Dermatol Clin 24 (2006) xi xii

Preface

Sunscreens

Zoe Diana Draelos, MD Guest Editor

Any area of medicine, including dermatology, focuses on the diagnosis and treatment of active disease and the prevention of either disease relapse or future new disease. In dermatology, few medications are more important in preventing serious disease than sunscreens. Sunscreens scatter or reflect ultraviolet (UV)-B or -A radiation from the sun. The same sun that gives the earth life, also damages DNAproducing actinic keratoses and causes precancerous growths indicative of mild DNA damage, and basal cell or squamous cell carcinomas, cancerous growths indicative of more severe DNA damage. UV radiation, in addition to other factors, also has been implicated in the most serious form of skin cancer, malignant melanoma. The realization that sun exposure causes skin cancer through photoimmunosuppresion and photodamage, however, has escaped many generations of young people who worship the sun wearing scant clothing in mid-day sun. The warming, energizing effect of the sun and the joy of frolicking outside on a sunny day cannot be ignored. Sunscreens provide a method of enjoying the sun in a safer manner. They are not meant to replace common sense in the selection of the time for outdoor activities or the use of protective clothing, but they are the only mechanism available for decreasing the chance of developing skin cancer at a later date.

Sunscreens have been somewhat controversial recently, as some argue that sunscreen use actually increases the risk of skin cancer by encouraging people to increase the amount of time they spend in the sun. This is not the intent of sunscreens. They are intended for use while in the sun for protection, not to extend sun exposure. Further controversy has been generated by nondermatologists who believe people are becoming vitamin D deficient because of sunscreen use. If only sunscreens were so effective as to block out all of the UV radiation. Although this argument is certainly valid, it is not a major concern, because the erratic application of sunscreens does not confer this degree of UV protection. The need for an improved understanding of sunscreens, including how they work, how they are formulated, and how they are used, formed the impetus to put together this issue. Sunscreens are unique in that they are classified as over-the-counter drugs. This means that they only can contain ingredients that have been approved and monographed by the US Food and Drug Administration. This has hampered the introduction of new sunscreen ingredients in the United States; the variety of sunscreens is much greater in Asia, Europe, and South America. This issue will focus on sunscreens as they are marketed and regulated in the United States with an eye to the future as to what new technologies might be expected.

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xii

preface

Sunscreens are the most important part of the preventative armamentarium of the dermatologist. Even though sunscreens are not prescription drugs, they do represent important drugs, and demand understanding. It is the goal of this issue to impart that understanding in a concise, thorough manner.

Zoe Diana Draelos, MD Department of Dermatology Wake Forest University School of Medicine Winston-Salem, NC, USA E-mail address: zdraelos@northstate.net

Dermatol Clin 24 (2006) 1 8

Solar Ultraviolet Radiation: Definitions and Terminology

Paul J. Matts, PhDT
Skin Care, The Procter & Gamble Company, Egham, Surrey, UK

Is UV (ultraviolet) a ray, or is it light, a wave, energy, or radiation? Does the A in UVA really stand for aging and the B in UVB for burning? Should one use a minimum or standard erythema dose? The definition of and terminology associated with UV and its effects on human biology have been, and continue to be, an area where there is abundant potential for confusion and inaccuracy. In recent years, matters have been made worse as the highly exacting field of photobiology has been popularized due to dramatic rises in the incidence of skin cancer in developed geographies and the ensuing need for national education programs. This article includes a brief review of modern definitions, nomenclature, and terminology associated with this topic.

Definition of ultraviolet radiation UV is only a relatively small component of a broad electromagnetic spectrum that is defined by wavelength and frequency. As shown in Table 1, the entire electromagnetic spectrum spans a huge waveband of radiation with wavelengths ranging from 1014 m (g radiation) to 104 m (radio waves). UV refers to a narrow waveband of radiation with wavelengths in the 107-m (hundreds of nm) range, spe-

cifically 100 nm to 400 nm. Radiation in the 400- to 700-nm wavelength region constitutes light, principally because the photoreactive cells of the human retina are sensitive only to this waveband, driving the phenomenon of human vision. Importantly, therefore, it is inappropriate to refer to UV as light, rather as ultraviolet radiation or UVR . According to quantum theory, light and other forms of electromagnetic radiation may at times exhibit properties like those of particles in their interaction with matter. The individual quantum of excitation of electromagnetic radiation is known as the photon (from the Greek word jXtXV, meaning light) and is symbolized by the Greek letter gamma (g). As electromagnetic radiation, thus, UVR is no exception and is quantized in photons. UVR is, therefore, a specific, narrow waveband of electromagnetic radiation that travels, quantized as photons, in waves. Waves are measured not only by their wavelength, however, but also by frequency. Whereas, wavelength is measured in meters, frequency is measured by the number of waves or cycles that pass a given point in 1 s (one cycle per second termed a Hertz [Hz]). Because electromagnetic radiation travels at a constant speed (approximately 300,000,000 m/s), wavelength and frequency are related on a fundamental one-to-one basis by Eq. 1: c f bk or f c=k or k c=f 1

T Skin Care, The Procter & Gamble Company, Rusham Park Technical Centre, Rusham Park, Whitehall Lane, Egham, Surrey TW20 9NW, UK. E-mail address: matts.pj@pg.com

where c is the speed of light (~300,000,000 m/s), f is the frequency in Hertz (cycles/s), and k is wavelength in meters. Shorter wavelength electromagnetic radiation, therefore, has a higher frequency. Frequency and energy are also related at a fundamental level through

