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    Sep 2013, Uli Osterwalder, Samantha Champ, Heike Flösser-Müller, Bernd Herzog

    The evolution of UVA protection

    Over the last two decades, enormous progress has been made with regard to UVA protection. Modern photostable UVAI and broad-spectrum UV filters are now available almost globally, and the various UVA assessment methods are about to be harmonized. However, sunscreens still require further improvement of UVAI protection and a few issues in the measurement methods still remain to be solved.

    Abstract

    The importance of an adequate ultraviolet A (UVA) protection has become apparent with an improved understanding of the mechanism of damage to tissues that is mainly triggered by UVA induced free radicals. Fortunately, more sunscreen actives for UVA protection have been developed and at present a great variety of UVA and broad-spectrum filters are available including Butyl Methoxydibenzoylmethane BMBM (Parsol 1789), Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine BEMT (Tinosorb® S), Diethylamino Hydroxybenzoyl Hexyl Benzoate DHHB (Uvinul® A Plus), Methylene Bis-Benzotriazolyl Tetramethylbutylphenol MBBT (Tinosorb® M), and Zinc Oxide ZnO (e.g. Z-Cote®). In parallel, UVA assessment methods have been created and further refined. The in vivo UVA Protection Factor (UVA-PF, measured by Persistent Pigment Darkening) inherently considers photostability, whereas pre-irradiation steps have been introduced only recently for the relative ratio methods such as UVA/UVB and the in vitro PPD determination. These methods serve to classify the UVA protection of sunscreens according to regional standards or classification systems. The world-wide highest UVA class of the Boots Star Rating system with a maximum of 5 stars requires much higher UVA protection than the European Recommendation (UVA-PF/SPF >> 0.33). Recently, methods have been developed to assess free radicals in the skin directly and to determine a Radical Skin/Sun Protection Factor (RSF). Our studies show that the RSF correlates well with UVA-PF, as expected. In daily care products, appropriate UVA protection is still strongly underrepresented, although every day’s exposure of our skin to even sub-acute UV(A) radiation is known to cause long-term damage in our skin. We advocate that the modern UV filters, methods and recommendations developed for sun care should also be applied in daily care.

    Introduction

    The importance of adequate ultraviolet A (UVA) protection has become apparent with an improved understanding of the mechanism of damage to tissues that is mainly triggered by UVA induced free radicals.

    Natural protection is provided by pigmentation in which melanin functions as the UV filter which of course absorbs all the way from UVB (280 nm) via UVA throughout the visible range. As people migrated into areas of less sun exposure some 100,000 years ago, pigmentation was reduced in order to allow more vitamin D synthesis[1,2]. Figure 1 shows how some protection against the sun was sacrificed and traded for the apparently greater evolutionary advantage of producing more vitamin D.

    Figure 1: Evolution of modern human skin photo types. Fair skin types developed after migration out of Africa into areas of less sun exposure because of the Vit. D3 advantage.

    During that evolution the average life expectancy was only half or less than it is today and hence photodamage was also of less relevance.

    As life expectancy increased, other behavioral patterns developed including the increasing desire to seek higher sun exposure in the last century. Figure 2 shows the trend towards exposing more and more skin and towards actively seeking the sun.

    Figure 2: Evolution of skin exposure over the last century (invention of the Bikini was 1946).

    The invention of sunscreens, i.e. topical sunburn protectants that helped tanning without sunburn, also supported this trend, along with the strong understanding towards the middle of the 20th century that a tan represented wealth and healthiness.

