocanic acid, and cytokines such as tumor necrosis factor and interleukin (IL)-10. In human beings, there is evidence showing that localized sunburn can impair contact hypersensitivity reaction.28 Moreover, UVA and UVB play a role in the pathogenesis of photosensitive diseases such as chronic actinic dermatitis, polymorphous light eruption, actinic prurigo, hydroa vacciniforme, and photoallergic or phototoxic drug reactions. Chronic exposure to UVR is known to result in the development of solar lentigines, photoaging, actinic keratoses, and squamous cell carcinoma. To minimize the deleterious effects of UVR, public education on photoprotective measures should be continued. The most effective one clearly is complete avoidance of sun exposure; however, this is obviously not practical or desirable. Seeking shade and minimizing sun exposure during its peak UVR (10 AM-4 PM) are recommended, recognizing that both measures would still result in potential exposure to significant doses of UV, especially UVA and visible light. The above should be combined with the use of appropriate clothing, wide-brimmed hat, sunglasses, and broad-spectrum sunscreen to achieve the optimal protection.29 In the following sections, these photoprotective measures will be reviewed.

NATURALLY OCCURRING PHOTOPROTECTIVE AGENTS Agents in the atmosphere and the environment Ozone (triatomic oxygen) is the major photoprotective agent formed in stratosphere. It absorbs large amounts of UVB and UVC; however, it absorbs little or no UVA and visible light. It functions as a barrier or filter to solar radiation of l \ 285 nm; this is the major reason that UVR with l \ 285 nm does not reach the earth’s surface. Ozone layer is not uniform in thickness. Concentration of ozone increases toward polar regions; however, in the past 15 years, decrease has been noted at the South Pole.30 UV reaching the earth’s surface increases approximately 3% per degree increase in latitude.31 Higher altitude has thinner atmosphere to absorb UVR, resulting in an increase of the intensity of UV by 8% to 10% for each 1000 ft of elevation.31 Time of the day of sun exposure also affects the UV intensity; at noon solar radiation passes through less ozone, resulting in more radiation reaching the earth. Chlorofluorocarbons used as aerosol propellants found in refrigerator and air-conditioning units can destroy ozone molecules. Ozone depletion has a significant impact on terrestrial UV exposure. It has been shown that sunburns and photosensitivity disorders increased after acute, sudden episodes of highly increased UVB radiation because of ozone depletion.30 It has been estimated that 1% decrease in ozone increases melanoma mortality by 1% to 2%.32 Pollutants, clouds, and fog can decrease the intensity of UVR reaching the earth’s surface by scattering; shorter wavelength is scattered more than longer one. Snow, ice, sand, glass, and metal can reflect up to 85% of UVB. Light-colored sand has been shown to reflect about one third as much UVR as snow and ice. Reflection of UVR from most ground surfaces is normally less than 10%. It should be noted that water is not a good photoprotectant, because UVR can penetrate through water to a depth of 60 cm so swimmers can potentially get significant UVR.33 However, densely-leafed trees can protect against UVB exposure.33 Naturally occurring biologic agents Normally epidermis can absorb radiation in the UVB and UVC range, reflect 5% to 10% of the spectral range of 250 nm to 3000 nm,34 and scatter most visible light. Chromophores are molecules that absorb light energy. The major cellular chromophores absorbing in the UVB wavelengths are pyrimidine and purine

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Table I. Factors affecting UV protection factor Construction of fabrics Thickness Type of fibers Laundering Hydration Stretch Chemical treatment Color Fabric-to-skin distance

bases in DNA, and proteins (especially tryptophan and tyrosine). Other proteins that absorb in the UVB range include nicotinamide adenine dinucleotide, quinones, flavins, and other heterocyclic cofactors such as tetrahydrobiopterin. Protein cofactors and soluble metabolites also absorb in the UVA range, but the specific UVA-absorbing molecules have been difficult to establish. When nucleic acid absorbs UVB radiation, DNA photoproducts, mainly cyclobutane pyrimidine dimers, are formed; if not repaired, these photoproducts can be mutagenic or cytotoxic. After exposure to longer wavelengths, the predominant result is the formation of oxidative photoproducts. The latter are mediated by reactive oxygen species, which can be generated in the presence of UVA, oxygen, and the appropriate chromophores such as NADH, flavins, and unsaturated lipids. Reactive oxygen species can cause oxidation of lipid and proteins, induce matrix metalloproteinases, and produce dyspigmentation. Urocanic acid, with a peak absorption spectrum at 277 nm,34 is located in the epidermis; it is considered to be one of the chromophores playing a role in acute photobiologic response. On absorption of photons, trans-urocanic is isomerized to cis-form, which has been implicated in UVR-induced immunosuppression and photocarcinogenesis. Melanin, a large opaque molecule present in the epidermis, can absorb throughout the UV and visible ranges; however, its absorption increases steadily toward shorter wavelengths over the broad spectrum of 250 to 1200 nm.34 When photoexcited, it can produce free radicals that contribute to tumor formation and chronic photodamage. Melanin can protect the skin by physically blocking and scattering the UVR; it converts the absorbed energy into heat rather than into chemical energy. The degree of photoprotection by epidermis varies depending on skin thickness and degree of constitutional skin pigmentation. This is the reason that sunburn tends to be severe on the face, for example, where skin is thin, and that photoaging is most prominent in individuals with skin phototypes I and II.

PHYSICAL PHOTOPROTECTIVE AGENTS Clothing Clothing is an excellent photoprotectant. UVB is scattered more by a given fabric compared with UVA. UV protectiveness of fabrics is expressed as ‘‘UV protection factor’’ (UPF), a term that was first used in Australia in 1996.35 UPF, which is analogous to SPF of sunscreens, is assessed by measuring transmission of UVA and UVB through given fabrics with a spectrophotometer. UPF is calculated by combining the UV transmission data with two weighting factor values, solar spectral irradiance and erythema effectiveness, at each UV wavelength. The latter accounts for the fact that UPF is a better reflection of the protectiveness of fabrics against UVB than UVA. This method was shown to be accurate and reproducible, particularly for samples with UPF below 50.36,37 It should be emphasized that UPF is an in vitro assessment. When in vivo studies assessing the UV protectiveness of fabrics on animal or human skin are performed, using erythema as an end point, the term ‘‘SPF’’ has been used by some investigators. However, to avoid confusion with the SPF universally used for sunscreen, it is more appropriate to use ‘‘UPF’’ for photoprotection of fabrics. To measure the minimal erythema dose (MED) of protected skin, a textile is placed over the skin on one side of the back. The incremental UVB doses for determining the MED of unprotected skin are multiplied by the UPF determined in vitro, with the product being the incremental UVB doses for MED testing of the protected skin.38 In vivo method can be done in 2 ways; an on-skin method whereby the fabric is applied directly to the skin of the test participants, and an off-skin method, in which the fabric is placed at the distance of at least 2 mm from the skin surface.39 Although there have been reports of good correlation between in vivo off-skin and in vitro methods, this finding has not been consistently reported.40,41 In practice, the in vitro method determined by spectrophotomeric assessment of the UV transmission seems to be the most suitable method for the evaluation of UV protection of textiles. Comite´ Europe´en de Normalisation (CEN), the European Committee for Standardization, is the major provider of European standards and technical specifications for fabric photoprotection.42-44 The recommended method is a spectrophotomeric method using equipment with an integrating sphere to determine UV protection of fabrics that are worn in close proximity to the skin, but not on the skin. Factors taken into account by this standard are UPF, broad-spectrum UV protection, and the design of the clothing. To fulfill this standard, the UPF should be greater than 30, and the average transmission in the

