Sunscreens and Photoprotection

Mechanism of Action

UV radiation greatly affects the skin, causing aging, sunburns, precancerous and cancerous lesions, and immunosuppression.[5] UV radiation has an immunosuppressive effect on the antigen-presenting cells within the epidermis and contributes to the likelihood of skin cancer.[4] There are three types of UV radiation: UVC, UVB, and UVA. The ozone layer absorbs 100% of UVC, 90% of UVB, and a minimal amount of UVA. For this reason, the depletion of the ozone layer increases UV transmission. UVA is associated with aging and pigmentation. It penetrates deep into the skin layer and produces free radical oxygen species, indirectly damaging DNA. UVA increases the number of inflammatory cells in the dermis and decreases the number of antigen-presenting cells.[6] UVB causes sunburn and DNA strand breaks. It causes pyrimidine dimer mutations, which are associated with nonmelanoma skin cancers.[7] 

Photoprotection involves both primary and secondary protective factors. Primary factors are sunscreens; these include physical barriers that reflect and scatter light and chemical barriers that absorb light. Secondary factors include antioxidants, osmolytes, and DNA repair enzymes, which help to limit skin damage by disturbing the photochemical cascade that occurs with UV sunlight.[5] 

Chemical sunscreens are known as organic sunscreens. Their mechanism of action is based on their chemical structure involving an aromatic compound conjugated with a carbonyl group. This structure allows high-energy UV rays to be absorbed, causing the molecule to achieve an excited state. As the molecule returns to the ground state, it will release the lower energy of longer wavelengths. The specific range of wavelength a sunscreen absorbs will vary. Chemical sunscreens consist of UVA and UVB blockers. UVB filters absorb the entire spectrum of UVB radiation (290 to 320 nm). UVA filters do not cover the entire spectrum of UVA radiation. Uva radiation is divided into UVA I (340 to 400 nm) and UVA II (320 to 340nm). Broad-spectrum sunscreens absorb UV radiation from both the UVA and UVB portions.[8]

UVB Blockers

• Aminobenzoates
• Cinnamates
• Salicylates
• Octocrylene
• Ensulizole
• Camphor derivatives

Aminobenzoates are the most potent UVB absorber but do not absorb UVA. Their use has declined due to para-aminobenzoic acid (PABA) sensitivity. PABA is a very effective UVB filter; however, it was reportedly the most common photoallergen and contact allergen. For this reason, it has limited use in sunscreen. Padimate O is the most commonly used PABA derivative; it has a good safety profile and is an effective UVB filter.[3]

Cinnamates have replaced PABA as the next most potent UVB absorber and include octinoxate (OMC) and cinoxate.[5] Octinoxate is the most commonly used UVB filter in the United States. It is not as potent a UVB absorber as padimate O; for this reason, other UVB absorbers are used in combination to increase the SPF. Octinaxate is not very photostable and degrades in the presence of sunlight after a short period. Cinnoxate is a less common choice.[3]

Salicylates are used in high concentrations as they are weak UVB absorbers. They are also used to increase the effect of other UVB filters. Two salicylates that are FDA listed are homosalate and octisalate. They function to decrease the photodegradation of other UV filters, such as oxybenzone and avobenzone. A water-soluble salicylate is trolamine salicylate.[3]

Octocrylene is a very safe chemical associated with a decreased likelihood of irritation, phototoxicity, and photoallergic potential.[9] When combined with other UV absorbers, it can increase the SPF formula.[5]

Ensulizole is a pure UVB filter and does nothing that affects UVA. It is a water-soluble compound commonly used in cosmetics for a lighter, less oily feel.[5] 

Camphor derivatives are not FDA-listed but are moderately effective UVB filters. A camphor derivative that is also a broad UVA filter is terephthalyidene dicamphor sulfonic acid.[3]

UVA Blockers

• Benzophenones
• Anthranilates
• Avobenzones
• Ecamsule

Typical benzophenones absorb mostly UVB; however, oxybenzone is considered a broad spectrum absorber as it can absorb UVA II as well.[5] It is the most commonly used benzophenone.[3] However, out of all the sunscreens, oxybenzone has the greatest likelihood of inducing contact or photo contact dermatitis. Oxybenzone is not considered photostable, and although not scientifically proven yet, there is a concern about carcinogenic and endocrine adverse effects.[5] Other FDA-listed benzophenones include sulisobenzone and dioxybenzone.[3] 

Anthranilates are very weak UVB and UVA filters and are less effective than benzophenones. As a result, clinicians rarely use them.[3]

