The sunscreen industry is achieving remarkable worldwide prominence by responding to the growing need for skin protection with fast-paced innovation. Increased consumer awareness of the harmful effects of sunlight has fueled the demand for improved photo protection. The need for broad-spectrum protection from both UVA and UVB rays has inspired scientists worldwide to research new cosmetic formulations and delivery systems. More effective sunscreen actives, emollients and novel cosmetic and functional ingredients have been regularly added to the formulator’s repertoire. Creativity in innovation has been hindered only by regulatory agencies and patent restrictions worldwide. Familiarity with the current restrictive regulations and patent law infringements has become integral to any research effort attempting to provide improved protection to individuals affected by the sun’s damaging effects. The increasing incidence of skin cancers and photo damaging effects caused by ultraviolet radiation has increased the use of sun screening agents, which have shown beneficial effects in reducing the symptoms and reoccurrence of these problems. Unlike the situation in Europe where sunscreen ingredients are considered under cosmetics guidelines, the FDA is required to define sunscreens as drugs since they are advertised to prevent sunburn and, more recently, the risk of skin cancer. In the USA, the FDA has been regulating this industry since August 25, 1978, with the publication of the Advance Notice of Proposed Rulemaking. Sunscreens are considered drugs and cosmetics and therefore must be governed by the FDA-OTC monograph. With the variety of sunscreen agents used in cosmetic and UV protection products, Australia, Canada, and the European Union (EU) have also developed regulatory protocols on safe sunscreen product use. Unlike the USA though, Australia has approved 34 active sunscreen ingredients and the EU has approved 28 of these ingredients. Current FDA regulations allow labeling of sunscreen products to a maximum of 30þ, despite the many products currently available with numbers as high as 100. From a cosmetic formulation point of view, increasing the SPF number in a product is governed by simple chemical principles.

 

Keywords: Melanoma, Carcinoma, Immunosuppression, Retinoids, Tretinoin, Photodamage

BACKGROUND

Ra (Re) was the primary name of the sun god of Ancient Egypt. According to Osiris myth, Nut, the mother of Osiris swallowed the setting sun (Ra) each evening and gave birth to him each morning. The Ancient Egyptians were well aware of the dangers of the sun. Their lands were scorched with heat. Women protected their skin, preferring light skin to dark in their cultural hierarchy of beauty. Recent discoveries written on papyri and the walls of several tombs unearthed ingredients and formulations in use in Ancient Egypt specifically addressing issues of sun damage to the hair and skin. Also, a brief historical review manifests the following interesting things indeed (Figure 1):

INTRODUCTION

Protection from sunlight is often equated with use of sunscreens, but this approach is too narrow, and protection should consist of a package of measures: avoiding overexposure to sunlight, using sunscreens, and wearing protective clothing. Solar ultraviolet (UV) radiation significantly influences the skin, causing aging, sunburns, precancerous and cancerous lesions and immunosuppression. UV radiation has an immunosuppressive effect on the antigen-presenting cells within the epidermis and contributes to the likelihood of skin cancer. If solar radiation is a primary risk factor for malignant melanoma, it is reasonable to conclude that reducing sun exposure via topical sunscreen use would be associated with reduced disease risk. Melanoma is more common in Whites than in Blacks and Asians. The incidence of non-melanoma skin cancer (NMSC) is dramatically increasing worldwide, despite the increased use of improved sunscreens. In 2014, the Surgeon General estimated that 2.2-5.0 million people were treated annually for NMSC. As the number of newly diagnosed skin cancers continues to rise, there is a need for additional preventative measures beyond sunscreens. UV radiation is the second most prevalent carcinogenic exposure in Canada, fifth in Switzerland and is similarly important in other countries with large Caucasian populations. Within the UK, Wales has among the highest rates of skin cancer annually and skin cancer diagnosis rates have increased 63% in 10 years. Australia and New Zealand having the world's highest skin cancers. People living in Australia and New Zealand are now advised to apply sunscreen every day when the UV index is predicted to reach 3 or above. Denmark has one of the highest incidences of melanoma in the world, although it is a relatively northern country. Implications for public health: Increased use of sunscreen as part of the daily routine to reduce incidental sun exposure will lead to decreased incidence of skin cancer in the future. There are 3 kinds of UV radiation: UVC, UVB, and UVA. The ozone layer ingests 100% of UVC, 90% of UVB and a negligible measure of UVA. Therefore, exhaustion of the ozone layer expands UV transmission. UVA is related with aging and pigmentation. It enters profound into the skin layer and creates free extreme oxygen species, in a roundabout way damaging DNA. UVA expands the quantity of incendiary cells in the dermis and diminishes the quantity of antigens introducing cells. UVB causes sunburn and DNA strand breaks. It causes pyrimidine dimer changes which are related with non-melanoma skin malignancies. Photo protection includes both essential and secondary protective variables. Essential variables are sunscreens; these incorporate physical barriers which reflect and dissipate light and substance barriers which ingest light. Secondary components incorporate cancer prevention agents, osmolytes and DNA repair enzymes which help to constrain skin harm by exasperating the photochemical cascade that happens by UV sunlight. People with black skin are much less susceptible to sunburn than white-skinned individuals. Black people living in the UK were more likely to use sunscreen as a form of sun protection, whereas sunscreen was the least popular modality in the two African countries with shade being the most common form of limiting sun exposure. A significant benefit from regular sunscreen use has not yet been demonstrated for primary prevention of basal cell carcinoma and melanoma. Concerning the prevention of actinic keratoses, squamous cell carcinomas, and skin aging, the effect of sunscreens is significant, but it remains incomplete. Some organic UV filters (PABA derivatives, cinnamates, benzophenones and octocrylene) have been described to cause photo allergy. Percutaneous absorption and endocrine disrupting activity of small-sized organic and nano-sized inorganic UV filters have been reported.