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UVA region should be smaller than 5%. Clothing design should cover the upper and lower body; the upper body protection should provide at least coverage from the base of the neck down to the hip and across the shoulders down to three fourths of the upper arm, whereas lower body coverage should cover from waist to patella.42 There are several studies investigated the UV protection of fabrics by using in vitro UPF.36,37,39,41,45-48 A study done in Europe found that 33% of summer clothing provided insufficient UV protection (ie, UPF \ 15), and only half of the fabrics had UPF 301, a requirement of the European standard.46 Factors that affect UPF are listed in Table I. They will be discussed in the following paragraphs. Construction of fabrics is an important factor; those with tightly woven fibers have higher UPF than loosely woven ones.45 Thicker fabrics transmit less UVR.49 Wool and synthetic materials such as polyester have high UPF whereas cotton, linen, acetate, and rayon have UPF less than 15. Polyester is not comfortable to wear in the warm weather; therefore, polyester blends that also have high UPF are frequently used instead.45 Denim provides UPF of 1700. Typical summer cotton T-shirts provides UPF of 5 to 9, and when it is wet, the UPF decreases to only 3 to 4.50 In animal models, this material did not prevent photocarcinogenesis.51 It has been suggested that fabrics that are appropriate for the patient who is photosensitive should have UPF over 30, which in animal study has been shown to protect against erythema and the development of premalignant lesions.51 Washing and wearing effect the UPF. It was shown that UPF increased significantly after washing because of shrinkage, which was most noticeable after the first washing.52 In general, hydration results in a reduction in the UPF because of the presence of water in the interstices of the fabrics, which leads to an increase in UV transmission.53 On the other hand, in fabrics made of viscose or silk, or in fabrics that have been treated with broad-spectrum UV absorbers, the UPF frequently increases when the textile becomes wet.53 In fact, Gambichler et al54 have concluded that one can not predict the UPF value of any given fabric when wet, because the value varies depending on the type of the fibers, and the change in scattering and absorption properties of the fabrics. Fabrics such as knitted textiles are prone to stretch which leads to decreased UPF. Lycra (DuPont, Wilmington, Del) may block 100% of UVR when lax, but when stretched, its UPF decreases to 2. UPF is also affected by chemical treatment of the fabrics, such as application of optical brightening

agents and UV absorbers, and bleaching of the fabrics. Optical brightening agents are conjugated compounds; on exposure to UV, they absorb the energy and fluoresce at the visible range. This results in an attenuation of the UV transmission, and brightening of the fabric. In a study where fabrics were washed with laundry additive containing UV absorber Tinosorb FD, fabrics that were treated with the detergent and UV absorber had significantly increased UPF than those exposed to water washing alone.47 Bleached cotton and viscose rayon provide relatively low UV protection compare with unbleached fabrics such as cotton and silk.49 Dark-color fabrics have greater UPF than light color ones.47,55 Another factor is the distance of the fabric from the skin. The closer the fabric is to the skin, the less photoprotection it affords. This is because by decreasing the distance between the fabric and the skin will result in a decrease in the diffuseness of the beam incident to the skin.40 Furthermore, the irregular porosity and nonuniform yarn structure of some textiles such as knitted nylon and polyester material may lead to a reduction of the UPF when placed directly to the skin.40,41 A study was conducted to evaluate the UPF of nylon stockings.55 Plain-knit stockings have different UPFs according to the color, thickness, body site, and stretching. As expected, dark-colored stockings have high UPF compared with light-colored ones. Denier, which is the unit for measuring how fine the threads are of materials such as nylon and silk, is another important determinant. Black stockings that are 10 denier have a UPF of 1.5, whereas those with 40 denier have a UPF of 3. Stretching has a significant effect on the UPF of stockings. When stretched to 30% of their original size, the UPF of 50-denier stockings decreased by 868%, whereas that of 15-denier stockings decreased by 103%. The larger decrease in the UPF seen in the higher denier stockings is a result of the opening of the tight weave with stretch, hence, allowing more UVR to penetrate.56 UPF of stockings at distal calf is higher than that of proximal calf, reflecting the degree of stretching at these sites.55 The most popular type of stocking has only 15 denier, which provides less than 2 UPF. To promote adequate photoprotection, it has been suggested that woman should use stockings of at least 40 denier.55 Hats Hats provide variable sun protection for head and neck, depending on the brim width, material, and weaving. A wide-brimmed hat ([7.5 cm) has SPF 7 for nose, 3 for cheek, 5 for neck, and 2 for chin. Medium-brimmed hats (2.5-7.5 cm) provide SPF 3 for nose, 2 for cheek and neck, and none for chin,

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whereas narrow-brimmed hats provide SPF 1.5 for nose, and little protection for chin and neck.33 Makeup Foundation makeup without sunscreen provides SPF 3 to 4 as a result of its pigment content. However, these pigments gradually lose their ability to create an even cosmetic film over the skin surface 4 hours after application because of the migration into the dermatoglyphs and accumulation in the follicular ostia, resulting in a decrease in their photoprotective property and aesthetic appearance.57 The decrease in SPF could occur more rapidly as a result of accidental removal, perspiration, sebum production, and tearing.57 It is recommended for patients who rely on their facial foundation for photoprotection to reapply the foundation at least every 2 hours when engaged in outdoor activity. Foundations containing UV filters with high SPF are now widely available; therefore, these products are ideal for daily photoprotection. Sunglasses Photochemical reactions can occur in ocular tissues leading to acute and chronic damage to the eyes after sun exposure.58 UVB radiation causes oxidative damage to the lens by the variety of free radical mediated reactions. It is now known that high-dose UVA can impair lens cellular and optical functions.59 Eyes, like other tissues, possess many defense mechanisms against photochemical reactions; one of them is antioxidants, which include macular xanthophyll pigment, lens chromophores, melanin, glutathione (GSH) peroxidase, superoxide dismutase, and heme oxygenase60; and radical scavengers such as vitamin E, vitamin C,61-65 beta carotene,65 and ubiquinone. These antioxidants were shown to prevent the changes in enzyme activities after UVB radiation.66 However, they might not be fully protective under strong oxidative stress. Furthermore, antioxidant levels decrease with age.58 Unfortunately, major ocular tissues such as lens and retina do not possess the capacity of cellular regeneration; therefore, damaged molecules accumulate during one’s lifetime.58,67 Different ocular issues absorb different wavelengths of radiation. For example, cornea and lens cortex, which are major UV filters, absorb primarily in the UVB range,68 lens nucleus and retina in young eyes absorb UVA, and retina absorb visible light.58 With age, the human lens undergoes numerous biochemical changes including a yellowing of nucleus and the decrease in essential antioxidant, resulting in the onset of nuclear cataract.69 Acute UVR and visible light effects on cornea and conjunctiva include photokeratoconjuctivitis, which heals