Avobenzones are considered broad-spectrum and have high efficacy against UVA I (>380 nm); however, they are very photo-unstable and lose from 50% to 90% of their particles after 1 hour of UV exposure. There are also reports that they degrade the UV filter octinoxate. UV absorbers such as octocrylene, benzophenones, salicylates, camphor derivatives, and micronized zinc oxide or titanium dioxide are used in combination to increase photostability.[3]

Ecamsule contains terephthalyidene dicamphor sulfonic acid, a very photostable product that is water-resistant with low systemic absorption. In animal studies, it prevented UVA-induced photoaging.[3]

Broad-spectrum sunscreens include methylene-bis-benzotriazolyl tetramethylbutylphenol (MBBT) and bis- ethylhexyloxyphenol methoxyphenyl triazine (BEMT). MBBT is advantageous as it is a large molecule that decreases the likelihood of systemic absorption or endocrine effects. It works as a combination of organic and inorganic filters, ultimately absorbing, scattering, and reflecting UV radiation. It decreases UVA transmission more than UVB. BEMT also does not affect the endocrine system and is photostable.[5]  

The mechanism of action of a physical sunscreen has its basis on the reflection and scattering of UV light in much the same way as clothing. The reflective properties determine the effectiveness of the sunscreens. These properties include the reflective index, the size of the particles, the film thickness, and the dispersion of the base—the higher the reflective index, the better the UV filter. Decreasing the size of the particles to a micronized form (10 to 50 nm) is more cosmetically appealing but leads to the protection of shorter wavelengths and increases the risk of systemic absorption.[8] A thick coating increases the degree of reflection but is cosmetically less appealing. Iron oxide can be an additive to increase absorption and improve UVA protection. Physical sunscreens consist of zinc oxide and titanium dioxide.[3]

Microfine zinc oxide protects against a wide range of UVA, including UVA 1 (340 to 400 nm). It is very photostable and does not react with other UV filters. It is more effective than titanium dioxide for UVA protection; however, it is less efficient against UVB radiation.[3][5]

Microfine titanium dioxide protects against UVA 2 (315 to 340 nm) and UVB but does not protect against UVA 1, as does zinc oxide.[5] It has a smaller particle size and higher refractive index than zinc oxide, causing it to appear white and making it cosmetically less appealing. Photochemical reactions cause zinc oxide and titanium dioxide to become less effective as a sunscreen. For this reason, silica and dimethicone coat these particles, stabilizing these inorganic filters.[3] 

As mentioned above, secondary photoprotection includes antioxidants, osmolytes, and DNA-repair enzymes, which help to limit skin damage by disturbing the photochemical cascade that occurs with UV sunlight. The mechanism of action of antioxidants is to reduce the reactive oxygen species (ROS) produced from UVA radiation. Naturally, these ROS become neutralized by antioxidants found naturally within the body, such as superoxide dismutase and catalase. These enzymes can become saturated within an overproduction of reactive oxygen species, resulting in a deficiency of antioxidants and damage to proteins and DNA. Topical antioxidants function from within the cell to decrease the shortage of antioxidants and can remain active for several days after application.[10][5]  

Many sunscreens include antioxidants such as vitamin C, vitamin E, silymarin, and green tea polyphenols. Vitamin C acts to protect against UV- damage, which results in sunburn and erythema.[5][11] Vitamin E has many protective actions, such as decreasing immunosuppression, erythema, photoaging, and photocarcinogenesis.[5][12][13][14] Silymarin comes from milk thistle plants, functioning to prevent lipid and lipoprotein oxidation and acting as a scavenger of reactive oxygen species. Topical application results in a decrease in UVB-induced sunburn cells and a reduction in the amount of UVB-induced pyrimidine dimers. In mice, it has been shown to reduce the amount of UVB-induced tumors.[15] Green tea polyphenols contain antioxidants that are more potent than vitamin C and E. They are anti-inflammatory and anti-carcinogenic. They function to scavenge singlet oxygen, superoxide radicals, hydroxyl radicals, peroxyl radicals, and hydrogen peroxide.[16]

Osmolytes are small molecules that stabilize the cell in stressful conditions by regulating hydration. Taurine and ectoine are osmolytes that protect against many UV effects and are components in many sunscreens.[5][17][18]

Administration

Sunscreen should be applied topically. Correct administration is key to the effectiveness of use. A liberal uniform film of sunscreen should be applied, and the application should be 15 minutes before sun exposure. The adequate amount to apply is 2 mg/cm^2, equivalent to 30 mL/ body application. Sunscreen should be reapplied every 2 hours and after sweating or swimming.[2]