POSITIVE EFFECTS OF UVR

Exposure to UVR is not always considered bad. In fact, UVR has been found to be particularly helpful in treating vitamin D deficiency, seasonal affective disorders, psoriasis, sarcoidosis, mycosis fungoides and numerous other cutaneous conditions. Within the epidermis, 7-dehydrocholesterol is converted to vitamin D (cholecalciferol) by UVB light. The elderly and young children are the ones who are particularly susceptible to vitamin D deficiency. Vitamin D deficiency can lead to rickets in children, osteomalacia in adults, osteopenia/osteoporosis, and factures in the elderly. The Institute of Medicine recommends the following vitamin D allowances: 400 IU for 0 to 12 months, 600 IU for 1 to 70 years and 800 IU for greater than 70 years. Light therapy is an inexpensive treatment and can be beneficial in treating certain diseases. Although it has been known for the last 100 years that UV light (particularly UVC with a wavelength range of 240-280 nm) is highly germicidal, its use to treat wound or other localized infections remains at an early stage of development. Candida auris is globally emerging yeast, causing severe infections in patients with underlying diseases. This yeast is responsible for several outbreaks within healthcare facilities, where it can be found on hospital surfaces and patient care devices. Spread from these fomites may be prevented by improving the decontamination of hospital surfaces. UV-C decontamination may constitute an effective adjunct to routine room cleaning. Additionally, difficult-to-treat psoriasis patients sometimes find relief with UVR. It is thought that UVR has both anti-proliferative and anti-inflammatory effects through down regulation of T-cell response to antigens. Studies have also shown improvement of the cutaneous effects of sarcoidosis with UVA-1 light and topical psoralen plus UVA (PUVA) therapy. PUVA and narrowband UVB has been shown to induce and maintain remissions of mycosis fungoides. Phototherapy is the use of light for reducing the concentration of bilirubin in the body of infants. However, the exposure to UV in childhood has been established as an important contributing factor for melanoma risk in adults and considering the high susceptibility to UV-induced skin damage of the new-born, related to his pigmentary traits, the UV exposure of the infant during phototherapy should be “as low as reasonably achievable,” considering that it is unnecessary to the therapy. Protective eyewear can be necessary during new-born assistance activities carried out in proximity of some sources. Most people judge sun exposure in non-erythemic doses as pleasant. Exposure to sunlight has been linked to improved energy and elevated mood. Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly occurs during autumn or winter and remits in spring. The prevalence of SAD ranges from 1.5% to 9%, depending on latitude. Evidence on light therapy as preventive treatment for patients with a history of SAD is limited, preventive treatment of SAD and the treatment selected should be strongly based on patient preferences. Light therapy, an effective treatment for seasonal affective disorder (SAD), may also be appropriate for MDD which is the second-ranked cause of disability worldwide. Bright light treatment, both as monotherapy and in combination with fluoxetine, was efficacious and well tolerated in the treatment of adults with non-seasonal MDD. The combination treatment had the most consistent effects [77-83].

SUNBURN

Sunburn and sunscreen facts

·         Sunburn and sun poisoning are forms of skin damage due to UV ray exposure. The symptoms can range from mild to severe and may require treatment.

·         Sunburn might be sun poisoning if there is blisters, hives or rash, fever and chills, nausea, dehydration, headache, pain and tingling, vision problems [1].

·         UV rays are most intense at noon and the hours immediately before and after (between 10 AM and 4 PM) [2-10].

·         Immediate symptoms of sunburn are hot, red, tender skin; pain when the skin is touched or rubbed; and dehydration; several days after exposure the skin may swell, blister and peel [3].

·         Most sunburns are mild and can be treated with home remedies such as applying damp cloths or compresses to reduce the pain, soaking in a tepid bath (with no soap), gently patting the skin dry, applying soothing creams or lotions, OTC pain relievers such as Tylenol or others, and moisturizing the skin [4].

·         Sunburn may cause permanent skin damage and skin cancer (malignant melanoma, basal cell carcinoma, squamous cell carcinoma) [5].

·         Persons with certain pigment disorders and individuals with fair skin are at most risk of sunburn [6].

·         Certain diseases and conditions pose a higher risk of sunburn (for example, albinism, lupus, porphyria, vitiligo and xeroderma pigmentosum) [7].

·         Some medications may increase sensitivity to sunburn (photosensitivity) [8,10].

·         Sun poisoning is caused by severe sunburn; its symptoms include fever, nausea, chills, dizziness, rapid pulse, rapid breathing, dehydration and shock [9].

·         UVA and UVB are mainly responsible for skin pathologies such as sunburns, cutaneous degeneration, photosensitivity, phototoxicity, photo-aging, immunosuppression and skin cancer [11-27].

·         Snow reflects up to 80% of the sun’s rays, sand reflects 15%, and grass, soil and water reflect 10%. Due to these factors, an individual sitting under a solitary standard beach umbrella can be exposed to up to 84% of the total UV radiation despite feeling adequately covered. For these reasons, it is best to seek deep shade [28].

·         Less than 50% of the SPF number claimed on the label is spread on the consumer's skin, meaning that a sunscreen with an SPF 30 will give the real protection of an SPF of 15. Therefore, SPF 60 should be recommended if real protection of 30 is desired. Significant injury, DNA damage, mutations and carcinogenesis can and do occur also with cumulative sub-erythemal UV exposure [29].

·         The SPF was created in 1956 by Schulze and it reflects the ratio between the lower amounts of UV energy required producing a minimal erythema on sunscreen protected skin and the amount of energy required to produce the same erythema on unprotected skin [30,31].

·         Since many of UV filters were shown to cross the blood-brain barrier (BBB), the risk for neurotoxicity also occurs [32-37].

·         Sunscreen compounds might block vitamin D synthesis or act as endocrine disruptor and lead to developmental toxicity. The effects of sunscreen on cutaneous synthesis of vitamin D induced by sunlight have been a subject of debate for recent years; however the newest analysis suggests that normal usage of sunscreen by adults do not decrease cutaneous synthesis of vitamin D [38].

·         The FDA is notoriously slow in approving sunscreen compounds, requiring exhaustive evidence of their safety. Indeed, FDA has approved only 16 sunscreen ingredients (14 organic filters and two nonorganic filters, including zinc oxide and titanium dioxide), while other areas of the world, like the European Union and Australia, have approved nearly twice as many [39].

·         FDA approved sunscreen ingredients are Aminobenzoic acid, Avobenzone, Cinoxate, Dioxybenzone, Homosalate, Meradimate, Octocrylene, Octinoxate, Octisalate, Oxybenzone, Padimate O, Ensulizole, Sulisobenzone, Titanium dioxide, Trolamine salicylate and Zinc oxide [40-44].