within 24 to 48 hours, whereas chronic changes are pterygium70 and pinguecula. Acute solar retinopathy,71 and chronic reduction of visual functions such as dark adaptation and visual acuity, have been found after unprotected exposure to sunlight.72 It should be noted that eyes of infants and juveniles transmit a higher amount of UV and visible radiation than eyes of elderly persons. For example, in the newborn, there is an UV transmission window around 320 nm with a 10% transmission; this window closes around 10 years of age. Of blue light, 70% to 80% is transmitted until about the age of 20 years, with a reduction to 40% at the age of 60 years.58 Chronic sun exposure to lens causes cataract and eye cancer.73 Cataract has been shown to correlate directly to sun exposure, especially to UVB radiation.74 Although UVA was believed to play little role in the past,73 it has now been found that sufficient UVA exposure from the sun, either from single exposure or several additive exposures, could result in photo-oxidative process in the epithelium of the lens, leading to lens cell damage and opacity.75 It has been estimated that 1% decrease in stratospheric ozone, which increases the transmission of UVB, would result in 0.7 6 0.1% higher rate of cataract.76 To provide proper eye protection, it has been recommended by major visual health organizations in the United States that sunglasses which absorb 99% to 100% of the full UV spectrum (up to 400 nm) should be worn, and additional protection of the retina can be provided by lenses that reduce the transmission of violet/blue light.58 Sunglass standard and its rationale have been reviewed.77 The efficacy of sunglasses against UV depends on their size and shape, UV absorbing materials that are incorporated in the lens, and reflection from the posterior lens surface.78 Clear glasses absorb the vast majority of radiation below 320 nm. In contrast, UVA radiation can pass through clear glasses; therefore plastic film containing zinc, chrome, nickel, or other metals that block UVR over a wide range needs to be used for protection against UVA. Darkly tinted glasses block longer wavelengths including UVA and visible light; however, they may block enough visible light to obscure vision.33 Expensive brands and polarizing sunglasses do not guarantee optimal UVA protection.79,80 The use of sunglasses may be associated with some risks, because they may induce behavioral changes by the wearers. It has been shown that wearers had a tendency to protect their entire body less when wearing sunglasses.81 Contact lenses have been shown to provide good protection for ocular lens as no UVR can leak around the sides of the lenses, or reflect back off their posterior surface as

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Table II. Sunscreen active ingredients listed in the Food and Drug Administration monograph Ingredients

Maximum concentration

Peak absorption l maximum (nm) or absorption range

Organic absorbers 1. UVB filters PABA derivatives PABA Padimate O (octyl dimethyl PABA) Cinnamates Octinoxate (octyl methoxycinnamate, Parsol MCX) Cinoxate Salicylates Octisalate (octyl salicylate) Homosalate Trolamine salicylate Others Octocrylene Ensulizole ( phenylbenzimidazole sulfonic acid) 2. UVA filters Benzophenones Oxybenzone (benzophenone-3) Sulisobenzone (benzophenone-4) Dioxybenzone (benzophenone-8) Others Butyl methoxydibenzoyl methane (avobenzone, Parsol 1789) Meradimate (menthyl anthranilate) Inorganic absorbers Titanium dioxide Zinc oxide

15% 8% 7.5% 3%

283 311 311 289

5% 15% 12%

307 306 260-355

10% 4%

303 310

6% 10% 3%

288, 325 366 352

3%

360

5%

340

25% 25%

Depending on particle size Depending on particle size

PABA, para-aminobenzoic acid.

can occur with regular sunglasses. However, contact lenses will not provide protection to the anterior parts of the eyes.82 Unfortunately there is currently still little concern by the public about eye protection. Surveys by telephone encounter and questionnaire found that knowledge of the public about the effects of sunlight on the eyes was low.83,84 Although most of the responders owned sunglasses, they only occasionally wore them.83 Window glass and windshields Normal clear window glass absorbs wavelengths below 320 nm, which represent UVB. Tinted plastic film can block a large portion of UVA (cutoff point at 370-380 nm). Darkly tinted glass provides significant protection against UVA and visible light. Federal Motor Vehicle Safety Standard 205 requires that the tinted glass used in automobiles should provide no less than 70% transmission of visible radiation.85 Companies such as 3M manufacture plastic films

containing zinc, chrome, nickel, or other metals that block UVR over a relatively wide spectrum, which are incorporated into windshields of cars.33 Because of differences in the safety standards and manufacturing process, windshields provides better UV protection compared with automobile side-window glass.

UV FILTERS Topical photoprotective agents In the United States, sunscreen agents are regulated by the Food and Drug Administration (FDA) as over-the-counter medications. There are 16 agents listed in the latest FDA sunscreen monograph (issued May 1999) (Table II).86 All but two are organic absorbers/filters; only titanium dioxide (TiO2) and zinc oxide (ZnO) are inorganic absorbers/filters. The terms ‘‘organic’’ and ‘‘inorganic’’ are now recommended by the FDA to replace ‘‘chemical’’ and ‘‘physical/nonchemical’’ filters, respectively. The first reported use of sunscreens in the world was in 1928, in the United States, with the

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commercial introduction of an emulsion containing two sunscreen chemicals, benzyl salicylate and benzyl cinnamate. Para-aminobenzoic acid (PABA) (l maximum, 283 nm), one of the first widely available organic sunscreen ingredients, was patented in 1943. PABA is water soluble and is a very effective UVB filter at 5% concentration in 50% to 60% alcohol base.87 A disadvantage of PABA is staining of clothing. In the past, PABA was the most commonly reported contact and photoallergen in sunscreens. In addition, PABA was found to be a potent carcinogen in vitro, although the in vivo significance is unknown.88 These considerations have limited its use in sunscreen products. Padimate A (amyl-p-dimethylamino-benzoate) was used as a filter for a few years. However, because of phototoxicity,89 it is no longer used, nor is it listed in the FDA monograph as an approved sunscreen ingredient. Octyl dimetyl PABA or padimate O (l maximum, 311 nm) is an effective UVB filter with a good safety profile. It is currently the most commonly used PABA derivative. It is less effective in photoprotection than PABA.87 Octinoxate (octyl methoxycinnamate [OMC], Parsol MCX, Escalol 557, Eusolex 2292) (l maximum, 311 nm) is less potent UVB absorber than padimate O; therefore, it requires additional UVB absorbers to achieve high SPF values in the final product. It is currently the most widely used UVB filter in the United States. Octinoxate has been reported to degrade into a photoproduct when exposed to sunlight for a short period of time, which leads to a decrease in UV absorption efficacy. There have been several studies performed to improve the photostability of cinnamate. Encapsulation of ethylhexyl-p-methoxycinnamate into nanoparticles consisting of polyD,L-lactide-co-glycolide resulted in a reduction of the photodegradation of this sunscreen from 52.3% to 35.3%.90 Another study showed that glyceridic esters of octinoxate has a longer photoprotective property in vivo compared with the native molecule.91 Cinoxate (ethoxy-ethyl-p-methoxycinnamate, Neo Heliopan E1000, Uvinul N-539) (l maximum, 289 nm), another cinnamate derivative, is a less commonly used filter. Salicylates are weaker UVB absorbers so they must be used in relatively high concentration. They are used to augment the effect of other UVB absorbers. Octisalate (octyl salicylate; l maximum, 307 nm) and homosalate (homomenthyl salicylate; l maximum, 306 nm) are agents listed in the FDA monograph. They are commonly used to minimize the photodegradation of other sunscreen ingredients