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2 Table 1 Approximate wavebands of the electromagnetic spectrum Electromagnetic radiation Gamma radiation X rays UV radiation Visible light Infrared radiation Microwaves Radio waves Waveband (m)

matts

1014 to 1910 1010 to 108 107 to 4107 4107 to 7107 7107 to 103 103 to 102 102 to 104

with aging or burning. Most recently, the subdivision of the 290- to 400-nm waveband into UVB and UVA has been reviewed, and there is now growing support for recognition of a further subdivision of the UVA waveband into: UVAI: 340 nm to 400 nm UVAII: 320 nm to 340 nm The UVAII subdivision now recognizes the relatively high erythemal potential (and, hence, biologic interaction) that the 320- to 340-nm waveband possesses when compared with the remainder of the UV spectral region (ie, UVAI, 340 nm to 400 nm). Although at first appearing confusing and even retrograde, this is actually a perfectly logical outcome of fitting rigid broad spectral regions to a continuous electromagnetic spectrum; after all, it would be nonsense to maintain that a UV photon of 319 nm is meaningfully different in biologic effect to one of 321 nm, even though they would be classed as UVB and UVA photons, respectively. As we shall see, creation of further subdivisions, such as those above, within these relatively large wavebands is acknowledgment of the broad gradation and range of biologic effect across the portion of electromagnetic spectrum occupied by UVR.

the Planck constant (the constant of proportionality relating the energy of a photon to frequency; Eq. 2): Qp hb f 2

where Q p is photon energy (electron volts or eV), h is the Planck constant (6.626 1034 J s), and f is the frequency in Hertz. Quite simply, the shorter the wavelength of electromagnetic radiation, the higher its respective frequency and energy. As regards expanding the definition of UVR, this is a very important relationship as the higher the energy of a UVR photon, the more reactive it is with human biology. This has led to a subdivision of the UVR waveband (100 nm to 400 nm) into three further spectral regions: UVC, UVB, and UVA, based principally on differing biologic effect. The bounds of these spectral regions were determined initially in the 1930s by W.W. Coblentz, of the U.S. National Bureau of Standards, and colleagues [1] by using the transmission properties of three common filters. A pyrex filter determined the UVC waveband (100 nm to 280 nm, germicidal UVR, absorbed almost entirely by stratospheric ozone), a barium-flint-pyrex filter, the UVB waveband (280 nm to 315 nm, so-called erythemal UVR, the lower end of this waveband also marking the upper cut-off for the absorption spectra of protein and DNA), and a barium-flint filter defined the UVA (315 nm to 400 nm; black light). These wavebands became endorsed at the 2nd International Congress on Light in Copenhagen in 1932 and again by the La Commission Internationale de lEclairage (CIE) in 1970 [2]. These spectral divisions are, therefore, somewhat arbitrary. Most modern dermatologists and photobiologists have redefined and cite these three wavebands thus: UVC: 200 nm to 290 nm UVB: 290 nm to 320 nm UVA: 320 nm to 400 nm Clearly, therefore, the origin of the A and B nomenclature of these wavebands has nothing to do

Ultraviolet radiation radiometric symbols, units, and nomenclature Before defining solar UVR, we must first introduce the language and terminology of radiometry, the science of measurement of electromagnetic radiation spanning wavelengths from 108 m to 103 m (including, of course, UVR). This should be differentiated from photometry, which relates to electromagnetic radiation detectable by the human eye (all terms, thus, weighted correspondingly by the eyes spectral response). To simplify the text of this short summary, the most commonly used radiometric terms and their respective meanings and recommended symbols are listed in Table 2. In general, radiometric units can be divided into two conceptual areasthose relating to (1) either energy or flux (ie, specific to a wave of electromagnetic radiation passing through space) and (2) those related to the geometric quantities of area and solid angle (ie, specific to the relationship of this radiation to either the source [radiant intensity and radiance ] or the object that is struck by it [irradiance ]).

solar uv radiation: definitions Table 2 Common radiometric terms, units, and recommended symbols Term Wavelength Flux Energy Radiant intensity Radiance Irradiance Dose (radiant exposure) Spectral irradiance Unit nm W J W sr1 W m2 sr1 W m2 J m2 W m2 k1 Recommended symbol k / Q I L E H Ek

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terminology

It should be noted that the terms described previously give no information about the distribution of these quantities as a function of wavelength. Spectral quantities, therefore, are derivative quantities per unit wavelength and usually have the prefix spectral and the term k1 in their units. When integrated over wavelength, they give the total quantity and are denoted by using the subscript k (eg, E k, I k, and so forth). Lastly, irradiance integrated over time gives expressions of dose (often used as a term in its own right), commonly referred to in radiometry as radiant exposure . For more information relating to radiometry symbols, units, and nomenclature (SUN), the reader is referred to the work and publications of the Consultative Committee on Photometry and Radiometry (CCPR; for useful links go to http://www1.bipm.org/ en/home), a subcommittee of the General Conference on Weights and Measures (CGPM).

Definition of extraterrestrial and terrestrial solar ultraviolet radiation So far, UVR has been discussed in general terms. Apart from artificial sources of this radiation, which forms a separate topic, human exposure to UVR can be attributed solely to the sun. Extraterrestrial UVR can be defined as solar UVR impinging on the outermost surface of the earths atmosphere. The solar constant I0 is the amount of energy received at the outermost surface of the earths atmosphere on a plane oriented perpendicular to the suns rays (at the mean distance of the earth from the sun). The generally accepted solar constant of 1368 W m2 is a satellite-measured yearly average. Variations of 3.4% in the distance of the earth from the sun due to the elliptical nature of the earths solar orbit (from