·         2 of the 16 main ingredients used in OTC sunblock products are safe, the FDA said. Moreover, the FDA is requesting more information on 12 ingredients among the 16 [45].

·         The FDA has changed its guidelines to address broad-spectrum sunscreen use, which involves UV-A and UV-B coverage; water resistance, to indicate the time duration the sunscreen is effective; and sun protection factor (SPF). SPF-15 or higher is recommended and can be labeled as reducing the risk of skin cancer and early skin aging [40].

·         PABA and trolamine salicylate — are not GRASE for use in sunscreens, are no longer permitted for use in OTC sunscreen products. No sunscreens sold in the United States contain PABA or trolamine salicylate [41,42].

·         For a decade, Environmental Working Group (EWG) has worked to raise concerns about sunscreens with oxybenzone, which is found in nearly all Americans, detected in breast milk and potentially causing endocrine disruption [43].

·         Hawaii recently enacted legislation that will ban the use of two major ingredients -oxybenzone and octinoxate-that have also been implicated in coral toxicity and will be banned. This creates a healthcare dilemma: Will the protection of coral reefs result in an increase in human skin cancers? [46-51].

Sunburn: Pathophysiology

Sunburn is a radiation burn to the skin caused by too much exposure to the sun’s UV rays or artificial sources such as tanning beds. Chronic sun exposure creates premature cutaneous aging, decreases immune response to environmental pathogens and increases the risk for developing premalignant and malignant neoplasms [52-77]. The biggest risk factors for sunburn are the amount of time the skin is exposed to UV rays, plus the intensity. Many factors such as time of day, medications, ozone depletion, high altitude, clear skies and skin phototypes influence sunburns [11]. Exposure to solar radiation has the beneficial effects of stimulating the cutaneous synthesis of vitamin D and providing radiant warmth. Unfortunately, when the skin is subjected to excessive radiation in the ultraviolet range, deleterious effects may occur. The most conspicuous is acute sunburn or solar erythema. Initially, UVR causes vasodilation of cutaneous blood vessels, resulting in the characteristic erythema. Within 1 h of UVR exposure, mast cells release preformed mediators including histamine, serotonin and tumor necrosis factor, leading to prostaglandin and leukotriene synthesis. Within 2 h after UV exposure, damage to epidermal skin cells is seen. Erythema usually occurs 3-4 h after exposure, with peak levels at 24 h [12]. Sunburns are graded as pink, red, and blistering. In contrast, thermal burns are graded by degree (first, second and third), but this classification should not be applied to sunburns because thermal burns have quite different sequelae, such as scarring and death, which are extremely rare consequences of sunburn. Keratoconjunctivitis or ocular sunburn can also be caused by UV radiation, and it follows a similar time course [13]. Studies have shown that UVA impairs the antigen presenting cell (APC) activity of the epidermal cells and thereby causes immune suppression, thus contributing to the growth of skin cancer [30]. In summary, UVA radiation can cause nuclear and mitochondrial DNA damage, gene mutations and skin cancer, dysregulation of enzymatic chain reactions, immune suppression, lipid peroxidation (membrane damage) and photoallergic and phototoxic effects.

On the molecular level, exposure to UV radiation can result in a covalent joining of pyrimidine (usually thymine) dimers. DNA repair mechanisms, such as nucleotide excision repair, base excision repair, or mismatch repair genes, do not recognize dimers; the mutations go uncorrected to the cell cycle. When mutated genes reach the cell cycle, if not repaired by the induction of the p53 pathway, a series of changes can result in malignant transformation and immunosupression. UV-induced immunosuppression contributes to skin cancer due to damage to DNA and inhibition of protective mechanism within the skin (Figure 2). A common type of sun-related skin damage is actinic keratosis (AK). Age, Fitzpatrick skin type 1 or 2 (Exhibit 1), and UV light are the major risk factors for developing AK. Most AKs do not progress into invasive squamous cell carcinoma (SCC), but the risk is still present. The risk of malignant transformation of an AK to SCC within one year is approximately 1 in 1,000. However, approximately 60% of invasive SCCs of the skin probably arise from AKs. If not treated or protected against additional sun damage, AKs may eventually progress to invasive SCC. Avoiding sun exposure and daily application of sunscreen statistically decreases the number of AKs [77].

The diagnosis of SCC has increased over the past 30 years. The most important risk factor for SCC is cumulative sun damage and age; the risk was greatest in those with more than 30,000 hours of cumulative lifetime sun exposure. UVA, UVB, PUVA and tanning beds have been shown to increase the incidence of cutaneous SCC. Prevention of SCC includes protection from the sun, including the use of protective clothing and application of sunscreen. Basal cell carcinoma (BCC) is the most common skin cancer and occurs most frequently on the face and head. In Caucasians, the incidence of BCC has steadily increased and the lifetime risk of developing BCC is 30% [78-86]. BCC arises from the basal layer of epidermis and its appendages. The most important risk factor is chronic UVR. Other known risk factors include fair skin, light eyes, red hair, chronic arsenic exposure, therapeutic radiation, immunosuppression, basal cell nevus syndrome and various other genetic pre-dispositions. Primary prevention is protection from sun exposure beginning at an early age [77]. Other than UVR, exposure to arsenic, radiation, chronic inflammatory conditions in skin and burns, scars, infections complications or even tattoos are also the contributing factors for BCC [87-96] (Figure 3).