including oxybenzone and avobenzone. Trolamine salicylate is primarily used for water-soluble sunscreen products because of its substantitivity. It is used in hair preparation as a photoprotective agent. Octocrylene (2-ethylhexyl-2-cyano-3, 3-diphenylacrylate; l maximum, 303 nm) is a photostable filter; it can improve photostability of the final product when combined with other sunscreens. Ensulizole ( phenylbenzimidazole sulfonic acid; l maximum, 310 nm) is a water-soluble UVB absorber. It is an aesthetically pleasing formulation. It is used to enhance the SPF of the final product, which may contain other organic and inorganic sunscreens. Camphor derivatives (eg, 4-methylbenzylidene camphor; l maximum, 300 nm) are moderately effective UVB absorbers. A notable exception is terephthalylidene dicamphor sulfonic acid, which is a broad UVA filter (see below). Camphors are approved to be used in the European Union; however, they are not listed in the 1999 FDA monograph. UVA filters include benzophenone (Bp), butyl methoxydibenzoylmethane (avobenzone; Parsol 1789), anthralinates, terephthalydene dicamphor sulphonic acid (Mexoryl SX), drometrizole trisiloxane (Mexoryl XL), methylene-bis-benzotriazolyl tetramethylbutylphenol (Tinosorb M), and bis-ethylhexyloxyphenol methoxyphenol triazine (anisotriazine, Tinosorb S). Although the mexoryls and tinosorbs are used in many parts of the world, they are not listed in the 1999 FDA sunscreen monograph. Oxybenzone (Bp-3; Eusolex 4360, Uvinul M-40) is the most commonly used Bp. It absorbs most efficiently in UVB and UVA2 range with two absorption peaks (l maximum, 288 and 325 nm). Although it is a broad-spectrum UVA filter,92 it is photolabile and can be oxidized rapidly; its oxidation will inactivate the antioxidant systems.93 Other Bps listed in the FDA monograph are sulisobenzone (Bp-4) and dioxybenzone (Bp-8). Butyl methoxydibenzoylmethane (avobenzone, Parsol 1789) has strong absorption in the UVA1 range (l up to 380 nm). Unfortunately, it has been shown that its photoprotective capacity decreased by 50% to 60% after 1 hour of exposure to sunlight.94 Furthermore, it has been reported that it strongly enhanced the degradation of OMC.95,96 Because both Bps and avobenzone are photolabile, they are frequently combined with octocrylene, salicylates, methylbenzylidene camphor, micronized ZnO, and/or TiO2 to enhance their photostability.97 Meradimate (menthyl anthralinate, Ensilizole; l maximum, 340 nm) absorbs mainly in UVA2 range; it is a weak UVA filter.98 Terephthalydene dicamphor sulfonic acid (Mexoryl SX; l maximum, 345 nm) is a broad-spectrum UVA

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absorber. It has been shown to prevent UVA-induced histochemical alterations in skin associated with photoaging in animal models.99 In human beings, Mexoryl SX applied before UVA exposure has been shown to prevent UV-induced changes, which include pigmentation, epidermal hyperplasia, decrease of skin hydration, and elasticity.100 Sunscreen containing Mexoryl SX significantly suppressed UVRinduced carcinogenesis in mice compared with preparation containing UVB absorber alone.101 After UV exposures, Mexoryl SX containing sunscreen also reduced cis-urocanic acid formation, and prevented the decrease in the number of epidermal Langerhans cells, changes which are known to play a role in immunosuppression.102 Drometriazole trisiloxane (silatriazole; Mexoryl XL; l maximum, 303 and 344 nm) is a photostable hydroxybenzotriazole. It consists of two chemical groups; 12-hydroxyphenylbenzotriazole, which is photostable and can absorb both UVA and UVB, and siloxane chain, which is liposoluble. Both of these mexoryls were developed by L’Oreal (Clichy, France). Methylene-bis-benzotriazolyl tetramethylbutylphenol (Tinosorb M; l maximum, 303 and 358 nm), a UV filter developed in Europe (Ciba Specialty Chemicals, Basel, Switzerland), has been shown to be a good broad spectrum sunscreen. It consists of microfine organic particles that are dispersed in the aqueous phase of sunscreen emulsions. Another agent is bis-ethylhexyloxyphenol methoxyphenol triazine (anisotriazine; Tinosorb S; l maximum, 348 nm), which is an oil-soluble broad-spectrum UV filter. Both have an excellent absorption across the UVA range. Both of them have high photostability as a result of their molecular structure that facilitates the dissipation of incident energy by intramolecular heat transfer and vibrational relaxation; therefore, no reactive intermediate species and no photolytic decomposition products are formed in the skin. Moreover, it has been shown that both tinosorbs can stabilize OMC95,96 and avobenzone.96 It has been reported that none of these tinosorbs possesses intrinsic estrogenic/antiestrogenic or androgenic/ antiandrogenic activity in vitro.103 These tinosorbs were developed by Ciba Specialty Chemicals, Switzerland. Inorganic or nonchemical sunscreen filters, TiO2 and ZnO, are photostable. They are not absorbed systemically and have had no report of sensitization reactions. Depending on the particle size, they protect against UVR by reflecting and/or absorbing UVR. Opaque inorganic sunscreen can protect against visible light-induced photosensitivity diseases such as the porphyrias.104

The factors that determine effectiveness of reflecting properties are reflective index, size of particles, dispersion in the base, and film thickness.105 Filter with higher reflective index has better reflective properties. Thick coating is necessary to achieve a sufficient degree of reflection, which makes the product cosmetically less acceptable. Iron oxide, which has a reddish color, is sometimes added to improve acceptability; it also improves UVA protection by its absorption property. Decreasing particle size into micronized form (10-50 nm), compared with 200 to 500 nm of nonmicronized form, results in less scattering of visible light, hence, improves cosmetic acceptability; however, it would shift protection toward shorter wavelengths by its property as an absorbency. It has been reported that micronized pigmentcontaining sunscreens can offer good protection against UVB-induced immunomodulation in human beings.106 Although they are now widely available, it should be noted that it is technically more difficult to prepare micronized preparations; if the dispersion is not optimal, the micronized particles may aggregate resulting in an increase in the particle size. Microfine ZnO (Z-cote) is becoming more popular because it is shown to protect over a wide range of UVA, including UVA1 (up to 380 nm). It is photostable and does not react with other organic sunscreens.107 It is more effective in UVA protection than microfine TiO2, which protect against UVB and UVA2, and is less protective against UVA1.107,108 TiO2 has higher refractive index (2.6) than ZnO (1.9), which makes TiO2 whiter (even though the particle size is smaller) and more difficult to incorporate into products that are minimally visible to the eyes.107 Moreover, TiO2 is more photoreactive than ZnO. Photoexcited micronized TiO2 has been shown to cause cell death in vitro, although no evidence exist on its in vivo toxicity.88,105 A consequence of the photochemical reaction is that it causes TiO2 and ZnO to be less effective as sunscreens. Therefore, TiO2 and ZnO particles are frequently coated with dimethicone or silica, which has been shown to be stable during the manufacturing process and after application of the product on the skin109; therefore, the efficacy of these inorganic filters can be maintained. Sun protection factor A widely accepted method of sunscreen efficacy measurement is SPF, which is defined as the ration of the dose of UVR (290-400 nm) required to produce 1 MED on sunscreen-protected skin (after application of 2 mg/cm2 of product) over the dose to produce 1 MED on unprotected skin. SPF-15 sunscreen can