    However, as more is understood about the effects of UV radiation on skin, it has become apparent that there is, of course, more skin damage beyond sunburn. Solar ultraviolet (UV) radiation is well recognized by dermatologists, cosmetic professionals and the public to be a major contributor to skin cancer and premature ageing of the skin. Many commercial skin care products and sunscreens have been developed with high sun protection factors (SPF) which have been proven to prevent sunburn and to reduce the risk of photo-carcinogenesis resulting from mutation of DNA and immune system suppression. However, these high SPF products do not all provide effective screening of UVA radiation[3]. UVA acts predominantly through sensitized oxidative processes and has been directly linked to premature ageing of the skin with its easily perceivable signs of wrinkles, reduced skin elasticity and pigment disorders. Additionally, it has been proven to contribute to skin cancer[4]. UV-induced premature skin ageing and skin cancer have also been found to be related to higher concentrations of aggressive free radicals and “Reactive Oxygen Species” (ROS), including the hydroxy radical, the super oxide anion, lipid peroxide radicals as well as hydrogen peroxide and singlet oxygen, which can be generated upon UVA radiation within the deep living layers of the skin. Table 1 shows the external and internal influence factors that lead to the formation of free radicals.

    Table 1: Generation of free radicals caused by various influences.

    UV radiation, and especially in the UVA region, is an important cause of free radical formation. Indeed, the greatest majority of free radicals in skin is generated by UVA radiation. UVB plays a minor role in the total amount of free radicals produced in skin[5]. Figure 3 shows the effectiveness spectrum for free radical formation, which has only recently been measured by Zastrow et al[6], and which shows its maximum in the UVAI region around 360 nm.

    Figure 3: UV Effectiveness Spectra (Action x Sun Spectra): Erythema[7], Free Radicals (ROS)[6] and Immuno-Suppression[8].

    The figure also shows the effectiveness curve of erythema formation[7] – with maximum in the UVB and of immuno-suppression (UVA) that has recently also been measured by Halliday et al[8]. From these spectra it becomes apparent that efficient absorption of UVAI light by suitable UV filters is crucial for the protection against free radicals and immuno-suppression in skin.

    However, UVA protection unfortunately continues to remain underrepresented in the majority of cosmetic products. Sunscreens with high SPFs have seduced people to stay much longer in the sun without the risk of getting sun-burned – but at the same time the people are exposed to extraordinary high, unfiltered doses of UVA light without perceiving any acute warning sign[3].

    Evolution of UVA and Broad-Spectrum UV Filters

    As the understanding of the interaction of UV radiation with the skin has deepened, the progress in the development of suitable new molecules to protect the skin against radiation has evolved as well. Over the last two decades, more sunscreen actives for UVAI protection have been developed [9]. At present, a great variety of UVAI and broad-spectrum UV filters are widely available. They are shown in Figure 4.

    Figure 4: Modern UVA filters and broad-spectrum UV filters. The classic UVA filter BMBM (S66) is shown before and after irradiation with 10 MED. All modern UV filters and ZnO are photostable.

    These UV filters, COLIPA numbers, and abbreviations of INCI names are listed in Table 2.

    Table 2: Cross-reference list of all UV filters used in the BASF Sunscreen Simulator (www.basf.com/sunscreen-simulator)

    • Time and Extent Application (TEA) pending at FDA
    • Approved in certain formulations up to 3% via New Drug Application (NDA) Route
    • Only approved as non-nano grade (> 100 nm)
    • Registration intended
    • Approval as active, e.g. 10% Tinosorb® M active = 20% Tinosorb® M
    • Positive scientific opinion available, not yet listed on Annex VI of EC/1223/2009; Germany: preliminary approval 25%
    • Positive scientific opinion available, not yet listed on Annex VI of EC/1223/2009 or elsewhere

    Figure 5 shows the evolution of these UVAI and broad-spectrum UV filters in the major regions from a regulatory point of view; Avobenzone (S66) and ZnO (S76) were the first in this category.