Epidemiological analysis reveals that annually in the United States alone, ~5 million skin cancer patients are treated, and that between 40 and 50% of Americans are susceptible to develop skin cancer at least once by the age of 65 [96]. More than 90% of melanoma cases in the United States are attributed to skin cell damage from UV radiation exposure. Skin cancer is the most common form of cancer, representing 40-50% of all cancers diagnosed in the US. Melanoma is the most serious form of skin cancer. Melanoma is responsible for the most skin cancer deaths, with about 9,000 persons dying from it each year [84]. Despite early screening and detection programs, the overall mortality rate from melanoma has remained stable or continues to rise. The incidence of melanoma has more than tripled in the Caucasian population in the United States over the past 30 years. An estimated 60-70% of cutaneous malignant melanomas are thought to be caused by UV radiation exposure. Two types of UV radiation are primarily responsible for causing carcinogenic skin damage: UVA (315 nm-400 nm) and UVB (280 nm-315 nm) [85]. Intense and intermittent sun exposure at a young age increases a patient's risk of melanoma. Individuals with five or more severe sunburns in childhood or adolescence have an estimated twofold greater risk of developing melanoma. Melanoma is commonly found on areas sporadically exposed to UVR, such as the back of the legs in women and the backs of men. UVB, UVA and PUVA therapy all have been proven to increase the risk of melanoma. Appropriate UVR protection decreases the risk of developing a melanoma or having a secondary melanoma. Studies indicate that decreasing recreational sun exposure following the diagnosis of primary melanoma can significantly decrease the chance of developing a second melanoma [77] (Exhibit 2).

The sun care industry

The U.S. sun care market size was estimated at USD 1.95 billion in 2016. The growing consumer awareness regarding the ill-effects of over exposure to ultraviolet (UV) rays on the undefended skin is expected to propel growth. Furthermore, rising utilization of organic sun care products owing to absence of synthetic chemicals in the formulation is expected to drive growth over the forecast period. The sunscreen manufacturers are actively using these formulations as it increases the endurance of skin cells against UV rays and enhances the self-defence mechanism. Enhanced standard of living coupled with increasing disposable income of the middle-class working population in economies of North America, including the U.S., is expected to propel sun care market growth over the forecast period. The industry players including L’Oréal are using nanotechnology by manipulating the materials at an atomic or molecular in order to enhance the efficiency of the product. Over the past five years, the Sunscreen Manufacturing industry has grown by 1.6% to reach revenue of $407m in 2018. In the same timeframe, the number of businesses has grown by 3.9% and the number of employees has grown by 1.5% [178-180].

CLASSIFICATION OF SUNSCREENS

Sunscreens are classically divided into physical or chemical sunscreens. Chemical sunscreen absorbs into the skin and then absorbs UV rays, converts the rays into heat and releases them from the body. Physical blockers are inorganic and reflect, scatter and/or absorb UVR. Physical UV absorbers like titanium dioxide and zinc oxide have been considered as highly protective agents against UVR. ZnO and TiO₂ combinations are particularly valuable because of their ability to filter both UVA and UVB radiations, providing broader UVR protection than that observed with individual component [95]. They are used in sunscreens as nanoparticles, which denotes a size <100 nm. The smaller size of these mineral particles increases their cosmetic acceptability by users as they are much less visible after application. ZnO has a broad UVA-UVB absorption curve, while TiO₂ provides better UVB protection. Overall, the human health risks with inorganic filters are extremely low given a lack of percutaneous absorption; however, there is potential risk when exposed via inhalation, prompting recommendations against spray sunscreen products with nanoparticles [111]. UV-A rays heavily contribute to both premature skin aging and skin cancer, while UV-B rays cause sunburn. Hence, the use of sunscreen is strongly encouraged by many healthcare practitioners in order to minimize or possibly eradicate the harmful effects of UV rays on our skin, keeping in mind, that about 90% of all skin cancers are associated with exposure to the sun’s harmful radiation. Protection against both UVB and UVA radiation is advocated. Most sunscreens combine chemical UV absorbing sunscreens and physical inorganic sunscreens, which reflect UV, to provide broad-spectrum protection. The correct use of sunscreens should be combined with the avoidance of midday sun and the wearing of protective clothing and glasses, as part of an overall sun protection regimen [94,95]. Unfortunately, inaccurate information is currently roaming the media and the Internet regarding the safety, toxicity, and acute side effects of the active ingredients currently used in sunscreens, therefore discouraging people from using sunscreens [92]. Chemical sunscreens are organic and generally aromatic compounds conjugated with a carbonyl group. They are designed to absorb high-intensity UVR, produce excitation to a higher energy state, and, with the return to the ground state, result in conversion of the absorbed energy into a longer, lower energy wavelength. Chemical sunscreens can be classified based on their portion of UV coverage. Commonly known ingredients for UVB sunscreen protection are Padimate O, octinoxate, octisalate, octocrylene and ensulizole. Commonly known Studies reveal that Persistent Pigment Darkening (PPD) to be a stable end point inducible by all the UVA wavelengths, not affected by fluence rate, i.e., a reliable endogenous UVA dosimeter in the skin [89]. Problems associated with chemical sunscreens are: (i) Requires about 20 min after application before it starts to work; (ii) Chemical sunscreens may cause side effects, such as erythema, edema and irritation (especially for those who have dry skin with a damaged moisture barrier) due to the multiple ingredients combined in order to achieve broad spectrum UVA and UVB protection; (iii) The higher the SPF (such as formulas of SPF 50 or greater), the higher the risk of irritation for sensitive skin types; (iv) The protection it offers gets used up more quickly when in direct UV light, so re-application must be more frequent. (v) Increased chance of redness for rosacea-prone skin types because it changes UV rays into heat which can exacerbate flushing; (vi) May clog pores for oily skin types [93]. The importance of adequate UVA protection has become apparent in recent years. The United States and Europe have different standards for assessing UVA protection in sunscreen products. The majority of tested sunscreens offered adequate UVA protection according to US Food and Drug Administration guidelines for broad-spectrum status, but almost half of the sunscreens tested did not pass standards set in the European Union. UVA sunscreen ingredients are oxybenzone, meradimate, avobenzene and tetraphthalydine dicamphor sulfonic acid [90,91]. Broad spectrum is a term designed to mean protection from both UVA and UVB. Problems associated with physical sunscreens are: (i) Can rub off, sweat off and rinse off easily, meaning more frequent re-application when outdoors as needed; (ii) The physical sunscreen agents impart high opacity to the topical preparation, which makes the formulated creams cosmetically unacceptable and leave a whitish layer on the skin, making some formulas incompatible for medium to dark skin tones; (iii) Can be less protective if not applied and re-applied generously and accurately since UV light can get between the sunscreen molecules and get into the skin [93]. There are few reports available on the application of Polymeric Nanoparticles (NPs) of physical and chemical sunscreen ingredients (titanium dioxide, zinc oxide, octyl methoxycinnamate, oxybenzone, octocrylene and luteolinon) to improve sun protection efficacy. UV-absorbing agents must accumulate within the upper skin layers in order to provide a dense light-absorbing layer and guarantee water resistance. Incorporation of antioxidants could provide additional benefit by scavenging free radicals. Natural polyphenols are attractive in this respect, due to their potential activity as photoprotectans and antioxidants [95].