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filter out 94% of UVB radiation, and SPF-30 sunscreen provides greater than 97% protection.110 Sunscreens have long been used to protect against acute effect of UVR; they are also now known to have protective effects on chronic UVR-induced changes, such as photoaging111 and skin cancer. Regular use of high-SPF sunscreen can reduce the number of actinic keratoses.112,113 It has been reported in human beings that cutaneous squamous cell carcinoma, but not basal cell carcinoma, can be prevented by regular use of topical sunscreen.114 In mice, compared with nonbroad-spectrum sunscreen, broad-spectrum sunscreen has been shown to be superior in protection against DNA damage and photocarcinogenesis, and in delaying tumor development.101 Sunscreen was reported to prevent UV-induced development of skin cancer in mice by decreasing the formation of cyclobutane pyrimidine dimers; it can also prevent other UV-induced immunologic effects such as epidermal Langerhans call depletion,115 and suppression of contact hypersensitivity and DTH.1,24,116-119 One study found that broadspectrum sunscreen could prevent UV inhibition of contact hypersensitivity to nickel in human beings.16 A study in human beings showed that application of sunscreen with SPF 30 before UVB exposure could prevent the decrease in the number of Langerhans cells in the irradiated site, and attenuate the UVinduced suppression of contact hypersensitivity to dinitrochlorobenzene.115 High-SPF sunscreen could prevent the suppression of contact hypersensitivity induced by UVB24,115 and minimize the sunburn cell formation.120 There is no evidence that sunscreen products with higher SPF and high concentrations of active ingredients would increase the risk of irritation or hypersensitivity.121 Immune protection factor When solar simulating radiation (SSR), which contains both UVA and UVB, is used, it is now clear that there is no correlation between SPF and the ability of sunscreen to prevent immunosuppression.122-127 SPF is a reflection of protection against erythema, a major biologic effect of UVB; UVA is known to play a significant role in immunosuppression. Immune protection factor is assessed by the ability of sunscreens to inhibit SSR-induced suppression of the induction arm of local contact hypersensitivity response, or the elicitation phase of delayed hypersensitivity response to recall antigens.123,125 Immune protection factor has a better correlation with the UVA protectiveness of sunscreen than with the SPF.122-127 At the time of this writing, a consensus statement on this topic is being developed.

UVA protection of sunscreen Currently there is no uniformly accepted standard method for measuring UVA protection of sunscreen.128 The more commonly used in vivo methods are IPD,129 PPD,130,131 and protection factor in UVA.132 Assessment of erythema induced after topical psolaren application and UVA exposure is no longer used because of concern for carcinogenicity. Among these methods, PPD is most commonly used because pigmentation remains stable between 2 and 24 hours, and it is sensitive for all UVA filters irrespective of their range of absorbency within the UVA range.131 Broad-spectrum protective effect can be evaluated in vitro by using spectrophotometry to assess the critical wavelength value, which is defined as the wavelength below which 90% of sunscreen’s UV absorbency occurs as measured at 290 to 400 nm.133 It has been demonstrated that critical wavelength value is commensurate with SPF.133 A consensus conference sponsored by the American Academy of Dermatology recommended that sunscreens with broad-spectrum label should have a critical wavelength of more than 370 nm, and a PPD or protection factor in UVA greater than 4.128 Factors affecting the efficacy of sunscreens There are several factors that interfere with the efficacy of sunscreens. The amount of sunscreen applied is the most important factor.134 It is known that in actual use, most people applied less than the amount used in testing (2 mg/cm2).135 A survey of sun protection behavior among beach goers in New England found an inadequate sunscreen application.136 It was also found that sunscreen application was inadequate for patients who are photosensitive. The overall median application thickness in general was only 0.5 mg/cm2; some sites such as back and sides of neck, temples, and ears were missed.137 Most sunscreen activity failure is caused by an inadequate application of sunscreen, and less than adequate frequency of reapplication.138 Because of its appearance, inorganic sunscreen is applied in a lesser amount than organic sunscreen, resulting in decreased efficacy. In a study of 25 volunteers, it was found that most people applied only two thirds the quantity of inorganic sunscreen compared with organic sunscreen; as such, inorganic sunscreen in actual use was estimated to provide half less SPF than organic sunscreen.139 Sunscreen on the skin may shed easily with rubbing, sweating, or water immersion. It has been recommended that sunscreen should be applied 20 minutes before sun exposure, and be reapplied every 2 to 3 hours after swimming or sweating. One study suggested applying sunscreen 15 to 30 minutes

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before going out to the sun, followed by reapplication 15 to 30 minutes after sun exposure to compensate for improper initial application.140 In another study, the protection against minimal UVR-induced erythema increases 3.1 times after a second application compared with the first application.141 Daily use of sunscreen is more protective against UV-induced skin changes than intermittent use of the same product.142 Another important factor is the effect of multiday sun exposure. Sensitivity to the sun increases on the second day of exposure, because UVB-induced erythema peaks at 24 hours; therefore, a higher SPF sunscreen is important for individuals who are expected to have multiday sun exposure. The use of sunscreen in childhood The importance of starting the use of sunscreen in childhood and teen-aged period was demonstrated in a study that estimated that regular use of sunscreen with an effective SPF of 7.5 for the first 18 years of life could reduce the lifetime incidence of nonmelanoma skin cancers by 78%.143 However, it should be emphasized that photoprotection should be done in all age group, because young people get about the same amount of UV exposure as those in other age groups, with older men getting the most exposure.144 The 1999 FDA Sunscreen Final Monograph recommends that physicians should be consulted for the use of sunscreen in children under 6 months of age,86 because their physiologic systems for metabolism and excretion of absorbed agents may not be fully developed.145,146 In our opinion, sun avoidance and the use of clothing and shade would be the most appropriate sun protection measures for this age group. When necessary, limited and infrequent use of sunscreen on exposed areas may be done. Sun protection practice and education In the United States, it was found that sun protection practices are still inadequate.147 A survey of 25,000 schoolchildren reported only 20% of them used sun protection regularly.148 In a survey published in 2000, most responders thought that children were too young to use sunscreen, and many still preferred tanned skin.149 The survey in day care centers found that although most of the caregivers were aware of the adverse effects of sun exposure and the need for sun protection, the use of sunscreen and protective clothing were limited.150 Although 100% of the surveyed day care centers stated that their staff applied sunscreen to the children, none applied it 15 to 30 minutes before taking the children

outside. Of the responders, 78% believed that sun exposure was related to temperature, and they applied sunscreen less frequently in autumn when it is cool, although the children still spent a large amount of time during the day in the sun.150 A telephone survey of 412 public elementary schools in the United States showed only 3.4% of the schools had sun protection policies, which included outdoor activities schedules designed to avoid sun exposure during the peak UVR period and the requirements for children to wear shirts with sleeves, hats with a brim, sunglasses, and sunscreen during outdoor activities. The most frequent reason cited for not having a policy was the lack of awareness of skin cancer problem, or the role that schools could play in preventing adverse sun exposure.151 In addition, existing policies in some schools discourage the use of personal sun protection by students. Most principals reported that students were outdoors between 10 AM and 2 PM, the daily period of peak UVR. Although 72.8% had shade structures, 67.3% reportedly covered less than one fifth of the ground.151 The Sunwise chool program, developed by the US Environmental Protection Agency, is the first national and health environmental education program for sun safety for children in elementary and middle schools. The goal is to provide sun protection education to at least 20% of the nation’s school by the year of 2005, to reduce the incidence of skin cancer and other UV-related health problems. The self-administered surveys by the students found that after the program, there was significant improvement of the understanding of the appropriate type of sunscreen to be used for outdoor play, UV index, and the need for hats and shirts when outdoors. Intentions to play in the shade increased, with more modest changes in intentions to use sunscreen. Attitudes regarding healthiness of a tan also decreased significantly.152 UV filters and photostability An ideal sunscreen should be stable photochemically, and dissolve or disperse easily and permanently in a vehicle. The more photolabile a filter, the more rapidly it is consumed after exposure to UVR.96,153 Photostability also depends on the filter, presence of other UV filters in the product, and solvent or vehicle. All UV filters, especially avobenzone,96 octinoxate (OMC), and octyl dimethyl PABA, are photolabile.153 Other UV filters are frequently used in the preparation as they are known to increase the photostability of the final product; these include ZnO, TiO2, octocrylene, the salicylates, and methylbenzylidene camphor.