a minimum at perihelion on approximately January 3 to a maximum at aphelion on approximately July 5) cause the actual intensity of solar radiation at the outer surface of the atmosphere to depart correspondingly from I0 by a few percent. Further minor fluctuations in solar output can be attributed to the 27-day rotation of the sun and a 22-year sunspot cycle. What is the quality, or spectrum, of this extraterrestrial irradiance? The Stefan-Boltzmann law predicts intensity output across varying wavelengths as a function of temperature and describes the ideal blackbody radiator. The sun approximates a blackbody radiator at a temperature of 5900 K and, as a result, approximately 8% of extraterrestrial solar electromagnetic radiation is UVR. Given that human exposure to solar UVR is normally limited to ground-level, what are the factors shaping the quantity and quality of this radiation reaching the earths surface? The overwhelming phenomena influencing these quantities are attenuation and scattering by the earths atmosphere. At altitudes greater than 40 km, stratospheric ozone drives a dramatic spectrally-dependent attenuation of solar UVR. As a result, lethal solar UVC wavelengths of 290 nm and lower are completely absorbed, UVB is strongly attenuated, but UVA is transmitted virtually unaffected. This effect can be seen in Fig. 1, constructed using data supplied by the Meteorological Service of Canada, showing the virtual onefor-one correlation between the stratospheric ozone absorption spectrum and resulting ground-level solar spectrum between 290 nm and 320 nm. Note the flat spectral irradiance of extraterrestrial solar light with its characteristic Fraunhofer lines. The spectral quality of ground-level solar UVR is shaped predominantly, therefore, by stratospheric ozone absorption, with a relatively constant attenuation of approximately 40% due to air molecules and background aerosols. It can be see that, whereas depletion of the ozone column would significantly impact surface UVB irradiance, there would be minimal effect on broadband UVA (a phenomenon that climatologists use to verify or otherwise increases in groundlevel UV due to ozone depletion). How does this weighted absorption affect groundlevel UV incidence? Quite simply, we inherit a solar spectrum that is relatively rich in UVA and poor in UVB. As an approximate guide, at noon on a midsummer day in Northern European latitudes, the unshaded surface irradiance in the UVB is less than 3 W m2, compared with a UVA irradiance of around 40 W m2 (Colin MH Driscoll, UK National Radiological Protection Board data, personal communica-

matts

Fig. 1. Spectral absorption of extraterrestrial ultraviolet radiation (UVR) by stratospheric ozone and consequent effect on the spectral irradiance of ground level solar UVR (290 nm to 320 nm). (Data from Vitali Fioletov, Meteorological Service of Canada.)

tion, 1999). As a percentage of total surface UVR irradiance (290 nm to 400 nm), therefore, UVB represents approximately only 5%, the balance being made up by UVA. The spectral irradiance of terrestrial UVR measured at 38S (Melbourne) and
1.4

38N (Albuquerque) at noon, under a clear sky is shown in Fig. 2. Because of this attenuation taking place high above the earths surface, solar altitude (that is, the elevation of the sun above the horizon) plays an

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Spectral Irradiance (W m-2 nm-1)

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Fig. 2. Spectral irradiance of terrestrial solar UVR measured at 38N (Albuquerque; dashed line ) and 38S (Melbourne; solid line ). (Data from Sayre RM, Cole C, Billhimer J, et al. Spectral comparison of solar simulators and sunlight. Photodermatol Photoimmunol Photomed 1990;7:159 65; and Gies HP, Roy CR, McLennan A, et al. UV protection by clothing: an intercomparison of measurements and methods. Health Phys 1997;73(3):456 64.)

solar uv radiation: definitions

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important role in determining atmospheric path length and, thus, disproportionate relative attenuation of UVB. Solar altitude varies with
 Time of day: diurnal variation  Season: due to the tilt of the Earths axis of

rotation, a 23.4 offset of the axis from a direction perpendicular to the Earths orbital plane that causes the Northern Hemisphere to tilt toward the sun in the summer and away from the sun in winter, as it moves through its orbit, an effect reversed in the Southern Hemisphere  Geography: latitude and longitude Quite simply, as the solar zenith angle (that is, the angle between the sun and a local line of zenith drawn from the earths center) increases and solar altitude decreases, the stratospheric ozone column becomes longer, driving a progressively greater attenuation of short-wave UVR. This results in a terrestrial solar spectrum that is relatively richer in UVA at dawn/dusk, in the winter months and at higher latitudes. In broad terms, therefore, one can say that terrestrial UVA irradiance is less subject to zenith angle

effects than UVB. It is a gross misrepresentation, however, to state that UVA irradiance is somehow constant throughout the day or year, a modern myth that has been widely propagated. UVA irradiance is subject to exactly the same diurnal, seasonal, and geographic fluctuations as UVB irradiance, only slightly less so. Several other factors determine the precise quality and quantity of UVR that reaches ground-level. These are summarized, together with those phenomena noted previously, in Table 3.

Artificial ultraviolet radiation sources Having defined extraterrestrial and terrestrial solar UVR, some short comment on artificial sources of UVR is necessary. These sources (eg, xenon-arc or fluorescent lamps) are used in a range of applications including phototherapy of specific skin diseases (eg, psoriasis, vitiligo) and standard industry test methods to measure the photoprotective properties of commercial sunscreen formulations (eg, sun protection factor [SPF] testing). The former applications tend to use sources filtered to produce highly artificial broad- or narrow-band UVA or UVB

Table 3 Summary of factors that determine quality and quantity of terrestrial ultraviolet radiation Factor Time of day Effect

Diurnal variation in UVR, with maximum irradiance at solar noon. Approximately 20% 30% of total UVR is received at the surface between 11 am and 1 pm; 75% is received between 9 am and 3 pm. High zenith angles at dawn and dusk drive disproportionate attenuation of short-wave UVR, resulting in solar spectrum slightly richer in UVA. Season Pronounced annual cycle driven primarily by tilt in earths axis, resulting in maximal irradiance in summer months, minimal in winter months in either hemisphere respectively. High zenith angles (h ) in winter (eg, h = 75 on December 22 vs h = 28 on June 21, in London [52N]) drive disproportionate attenuation of short-wave UVR, resulting in solar spectrum slightly richer in UVA in winter months. The degree of seasonal variation, however, is latitude-dependent, with least variation seen at the equator. Geography Terrestrial UVR incidence increases with decreasing latitude, with highest irradiance and annual surface dose values recorded at the equator. Altitude A 1-km increase in altitude results in a 10% 25% increase in UVR irradiance, depending on wavelength. At 300 nm, a 24% change has been recorded vs a 9% change at 360 nm, over a vertical kilometre. These spectral differences can be attributed to the relative contributions of Rayleigh scattering, ozone absorption and aerosol at these different wavelengths (at 300 nm, 27%, 57%, and 16% respectively; at 360 nm, 54%, 0%, and 46% respectively). Surface reflection The albedo (the fraction of radiation striking a surface that is reflected by that surface) of various surfaces can cause significant variation in local ambient UVR (eg, although most ground surfaces have albedos of <10%, snow has values of 30% 80% and sand 15% 30%. Water reflects only little incident UVR [<5%]). Cloud cover Mie scattering accounts for an attenuation of ground-level UVR with little spectral dependence. Attenuation is fairly unpredictable, with the following main factors to be taken into consideration: fractional sky coverage, cloud opacity, cloud height, solar zenith angle. Subsidiary factors include: condensed water distribution in three dimensions, solute present in condensate and other trapped chromophores/aerosols. In general terms, scattered light clouds have little effect on surface UVR and complete light cloud cover reduces surface UVR by about 50%.

