Editor’s note: This two-part article is controversial. In part I, it reviews a number of concerns about the safety of traditional sunscreens. In part II, scheduled for February, the authors propose new approaches to move past these issues. Whether or not you feel these concerns are valid, this article is presented in the spirit of advancing cosmetic science to provoke thought, and in no way suggests consumers should stop using sun protection. We invite you to engage in this discussion by emailing email@example.com or commenting on our Cosmetics & Toiletries LinkedIn page.
Modern sun care should go beyond sunglasses and high-SPF lotions. Consumers, marketers and the scientific community seek means to protect against not only all spectra of radiation, but other harmful agents including peroxides, nitrogen and sulfur oxides, free radicals and other solar-activated molecules including ozone, either present in the atmosphere or generated in the body.
Reactive oxygenated and nitrogenated species are represented by superoxide anion radical, hydroxyl, alkoxyl and lipid peroxyl radicals, nitric oxide and peroxynitrite.1 The formation of such agents in the body can occur via a combination of sun, moisture, UV absorbers and photo-unstable ingredients inadvertently formulated or generated in situ in skin care products. Their contact with human skin can set in motion a cascade of inflammatory responses.
Zinc oxide nanoparticles, for example, have been found to induce oxidative and nitrosative stress in human monocytes, leading to increased inflammatory response via activation of redox sensitive NF-κB and MAPK signaling pathways.2 Titanium dioxide nanoparticles have been shown, in a cell bioassay test, to dose-dependently increase DNA damage, lipid peroxidation and protein carbonylation, and significantly decrease the activities of superoxide dismutase, catalase, total glutathione levels and total antioxidant capacity—all of which indicates oxidative stress.3 The wide application of zinc oxide and titanium dioxide nanoparticles in, for example, cosmetics, paints, biosensors, drug delivery, food packaging and as anti-cancer agents, also increases the risk of human exposure to such materials.
An understanding also has grown for how UV-induced changes in the skin culminate in UV-induced immunosuppression and are implicated in the cascade of events related to non-melanoma skin cancer. But this holds promise for the development of more effective protection strategies.4
There is also the misguided belief that “the higher the SPF, the better a sunscreen.” Indeed, an SPF 15 product absorbs about 94% of UVB rays; SPF 30 absorbs nearly 97%; and SPF 45, about 98%—but these numbers represent UV absorption, not transmission. So a higher SPF may not in fact be better. Put another way, for an SPF of 15, 6% of UV is still transmitted to the skin. With an SPF of 30, only 3% can reach the skin. So based on these calculations, an SPF 15 allows twice as much UV to reach the skin as the SPF 30. But again, this UV is absorbed by the UV filter, and since SPF 30 filter(s) absorb twice as much as the SPF 15, depending on the filter(s), this puts the higher SPF formula at a greater risk for secondary reactions.
Of course, higher SPFs can be obtained using various combinations of filters and vehicles. There also is no evidence that higher concentrations of UV filters have anything to do with skin penetration; although sunscreen over-use or misuse, such as failure to re-apply, can lead to an increased risk of skin cancer.5 In fact, one study gave inconclusive results for skin protection while sunbathing with and without sunscreen due to a variance in application.6
Taken together, more effective and safer sunscreen actives are warranted. While some exist, their availability has been limited in certain countries due to regulatory restrictions; i.e., where SPF products are regulated as drugs. This makes finding alternatives a high priority.7
So the question now becomes: If certain and/or higher levels of UV filters are used, and they can produce unwanted agents from secondary reactions, how does the UV protection they provide compare with the undesired entities they might produce? This article considers the mechanisms of sunscreens and identifies several next-generation technologies that hold potential for developing safer and more effective sun protection formulas.
Why Use Sunscreens?