FDA APPROVED SUNSCREEN INGREDIENTS: LITERATURE REVIEW

Aminobenzoic acid

Aminobenzoic acid is a Vitamin B Complex Member. The chemical classification of aminobenzoic acid is Vitamin B Complex Compounds. In 1943, p-aminobenzoic acid (PABA) was patented. Red petrolatum was used by the United States military as a sunblock during World War II. The initial compounds were primarily ultraviolet B radiation (UVB) blockers as it was to blame for the most observable effect, sunburn [48]. When exposed to light, aminobenzoic acid (para-aminobenzoic acid or PABA) absorbs UV light and emits excess energy via a photochemical reaction that may cause damage to DNA. Because DNA defects contribute to skin cancer, aminobenzoic acid is no longer widely used in sunscreen formulations. Aminobenzoic acid may also increase oxygen uptake at the tissue level and may enhance monoamine oxidase (MAO) activity to promote the degradation of serotonin, which in excess, may lead to fibrotic changes [46]. 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 (Figure 8) [47]. 

Avobenzone

UVA blockers, considered broad spectrum and have a high efficacy against UVA I (>380 nm); however, they are very photounstable and lose from 50% to 90% of their particles after 1 h of UV exposure. It is also reported that they degrade the UV filter octinoxate [40,59]. Avobenzone is the most widely used UVA filter in sunscreen lotion and it is prone to degradation in the presence of sunlight/UV radiation, they show a significant skin penetration [56]. 30% HPCD-Avobenzone system was the most photostable following UVA exposure at various regimens and also enabled photoprotective efficiency in vivo, evidenced by lower levels of sunburn cells and skin edema induction [60]. To overcome the photo-instability of avobenzone, various photostabilizers have been used as additives, including antioxidants such as vitamin C, vitamin E and ubiquinone. The dual role of glutathione as a skin whitening agent and a photostabilizer of avobenzone may be useful for the development of multipurpose cosmetic lotions [49]. Avobenzone is dibenzoyl methane derivative. It is oil soluble crystalline solid [50,58]. Mesoporous silicas (MSs) containing avobenzone or oxybenzone effectively ameliorated UVA-induced skin disruption and reduced the possible toxicity elicited by percutaneous penetration [56]. Photosensitization by drugs is a problem of increasing importance in modern life. This phenomenon occurs when a chemical substance in the skin is exposed to sunlight. Photosensitizing drugs are reported to cause severe skin dermatitis, and indeed, it is generally advised to avoid sunbathing and to apply sunscreen. In this context, the NSAID diclofenac is a photosensitive drug, especially when administered in topical form. avobenzone provides partial photoprotection to diclofenac from photocyclization to carbazole derivatives [52]. Avobenzone is widely used in various personal care products, is present in swimming pools, and is toxic to aquatic organisms. Avobenzone induces mitochondrial dysfunction-mediated apoptosis leading to abnormal placentation during early pregnancy [53]. Avobenzone was more unstable/toxic than octyl p-methoxycinnamate (an organic UV-B filter originally developed in the 1950s, has been one of the most widely used sunscreens for decades) [54,55]. Octocrylene helps stabilize avobenzone, which is good, but it is a known endocrine disruptor that also releases free radicals (Figure 9) [57].

Oxybenzone

Oxybenzone is a benzophenone derivative used as a sunscreen agent. Oxybenzone absorbs UVB and UVA II rays, resulting in a photochemical excitation and absorption of energy [116]. Oxybenzone (Benzophenone-3) is an emerging human and environmental contaminant used in sunscreens and personal care products to help minimize the damaging effects of ultraviolet radiation. The Center for Disease Control (CDC) fourth national report on human exposure to environmental chemicals demonstrated that approximately 97% of the people tested have oxybenzone present in their urine, and independent scientists have reported various concentrations in waterways and fish worldwide. Oxybenzone can also react with chlorine, producing hazardous by-products that can concentrate in swimming pools and wastewater treatment plants. Moreover, adverse reactions could very well be increased by the closed loop of ingesting fish contaminated with oxybenzone and/or washing the ingredient off our bodies and having it return in drinking water as treatment plants do not effectively remove the chemical as part of their processing protocols. In humans, oxybenzone has been reported to produce contact and photocontact allergy reactions, implemented as a possible endocrine disruptor and has been linked to Hirschsprung's disease. Environmentally, oxybenzone has been shown to produce a variety of toxic reactions in coral and fish ranging from reef bleaching to mortality (Figure 10) [117].

Dioxybenzone

Dioxybenzone is an approved sunscreen ingredient in concentrations up to 3% [67]. The benzophenone sunscreens, octabenzone (UV-1) and dioxybenzone (UV-2) were found to exhibit significant chemopreventive activity against mouse skin carcinogenesis which correlated with their antioxidant potency [63]. In a study aimed to qualify photo-safety screening, benzophenone derivatives and ketoprofen exhibited significant reactive oxygen species (ROS) generation upon exposure to simulated sunlight; however ROS generation from sulisobenzone and dioxybenzone was negligible [68]. Polymerization with natural polymer pullulan not only provides a long polymer backbone to dioxybenzone, but also keeps the distance between benzene rings of the dioxybenzone and prevents reduction of photoabsorption intensity. UV/Vis spectrophotometry confirmed that dioxybenzone-pullulan polymer and dioxybenzone demonstrated similar UV absorption. Dioxybenzone showed higher plasma concentration after multiple applications compared to that of dioxybenzone-pullulan polymer [64]. Chlorine is used as a chemical disinfectant in swimming pools. Its reactivity suggests sunscreen components might be chlorinated, altering their absorptive and/or cytotoxic properties. Chlorinated oxybenzone and dioxybenzone (caused significantly more cell death than unchlorinated controls. In contrast, chlorination of sulisobenzone actually reduced cytotoxicity of the parent compound. Exposing a commercially available sunscreen product to chlorine also resulted in decreased UV absorbance, loss of UV protection, and enhanced cytotoxicity [65]. Bromal hydrate was also detected as one of the byproducts generated by oxybenzone and dioxybenzone, which is highly toxic; the “positive halogen” properties of bromal hydrate are responsible for its high toxicity [66]. In addition to allergic reactions, concerns have been raised about the relative ease of which benzophenone is absorbed into the skin and may promote generation of potentially harmful free radicals (Figure 11) [69].