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spectra, whereas sources filtered to produce solarsimulated UVR are used in SPF testing. With both types of filtered source, accurate measurements (using a calibrated spectroradiometer ) of output spectrum shape and power are absolutely critical. Without these measurements, the terms UVA, UVB, or solarsimulated are meaningless and misleading, and interpretation of biologic effect is impossible. Solarsimulated UVR is a filtered approximation of a ground-level measurement taken at a specific latitude, in prevailing weather conditions, using specific instrumentation. In this sense, a filtered lamp can never hope to replicate ground-level solar UVR, and this should be recognized when considering in vivo photoprotection testing (and particularly when considering biologic endpoints driven by heavily filtered nonsolar spectra, eg, so-called persistent pigment darkening).

Measurement of biologically effective dose of solar ultraviolet radiation in humans While other authors will review the wide range of biologic effects exerted by solar UVR in the human model, this is not the intent of this section. What we are concerned with here is the question of a standardized means of measuring and communicating the deleterious human biologic effects of solar UVR. While acknowledging that solar UVR may exert damaging effects on other human biology (eg, the tissues of the eye), this article is focused on skin, the human biologic substrate with most surface area (approximately 2 m2 in an average adult human) and at most risk from solar UVR exposure. In seeking a standardized means of expressing UVR skin damage in a human individual, one needs to use skin itself as a meter, ideally in vivo, using a damage endpoint that responds to solar UVR in a predictable manner. Ideally, this damage endpoint will be acute (ie, will present within a short period of time after solar UVR exposure), easily measurable, providing interval data that can be subjected to parametric statistical procedures for further analysis. Lastly, the value obtained from this measure should ideally also reflect inherent susceptibility to a broad range of other solar UVR damage. Bearing in mind the ideal requirements noted earlier, erythema or acute sunburn provides a solar UVR damage endpoint that fulfils these criteria to a great extent. Erythema presents as a visible reddening of UVR-exposed skin due to dilation of vasculature in the dermal plexus and corresponding increase in dermal blood fraction volume. Although many possible peripheral mechanisms are still debated,

the underlying cause of UVR-induced erythema appears to be pro-inflammatory. Although an acute response, there is a time-course of expression that, in Caucasian skin, commences with an initial presentation of barely perceptible reddening by approximately 4 hours after exposure, proceeding to full presentation within approximately 8 to 12 hours of exposure (fading within 1 to 2 days) [3,4]. The dose required to elicit this response is termed the minimum erythema dose (MED) and varies from individual to individual, depending on several factors including epidermal melanin fraction volume (a function of ethnicity and tanning status) and stratum corneum thickness. The MED is often used as an expression of biologically effective dose (BED) in its own right, but it must be understood that an MED value is linked intrinsically with the individual from whom the measurement was taken. For example, even taking the classic semiobjective Fitzpatrick classification (based on susceptibility to sunburn and propensity to tanning), while an overall increase in mean MED (J cm2) is observed that is commensurate with skin type, intratype variability in MED is not inconsiderable [5]. Although an MED is a critical descriptor of individual susceptibility to erythemally effective UVR, therefore, it cannot be understood as a standard term. To understand a more recent attempt to standardize a UVR erythemal BED, one must first appreciate that for any biologic response produced by electromagnetic radiation, it is critical to define the relative effectiveness of energy at different wavelengths in producing this effect. An action spectrum is a parameter that describes this spectral biologic response and is used as a weighting factor for the UVR spectrum to derive the actual BED for a given effect. The effect of using an action spectrum in this way can be described mathematically as in Eq. 3: biologically effective irradiance Z 400 S kAkd k mW cm2
290

where S (k ) is the source spectrum and A (k ) is the action spectrum in question. When integrated over time, the UVR BED for the endpoint in question can be derived from this irradiance value. Several attempts have been made to measure a UVR action spectrum for erythema in human skin, all using a barely perceptible reddening of the skin, 8 to 24 hours after exposure to varying doses of different wavelengths of UVR as an endpoint [6 10]; it is the reciprocal of this dose that is plotted against wavelength to provide the apparent erythema action

solar uv radiation: definitions

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spectrum . Unsurprisingly, these various action spectra show some variability (inherent with biologic systems) and, therefore, some of these were combined to generate a reference erythema action spectrum that has been adopted by the CIE [11] and shown in Fig. 3. It can be seen clearly that UVR wavelengths up to 300 nm are the most effective in eliciting erythema and, thus, the remainder of the action spectrum is normalized to unity at this waveband. There is an approximate two-decade reduction in erythemal effectiveness from 300 nm to 320 nm and a further decade reduction to 340 nm. In general terms, therefore, despite its prevalence in terrestrial UVR, the UVA waveband is approximately 1000 times less effective than the UVB waveband in eliciting erythema in human skin. The term standard erythema dose (SED) has been proposed, therefore, to overcome the inherent individual variability associated with the MED term [12]. The SED represents a fixed dose of 100 J m2 and is weighted by the CIE erythema action spectrum and the spectral power distribution of the source. In theory, this should mean that the SED is now independent of (1) the specific spectral power distribution of the source and (2) individual erythemal thresholds. This has since been borne out in studies by Harrison and Young [5]. The SED term in no way negates the value of the MED; the two terms are equally valid but are used to describe quite separate concepts.

