Mark F. Naylor, MD
Kevin C. Farmer, PhD
The majority of the commercially available sunscreens today are a combination of agents from several chemical groups. Para-aminobenzoic acid (PABA) was an early chemical sunscreen agent that was frequently associated with contact and photocontact sensitivity reactions, had poor substantivity characteristics, often discolored clothing, and is rarely found in sunscreen formulations today . However, the para-aminobenzoic acid esters (primarily octyl dimethyl para-aminobenzoic acid) are commonly used in many formulations and have not been associated with the solubility and sensitivity problems of PABA. Other sunscreen agents include compounds from the salicyclate, cinnamate, benzophenone, anthranilate, and dibenzoylmethane groups. Ethylhexyl p-methozycinnamate and octyl methoxycinnamate are commonly used cinnamates. These agents rarely cause contact dermatitis and are very insoluble in water. The salicylates are weak UV absorbers, but are highly water insoluble and sensitization is rare. The salicylates are considered to be one of the safest sunscreens, even when used in high concentrations . The most widely used salicylates are homosalate and octyl salicylate. The anthranilates and benzophenones are compounds that absorb UV into the A spectrum. Agents in these two groups are often included with other compounds to provide broad-spectrum UV protection. Oxybenzone and dioxybenzone are commonly used benzophenones, and are also found in products other than sunscreens such as soaps and shampoos and have been reported to cause sensitization problems in some individuals . Avobenzone is a dibenzoylmethane compound that exclusively absorbs in the UVA range.
Sunscreen Protection From UV
While a primary goal of sun protection should remain the prevention of sunburns, this is not the only worthwhile goal. Incremental damage occurs with each exposure to UV radiation, even with doses that do not produce erythema [69, 128-130]. This damage is cumulative with time and the magnitude of the exposures. Over the years, total time in the sun is reflected by wrinkles, blotchy pigmentation, and with enough exposure, skin cancer. The age at which these effects become noticeable depends primarily on how much natural pigment the skin has and the total accumulation of UV exposures. The advent of commercially available, high potency transparent chemical sunscrees represents a significant technical advance in our ability to protect against such changes that has yet to be fully exploited.
Chemical sunscreens "block" the penetration of UV radiation through the epidermis by acting as filters and absorbing and reflecting high energy UV. The sunscreen molecules (alternating single and double bond structures) absorb the high energy UV photons causing the electronic structure to move to a higher energy state. This energy is dissipated by resonance delocalization and conversion to lower energy long-wave radiation which is then re-emitted as heat [131, 132]. A certain amount of UV light will enter the epidermis, and no chemical sunscreen blocks 100 percent of all incident UV radiation.
The terminology used on sunscreen labels can be confusing to the consumer and the health professional. The protection provided by a sunscreen is indicated by the SPF listed on the product label. A "sunblock" is considered to be any sunscreen with an SPF of 15 or more. In theory, an SPF 15 sunscreen may absorb more than 92 percent of incident UVB radiation. An SPF 30 sunscreen may absorb 96.7 percent, and an SPF 40, 97.5 percent of incident UVB radiation .
The SPF value of a sunscreen is defined as the ratio of the energy required to produce a minimal erythema dose (skin reddening or minimal sunburn) through the sunscreen compared to the energy required to produce the same reaction in the absence of the sunscreen . Based on this definition, an individual who burns after 30 minutes of sun exposure can extend the period of time until a burn begins to 2 hours with an SPF 4 sunscreen. However, as discussed further below, a sunscreen with a measurable SPF of 30 (15 hours of theoretical burn protection in this same individual) may not in fact be protected from UV-induced erythema for an entire day of continuous sun exposure.
The greatest value of tanning in the context of sunscreen use is to potentiate the effect of sunscreens. Transparent chemical sunscreens work by enhancing the natural resistance to sunlight, which is in turn a function of the degree of melanin skin pigmentation. To the extent that a sunscreen fails in blocking all incident ultraviolet (which it certainly will, since no currently available transparent sunscreen is an absolute block), some tanning will occur, and the individual will then benefit from the additional protection that the limited tan affords. This limited tanning will actually have a synergistic UV protective effect due to the way that sunscreens work, since sunscreens essentially magnify the natural resistance to ultraviolet damage intrinsically present in the skin. The number of ultraviolet photons required to tan non-sunscreen protected skin to achieve comparable levels of sun resistance would be many times higher than in sunscreen protected skin, if indeed a comparable level of protection were even possible from tanning alone. In other words, people using strong sunscreens continuously will probably get less total ultraviolet exposure, less total DNA damage, and less ultraviolet effect than they would with natural tanning. Whatever one's ability to tan, it can be anticipated that there will be less DNA damage done by a given amount of sun exposure with a 45 SPF sunscreen in place than without it.
Sunscreens & Aging
Animal studies have shown that sunscreens can prevent UV-induced wrinkling . Animal studies have demonstrated that sunscreens with good UVA coverage can prevent sagging and wrinkling due to high intesity UVA . Recent evidence indicates that daily sunscreen use decreases the abnormal elastotic layer characteristic of the elastic damage of actinically injured human skin suggesting that the benefits seen in animal models may also extend to humans .