First, it is important to consider why sunscreens are necessary. Sunscreens as well as clothing, sunglasses and other physical approaches can protect the skin against the detrimental effects of photo-exposure. UV can penetrate the skin (see Figure 1), where it mainly produces reactive oxygen species (ROS). This leads to DNA, cell and tissue damage.8 It alters immune function,9 causes skin pigmentation via tyrosinase activation, and is responsible for visual photoaging.10
UV-induced skin damage can further trigger a cascade of DNA damage response signaling pathways, including cell cycle arrest, DNA repair and apoptosis (cell death).11 UV also induces genotoxic stress12 and UVA in particular is implicated in the etiology of photo-dermatoses and photo-contact allergy.13 Exposure to UV affects regulatory and dendritic cells as well, causing chemokines and cytokines to be released from the skin.14
As a consequence, to provide minimally adequate protection, sunscreens need, among many other elements, an efficient combination of UVA and UVB filters. Not surprising, one study15 of the effects of different solar spectra on the development of free radicals suggests current solar protection schemes should be entirely reconsidered—i.e., that a comprehensive protection scheme must shield against not only UVA and UVB, but also visible and near infrared energy. Existing examples of infrared-protective active agents include mitochondrially-targeted antioxidants.16 In the end, it’s all about effective and safe sun protection.17
Two main approaches are taken to formulate UV protection: physical (also inorganic or mineral) and chemical (also organic or synthetic). As is well-known, physical or mineral sunscreens, such as zinc oxide or titanium dioxide, physically prevent solar radiation from penetrating the stratum corneum. Previously, these were believed to act by reflecting UV rays similarly to white paint reflecting light but recent work has shown they also work partially by absorbing UV.18
It is interesting that the mechanism of UV-blocking function of inorganic oxides is not clear. While for TiO2, for example, some believe it provides UV protection by reflecting and/or scattering most of the UV rays through its high refractive index. Others believe it absorbs UV radiation due to its semi-conductive properties. A band theory also has been proposed; i.e., if the energy per photon is smaller than the band gap, the light cannot excite electrons from the valence to conduction band. So, the photon will pass through the material without being absorbed. If the energy is larger than the band gap, the light will excite electrons and be (partially) absorbed.19
Organic or chemical sunscreens, such as avobenzone or oxybenzone, absorb UV radiation through their conjugated chemical bonds, which causes them to reach an excited state. These excited state molecules then return to their normal state by transforming the absorbed energy into visible light, heat or phosphorescence. However, such transformations can initiate secondary reactions in skin. As stated, exposure to UV radiation triggers a cascade of chemical reactions, and molecular products (photolesions) from such reactions have been isolated that are potentially unsafe for the cellular system. The early steps of UV absorption by DNA and generation of excited electronic states, leading to photolesions, have been studied.20
Relative to the dissipation of excited-state energy in organic sunscreens, the triplet-triplet UV absorption, phosphorescence and phosphorescence-excitation spectra of benzophenone, methyl anthranilate, ethylhexyl triazone, methylphenyl cinnamate, 2-ethylhexyl salicylate and homomenthyl salicylate have been studied.21 The results could pave the way for the development of more effective sunscreens with reduced phototoxicity.
Another consideration is the body’s own natural sunscreens, eumelanin and pheomelanin, which provide protection by absorbing solar radiation and dissipating it as heat—without detriment to their polymeric structure.22
Upon Application and Exposure
What happens to sunscreen after it is applied to skin? First, consider consumers prefer formulas that rapidly absorb without an oily feel or white appearance. For these effects, chemical (organic) sunscreens generally work best. However, in one study, oxybenzone was shown to rapidly photo-oxidize, yielding oxybenzone semiquinone, which reacted with thiol (-SH) groups on several antioxidant enzymes such as thioredoxin reductase and glutathione peroxidase. So while oxybenzone is an excellent broad spectrum UVA filter, its skin absorption23 and rapid oxidation, followed by the inactivation of the described antioxidant systems, suggests it could be harmful to the epidermis.
In relation, a study using an animal model found the protective capability of organic sunscreens may decrease upon UV exposure, and the sunscreens could behave as photo-oxidants. Furthermore, they can form degradation products under UVR that either inhibit enzymes or generate reactive species in the skin.24 Additionally, oxybenzone has been found to react rapidly with chlorine, such as that found in swimming pools. The stable transformation product 2,4,6-trichloro-3-methoxyphenol was identified, as were high amounts of chloroform, trichloroacetic acid, dichloroacetic acid and chloral hydrate; and significantly elevated genotoxicity has been observed from chlorinated oxybenzone byproducts.25
An understanding has grown for how UV-induced changes in skin culminate in immunosuppression. This holds promise for more effective protection strategies.
TiO2 composites also are sometimes used as UV filters in sunscreen products in combination with the organic sunscreens butyl methoxydibenzoyl methane (avobenzone) and octyl methoxycinnamate (OMC). Most formulators know to avoid this combination since TiO2 nanocomposites (NCs) promote the photolysis of OMC.