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0.1 0.01

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Fig. 4. La Commission Internationale de lEclairage (CIE) erythema action spectrum (solid line ) overlaid with that for DNA damage (long dashed line ), nonmelanoma skin cancer (dotted line ), and thymine dimer induction (square dotted line ). (Data from Refs. [10,11,13,14]).

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0.1 0.01 0.001 0.0001 0.00001

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Does the erythema action spectrum only provide information about the relative effectiveness of UVR in eliciting an unwanted vascular response in skin and, therefore, only a limited description of biologic damage? The short answer from this author is a firm no. In Fig. 4, the CIE erythema action spectrum has been overlaid with the widely accepted action spectra for DNA damage [13], nonmelanoma skin cancer [14], and thymine-dimer induction [10]. All spectra are comparable, each with clear maximal effectiveness at 300 nm and at least a three-decade reduction in effectiveness from 300 nm to 320 nm and beyond. All these endpoints appear to reflect a common damage mechanism. As erythema can be understood as a surrogate for skin cancer-related endpoints, therefore, methods that use erythema as an endpoint for measuring protection against sunburn (ie, the in vivo SPF test) are also an indirect measure of protection against these other forms of cutaneous UVR damage. The erythemal response of skin to UVR, therefore, is of primary importance, and a proper understanding of correct associated terminology is absolutely essential.

Relative spectral response

Wavelength (nm)

Fig. 3. La Commission Internationale de lEclairage (CIE) erythema action spectrum. (Data from Standard CIE. Erythema reference action spectrum and standard erythema clairage; dose. Vienna: Commission Internationale de lE 1998 [CIE S 007/E-1998].)

Summary As the field of photobiology continues to grow with concurrent integration of its findings and

matts In: Urbach F, Gange RW, editors. The biological effects of UVA radiation. New York7 Praeger; 1986. p. 57 65. Anders A, Altheide HJ, Knalmann M, Tronnier H. Action spectrum for erythema in humans investigated with dye lasers. Photochem Photobiol 1995;61(2): 200 5. Kollias N, Malallah YH, al-Ajmi H, et al. Erythema and melanogenesis action spectra in heavily pigmented individuals as compared to fair-skinned Caucasians. Photodermatol Photoimmunol Photomed 1996;12(5): 183 8. Young AR, Chadwick CA, Harrison GI, et al. The similarity of action spectra for thymine dimers in human epidermis and erythema suggests that DNA is the chromophore for erythema. J Invest Dermatol 1998;111(6):982 8. Standard CIE. Erythema reference action spectrum and standard erythema dose. Vienna7 Commission Interna clairage; 1998 [CIE S 007/E-1998]. tionale de lE Diffey BL, Jansen CT, Urbach F, Wulf HC. The standard erythema dose: a new photobiological concept. Photodermatol Photoimmunol Photomed 1997; 13(1 2):64 6. Setlow RB. The wavelengths in sunlight effective in producing skin cancer: a theoretical analysis. Proc Natl Acad Sci USA 1974;71(9):3363 6. de Gruijl FR, Van der Leun JC. Estimate of the wavelength dependency of ultraviolet carcinogenesis in humans and its relevance to the risk assessment of a stratospheric ozone depletion. Health Phys 1994; 67(4):319 25.

recommendations into public policy, there is an increasing need for the use of correct and standardized terminology and nomenclature in this highly technical discipline. A proper understanding of the origin of many of the terms that are taken for granted and consequently misused should help to facilitate clear and correct communication, free of myth and confusion.

[8]

[9]

References
[10] [1] Coblentz WW, Stair R, Hogue JM. The spectral erythemic reaction of the human skin to ultraviolet radiation. Proc Natl Acad Sci USA 1931;17(6):401 5. [2] CIE International Lighting Vocabulary. Paris. Bureau Central de la Commission Internationale de lEclairage 1970. [3] Olson RL, Sayre RM, Everett MA. Effect of anatomic location and time on ultraviolet erythema. Arch Dermatol 1966;93:211 5. [4] Farr PM, Besag JE, Diffey BL. The time-course of UVB and UVC erythema. J Invest Dermatol 1988;91: 454 7. [5] Harrison GI, Young AR. Ultraviolet radiation-induced erythema in human skin. Methods 2002;28:14 9. [6] Parrish JA, Jaenicke KF, Anderson RR. Erythema and melanogenesis action spectra of normal human skin. Photochem Photobiol 1982;36:187 91. [7] Gange RW, Park YK, Auletta M, et al. Action spectra for cutaneous responses to ultraviolet radiation.

[11]

[12]

[13]

[14]

Dermatol Clin 24 (2006) 9 17

An Overview of Ultraviolet Radiation, Sunscreens, and Photo-Induced Dermatoses

N.J. Lowe, MD, FRCPa,b,c,T
a

Department of Dermatology, University of California School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA b Clinical Research Specialists, Santa Monica, CA, USA c Clinical Research Specialists, London, UK

The incidence of sunlight-induced skin aging and skin cancers has been increasing in many parts of the world. In particular, the incidence of melanoma skin cancer has shown a well-documented increase in several continents over the last few years [1]. Many authorities are recommending primary prevention programs to reduce cutaneous photodamage and skin carcinogenesis. An integral component of these programs is the use of protective clothing [2] and effective sunscreens [3,4]. Most modern sunscreens have highly efficient absorption or reflecting capabilities throughout ultraviolet B (UVB), partly ultraviolet A (UVA), and in some instances infrared wavelengths. Over the last several years, more efficient sunscreening ingredients have been developed for improved skin protection [5 8]. More recently, direct evidence has been derived from a large population study in Australia of the effectiveness of sunscreens in their ability to reduce the incidence of solar keratoses [4]. This article reviews the protectiveness of sunscreens and assays that predict their levels of protection.