Cinoxate

Ester derivatives such as ethylhexyl methoxycinnamate (octinoxate), isoamyl p-methoxycinnamte (amiloxiate), octocrylene and cinoxate are used in cosmetics all over the world as UV filters. However, their maximum concentrations in cosmetic products are restricted due to their adverse effects, which include contact and a photocontact allergies, phototoxic contact dermatitis, contact dermatitis, estrogenic modulation and generation of reactive oxygen species. 4-hydroxycinnamic acid, which is currently indexed as a skin-conditioning cosmetics ingredient, has been widely tested in vitro and in vivo as a new drug candidate for the treatment of hyperpigmentation [61]. Cinnamates have replaced PABA as the next most potent UVB absorber and include octinoxate (OMC) and cinoxate (2-ethoxyethyl-methoxycinnamate). Cinoxate is less commonly used [62]. Major Key players with cinoxate are Major Key Players are Parchem (US), Carbosynth Limited (UK), Synchem UG & Co. KG (DE) (Figure 12) [110].

Octinoxate

Octinoxate (Octyl Methoxycinnamate, OMC) is a cinnamate ester and common ingredient in sunscreen and other skin care products to minimize DNA photodamage. It was originally developed in 1950's as an organic UV-B filter that absorbs UV-B rays from sun. It is often combined with nanoparticles or other water-resistant liposomes in formulations to increase the localization at the epidermis and decrease the risk of percutaneous absorption [105]. OMC is the most commonly used UVB filter in the US. 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. OMC is not very photostable and degrades in the presence of sunlight after a short period of time. OMC is a potent UVB absorber and is the most frequently used sunscreen ingredient. The efficacy of OMC can be further increased when encapsulated in polymethyl methacrylate microsphere [62]. Due to low water solubility (<1 mg/L), OMC is suitable for most waterproof sunscreen formulations [106]. Hawaii legislature passed a bill that outlaws products that contain Oxybenzone and OMC, effective January 2021. The bill is based on studies that show that oxybenzone may harm coral larvae and that both compounds may “bleach” coral, causing it to lose symbiotic algae [107-109]. OMC has been detected in human urine, blood and breast milk, which indicates that humans are systemically exposed to this compound. OMC is an endocrine disruptor that mimics estrogen and can disrupt thyroid function (Figure 13) [112,113]. 

Homosalate

Homomenthyl salicylate or 3,3,5-Trimethylcyclohexyl Salicylate. After topical application of gel, the bioavailability of HMS was 5.4 ± 1.1 and 4.2 ± 0.6% for high and low doses (10 and 20 mg), respectively. Homosalate (HMS) is an UV filtering agent used in sunscreens and other cosmetics for skin protection purposes. It is a viscous or light yellow to slightly tan liquid or oil, derives from salicylic acid [70,71]. Salicylates are weak UVB absorbers and they are generally used in combination with other UV filters. Both octisalate and homosalate are water insoluble that leads to their high substantivity, which is the ability to retain its effectiveness after exposure to water and perspiration [72]. HMS does not have endocrine disruptor effects on thyroid function and the pubertal development of female and male rats [73]. Another study says HMS is a potential endocrine disruptor and studies in cells suggest it may impact hormones. In addition to direct health concerns following homosalate exposure, the chemical may also enhance the absorption of pesticides in the body [75]. Homosalate suppressed the ear edema response to dinitrobenzene; a possible mechanism of action of the salicylates is suppression of COX (Figure 14) [114].

Octisalate

Also, Ethylhexyl salicylate, a benzoate ester and a member of phenols. It derives from a salicylic acid. Salicylates are weaker UVB absorbers. It has an approved usage level of 3 to 5% in both US and EU and is a good solubilizer for benzophenone 3. In suntan lotions, it is used as a preservative and antimicrobial. This salicylate salt is found in wintergreen leaves [115]. They have a long history of use but were supplanted by the more efficient PABA and cinnamate derivatives. They are generally used to augment other UVB absorbers. With the trend to higher SPFs, more octisalate or octyl salicylate (ethylhexyl salicylate) is being used followed by homosalate or homomenthyl salicylate. Both materials have the ability to solubilize oxybenzone and avobenzone [97]. Both homosalate and octisalate were found to suppress experimental autoimmune encephalomyelitis (EAE), a widely used animal model of Multiple sclerosis (MS). Thus, salates may be useful new insight into mechanisms of controlling autoimmune disease (Figure 15) [114].

Meradimate (menthyl anthranilate)

Meradimate, before known as menthyl anthranilate, is used in a maximal concentration of 5% in different products as a UV filter. It is currently required to be named as meradimate in all FDA approved OTC products. Meradimate is approved by the FDA and Health Canada to be used as an ingredient in sun blocking products Meradimate is a monoterpenoid, a broad-spectrum ultraviolet absorber used as a chemical filter in commercial sunscreens [76]. A moderately effective UVA protector not permitted for use in Europe or Japan. Its protective effective action does not cover completely the UVA rays as it only reaches 336 nm. This has been proven even though meradimate has a theoretical protective coverage range between 200-380 nm. Its function is related to the intrinsic structure of meradimate which is an ortho-disubstituted aminobenzoate. This structure allows easy electron delocalization and shifts in the maximum absorption. Poor photoprotection reported by Rodrigues et al. [76] makes it a poor choice for an efficient, efficacious sunscreen chemical filter (Figure 16).