The photo-oxidation of other organic sunscreens and their relevance to human safety have also been reported.26 For example, the high-resolution spectroscopy of cinnamate-based UV filters has shown the excited state dynamics of a delicate balance between favorable and adverse, skin-damaging effects. Contrary to common belief, the excitation to the “bright” ππ* state does not directly lead to repopulation of the electronic ground state. Instead, internal conversion to another electronically excited state, identified as the “dark” nπ* state, is a major decay pathway that impedes fast energy dissipation, resulting in photo-oxidation and the formation of ROS in the skin.27
The human epidermis defends against reactive oxygen species (ROS) generated by UV or x-ray exposure, as well as heat and radiation energy sources. In particular, the roles of thioredoxin (T) and thioredoxin reductase (TR) in the skin are well-recognized. Thioredoxin has been shown to protect against both UVB-induced skin injury and damage by peroxides.28 Thioredoxin reductase brings oxidized thioredoxin to its reduced state by nicotinamide adenine dinucleotide phosphate (NADPH).
Reduced thioredoxin then serves as an electron donor for thioredoxin peroxidase (TPx), which subsequently reduces H2O2 to H2O. This is crucial since UVB generates H2O2 in the epidermis in a dose-dependent manner.28 Furthermore, this TR/T/TPx system in epidermal cells controls cofactor (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH(4)) homeostasis.
In the case of oxybenzone, however, UVB photo-oxidation may deactivate thioredoxin reductase in darker-skinned individuals by Michael addition of oxybenzone semiquinone to the thiolate active site of this enzyme. This is illustrative of how photo-oxidized oxybenzone can cause melanocyte cytotoxicity in darker-skinned individuals—potentially posing a greater risk than bypassing this sunscreen type altogether.29
Potential Side Effects
The potential for side effects from chemical UV filters in cosmetics has been studied, taking three key observations into consideration: 1) the use of sunscreens containing chemical UV filters is increasing worldwide, 2) sunscreens should protect against malignant melanoma but its incidence is rising, and 3) several UV filters are suspected of endocrine disruption.30, 31
Regarding point 2, in a case-control study from southern Sweden, the association between sunscreen use and malignant melanoma was evaluated. Sunscreen users reported greater sun exposure than non-users. In individuals who used sunscreens, however, their risk of malignant melanoma did not decrease. Instead, a significantly elevated ratio for developing malignant melanoma after regular sunscreen use was found32—although a recent study provides contradictory results.33 In another study, no significant protection against skin cancer by sunscreen use was reported.34 These inconclusive reports suggest the need for more studies in this area, and the use of sunscreens as the sole means of protection against solar-initiated skin cancer warrants caution.
For point 3, the endocrine-disrupting property of several sunscreen actives has received much attention in recent years. In relation, it seems pertinent to evaluate whether exposure to UV filters contributes to possible adverse effects on the developing organs of fetuses and children.35 Benzophenone derivatives have been detected in more than 95% of randomly collected human urine samples from adults and premature infants, and these derivatives may have estrogenic potential.36
Increasing consumer awareness of this concern, albeit contradictory in some aspects, requires the further risk assessment of sunscreens.37 Benzophenone derivatives are UV-absorbing chemicals used widely in pharmaceutical, cosmetic and industrial applications. Studies of their potential endocrine-disrupting properties have focused mostly on their interaction with human estrogen receptor alpha (hERalpha). In one test, for example, endocrine receptors of human and fish origin were used to assess the potential effects of benzophenone derivatives. Overall, the observed anti-androgenic potencies of these derivatives support further investigation of their role as endocrine disrupters in humans and wildlife.38
In another recent study, the UV filters 3-benzylidene camphor and benzylidene camphor sulfonic acid were found to competitively inhibit progesterone-induced Ca2+ signals. However, in vivo studies are needed to investigate whether the UV filter affects human fertility;39 as mentioned, benzophenone has been detected in randomly collected human urine samples and it could have estrogenic potential.36 Indeed, the potential exposure hazards of several sunscreen agents on human health are an active area of research.40