History of sunscreens In 1928, the worlds first commercial sunscreen an emulsion of benzyl salicylate and benzyl cinnamatewas developed in the United States. In the 1930s, a phenyl salicylate appeared on the Australian market. In 1935, lotions of quinine oleate and quinine bisulfate were available in the United States. In 1943, p -aminobenzoic acid (PABA) was patented, introducing this popular agent and subsequently its derivatives. The United States military used red petrolatum, a physical blocking agent, as a sunblock during World War II. Other UV-filtering agents, including glycerol PABA, 2-ethylhexyl salicylate, digalloyl trioleate, homomenthyl salicylate, and dipropylene glycol salicylate, were developed subsequently [5]. Most of the early agents were directed toward UVB, the portion of the solar spectrum responsible for the most obvious effect, the familiar sunburn. Recent history 4-T-butyl-40-methoxydibenzoylmethane (avobenzone or Parsol 1789) was developed and tested in the 1980s. Broadly effective against the UVA spectrum, it is now marketed in combination with UVBblocking agents. These formulations provide broadspectrum chemical sun protection to consumers in the United States [6,7]. But recent reports suggest it becomes photoinstable in some formulations [8] (Robert Sayre, personal communication, 2004).

Parts of this article are from Baran R, Maibach H, editors. Textbook of cosmetic dermatology. 2nd edition. London: Martin Dunitz; 1998; with permission. T Department of Dermatology, University of California School of Medicine, University of California at Los Angeles, Los Angeles, CA. E-mail address: nlowecrs@aol.com

0733-8635/06/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2005.08.001

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Micronized reflecting powders have been made available more recently from a variety of manufacturers. Unlike traditional physical blockers, micronized reflecting powders are less visible, yet provide broad-spectrum protection against UV radiation. Antioxidants such as tocopheryl acetate and vitamin C products are also being incorporated with sunscreens as putative free-radical scavengers. They may offer modest sunprotection (eg, up to sunscreen protection factor [SPF] 4); it is not clear if they lead to post-UV repair by free radical quenching [9]. New developments Terephtalylidene dicamphor sulfonic acid (Mexoryl SX), a more recent compound approved in Europe and Canada but not yet in the United States, has shown excellent photostablity and is frequently formulated with avobenzone and UVB absorbers as a broad-spectrum sunscreen. It is likely that sunscreens containing these new filters will be more effective against diseases such as melasma and polymorpheus light eruption (PMLE). More recently a newer development available in Europe is bisethylhexyloxyphenol methoxyphenyl triazene (Tinosorb S). This broadband sunscreen filter also lends photostability to avobenzone-containing sunscreens [8]. Again this filter may give more protection for UVA-sensitive diseases such as PMLE. Bisethylhexyloxyphenol methoxyphenyl triazene containing formulations show good efficacy (personal observations, 2004). Further studies are needed to determine whether these recent filters improve protection against photoaging and UV-induced skin cancer.

assessed for erythema. The amount of exposure necessary to generate uniform but barely detectable erythema is determined. The next day, sunscreen is applied uniformly with a pipette at 2 mg/cm2 or mL/cm2. The sunscreen is allowed to dry for 15 minutes, and then the subject is irradiated for incrementally increasing times, based on the estimated SPF, which is usually determined spectrophotometrically. The volunteer is asked to return again 24 hours later, at which time the skin is re-examined. The SPF is then calculated from the ratio of the protected minimal erythema dose to the unprotected minimal erythema dose [10]. There is some controversy about whether SPF thus defined accurately reflects the action spectra for induction of skin cancer in humans. Also, application of 2 mg/cm3 correlates with using at least 29.6 mL (1 oz) over the bodys surface. Because studies have revealed that most individuals apply about 22.2 mL (0.75 oz, 1.5 mg/cm2 or mL/cm2), the usage SPF may be significantly less than the listed in vivo SPF [11]. SPF is a measure of UVB plus UVA protection, provided that a suitably filtered xenon arc solar simulator is used. For SPF assays, the author uses a 1000-W xenon-arc solar simulator (Oriel) and a 2-mm thick Schott WG 320-nm filter plus a UG 11 filter.

Evaluation of protection against ultraviolet A Currently, there is no consensus regarding an ideal in vivo assay to assess protection against UVA. The UVB spectrum readily causes erythema and can be used for the SPF assay [10]; UVA can cause erythema, but only after a much larger dose. However, the action spectra for other UVA-induced phenomena (eg, photosensitivity dermatitis, photoaging, and development of melanoma and nonmelanoma skin cancer) are not defined specifically. A variety of different assays have been described for evaluation protection against UVA [12]. Phototoxic protection factor The phototoxic protection factor (PPF) was developed to try to decrease the UVA dose necessary to achieve a detectable difference in erythema [6]. This involves sensitizing the subjects skin with 8-methoxypsoralen (8-MOP) either topically or orally, and then comparing the minimal erythema dose, as for UVB sunscreen testing. This is a reliable assay, with clearly defined visual erythema, but can result in long-term pigmentation of skin sites [6]. This has a minimal risk for the volunteers, because each skin site is irradiated only once.

Evaluation of sunscreening agents Evaluation of sunscreen protection factor The US Food and Drug Administration (FDA) approved technique to assess the efficacy of a sunscreen against sunburn is determination of the SPF [8]. The SPF is defined as the ratio of the time of UV exposure necessary to produce minimally detectable erythema in sunscreen-protected skin to that time for unprotected skin. A typical testing protocol is as follows. Skin in a nonexposed area, such as the buttocks or lower back, is covered with lightproof adhesive foil; 1-cm2 areas of foil are removed sequentially so that each area receives a defined dose of UVB. The following day, the patient returns to be examined, and the areas are