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In the past few years, there are newly developed filters that are photostable. These include terephthalylidene dicamphor sulfonic acid (Mexoryl SX), drometriazole trisiloxane (Mexoryl XL), methylenebis-benzotriazoyl tetramethylbutylphenol (Tinosorb M), and bis-ethylhexyloxyphenol methoxyphenol triazine (Tinosorb S). Tinosorb has been used successfully to improve the photostability and efficacy of sunscreens containing avobenzone and ethylhexyl methoxycinnamate.96 Sunless tanning agent Agents that enhance skin pigmentation naturally have been shown to provide some photoprotection.154 Dihydroxy acetone (DHA), the active ingredient of sunless tanning preparations, can protect against UVA and the low end of visible region by its oxidation effect that changes skin color to orangebrown.85 The color remains adherent to the stratum corneum and is not easily washed off because it binds chemically to the stratum corneum,155 and it does not interfere with normal skin function.156 However, tanning induced by DHA results only in a SPF of 2. In the past few years, application of DHA as a spray has become popular. Currently, there are no data on the safety of potential inhalation of aerosolized DHA particles. Controversies concerning sunscreens Some sunscreens such as oxybenzone,93 PABA,157 padimate O,158 and TiO2159 have been reported to interact with the skin when exposed to the sun. They can be activated to produce free radicals, and consequently have the potential to damage cellular DNA. PABA-ester has been reported to penetrate human epidermis and may selectively damage melanocytes in the skin.160 There is controversy about mutagenicity of PABA and its derivatives; some studies stated that PABA is a weak mutagen, whereas others indicated that it is neither mutagenic nor photomutagenic.161 In vitro and in vivo studies of photogenotoxicity and cytotoxicity of PABA have been reviewed.88 It is known that all organic sunscreen agents may induce adverse effects such as irritant, allergic contact reaction, photoallergy, and phototoxic effects.161 Contact and photocontact sensitivity to sunscreens has been reviewed; currently, Bp-3, a commonly used UVA filter, is the most common photoallergen.162,163 UVA filters such as isopropyl dibenzoyl methane (Eusolex 8020; removed from the market in 1993),164 avobenzone (butyl methoxydibenzoyl methane; Parsol 1789),164-168 oxybenzone (Bp-3),169 and sulisobenzone (Bp-4), and

UVB filters such as PABA, padimate O (octyl dimethyl PABA), methylbenzylidene camphor,166 octinoxate (OMC), and ensulizole ( phenylbenzimidazole sulfonic acid)162,170 have all been reported to induce contact allergic and photoallergic reactions. It should be emphasized that considering the widespread use of sunscreen, contact and photocontact allergic reactions to sunscreen are uncommon.163 Although it has been reported that regular use of sunscreen can affect vitamin D synthesis in some persons171,172 several clinical trials have shown that long-term use of sunscreen had little or no effect on vitamin D levels, and did not induce secondary hyperparathyroidism or osteoporosis.173-175 Schlumpf et al176 reported in vivo and in vitro estrogenicity of UV filters. They found that UVB and UVA filters, specifically, Bp-3, homosalate, 4-methylbenzilidene camphor, OMC, and octyl dimethyl PABA, increased MCF-7 breast cancer cells proliferation in vitro; this effects can be blocked by estrogen antagonist in vitro. Using immature Long-Evans rats, in vivo uterotrophic assay showed that the uterine weight was dose-dependently increased by 4-methylbenzilidene camphor and OMC, and weakly by Bp-3 administered by oral route. Dermal application of 4-methylbenzilidene camphor to immature hairless rats also increased uterine weight. Another study found estrogenic effect of some hydroxylated intermediates of 2-hydroxy-4-methoxy-Bp in vitro.177 However, the endocrine effect of these UV filters is still controversial, and questions have been raised about the experimental models and techniques used.178 In addition, as analyzed by the Scientific Committee of Cosmetic Products and Non-Food Products, the European group based in Brussels, Belgium, the relative estrogenic potencies of the UV filters, both in vitro and in vivo, were about 1 million times less than that of the positive control substance, estradiol.179 The animal model used for the dermal application test was considered to be inappropriate. In the in vivo animal experiments, the topical exposure to UV filters was unrealistically high compared with potential human exposure scenarios; furthermore, important technical shortcomings were noted in the in vivo animal studies. Therefore, currently, the biologic relevance of the estrogenic effect of UV filters tested has not yet been established.

ANTIOXIDANTS The skin has an antioxidant defense mechanism to deal with UV-induced oxidative stress. However, when there is excessive sun exposure, the body may not be able to completely neutralize the free radicals generated by UV exposure, which can lead to

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photocarcinogenesis, immunosuppression, and photoaging. Examples of antioxidant enzymes are GSH peroxidase, catalase, and superoxide dismutase, whereas nonenzymatic antioxidants include GSH, alpha tocopherol, and beta carotene. Antioxidants have been administered both orally and topically; they are less potent than sunscreen in preventing sunburn.180 The advantage of oral administration is the ability to protect the entire skin surface without being affected by washing, perspiration, or rubbing. The limitation of topical antioxidants is their poor ability to diffuse into the epidermis. Moreover, they tend to be unstable, and the effectiveness depends on the concentration. Carotenoids, colorful compounds found in many plants, have antioxidant properties that can protect cells from oxidative damage; its oral supplementation has not been shown to be necessary in healthy individuals.181 Increasing macular carotenoids level by supplementation with lutein and zeaxanthin (the carotenoid of the macula) can protect against lightinduced retinal damage and aged-related macular degeneration.182 Beta carotene (120-180 mg/d) has been reported to diminish the photosensitivity in patients with erythropoietic protoporphyria,183-186 whereas it has little effect in healthy human beings.187 Beta carotene has also been shown to inhibit UVinduced carcinogenesis in mice.184,187 In a 4.5-year study involving 1383 patients in Australia, no beneficial effect of beta carotene was demonstrated for the prevention of the development of basal cell carcinoma; however, beta carotene was protective against the development of squamous cell carcinoma.114 Synergistic effects have been demonstrated by the combination of several antioxidants.188-190 Combination of high dosage of oral antioxidants, namely, 3 g/d of L-ascorbic acid (vitamin C) and 2 g/d of alpha tocopherol (vitamin E) for 50 days resulted in an increase in the MED to SSR; no increase was noted for patients treated with either of the antioxidants alone.189 In a subsequent study, the same group reported protection against SSR-induced suppression of contact hypersensitivity reaction to nickel sulfate in patients treated with the above combination of antioxidants, whereas no effect was noted on the reaction to a topical irritant.190 In healthy individuals, 6 months of daily oral supplementation with 400 IU of vitamin E did not result in any clinical or histologic protection in UV-induced skin damage.191 Topical antioxidants are inefficient UV filters and have low SPF; therefore, they are commonly used in combination with sunscreen to enhance their efficacy. Topical vitamin E provides photoprotection by both antioxidant and UV absorptive properties;