In yet another study, zinc oxide (ZnO), which is known to deliver broad UV protection, was assessed in both its micronized and nano-sized form for potential toxicity. Depending on the formula composition, topically applied ZnO did not appear to penetrate the viable epidermis.41 However, the reaction of water with ZnO on the skin surface was found to increase zinc ion levels in the stratum corneum, viable epidermis and subsequently, in systemic circulation and urine.42
A recent hazard analysis of zinc oxide and titanium dioxide nanoparticles showed both materials could cause DNA damage,43 and exposure to titanium dioxide nanoparticles resulted in microglia activation, reactive oxygen species production and the activation of signaling pathways involved in inflammation and cell death, both in vitro and in vivo.44 And contrary to the findings stated above, another study suggested some penetration of coated and uncoated nano-sized ZnO (ZnO-NP) into the viable stratum granulosum epidermis.45 Thus, the safety of ZnO and TiO2 nanoparticles in sunscreens has been reviewed, albeit with contradictory conclusions.46
In a related study of radiolabeled zinc oxide, levels of Zn68 in blood and urine from human panelists using a nano sunscreen appeared to be higher than subjects using a bulk sunscreen. It was not known whether Zn68 absorbed as ZnO particles, soluble Zn or both.47 A rat model study revealed similar results for both nano- and larger size ZnO sunscreens.47 However, comparative data is lacking. As such, an international collaboration is needed to understand the potential for dermal absorption of not only micronized and nanoparticles but also their detection under normal conditions of sunscreen use.48
The use of sunscreens can have indirect implications as well, primarily by giving consumers a false sense of security so they remain for too long in the sun without proper protection. In fact, sunscreen users reported significantly more sunburns and were even more likely to use indoor tanning devices than non-sunscreen users.49
Recent evidence also suggests both organic and inorganic UV filters used widely in sunscreens and other personal care products may also impact ecosystems. Sunscreen compounds are released into the coastal aquatic environment in significant amounts from beach-goers, and the effects of these potential pollutants on microbiota are not well-known.
Phytoplankton, for example, is a key component of the microbiota, and any change in its natural population can affect the structure of aquatic biota. In one experiment50 performed outdoors with natural UV light and without it, four species of mixed microalgae were exposed to three commercial sunscreens with variable titanium dioxide concentrations. The toxicity mediated by hydrogen peroxide production associated with the concentration of TiO2 NPs was examined; the organic compounds in the sunscreens also were taken into account. The results indicated the sensitivity of microalgae to sunscreens and TiO2 nanoparticles could produce a change in the dynamics of phytoplankton populations and provoke undesirable ecological effects.50
In another study, the toxicities of five types of TiO2 nanoparticles with different particle sizes (10-50 nm) and crystal phases were investigated using Escherichia coli as the test organism. The effect of water chemistry on the nanotoxicity also was examined. Transmission electron microscopy showed the concentration build-up of the anatase TiO2, especially of smaller particle sizes on the cell surfaces, leading to membrane damage and internalization.51
Photo-oxidized oxybenzone can cause melanocyte cytotoxicity in darker-skinned individuals—potentially posing a greater risk than bypassing this sunscreen type altogether.
In yet another study, eight different nano-sized TiO2 suspensions of five different concentrations were tested in conjunction with changes in water quality parameters (pH, temperature and ionic strength), light sources and light intensities, to mimic different environmental conditions. The results indicated nano-TiO2 particles, both in the absence and presence of a light source, i.e., photoactived, induced lipid peroxidation and disrupted cellular respiration.52
Besides TiO2, the widespread use of benzophenone-3 (BP-3) in sunscreens and other consumer products has resulted in its release into the water environment, hence its potential impact on aquatic ecosystems has become a concern. BP-3 transforms into three major metabolites in vivo: benzophenone-1 (BP-1), benzophenone-8 (BP-8) and 2, 3, 4-trihydroxybenzophenone (THB). BP-1 has a longer biological half-life than its parent compound and exhibits greater estrogenic potency in vitro. BP-3 has been detected in water, soil, sediments, sludge and biota. The maximum detected level in ambient fresh water and sea water is 125 ng/L and 577.5 ng/L, respectively; and in wastewater influent, 10,400 ng/L.