Clothing is a form of photoprotection, which can be measured using the UV protection factor.[5] This metric measures the transmission of UVA and UVB through a given fabric. In animal studies, research showed a UPF over 30 to protect against erythema and premalignant lesions. Whether the fabric is wet or dry may increase or decrease UPF based on the type of fabric. Light-colored fabrics have decreased UPF compared to dark-colored fabrics.[3]  Overall, clothing provides a balanced amount of protection against both UVA and UVB, and a loose-fitting colored fabric is the best form of photoprotection.[5]

Hats are a variable form of photoprotection dependent on the brim width, material, and weaving. A hat with a brim width of more than 7.5 cm has an SPF of 7 for the nose, 5 for the neck, 3 for the cheeks, and 2 for the chin. A hat with a brim width of 2.5 to 7.5 cm has an SPF of 3 for the nose, 2 for the neck and cheek, and 0 for the chin. A hat with a brim of less than 2.5 cm has an SPF of 1.5 for the nose and a minimal amount for the chin and neck.[3]

The pigment content of makeup provides an SPF of 3 to 4, even if there is no sunscreen included; however, this photoprotective effect is lost 4 hours after application. Many foundations now include UV filters to provide photoprotection.[3] 

Sunglasses are a form of photoprotection for the eyes. Sun exposure can result in many eye conditions, such as cataracts, which direct result from sun exposure, specifically UVB radiation. Chronic exposure results in the formation of cataracts and eye cancer. Sunglasses should absorb 99% to 100% of the full UV spectrum. Contact lenses can also provide photoprotection for the ocular lens; however, they do not protect the anterior portion of the eye.[3] 

Car windshields offer UV protection. The Federal Motor Vehicle Safety Standard No. 205 mandates that the tinted glass in cars provide no less than 70% transmission of visible radiation. The windshields of cars contain zinc, chrome, nickel, and other metals which block UV radiation. The windshield of the vehicle is more photoprotective than the side window glass of the automobile.[3]

Adverse Effects

Adverse effects of sunscreen include four types of contact dermatitis: irritant, allergic, phototoxic, and photoallergic.[8] In Germany, a 15-year study of patch and photo patch testing demonstrated that the most common reaction to sunscreen is a nonimmune-based irritant response.[2] The most common UV filters that cause adverse effects are benzophenones and dibenzoylmethanes, with the most common photoallergen being benzophenone-3 (BP-3), as it is a derivative of PABA. For this reason, benzophenone 3 is not used frequently in the United States.[2]  Some studies have associated sunscreen use with melanoma due to the users' false sense of security, which may increase the duration in the sun, resulting in UVA formation and malignant changes.[8] Phototoxic and allergic contact dermatitis are usually the results of UVA (320 to 400 nm) and visible light ranges (400 to 800 nm). UVA is capable of penetrating the reticular dermis and is the cause of most photosensitivity reactions.[19]

An American study revealed that UV filters are the most common cause of positive photo patch testing.[20] Risk factors that can lead to sunscreen allergy are unknown but are more likely to be sex, prior photodermatosis, use of sunscreen on damaged skin, working outdoors, and atopy. It was previously a concern that regular sunscreen use would result in vitamin D deficiency; however, vitamin D levels are not significantly affected by the regular use of sunscreen.[2]

The adverse effects of physical sunscreen are due to the usage of nanoparticles, which have a more beneficial cosmetic effect. The increased surface area of nanoparticles can result in a greater level of catalytic reactions, increasing the production of free radicals and damage to DNA and proteins. These smaller particles can form complexes with the protein that can behave as haptens, inducing autoimmune conditions.[5][21]

Three observations led to the review of animal and human studies regarding the adverse effects of UV filters:

• An increase in sunscreen use
• An increase in the incidence of malignant melanoma
• An increase in experimental studies demonstrating UV filters have adverse endocrine effects

In vivo and in vitro animal studies have shown multiple potential adverse effects of UV filters within sunscreen. These adverse effects include endocrine dysfunction of the reproductive and developmental systems. The UV filters of concern include BP-3, 4-MBC, and OMC. An anti-estrogenic effect was strongly associated with BP-3 as well as 3-BC, 4 MBC, and OMC. This finding was based on the uterine weight of immature rats. UV filters demonstrated the anti-estrogenic effect of HMS, OD-PABA, and PABA in yeast expressing human estrogen receptor a. After exposure to UV filters, 3-BC, and 4—MBC, there was a delay in male puberty and reduced prostate weight. The mechanism of action behind the reproductive toxicity may be due to alterations in proteins of the gene expression of estrogen receptor, androgen receptor, progesterone receptor, insulin-like growth factor I, complement proteins, nuclear receptor co-repressor, and steroid receptor coactivator 1 in the uterus and prostate. In a 90-day study with BP-3, fertility was affected in male mice. This finding was demonstrated by decreased sperm density in a dose-related manner following dermal exposure in mice and oral exposure in mice and rats.[20]