topical application of alpha tocopherol, the most biologically active form of vitamin E, has been shown to decrease UV-induced skin cancer in mice.192 When exposed to radiation, alpha tocopherol can convert to UV-absorbing dimer and trimer, that function similar to a sunscreen.193 However, unlike a typical sunscreen, topical alpha tocopherol did not prevent skin edema induced by UVR in mice.194 In a mouse model, only high doses of topical alpha tocopherol prevented SSR-induced reduction of epidermal Langerhans cell density and suppression of contact hypersensitivity by inhibiting epidermal lipid peroxidation.194 In mice, topical alpha tocopherol has been shown to suppress UVB-induced photocarcinogenesis and DNA photodamage by inhibiting thymidine dimer formation.195 Alpha tocopherol is retained within cells and nuclei; therefore, it produces significant protection against DNA photodamage.195 Other vitamin E compounds such as alpha tocopherol acetate, a common ingredient in commercially available sunscreen, have not been shown to be effective.195,196 Alpha tocopherol acetate has less photoprotective effect because of its lower absorptivity in UVB range. Furthermore, it does not convert to alpha tocopherol when absorbed into the skin.196 Topical vitamin C (L-ascorbic acid) can prevent erythema, sunburn cell formation, and psoralen-UVA (PUVA)-mediated phototoxic reactions.197 It has also been shown to prevent UV immunosuppression and prevent the suppression of contact hypersensitivity in animals. With appropriate formulation, topical vitamin C can penetrate the skin and increase the level in epidermis more than 20-fold. After 3 days of topical application, skin tissue is saturated, establishing a reservoir that has a measurable half-life of 4 days. Derivatives of vitamin C are stable, but they do not get into the skin nor are they converted to L-ascorbic acid. Similar to the synergistic effect observed with oral antioxidants, combination of topical vitamin C and E has been shown to be protective against the acute effects of SSR in animal models. Best protection was observed in animals treated with both agents; protective effect, albeit less, was also seen in animals treated with either agent alone.198,199

OTHER PHOTOPROTECTIVE AGENTS There are a number of other agents that have been shown to have photoprotective properties; most are in various stages of investigations. These are listed in Table III. Calcitriol (1,25-dihydroxyvitamin D3) is the active form of vitamin D. Topical application of calcitriol has been shown to inhibit UVB-induced sunburn cell

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Table III. Other photoprotective agents Agent

Source

Photoprotective properties

Calcitriol (1,25-dihydroxyvitamin D3)

Synthesized in kidneys

Caffeic acid and ferulic acid Polypodium leucotomos Zinc 2-Furildioxime Cadmium chloride Polyphenolic compounds Cistus Butyrated hydroxytoluene Isoflavones Isoflavone metabolites -Genistein

Plants and vegetables Plant extract Synthetic Synthetic Green tea Mediterranean shrubs Preservatives, additives Plants Soybean Red clover Plant Tamarind seeds

-Aloe poly/oligosaccharide N-acetylcysteine

Aloe barbadensis Synthetic

T4 endonuclease V Thymidine dinucleotide

Bacterial DNA excision enzyme Synthetic

Omega-3 polyunsaturated fatty acid Celecoxib

Fish oil

formation by inducing the expression of metallothionein (MT), a potent radical scavenger in mice skin.200 Caffeic acid and ferulic acid are two hydroxycinnamic acids largely present in plants (usually in seeds and leaves) and also in vegetable foods, such as olives and olive oil. Applied topically, both of them can protect against UVB-induced erythema in vivo and in vitro.201 Their photoprotective effect is correlated to their antioxidant/radical scavenging effectiveness. Ferulic acid is used as photoprotective ingredient in many skin lotions and sunscreens. Because of its potent antioxidant effect, it is frequently added to cosmetic lotion to prevent photodamage, and also added to foods to inhibit lipid peroxidation and oxidative spoilage.202 In human beings, oral and topical administration of extract of a plant, Polypodium leucotomos, is found to be photoprotective against PUVA-induced phototoxic reaction and pigmentary and histologic changes.203 In human beings and animal models, it exhibits antioxidant,204 anti-inflammatory, and pho-

Antioxidant and anti-inflammation Antioxidant Iron chelator Induction of metallothionein Antioxidant Free radical scavenging Synthetic antioxidant Antioxidant Protection against UV-induced inflammation and immunosuppression

-Equol Caffeine Plant oligosaccharides -Xyloglucans

Synthetic

Induction of metallothionein (scavenger of free radicals) Antioxidant and radial scavenging

Enhancement of apoptosis Prevention of UVB-induced systemic immunosuppression Increase of glutathione level (endogenous antioxidant) Repair of cyclobutane pyrimidine dimmer Enhancement of melanogenesis, increase of DNA repair Decrease of sunburn cell formation, antiinflammation Cyclooxygenase 2 inhibitor

toprotective properties against photo-oxidative stress induced by UVR, with and without the presence of the photosensitizing agent 8-methoxypsolaren.205 After topical and oral administration, P leucotomos was found to increase the UV dose required for IPD, MED, minimal melanogenic dose, and minimal phototoxic dose.206 It does not have absorption in either UVB or UVA range.205 Zinc, the important trace mineral for DNA protection against oxidative stress, has been shown to decrease UVA1-induced early and delayed apoptosis in human fibroblasts.207 Zinc supplementation protects against UVA-induced DNA damage in human skin fibroblasts.208-210 Divalent zinc ion, topical form of zinc, has been shown to provide antioxidant photoprotection for skin by two mechanisms; zinc ions may replace redox active molecules, such as iron and copper; alternatively, it may induce the synthesis of MTs, sulhydryl-rich proteins that protect against free radical.211,212 It has been shown to protect mouse skin again UVA- and UVB-induced sunburn cell formation.213

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Iron is known to produce photodamage by acting as a catalyst in oxygen free radical formation. Iron chelator 2-furildioxime (FDO) applied topically can prevent UV-induced erythema, sunburn cell formation, epidermal thickening, infiltration of inflammatory cells, and induction of epidermal ornithine decarboxylase.214 However, FDO does not have high SPF. Topical FDO is significantly more potent when combined with other UV filters, with the SPF increases from 4 (FDO alone) to over 30 (FDO plus SPF 4 sunscreen). FDO and sunscreen combination also can delay the onset of photocarcinogenesis and skin wrinkling in mice.215 The photoprotective capacity of cadmium chloride-induced MT, an antioxidant, has been shown both in vivo and in vitro. It was found that MT-null mice, which are deficient in MT-1 and MT-2 genes, developed greater number of sunburn and apoptotic cells than those observed in normal mice on exposure to UVB radiation.216 There are several antioxidants in plants that are commonly consumed by human beings. Dietary flavonoids and polyphenolic compounds are found in fruits (eg, blueberries, grapes, tomatoes, oranges, other citrus fruits), vegetables (eg, cucumber, broccoli), oils (eg, olive), and beverages (eg, green tea, red wine).20 Green tea, a popular beverage especially in Asian countries, contains polyphenolic compounds, which can inhibit UVR-induced skin erythema, carcinogenesis, and immunosuppression. These compounds also exhibit anti-inflammatory activity in animals and human beings when applied topically or administered orally.217-221 It has been demonstrated in animals and human beings that topical application of (-)- epigallocatechin-3-gallate, major polyphenolic compounds that are potent antioxidants in green tea, before UVB exposure can protect against UVB-induced reactive oxygen species-associated inflammation, photoaging, suppression of contact hypersensitivity, and photocarcinogenesis.217 This was associated with inhibition of UVB-induced infiltration of leukocytes, particularly CD11b-positive cells; UVB-induced increase in myeloperoxidase activity, a marker of leukocyte infiltration, was also suppressed. Epigallocatechin-3-gallate has also been reported to inhibit UV-induced lipid peroxidation, and to restore UV-induced decrease in GSH level.220 It can also prevent cyclobutane pyrimidine dimer formation222 and reduce prostaglandin metabolites, particularly PGE2, which plays a major role in skin tumor promotion.219 Green tea extracts also can prevent the acute effect of sunlight by decreasing the number of sunburn cells in a dose-dependent manner.223 It should be noted that green tea poly-