Sunscreens & Immune Effects of UV
DNA damage in the form of cyclobutane dimers appears to be a key factor associated with adverse immune consequences of ultraviolet exposure [83, 136]. Since sunscreens prevent pyrimidine dimer formation it is not surprizing that they can also prevent the principle adverse immunologic consequences of ultraviolet exposure including epidermal Langerhans cell depletion, loss of contact hypersensitivity and enhanced susceptibility to transplanted tumor cells [137, 138].
Sunscreen Use and Skin Cancer Risk
Sunscreens prevent DNA damage [139, 140], and in particular, pyrimidine dimer formation [141, 143]. Since UV-induced changes in DNA and pyrimidine dimers in particular are thought to underpin the carcinogenic effect of ultraviolet , it stood to reason that sunscreens would be useful in preventing UV-induced tumors.
Sunscreen use for the purpose of preventing ultraviolet-related cancers has been widely advocated, but little data has been available until recently to support this premise. Now two separate studies, one in the United States and one in Australia, provide evidence documenting the value of sunscreen use in preventing pre-cancerous skin lesions [145, 146]. The American study evaluated the formation of pre-cancerous skin lesions (actinic keratoses, or AKs) for a period of 2 years in a randomized, controlled clinical trial between volunteers in a sunscreen group (SPF 29) and a placebo group. Both groups were similar in their potential for sun-induced neoplastic lesions. Individuals in the sunscreen group averaged 13.6 AKs per year compared to 27.9 AKs per year in the placebo group. The difference between the two groups was statistically significant. When all risk factors were accounted for, the use of a sunscreen resulted in a 36% reduction in the annual rate of AK formation .
The Australian study was a randomized, controlled clinical trial evaluating AK formation in 588 people over a period of 7 months during the summer . The study compared an SPF 17 sunscreen to placebo. At the end of the study the placebo group had a total of 508 new AK lesions (mean increase of 1.0) compared to 333 in the sunscreen group (mean decrease of 0.6). A dose-response relationship was also found in the amount of sunscreen used in the treatment group. The number of new lesions was 23 percent of the initial number present for study subjects using less than 500 gm of sunscreen, compared to 12 percent of the initial number for those using more than 1000 gm .
In both the American and the Australian studies, volunteers were asked to apply the product (sunscreen or placebo) on a daily basis during the entire study period. Therefore, the potential long-term benefits may not be as pronounced in the general population where individuals often use a sunscreen only when the expected exposure is thought to be potentially excessive. The current mindset of many people is to use a sunscreen only when a sunburn may be expected without some type of protection.
These studies provide evidence that sunscreens used on a regular basis provide substantial protection from sun induced skin lesions. Unpublished observations from the 2 year American study noted that the formation of actinic keratoses in the placebo group diminished in the winter months, but did not go to zero. Those with the highest levels of sun damage in the placebo group had substantially more AKs during the winter than comparable individuals in the sunscreen treated group. Therefore, individuals with the worst sun damage may benefit from continual (year-round) use of a sunscreen. Other high risk groups that may benefit from the year-round use of sunscreens include outdoor enthusiasts (e.g., runners, golfers, cross-country, and downhill skiers, etc.) and individuals with vocations (e.g., military, ranchers, construction workers, etc.) who spend significant time exposed to the sun in the middle of winter. Some of these individuals may experience equivalent amounts of sun exposure to the face, neck, and arms in winter and summer.
There are several additional reasons for some individuals to use a sunscreen during the winter months. UV damage may be intensified by reflection from the snow, windburn, and at high elevations [148, 149]. Heat, humidity and wind can also intensify UV effect [148, 150]. The UV protective-high level atmospheric ozone layer is also typically thinner in the winter months, which may allow additional UV penetration and damage .
Due to a number of prohibitive factors, including cost, methodological difficulties and ethical dilemmas, prospective human trials of sunscreens for the prevention of melanoma have not yet been done. As has been previously reviewed, there is still ample reason to believe that broad-spectrum, high SPF sunscreens, which protect mainly in the UVB and short UVA spectrum are useful for the prevention of melanoma as well as non-melanoma skin cancer.
High SPF Sunscreens and FDA
The U.S. Food and Drug Administration has taken a position against the continued labeling of high SPF formulations, and has stated that the maximum SPF should not exceed 30 due to the additional costs and risks from increased concentrations of active ingredients . This is in spite of the fact that other than the expected occurrence of occasional allergic, phototoxic, and photoallergic cutaneous reactions, there is virtually no published evidence of harm from using high SPF sunscreen formulations.