    Figure 5: The evolution of UV filters in major regions (for identification check Table 2)

    In the 90's, the French company L’Oréal was the first one to start to develop modern UVAI and broad-spectrum UV filters, leading the way with their Mexoryl broadband filters, which, however, have remained proprietary so far (S71, S73). In the year 2000, the first broad-spectrum UV filters MBBT and BEMT (S79, S81) which had become widely available, were approved in Europe and South America (S79, S81). They quickly have become widely available. At the same time, DPDT, a water-soluble UVAI filter was introduced (S80). In 2005, DHHB, an oil-soluble UVAI filter, was approved in Europe (S83). All new UV filters were first introduced in Europe. Within a few years, approvals followed in Australia and Japan and South America. In the USA the approval process takes much longer, which is due to the regulation of sunscreens as over-the-counter drugs. The first modern broad-spectrum UV filters (S79 and S81), which are closest to US approval, are not yet approved in the US, although they are more than 13 years approved, in Europe. This, unfortunately, highlights the fact that the US is more than a decade behind the rest of the world in its development of progressive sunscreens. ZnO (S76) is not considered a UV absorber in Japan and in Europe it is still awaiting final approval. S66 and S71 first entered the US system via New Drug Application (NDA).

    It is worth discussing a few UV filters in more detail. The pioneer UVA filter BMBM (S66, Avobenzone) was first approved in the USA via the so-called “NDA route” (New Drug Application) as part of a particular drug formulation. About 10 years later Avobenzone was promoted to monograph status which allowed any sunscreen manufacturer to use it. The situation with the proprietary UV filter TDSA (S71) was similar as that with BMBM, whereby L’Oréal had achieved the approval of the filter in some defined formulations through this NDA route. TDSA is now waiting for the FDA’s approval to be implemented to the sunscreen monograph. The modern UVAI/broad-spectrum UV filters MBBT and BEMT (S79, S81) are currently closest to US approval. They have already passed the first hurdle of the alternative pathway of approval in the US – the TEA (Time and Extent Approval or Application) process at the end of 2005, through the granting of a notice of eligibility. Their safety and efficacy data has been under review since 2006.

    A special case is presented by the inorganic UV filter microfine Zinc Oxide (S76, ZnO). ZnO is perceived completely differently in the major sun care regions. It has been on the US sunscreen monograph since 1978 and on the Australian TGA list since 1984. In Japan it is defined as a scattering agent, i.e. not even a UV absorber, and can be used in formulations without any limit. In Europe, the situation regarding ZnO is the most complex. There is no official status for the microfine (nanograde) ZnO, except for Germany where it is regularly approved for another three years[10]. However it is tolerated in most other countries in Europe. The European Scientific Committee has recently issued a positive statement on the ‘nano grade’ material (< 100 nm)[11].

    Evolution of UVA Assessment Methods

    In parallel to the evolution of the UV filter technology, UVA assessment methods have been created and further refined. Figure 6 shows this development which started in Europe and Australia.

    Figure 6: The evolution of UVA assessment methods (in vivo in red, in vitro in blue). IPD Immediate Pigment Darkening, PPD Persistent Pigment Darkening, CW Critical Wavelength.

    It was again the French company L’Oréal that developed a specific in vivo method for UVA assessment[12]. Their in vivo UVA Protection Factor (UVA-PF), measured by the Persistent Pigment Darkening endpoint inherently considers photostability. The PPD method was soon adopted by the Japanese trade organization JCIA[13]. Australia developed the first in vitro method, solely based on transmission measurements[14]. Less than 10% transmission in the UV range from 320-360 nm was their pass/fail criterion to claim broad-spectrum UV protection. This was a criterion that could at that time only be achieved by sunscreens containing UVA filters, it did however not take into account photostability. In Europe, the development of in vitro methods started with the development of the UVA/UVB ratio and the critical wavelength by Diffey[15]. The British retailer company Boots adopted the UVA/UVB ratio[15] to the specific so-called Boots star rating system and made it mandatory for all sunscreens sold in their stores[16]. This had a significant effect on the improvement of UVA protection in the UK[17]. A third company, Beiersdorf, later developed a UVA index method[18] which later became the DIN standard UVA index[19] which in turn became the basis of the current PPD in vitro method described in the COLIPA guideline[20]. The latter was the first in vitro method that contains a pre-irradiation step in order to take into account the decreased photostability of certain sunscreens. Recently, Boots has also introduced a pre-irradiation step[21] and they dropped the one and two star rating. PPD in vivo or in vitro together with the critical wavelength (CW) are the basis for the 2006 EC recommendation[22]. In their “Final Rule” (2011) the US American FDA abandoned the 4 star in vitro UVA/UVB and the in vivo PPD system that had been proposed in 2007[23]. Instead they introduced the Critical Wavelength with a cut off criterion at 370 nm as the sole criterion for the broad-spectrum claim[24]. Australia adopted the in vitro ISO 24443[25] method in 2012. Japan is the only region left with a mandatory in vivo test for UVA protection. In 2013 they added a further “+” on their UVA-PF scale. A PPD value > 16 is required to claim PA++++. A future task will be to harmonize the UVA assessment methods on a global level (ISO TC 217 WG7).