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Ultraviolet A erythema protection factor The UVA erythema protection factor (APF) is defined analogously to SPF and assesses the time to induce erythema in UVA-exposed skin. The reliability of such testing is of some question because of the inadequacy of current filters and the long deviation of irradiance with many solar simulators. However, Cole and Van Fossen [13] have described a high-intensity UVA source that they contend is a more effective method to assess UVA protection based on either erythema or tanning in an unsensitized individual. The author has also evaluated this assay using a 1000-W xenon-arc solar simulator (Oriel) filtered with 2-mm thick WG 345 nm plus UG 11 filters. The assay is reproducible, and it can also be used for evaluating water-resistant sun protection against UVA. Pigment-darkening protection factor Immediate pigment darkening (IPD), a UVA and visible spectrum-mediated transient oxidation of preexisting melanin, has also been used to evaluate UVA sunscreen efficacy [14]. This method has been criticized because it must be performed on individuals with darker skin. Pale-skinned individuals, who are the most in need of protection, do not demonstrate easily measurable IPD [15]. The delayed pigment-darkening response evaluated 2 hours after UVA radiation may be more reproducible [16]. The author has also investigated this assay. It requires more UVA energy than for IPD, but it is more reproducible and is practical with a greater variety of skin phototypes than the ID assay. In vitro transmission protection factor The transmission protection factor is defined as the ratio of the photocurrent measured by a spectroradiometer through Transpore TM tape (3M Company, St. Paul, Minnesota) to the photocurrent measured through sunscreen-coated tape at a given wavelength. According to Diffey and Robson [17], this in vitro method provides close agreement with in vivo recorded SPF data. Other techniques include spectrophotometrically comparing sunscreen applied to either a quartz crystal or excised epidermis. Substantivity Substantivity is the characteristic of a sunscreen that reflects how effectively the advertised degree of protection is maintained under adverse conditions, including repeated water exposure of sweating. According to the US FDA, a sunscreen is declared water-resistant if it can maintain its original SPF after two 20-minute immersions. A sunscreen is very

water-resistant if it retains its protective integrity after four 20-minute immersions [10]. Substantivity is of enormous importance, because sunscreens are used outdoors in settings where abundant sweating and repeated immersion in water are common.

Active sunscreen ingredients Protectants against UVB p -Aminobenzoic acid PABA (Table 1) has been available since 1943 and was popular in the 1950s and 1960s. Today, PABA is used infrequently as a sunscreen for a variety of

Table 1 US Food and Drug Admininstration approved sunscreen ingredients in the United States for 1997 Chemical UVA absorbers Oxybenzone Sulisobenzone Dioxybenzone Methyl anthranilate Avobenzone Terephtalylidene dicamphor sulfonic acida Bisethylhexyloxyphenol methoxyphenyl triazeneb UVB absorbers PABA p-Amyldimethyl PABA (padimate A) 2-Ethoxyethyl-p-methoxycinnamate Digalloyl trioleate Ethyl 4-bishydroxypropyl aminobenzoate 2-Ethylhexyl 2-cyano-3,3-diphenylacrylate 2-Ethylhexyl p-methoxycinnamate 2-Ethylhexyl salicylate Glyceryl PABA Homomenthyl salicylate Dihydroxyacetone Octyldimethyl PABA (padimate O) 2-Phenylbenzimidazole-5-sulfonic acid Triethanolamine salicylate Physical blockers Red petrolatum Titanium dioxide Others Bisethylhexyloxyphenol methoxyphenyl triazeneb
a b

Approved (%) 26 5 10 3 3.5 5 23

15 13 8 10 25 15 7 10 2 7.5 35 23 4 25 0.25 3 1.4 8 1.4 5 12 30 100

Mexoryl SX (Europe). Tinosorb (Europe).

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reasons. Its absorption peak at 296 nm is relatively far from the UVB-induced erythema peak at 307 nm. It is poorly soluble in water and must be used as a 5% to 15% solution in alcohol. After application, PABA penetrates the stratum corneum effectively, where it is trapped and remains bonded by hydrogen bonding to epidermal proteins. This greatly enhances its substantivity but also increases the risk of contact or photocontact dermatitis. Sensitivity of this sort is seen in up to 4% of the population [18]. It can cause a stinging sensation when applied and stains both cotton and synthetic fabrics. After photo-oxidation, this can leave a permanent yellow discoloration. PABA is no longer commonly used in sunscreens. p -Aminobenzoic acid derivatives PABA esters are created by the addition of hydrocarbon groups to the PABA molecule. Many of these molecules are improvements over PABA in that they are water-soluble and do not penetrate the stratum corneum. In the past, the most widely used of the PABA derivatives was padimate O, or octyldimethyl PABA, although it is now used in few sunscreens. Salicylates The salicylates are ortho -distributed aromatic compounds with a peak absorption of about 300 nm. Two compounds of this type, octyl salicylate and homomenthyl salicylate (homosalate), are currently approved in the United States. Although not very effective as sunscreens, they have the benefit of being exceptionally stable, essentially nonsensitizing and water-insoluble, leading to high substantivity. They are also useful as solubilizers of other poorly soluble sunscreen ingredients, such as the benzophenones. Cinnamates 2-Ethylhexyl-p -methoxycinnamate (Parsol MCX; absorption maximum 310 311 nm), 2-ethoxyethylp -methoxycinnamate, and octyl methoxycinnamate are available in the United States. These are effective in blocking UVB but have poor substantivity and are generally found in combination with other agents. Cinoxate, the cinnamate most often seen with other cinnamates, is found in balsam of Tolu, coca leaves, and cinnamon oil. Triazines Bisethylhexyloxyphenol methoxyphenyl triazene has recently been approved in Europe as a broadspectrum absorbing agent between about 280 and 380 UV. It is photostable and adds to the stability of other products [8].

Protectants against UVA Benzophenones Benzophenones are aromatic ketones that absorb predominantly in the UVA portion of the spectrum, between 320 and 350 nm. For example, oxybenzone has an absorption maximum of 326 nm in polar solvents, compared with 352 nm in nonpolar solvents. Benzophenone-3 (sulisobenzone) and dioxybenzone are also approved for the United States market. Oxybenzone is frequently implicated as the etiologic agent in photocontact allergy, although reactions have also been reported with dioxybenzone [18,19]. Dibenzoylmethanes Dibenzoylmethanes are substituted diketones that undergo keto enol tautomerism on absorption of UV radiation. The keto forms have a UV absorption maximum of 260 nm, whereas the enol forms absorb above 345 nm. Avobenzone, with an absorption maximum at 355 nm, is the only agent of this class available in the United States. Although these compounds are capable of a high degree of UV absorption [10], they are unstable and in some formulations can undergo photoisomerization to compounds that are not protective. Avobenzone suffers a loss of protective power through photodegradation [20]. Even avobenzone does not provide significant protection against UVA radiation close to 400 nm [6]. Photoinstability of sunscreens Concerns have recently been expressed about the stability of certain sunscreen ingredients when exposed to sunlight. Some examples of photounstable sunscreen filters include combinations of Avobenzone and octyl-methoxycinnamate. The formulation and the choice of other active ingredients are of key importance in stabilizing some filters (for example avobenzone stabilized with terephtalylidene dicamphor sulfonic acid; see also earlier comments on bisethylhexyloxyphenol methoxyphenyl triazene). Physical blockers Physical blocking agents, such as zinc oxide, titanium dioxide, iron oxide, kaolin, ichthammol, red veterinary petrolatum, talc (MgSiOx ), and calamine are composed of particles of a size that scatter, reflect, or absorb solar radiation in the UV, visible, and even infrared ranges. Twenty percent zinc oxide, 20% titanium dioxide as well as 1% iron oxide have been spectrophotometrically demonstrated to reduce trans-