Octocrylene

2-Ethylhexyl-2-cyano-3,3 diphenylacrylate or octocrylene is chemically related to cinnamates. It can be used to boost SPF and improve water resistance in a given formulation. Octocrylene is photostable and can improve the photostability of other sunscreens. It is expensive and can present difficulties in formulation [97]. The absorption profile of octocrylene spans from 290 to 360 nm with peak absorption at 307 nm. The compound has an excellent safety profile with low irritation, phototoxicity, and photoallergic potential. Octocrylene may be used in combination with other UV absorbers to achieve higher SPF formulas and to add stability. [62]. Photostability refers to the ability of a molecule to remain intact with irradiation. Photostability is potentially a problem with all UV filters. This issue been raised specifically with avobenzone. This effect may degrade other sunscreens in a formulation, including octyl methoxycinnamate. Octocrylene and some of the newer sunscreens, including BEMT, stabilized avobenzone [97]. Chlorination reactions showed that only octocrylene was stable in chlorinated seawater [66]. UVA and UVB screening potentials of octocrylene and zinc oxide formulations were compared in the 290-400 nm wavelength region. Zinc oxide loaded SLN suspensions were found to be more effective in the UVA region while octocrylene loaded ones performed better in the UVB region [98]. Octocrylene appears to be a strong allergen leading to contact dermatitis in children and mostly photoallergic contact dermatitis in adults with an often-associated history of photoallergy from ketoprofen. Patients with photoallergy from ketoprofen frequently have positive photopatch test reactions to octocrylene. These patients need to be informed of sunscreen products not containing octocrylene, benzophenone-3, or fragrances [99,100]. The clinical studies show that octocrylene is both a photocontact allergen and a contact allergen [103]. Octocrylene's ability to cause contact allergy is probably attributable to its reactivity towards lysine [101]. A reduction of the UV filter in the formulation packed in HDPE/LDPE material can occur over time, reducing the protective effect of the product when applied to the skin [102]. Wide application in cosmetics leads to contamination of the aquatic environment, mainly affects transcription of genes related to developmental processes in the brain and liver as well as metabolic processes in the liver (bioaccumulation study in male zebrafish) (Figure 17) [104].

Padimate O

Padimate A and Padimate O were introduced as substitutes for PABA to reduce the number of reactions seen with PABA. Ethylhexyl dimethyl PABA is also known as padimate O, OD-PABA or octyl dimethyl p-aminobenzoate. It is a viscous liquid tends to retain on the surface of the stratum corneum with little penetration. It has a very low potential for sensitization. Ester derivatives of PABA became more popular with greater compatibility in a variety of more substantive vehicles and a lower potential for staining or adverse reactions. Padimate O is an active sunscreen agent in cosmetics and over-the-counter sunscreen drug products in concentrations up to 8%, as regulated by the FDA. No irritation was reported when both eyes are washed and left unattended. 5% ethylhexyl dimethyl PABA mixed with mineral oil applied to rabbit skin did not cause irritation and no skin sensitization in guinea pigs with the same. High concentrations of padimate O may be toxic to the epididymis and caution should be exercised when administering this substance to infants younger than six months of age due lack of understanding of its metabolism and absorption. It is widely used as an ingredient in many cosmetics at an average concentration of 1.25% (0.5-2.0%) in Korea. It is toxic to the following four organs: testis, epididymis, spleen, and liver. In addition, experiments using human keratinocytes found that ethylhexyl dimethyl PABA inhibits cell growth and DNA synthesis at low concentrations, and halted the cell cycle of malignant melanoma cell line (MM96L) at the G1 phase. According to the EWG database, it is used in many products including lipstick, conditioner, shampoo, anti-aging agents, hair spray, and sunscreen. No significant reproductive toxicity, genotoxicity, carcinogenicity, skin sensitization, skin irritation or phototoxicity was observed in response to Padimate O administration (limited studies there, requires further investigations) (Figure 18) [97,118,119].

Ensulizole

2-phenylbenzimidazole-5-sulfonic acid/ Phenylbenzimadazole sulfonic acid or ensulizole is a water-soluble UVB absorber that can be used in the water phase of emulsion systems. It is commonly found in cosmetic products and sunscreen formulas in combination with other UV filter compounds due to its minimal protection against UV-A wavelengths, indicated to be used as an UV-B-absorbing molecule in sunscreen formulations. In contrast to most oil-soluble sunscreen ingredients, allowing for a less-greasy, more aesthetically pleasing formulation such as a daily use moisturizer containing sunscreen. Phenybenzimidazole sulfonic acid boosts the SPF of organic and inorganic sunscreens. It can also be used in clear gels owing to its water solubility. Due to its water solubility, ensulizole is commonly used in products formulated to feel light and less oily. It was demonstrated by studies that ensulizole treatment provided protection against cyclobutane pyrimidine dimers and photosensitized the formation of oxidized guanine bases after UV-A or UV-B exposure. According to the FDA, the maximal approved concentration of ensulizole is 148 mM although concentrations ranging between 74 and 148 mM can be found in commercial sunscreen products. Ensulizole is capable of generating reactive oxygen species, including singlet oxygen upon photoexcitation. Based on the findings in vitro and in cellulo, ensulizole induces damage on the DNA, causes DNA strand breaks and photosensitizes the formation of oxidized guanines via type I and II photosensitization mechanisms following UV-A or UV-B irradiation (Figure 19) [87,120-125].

Sulisobenzone

A benzophenone does not undergo decomposition to an inactive form if it does not couple to target molecules. Instead, it degrades from the photo-excited state back to its initial state, so it can be once again photolyzed to an active state. This process increases the likelihood that the benzophenone will couple to a target molecule during the photoreaction. Benzophenones are used as photoinitiators, fragrance enhancers, ultraviolet curing agents, and, occasionally, as flavor ingredients; they are also used in the manufacture of insecticides, agricultural chemicals, and pharmaceuticals and as an additive for plastics, coatings, and adhesives. The UV-filter substance Sulisobenzone (BP-4) is widely employed in sunscreens and other personal care products. Sulisobenzone is approved by the FDA in concentrations of up to 10% and in Canada, is approved by Health Canada at the same concentrations. It works to filter out both UVA and UVB rays, protecting the skin from sun UV damage. The benzophenones are a group of aromatic ketones that have both pharmaceutical and industrial applications. Benzophenones may be found organically in fruits such as grapes, used primarily as a UVA absorber, but boosts SPF values in combination with other UVB absorbers. Sulisobenzone water soluble, somewhat unstable, and used with less frequency. It can cause skin and eye irritation. Does not penetrate the skin to a large degree, but enhances the ability of other chemicals to penetrate. Safety use in sunscreen is questionable (Figure 20) [88,126-130].