There are, in fact, a number of reasons why high SPF formulations (> 30 SPF) may be the best choice for high risk individuals, especially when sun exposure is expected to be extensive. Rubbing, sweating, and water immersion diminish the effectiveness of all sunscreens, requiring frequent re-application of the product even with supposedly waterproof or sweat proof formulations. Another factor which enhances the damaging effects of lengthy exposures is a time-dependent diminution of SPF effect not related to removal of the product from rubbing or washing. Experiments in the hairless mouse model found a significant decrease in measured SPF occurring within the first few hours following sunscreen application . Studies in humans confirm that single applications of an SPF 25 sunscreen are frequently inadequate to prevent erythema, and that multiple applications are required to completely suppress erythema, even from a single day's sun exposure.
A final factor which may not be fully compensated for, even with repeated application, is the effect of multi-day UV exposures . A significant multi-day exposure to sunlight (e.g., all day Saturday and Sunday) increases the sensitivity of the skin to UV damage on the second day of exposure. This means that even if the sunscreen functions as predicted by the rated SPF to prevent erythema on the first day of exposure, the heightened sensitivity on the second and subsequent days of exposure may lead to erythema development which would not have been predicted based soley on extrapolations of the SPF. In such instances, a sunscreen with an SPF > 30 may provide significantly better protection from UV damage, particularly in susceptible individuals .
The current focus on erythema as the standard against which sunscreen potency is measured may have led to the assumption that erythema prevention is also the only important goal of sun protection, and ultimately to the FDA's position against sunscreens more potent than 30 SPF. This assumption ignores experimental evidence that significant UV-induced damage occurs prior to the development of perceptible UV-induced redness. Human research using sunburn cells as the measure of UV damage supports the existence of significant sub-erythemal DNA damage in the skin, and the value of high SPF sunscreens in preventing it .
Sunburn cells are keratinocytes that have been subjected to a lethal dose of dose of UV radiation, and are produced in appreciable numbers by sub-erythemal UV exposures . Sunburn cell formation is thought to be triggered by the presence of extensive UV-induced DNA damage. Kaidbey compared the generation of sunburn cells between sunscreens of SPF 15 and SPF 30 when exposed to equivalent doses of UV radiation . Significantly higher numbers of sunburn cells (mean 7.45 vs. 2.96) were found in the SPF 15 treated skin compared to the SPF 30 treated skin . Perhaps more importantly, tumors can readily be induced in experimental animals by repeated sub-erythemal doses of UV radiation [68, 69]. These animal studies provide strong evidence that DNA damage in the form of carcinogenic mutations can occur with sub-erythemal UV exposure.
SPF testing is designed to evaluate protection against erythema produced by natural sunlight, and therefore denotes principally the degree of protection against UVB, since the amount of UVA received from sunlight does not produce significant erythema. The only ingredient approved by the FDA for protection against UVA radiation is avobenzone. However, if a product contains ingredients that absorb UV between 290-320 nm it can be labeled as a broad-spectrum sunscreen, meaning it will provide protection against both UVB and short wave UVA radiation . Although UVA (315-340) coverage has so far proved difficult to quantify, it may be important to do so, since animal data indicates that it can contribute to the carcinogenic spectrum of ultraviolet radiation [66, 68, 117, 157, 158]. It is uncertain whether the solar intensity of long wave UVA is sufficient to produce any carcinogenic effect in normal humans. However, the weight of available evidence clearly indicates that the UVB (290-315) and short wave UVA (315-320) portion of the solar spectrum is the most important in terms of skin cancer genesis. Because of this, it is appropriate to focus efforts to limit exposure to ultraviolet light on these wavelengths. Since the spectral coverage of high SPF broad spectrum sunscreen products now commercially available includes this region of ultraviolet wavelengths, sunscreens can be expected to have a substantial impact in reducing the incidence of melanoma and non-melanoma skin cancer in those individuals who use them regularly.
Safety of Sunscreens
Apart from cutaneous problems, (i.e., allergic contact reactions and photocontact reactions), few if any systemic adverse reactions to sunscreen use have been reported in the literature. There are conflicting reports of the bacterial mutagenicity of certain sunscreen agents, namely PABA and 2-ethyl hexyl p-methoxycinnamate [159-163]. Whether this is due to contaminants of some batches of sunscreens with chemical byproducts or photochemical derivatives of the parent compounds is also unclear [160-164]. The significance of these findings for products containing these agents is uncertain, but it is clear that any potential for genotoxicity is far outweighed by the ability of these agents to protect against the much more potent genotoxic effects of UV radiation [165, 166].
Laboratory data collected during the American sunscreen study (complete blood count, urinalysis, blood chemistry), did not note any consistent blood abnormalities between those treated with sunscreen and those treated with placebo . While there are anecdotal reports of vitamin D deficiency in chronic sunscreen users, unpublished data from the American sunscreen study did not reveal any significant difference in vitamin D levels between the sunscreen and placebo-treated groups, suggesting that this is an uncommon occurrence. This suggests that in most cases, dietary vitamin D intake is sufficient to prevent clinical vitamin D deficiency. If there is any doubt about dietary vitamin D intake, a multivitamin containing vitamin D can be recommended to forestall any potential problems in particular individuals.
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