Other sunscreens routinely detected in the environment include butyl methoxy dibenzoylmethane, ethylhexyl dimethyl p-aminobenzoate and 4-methylbenzylidene camphor. Considering the limited ecotoxicological information currently available, further studies on environmental monitoring in aquatic ecosystems are warranted.53
In relation, there is a pressing need to standardize methods that represent realistic environmental conditions to evaluate the ecotoxicity of sunscreens in aquatic media. Interestingly, it was found that the organic matter present in aquatic systems interfered in the toxicological estimation of titanium dioxide in a river ecosystem.54
Lab-scale water-sediment test systems have shown55 sorption to be the primary mechanism for removing UV filters from the sunscreen formula water phase. Furthermore, biotransformation is the predominant factor for the degradation of these compounds in water-sediment systems. Additionally, the UV filters tested were found to be slightly resistant to the microbes in these sediment systems, with DT50 and DT90 values. Here, the disappearance time (DT) describes the time in which the initial total mass of the UV filters in the whole system is reduced by 50% and 90%, which ranged between 18 and 31 days, and 68 and 101 days, respectively.55
Sunscreens collect in swimming pool water as well, which becomes a sink full of chlorinated and UV-degradation byproducts. In fact, concentrations in the μg/L range have been found for benzophenone and crylene derivatives in swimming pools.56
Recent studies have evaluated the bioaccumulation and biomagnification of organic sunscreen compounds in both fresh and salt water, and terrestrial food chains including: animal species, e.g., macroinvertebrates, fish and birds; habitats such as lakes, rivers and the sea; and benzophenone and camphor UV filters. Biomagnification in predator-prey pairs, for example bird-fish and fish-invertebrates, was observed. Ecotoxicological data and preliminary environmental assessment of the risk of UV filters also have been discussed.57 Lipophilic sunscreens were prevalent with concentrations of up to 7,112 ng/g homosalate in mussels and 3,100 ng/g homosalate in fish. High concentrations have also been reported for 4-ethylbenzilidenecamphor, up to 1800 ng/g, and octocrylene at 2,400 ng/g;57 although it should be noted that the source of these chemicals, i.e. from sunscreens, and/or the effects of their presence was not established.
In another study, the occurrence and distribution of eight UV filters including benzophenone, benzophenone-3, ethylhexyl methoxy cinnamate, 4-methylbenzylidene camphor, 2-ethylhexyl 4-dimethylaminobenzoate, 2-ethylhexyl salicylate, isoamyl benzoate and benzyl cinnamate in eleven sites among three rivers, five sewage treatment plants, and four wastewater treatment plants located in different parts of Korea was investigated.58 The biological treatment processes favored the removal of UV filters. However, complete removal was not achieved before discharge into the rivers58 and a risk analysis indicated that benzophenone-3 and ethylhexyl methoxy cinnamate discharged from treatment plants may pose high risk to fish in the local environment.59
Lab-scale water sediment test systems have shown sorption to be the primary mechanism for removing sunscreen filters from the sunscreen formula water phase.
Circling back to the initial concern: the safety of sunscreens. As noted, some evidence suggests organic sunscreens and inorganic nanoparticulate sunscreens can penetrate the skin. Thus, the assessment of their potential to cause skin sensitization and damage are of high importance both from product safety and regulatory viewpoints.60
While sunscreens have been used for decades with no serious safety issues, recent work has brought consumer concerns to light that merit further research. For example, relative to the prevention of basal cell carcinoma and melanoma, a significant benefit from regular sunscreen use has not yet been demonstrated. Sunscreens also do not prevent actinic keratoses, squamous cell carcinomas, or skin aging.5 And a number of organic UV filters, e.g., PABA derivatives, cinnamates, benzophenones and octocrylene, have been reported to cause photo-allergy.13
Furthermore, as described, the endocrine-disrupting activity of small-sized organic and nano-sized inorganic UV filters has been reported.61 Also, sunscreens impair vitamin D synthesis—the deficiency of which has become a public health concern.62
Of course, contrary opinions exist.63 For instance, a number of patients who reported photo-contact allergy to octocrylene may have previously used other topical products containing the non-steroidal anti-inflammatory drug ketoprofen. But contact allergy from octocrylene-based sunscreens in the absence of ketoprofen also occurs, mostly in children.64
Another issue is with benzophenone (BP), which as noted can be released in the environment from sunscreens and is a suspected indirect endocrine disrupter. While BP itself has not shown estrogenic activity, two estrogenic photoproducts were detected after irradiating an aqueous solution of BP with UV or sunlight: 3-hydroxy BP (BP-3OH) and 4-hydroxyBP (BP-4OH). The formation of H2O2 also was found with increasing levels of UV, and the addition of H2O2 to the BP solution increased BP-3OH and BP-4OH production under UV irradiation.
These results suggest the involvement of photochemically generated H2O2 and hydroxyl radical in BP hydroxylation. Notably, BP-4OH is more potent than BP-3OH for promoting estrogen receptor-mediated transcription and uterotrophic activity. Therefore, it can be concluded that BP can be converted into ring-hydroxylated derivatives that have estrogenic activity after exposure to UV.65 Considering all the concerns described, it is worth exploring how to take sunscreens in a new direction. Recent research has focused on nature’s approaches to protecting living organisms; this will be the focus of part II in this series, to appear in the February Cosmetics & Toiletries.
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