Trolamine salicylate

Trolamine salicylate is an organic compound or a salt formed between triethanolamine and salicylic acid. Triethanolamine neutralizes the acidity of the salicylic acid. It is a topical analgesic used for temporary relief of minor pain associated with arthritis, simple backache, muscle strains, sprains, and bruises. Unlike other topical analgesics, trolamine salicylate has no distinct odor which improves patient acceptability. Trolamine or triethanolamine salicylate has good water solubility. It is mostly used for water soluble sunscreens to help increase the SPF of cosmetics owing to their substantivity to the skin. It also displays low systemic absorption upon dermal or topical administration and has low skin irritant properties. Approved in both the US and Canada, trolamine salicylate is used in concentrations of up to 12%. It filters UVB rays, but has no effect on UVA rays, which means it cannot be relied on alone as a sunscreen. It has found to cause photocontact dermatitis (Figure 21) [106,131,132].

SUNSCREEN VS. CORAL REEF

While covering less than 1% of the ocean surface, coral reefs provide habitat for nearly one third of marine fish species as well as 10% of all fish captured for human consumption. Coral reefs also provide major essential benefits to people, like food production, tourism, biotechnology development, and coastal protection. There is strong evidence that some sunscreen ingredients, especially oxybenzone, are harmful to corals if the concentration in water is high. In some situations, primarily related to the number of swimmers and the geography of the shoreline, concentrations of oxybenzone far exceed the levels shown to be harmful to corals [181]. In 2015, the non-profit Haereticus Environmental Laboratory surveyed Trunk Bay beach on St. John, where visitors ranged from 2,000 to 5,000 swimmers daily, and estimated over 6,000 pounds of sunscreen was deposited on the reef annually. The same year, it found an average of 412 pounds of sunscreen was deposited daily on the reef at Hanauma Bay, a popular snorkeling destination in Oahu (Hawaii) that draws an average of 2,600 swimmers each day. Over the past three years, one-fifth of the world’s coral reefs have died off — and there is a growing awareness that sunscreen is playing a role. From 6,000 to 14,000 tons of sunscreen slide off of humans into coral reef areas each year, exposing the gorgeous underwater ecosystems to chemicals that can kill them. Global warming is the main reason that coral reefs are dying — but sunscreens play a role, too [182]. Danovaro et al. [184] revealed that sunscreens, by promoting viral infection, potentially play an important role in coral bleaching in areas prone to high levels of recreational use by humans. Coral bleaching has negative impacts on biodiversity and functioning of reef ecosystems and their production of goods and services. This increasing world-wide phenomenon is associated with temperature anomalies, high irradiance, pollution, and bacterial diseases. Hard-coral bleaching and the increase in viral abundance in seawater were also seen after coral treatment with mitomycin C, an antibiotic commonly used to induce the lytic cycle in latent viral infections [184]. Unfortunately, the World Conservation Institute estimates that 20% of coral reefs are already destroyed, another 25% are in great immediate threat, and another 25% will be threatened by 2050 [185].

Epilogue

The skin stratum corneum acts as a barrier that isolates the organism from the environment and avoids water loss from tissues. Such a sealed sheath is essential for the physiological processes of the skin and of the entire body, but poses problems for the topical delivery of substances to the tissues. This kind of hindrance has been known since ancient times and has been empirically approached, e.g. by the use of greasy or oily materials in skin care applications. Technological achievements in the topical administrations of medicaments and in skin care products have led to the development of vehicles and penetration enhancer and to the design of technologically advanced formulations. Although synthetic chemical structures have been abundantly used in this field, traditional practices and scientific studies have shown through the years that botanical sources can provide all kinds of elements for vehiculating drugs and active compounds and for enhancing their permeation through the skin. There is wide variability in price, SPF protection, and product claims among commercially available sunscreens. Cosmetic elegance is one of the most important positive features, followed by product performance. Dermatologists should counsel patients that sunscreen products come with numerous marketing claims and varying cosmetic applicability, all of which must be balanced with adequate photoprotection. In addition, consumers should be advised to select a product with broad-spectrum coverage, an SPF of 30 or higher, and water and/or sweat resistance in the setting of water activities or high ambient temperatures. UV filters are analyzed in their pure form by ingredient suppliers and also by cosmetic companies that purchase those filters for incorporation into their finished products. Once these UV filters are included into cosmetic finished products, they also need to be analyzed for both quality control and regulatory compliance. Use of sun screening agents is beneficial in minimizing the occurrence of skin cancers in people with fair skin. However, the same effect on Asian skin is debatable, as this skin type is considered to be resistant to skin cancers. Sunscreen use is advisable in young adults to prevent and minimize other photodamaging effects. Affordability and proper application techniques are the challenges that must be addressed in order to achieve regular sunscreen usage.

ARTICLE SUMMARY

Promoting sunscreen use is an integral part of prevention programs aimed at reducing UV radiation-induced skin damage and skin cancers. Protection against both UVB and UVA radiation is advocated. Despite the efforts of physicians and regulatory authorities to spread awareness regarding sunburn, skin cancer, and the benefits of regularly using sun screening agents, treatment adherence is low. Providing cosmetically acceptable preparations and educating people about following the application instructions, is a challenge often faced by treating physicians. Pricing sunscreens reasonably and making them water resistant and non-sticky are a few of the challenges faced by manufacturers. Manufacturers must also consider sensitization reactions, especially in those having eczema or photo dermatoses. Sun protection factor (SPF) is affected by application density, water resistance and other factors. An adequate SPF for an individual should be balanced to skin phenotype and exposure habits. The correct use of sunscreens should be combined with the avoidance of midday sun and the wearing of protective clothing and glasses, as part of an overall sun protection regimen. The FDA approved sunscreen ingredients are extensively reviewed. A clear and straightforward recommendation on their safety and efficacy still remains a big challenge.

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