phenols has an absorption maxima at 273 nm; therefore, it does not function as a filter of UVB.223 Cistus includes many typical species of Mediterranean shrubs; it is used as antidiarrhetics and anti-inflammatory agents. It contains flavonoids that were considered to be chain-breaking antioxidants that interrupt the oxidative chain by reacting with intermediates and forming stable products. Crude aqueous leaf extracts from Cistus have free-radical scavenging capacity, and lipid peroxidation inhibition property in rat liver microsomes. They have been reported to offer excellent photoprotection for skin in mice.224 Dietary butylated hydroxytoluene is a synthetic antioxidant compound commonly used as a preservative in lipid-containing products (such as cosmetics), and as an additive in various foods. It has been shown to inhibit UV-induced erythema, ornithine decarboxylase activity, carcinogenesis, and photoagaing. The mechanism of action is not clearly known, but it is believed to decrease the dose of UVR reaching epidermal target sites by absorptive properties.225 Dietary butylated hydroxytoluene has been shown to provide protective effect equivalent to SPF of 3.2.226 The isoflavones that occur in many plants constitute a class of phytoestrogens and have modulating effects on estrogenic physiology; they are also effective antioxidants.227 Plant-derived isoflavone metabolites such as genistein from soybean and equol from red clover have been reported to protect against UVinduced inflammation and immunosuppression in a dose-dependent manner when applied topically on hairless mouse skin after UV exposure.227 Caffeine, applied topically to mice for 18 weeks after a 20-week exposure of these mice to UVB, resulted in markedly decrease in the formation of nonmalignant and malignant tumors.228 The mechanism has been shown to involve the ability of caffeine to enhance apoptosis in tumor tissues.229 Plant oligosaccharides such as xyloglucans from tamarind seeds and aloe poly/oligosaccharides from Aloe barbadensis have been shown to prevent UVBinduced systemic immune suppression by reducing IL-10 production in mice.230 The ability of aloe gel to prevent suppression of contact hypersensitivity decays rapidly after manufacture. In contrast, the protection against systemic suppression of DTH induced by aloe is stable over time.231 It is believed that aloe contains multiple immunoprotective factors that prevent UV-induced suppression of DTH, but the precise structure is not yet known. N-acetylcysteine (NAC) is an agent that increases the levels of glutathoine, an endogenous antioxidant. Topical application of NAC before UVB

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exposure can protect against immunosuppression in mice.232 Moreover, NAC has been shown to have antioxidant properties against UVA cytotoxicity in human fibroblasts.208 The mechanism of action is still not known; however, it has been reported that the photoprotective effect of NAC and glutathione ethylester did not correlate to GSH levels.233 UVB can induce immunosuppression by generating damage to DNA. Topical DNA repair enzymes, which convert cyclobutane dimers into their original DNA, have been used as photoprotective agent.234 This mechanism of action is different from that of sunscreen, which prevents photodamage by minimizing DNA damage. Photolyase, a DNA repair enzyme, is present in numerous prokaryocytes and eukaryocytes. When applied immediately after UVB exposure, it can decrease the number of UVBinduced dimers by 40% to 45% in human skin.235 T4 endonuclease V is a bacterial DNA excision repair enzyme that specifically repairs cyclobutane pyrimidine dimers in DNA. When prepared in liposome form (as T4N5 liposomes) and used as topical treatment, it was able to remove dimers in DNA in the epidermis of animals and human beings, and nearly completely prevented UV-induced upregulation of IL-10 and tumor necrosis factor-alpha messenger RNAs.236 Treatment of patients with DNA repair deficient disorder such as xeroderma pigmentosum resulted in increasing the removal of DNA damage in the skin in the first few hours after treatment.237 Topical application of T4N5 for 1 year lowered the rate of development of actinic keratoses and basal cell carcinomas for patients with xeroderma pigmentosum.238 Application of T4N5 immediately after UV exposure partially protects against sunburn cell formation, local suppression of contact hypersensitivity, and suppression of DTH. However, it has little or no effect on UV-induced skin edema.239 UV irradiation generates short DNA fragments during the course of excision repair process. One such small single stranded DNA fragments, thymidine dinucleotides, has been extensively studied. It can mimic cellular responses to UVR including enhanced melanogenesis,240-243 increased DNA repair and reversible cell growth arrest,240,244 increased tumor necrosis factor-alpha expression and secretion, and induction of IL-10 expression in keratinocytes.243 Some of these effects are mediated through activation of p53244 and increased messenger RNA levels for the responsible proteins, consistent with transcriptional upregulation. In human fibroblasts, it has been reported that pretreatment with thymidine dinucleotide primes these cells to develop UV-protective response through activation of p53 and p53-

up-regulated proteins, which in turns participate in protective response such as enhanced DNA repair. Therefore, pretreatment with thymidine dinucleotides enables the cells to response more efficiently to subsequent UVR without the requirement for prior DNA damage.245 Fish oil, which is rich in omega-3 polyunsaturated fatty acid, has been shown to have photoprotection effect. In clinical trial, there was decreased UVBinduced sunburn cell formation and inflammation after 3 months of fish oil ingestion. Furthermore, ingestion of fish oil was shown to reduce UVA provocation response; therefore, it has been recommended to be used in patients with polymorphous light eruption.246 However, because of the relatively large amount of fish oil that needs to be ingested to get the desired effect, and the availability of other effective therapy for polymorphous light eruption, fish oil is not widely used in the management of this condition. In mice, after chronic UVB exposure, intensed expression of cyclo-oxygenase 2 has been demonstrated in squamous cell carcinoma induced by such treatment. Increased cyclo-oxygenase 2 expression has also been reported in human actinic keratoses, squamous cell carcinoma, and basal cell carcinoma.247 Oral administration of celecoxib, a cyclooxygenase 2 inhibitor, has been shown to decrease UVB-induced photocarcinogenesis in hairless mouse model.248 Repeated suberythemal dose UVR exposure could augment photoprotection by increasing the thickness of stratum corneum and melanin pigment content; the latter would occur most prominently in people whose skin tans easily. However, the effects are not long lasting. Another method to promote epidermal thickness and tanning is by using PUVA, which produces more sustained effects. PUVA-induced photoprotection is a rationale for its use in the management of various photosensitive diseases.97

SUMMARY Much progress on photoprotection has been made since PABA was patented in 1943. At present, recommended photoprotective measures include sun avoidance during the peak UVR (10 AM-4 PM), the use of photoprotective clothing, wide-brimmed hat, sunglasses, and the use of broad-spectrum sunscreens. There are many other agents with photoprotective properties, which range from antioxidants to plant extracts to DNA repair enzymes. Continued investigations in this area should result in the development of even more effective photoprotective agents in the future.

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