    There are several open points in the search for non-invasive methods that could be able to replace the ethically questionable in vivo assessment. The most important issues of the commonly applied in vitro transmission measurement are the substrate used and its pre-treatment (Quartz, PMMA, others; moulded or sand-blasted), the way the sunscreen product is applied onto the substrate, and the pre-irradiation dose (2/3 SPF, “low dose”, integrated spectrum, others). An interesting alternative method may be Diffuse Reflectance Spectroscopy (DRS)[26]. The fact that DRS measures in vivo and is practically non-invasive makes the method very attractive.

    Evolution of UVA Standards

    The UVA assessment methods serve to classify UVA protection of sunscreens according to regional standards or classification systems. Figure 7 compares the UVA assessment of five SPF 20 sunscreens that were all purchased or produced in 2008. Their performance was simulated on the latest version of the BASF Sunscreen Simulator based on their UV Filter composition (Table 3).

    Figure 7: The evolution of sunscreen quality with regard to sun protection.

    Table 3: Composition of samples A – E used in Figure 7 (For INCI names see Table 4).

    These five samples A-E of SPF 20 sunscreen differ greatly in their ability to protect against UVA radiation. Sunscreens A and B are old-fashioned UVB-biased sunscreens that do not qualify as “broad-spectrum” protection by any standard. Sunscreens C, D and E fulfill the EC recommendation[22] and qualify for the highest JCIA rating before 2013, i.e. PA+++. The distinction between C, D and E can only be seen with the Boots Star Rating and the newly introduced Japanese PA++++ criterion. The highest UVA classes of Boots Star Rating (5 stars) provide better UVA protection than by the European Recommendation (UVA-PF/SPF > 0.33).

    Figure 8 shows commercial European sunscreens between SPF 4 and 60 that comply with the EC recommendation[27], i.e. all values are above the red line UVA-PF = 0.33 SPF. The average UVA-PF over all sunscreens is UVA-PF = 0.5 SPF. We also see the relationship to the other pass/fail or highest category criterion in Australia and Japan (PA++++). They are both absolute criteria disconnected from the SPF value.


    Figure 8: The evolution towards spectral homeostasis. UVA protection and SPF of commercial sunscreens in Europe (2008), compliant with EC recommendation (UVA-PF > 0.33 SPF)[27]

    Sunscreens above SPF 12 and SPF 24 which fulfill EC requirements thus also meet the Australian and Japanese UVA standards : AUS (grey): PPD > 4, JAP (blue): PPD > 8). There are a few sunscreens close to uniform UV protection (Spectral Homeostasis: UVA-PF = SPF, i.e. equal protection over the whoel UVB_UVA range). An SPF 4 sunscreen that complies with the Australian UVA standard already complies with spectral homeostasis, and so would an SPF 8 sunscreen that complies with the Japanese PA+++ category. Above SPF 24, the UVA protection is higher according to EC recommendation than according to the highest Japanese category. The highest UK category (ratio > 0.9 or 0.95) go beyond the EC recommendation towards spectral homeostasis. There are currently no sunscreens beyond homeostasis, i.e. with a UVA biased profile in the UVA-PF > SPF territory. But with view to daily protection and vitamin D synthesis in the skin (via UVB), it may be discussed whether such sunscreens with a UVA bias and greater UVB transmission make sense.