Experimental studies in humans have demonstrated an increased permeability of the UV filters BP-3, 4 MBC, and OMC. Levels were detectable in the plasma 1 to 2 hours after exposure. The study also demonstrated a difference in concentration based on gender. Male urine and plasma concentration samples were higher than female samples. A Swiss study of human breast milk revealed that 85% of the sample contained UV filters. Bisphenol and BP-3 share a similar chemical structure. Bisphenol can cross the blood-placenta barrier, so the assumption is that BP-3 can also cross the placenta. An increased concentration of BP-3 in a mother's urine was associated with decreased birth weight in girls and increased birth weight and head circumference in boys.[20]

Contraindications

Although photoprotection is indicated in all age groups, the 1999 FDA Sunscreen Final Monograph recommended that parents of children under the age of 6 months should consult a physician before sunscreen administration in this age group. This recommendation is due to the lack of infant metabolism development and excretion of the chemically absorbed agents within sunscreen. If sunscreen is necessary, it should be limited and infrequently used on sun-exposed areas of the body only.[3]

Monitoring

The FDA regards and regulates sunscreen as an over-the-counter medication. The efficacy of sunscreen is determined by UVB protection, which is measured by the sun protection factor (SPF) and substantivity. SPF is the ratio of the smallest dose of UVB radiation required to produce minimal erythema on sunscreen-protected skin compared to the necessary dose of UVB to produce the same amount of erythema on non-protected skin. SPF is a better predictor of protection against UVB since it is 1000 times more erythemagenic than UVA. An SPF-15 can block 94% of UVB radiation, while an SPF-30 can block 97% of UVB radiation.[3] Substantivity is the ability of a sunscreen to withstand adverse conditions such as water and sweat. The FDA has defined terminology to label substantivity. Water-resistant refers to a 40 minute time interval of maintained photoprotection with water immersion and moderate activity. Very water-resistant refers to effectiveness for 80 minutes. Both terms can qualify as sweat-resistant.[5]

Toxicity

Regarding contact dermatitis, the first step is to avoid the causative agent. Patch testing can help identify the etiologic agent. The results of patch testing can be listed on the American Contact Dermatitis Society website, which can provide patients with a list of non-allergenic products that can be used. Treatment includes topical steroids for local reactions. Severe reactions require the use of systemic steroids. If oral steroids are ineffective, immunosuppressants such as oral cyclosporine, methotrexate, or mycophenolate mofetil a. For mild-to-moderate dermatitis, calcineurin inhibitors, pimecrolimus, and tacrolimus are options.[8]

With photoallergy and phototoxicity, UVA radiation is usually a requirement to precipitate the reaction. The patient should avoid the etiologic agent, but if avoidance is not possible, the patient should avoid direct sunlight and tanning beds and wear protective clothing and non-allergenic sunscreen.[8]

Barrier creams and high-lipid moisturizers can help to prevent and improve irritant contact dermatitis.[8]

Enhancing Healthcare Team Outcomes

An estimated 1 million new cases of nonmelanoma skin cancer occur every year. The numbers have increased significantly over the last 20 years within the United States and Europe. A research survey completed in 2005 revealed limited awareness of nonmelanoma skin cancer and prevention in the U.S., Australia, and Europe. For most individuals, healthcare providers are not the primary source of information for sun protection measures. The media plays a significantly influential role; however, there is minimal long-term behavioral change. These findings support the importance of engaging healthcare professionals to increase patient education regarding photoprotection and its role in preventing nonmelanoma skin cancer.[22] 

This is where a coordinated interprofessional effort from the interprofessional healthcare team, including clinicians, nurses, and pharmacists, can help patients avoid UV exposure and protect their skin. Since retail pharmacists are uniquely positioned where sun protection products are sold and can also see if the patient is taking any medications with potential phototoxicity, they can exert a significant influence in this regard. Nurses can also counsel patients, and all team members should be aware of patients with fair skin, who present with significant or frequent burns, or who have a high level of UV exposure because of work. WIth a coordinated interprofessional effort, patients can achieve the best outcomes with the fewest adverse events. [Level 5]