    Evolution of Daily Skin Protection

    Daily skin protection is expected to keep the skin young, supple and healthy. Hence, appropriate protection should help prevent the premature UV-induced formation of lines and wrinkles, loss of elasticity and pigment disorders. Scientific research has brought evidence that any exposure to event sub-acute doses of UV light, and especially to UVA radiation is the major source of premature skin ageing (photoageing). This has led to the introduction of UV protection in daily skin products. However, despite this knowledge about the long-term effects of UVA radiation, UV protection on a daily basis is still mainly UVB focused, although the risk of getting sunburned during a normal working day is rather low. Currently, SPF 15 is recognized as the market benchmark – but the trend is moving towards much higher SPF levels – like in sun protection products. Thanks to the EC recommendation[22] requiring a minimum UVA protection with a UVA-PF of min 1/3 SPF for sun care products, the level of UVA protection in some daily care products has improved although the EC recommendation is only intended to be applied on sun protection products.

    However, due to the cumulative effect of suberythemal UV exposure and the predominance of UVA-induced long-term effects on premature skin ageing – the level of UVA protection in daily care products should be even higher than 1/3 SPF towards spectral homeostasis. As the human skin has adapted during evolution to the specific profile of the solar spectrum reaching the earth, daily protection should not change this profile, in order not to unnecessarily engage in an experiment with unknown outcome.

    Currently, the level of UVA protection is determined via the artificial PPD endpoint. Free radicals and reactive oxygen species can be regarded as the first step in a number of detrimental chain reaction cascades. Recently, methods have been developed to assess free radicals in skin directly and to determine a Radical Skin/Sun Protection Factor (RSF)[28]. In our studies we could show that the RSF correlates well with the level of UVA protection as expected (Figure 9).

    Figure 9: Correlation between Radical Skin/Sun Protection Factor RSF and UVA-PF at SPF 20 samples. Good UVA protection also means good protection from free radicals[26]. Day creams that should protect from free radicals require good UVA protection.

    High UVA-PFs and high RSFs can be best achieved with sunscreens that contain an efficient and photostable UVAI filtering system. Interestingly, we found in our study that the tested market products containing antioxidants and none or only poor UVA protection exhibited only poor radical protection[29]. It could be shown that UVA protection has a much more pronounced effect on the prevention of UV-induced free radicals than antioxidants. However, antioxidants are necessary and able to neutralize free radicals still which are still formed in the skin - as a second line of defense. In order to inactivate free radicals, antioxidants have to penetrate the skin, to replenish and to support the skin’s own antioxidative defense system. This can be achieved by regular and long-term application of antioxidants via topical (day cream and night cream) and/or oral application.

    A strategy for ‘good/adequate’ daily skin protection every day should comprise[30]:

    • Adequate and photostable broad-spectrum UV protection with focus on sufficient UVA protection to prevent the formation of free radicals.
    • Adequate levels of antioxidants in the skin to replenish and support of the skin’s own antioxidative capacity.

    A first step towards adequate daily UV protection would be the adaption of the requirements for sunscreen products (EU recommendation) on daily care products. The evolution of UVA protection in sunscreens clearly demonstrates the tremendous progress that can be achieved when authorities, trade organizations or even an individual powerful retail company takes the lead and sets standards.

    Conclusion

    Our overview over the evolution of UVA protection shows that enormous progress has been made over the last two decades. Modern photostable UVAI and broad-spectrum UV filters are now almost globally available and enable the huge improvement in UVA protection towards spectral homeostasis (Figure 10).

    Figure 10: The evolution (reduction) of UVAI exposure of the skin (in silico experiment on Sunscreen Simulator for SPF 30)

    The various UVA assessment methods are about to be harmonized globally by an ISO task force, but there remain a few unresolved issues in the measurement methods. The UVA protection categories developed regionally, first in Australia, UK and Japan, leading to a significantly improved UVA protection in those regions and other places where these classification systems are used. With the publication of the EC recommendation a further significant improvement of UVA protection has been achieved. There is even the possibility of achieving practically uniform UVB-UVA protection (spectral homeostasis) at least for low to moderate SPFs. For daily care, comparable recommendations from sun care should be applied.

    Table 4: List of UV filter abbreviations, INCI Declarations, USANs and Trademarks.

    Note

    A previous version of this article entitled „Evolution of UVA Protection“ authored by Uli Osterwalder, Dr. Samantha Champ, Dr. Heike Flösser-Müller, BASF SE, Ludwigshafen, Germany; Dr. Bernd Herzog, BASF Grenzach GmbH, Grenzach-Wyhlen, Germany was first published in Cosmetic Science Technology 2010, pp. 70-79.

    References

    • Jablonski NG and Chaplin, G. (2000). The evolution of human skin colouration. J Hum Evol 39: 57-106.
    • Ke Y, Su B, Song X, Lu D, Chen L, Li H, Oi C, Marzuki S, Deka R, Underhill P, Xiao C, Shriver M, Lell J, Wallace D, Wells RS, Seielstad M, Oefner P, Zhu D, Jin J, Huang W, Chakraborty R, Chen Z, Jin L (2001). African origin of modern humans in East Africa: a tale of 12000 Y chromosomes. Science 292: 1151-1153.
    • Haywood R, Wardman P, Sanders R, Linge C, Sunscreens Inadequately Protect Against Ultraviolet A-induced Free Radicals in Skin: Implications for Skin Ageing and Melanoma?, J Invest Dermatol 121:862-868, 2003
    • Wang SQ, Setlow R, Berwik M, Polsky D, Marghoob AA, Kopf AW and Bart RS, Ultraviolet A and melanoma: a review, J Am Acad Dermatol, 2001;44, 837-46
    • Zastrow L, Herrling T, Berliner LJ, Ferrero L, Groth N IFSCC Magazine – vol.6, no.4 (2003) 295-301
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    • McKinlay, A.F. and Diffey, B.L., 1987. A reference action spectrum for ultraviolet-induced erythema in human skin. CIE Journal, 6, 17-22, 1987
    • Halliday G, Renwick Y, Damian D, UVB, UVA and interactive effects are immunosuppressive in humans, ASP meeting, Burlington, CA, 20-25 June 2008
    • Osterwalder U, Herzog B: Chemistry and properties of organic and inorganic UV filters. In: Clinical guide to sunscreens and photoprotection (Lim HW, Draelos ZD, eds), New York: Informa Healthcare, 2009, 11-38
    • Bundesgesetzblatt Jahrgang 2008 Teil I Nr. 19, Artikel 1, p.855, ausgegeben zu Bonn am 24 Mai 2008
    • European Commission, SCCS opinion, ADDENDUM to the OPINION SCCS/1489/12 on Zinc oxide (nano form) COLIPA S76 SCCS/1518/13, 23 July 2013
    • Chardon A, Moyal D, Horseau C, Persistent Pigment-Darkening Response as a Method for Evaluation of Ultraviolet A Protection Assays. In “Sunscreens: Development, Evaluation, and Regulatory Aspects”, 2nd ed., ed.: Lowe, N.J., Shaath, N.A., Pathak, M.A.; Marcel Dekker Inc., New York 1997, 559-582
    • JCIA Measurement Standard for UVAUV-A Protection Efficacy. Japan Cosmetic Industry Association – JCIA 9-14, Toranomon 2-Chome, Minato-Ku Tokyo, p 105 (1995)
    • AS/NZS (1998) Australian/New Zealand Standard AS/ NZS, 2604
    • Diffey, BL, A method for broad-spectrum classification of sunscreens, Int. J. Cosm. Sci., 16, 1994, 47-52

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