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mittance in the UVA and visible ranges to a maximum of approximately 20%. The combination of the zinc and iron oxides is synergistic, effectively reducing transmittance in the UVA and visible ranges to as low as 1.5%. Older physical blockers had the disadvantage that they were comedogenic, had to be applied in a relatively thick layer, and melted in the sun, staining clothing. They were opaque and therefore visible, making them cosmetically undesirable for many individuals. Recently developed micronized preparations now available in the United States provide an excellent option within this class of sunscreens. Micronized physical blockers are suspensions of finely ground material, such as titanium dioxide, that reflect at wavelengths shorter than the visible spectrum. Because they do not reflect in the visible spectrum, they are invisible and thus more cosmetically acceptable. Micronized titanium dioxide is chemically stable and does not cause any photoallergic or contact dermatitis. Micronized sunscreens are more effective at the shorter UV wavelengths. A major difficulty in formulating micronized sunscreens is preventing agglomeration of the particles. If this occurs, the portion of the spectrum reflected will shift into the visible range and the product will have characteristics of traditional opaque physical blockers. Systemic photoprotection Over the years, a variety of systemic agents has been investigated as oral agents for sunscreening purposes. The appeal is threefold. First, oral agents are convenient. Second, they provide coverage for the entire body. Finally, oral agents are likely to eliminate

the concern over substantivity so critical for topically applied products. Included in the list of these products are PABA, antihistamines, aspirin, indomethacin, retinol, ascorbic acid and a-tocopherols (ie, vitamins A, C, and E), corticosteroids, psoralens, b-carotene, and antimalarials. The last three are used in some individuals afflicted with certain photosensitivity dermatoses.

Sunscreen: clinical usage and efficacy Sun protection for normal skin It is well established that prolonged exposure to UVB leads to deleterious effects on human skin, including photoaging and nonmelanoma skin cancers (NMSC). People should use sunscreens, depending on their skin phototype as described in Table 2. Additionally, all individuals should be encouraged to stay indoors or seek shade during the peak hours of solar radiation flux from 10 am to 2 pm. A hat or a sun visor is a useful addition. Patients with pale complexions should be reassured that fair skin is attractive. Those who insist on darker skin should use a self-tanning lotion containing dihydroxyacetone (DHA). Tanning salons should be avoided, because intense UVA exposure provides limited protection and induces photoaging and photoallergic responses. Persons who spend a significant amount of time outdoors, particularly in areas of high solar flux, should be cautious about the immediate and longterm risks from UV exposure and should be advised about how to protect themselves properly. Such individuals include naturalists, skiers, hikers, bicyclists, fishermen, mountain climbers, and gardeners,

Table 2 Skin types and suggested sunscreen protection factors Suggested SPF Type I II III IV V VI Characteristic Always burns easily, never tans Burns easily, tans slightly Sometimes burns, then tans gradually and moderately Burns minimally, always tans well Burns rarely, tans deeply Almost never burns, deeply pigmented Examples Celtic or Irish extraction; often blue eyes, red hair, freckles Fair-skinned individuals; often have blond hair; many whites Mediterraneans and some Hispanics Darker Hispanics and Asians Middle Easterners, Asians, some African Americans Some African Americans Routine day 15 12 15 8 10 68 68 68 Outdoor activity (waterproof ) 25 30 25 30 15 15 15 15

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as well as members of certain professions (eg, farmers and farm workers, lifeguards, and postal delivery persons). Finally, this information should be disseminated to children at an early age. Childhood is typically the time of life when maximal sun exposure occurs. Childhood sunburns are implicated in increasing risk for malignant melanoma and NMSC and thus should be avoided assiduously. It has been calculated biostatistically that if children consistently used an SPF 15 sunscreen through to the age of 18, the occurrence of NMSC could be reduced by 78%. Sunscreen protection against actinic keratoses In previous animal studies, sunscreens possessing an SPF of 15 or greater were found to be capable of reducing the incidence of cutaneous preneoplasia and neoplasia [4]. In a recent investigation of a large population of Australians, the daily use of a sunscreen that contained a combination of 8% 2-ethylhexyl-p -methoxycinnamate and 2% avobenzone (which had an SPF of 17) resulted in a significant reduction in the number of new actinic keratoses appearing in the sunscreen-protected population, compared with the placebo-cream control population [4]. This study was conducted in 588 individuals over one Australian summer. It confirmed the importance of daily sunscreen protection and the ability of human skin to undergo apparent repair during sunscreen protection. The reversal of epidermal dysplasia suggests that the daily use of effective sunscreens should be an important part of any community program for reduction of UV-induced skin carcinogenesis and aging.

sunscreen as well as removing the offending phototoxic agent. Many plants produce photoactive substances, such as furocoumarins (particularly psoralens), can induce phototoxic reactions. This particular category of phototoxic reactions is termed phytophotodermatitis. It has been noted in vegetable pickers and other food handlers, as well as naturalists. Flower leis given to visitors in Hawaii have also been implicated. Phytophotodermatitis is commonly exploited by dermatologists as part of a therapeutic regimen to control psoriasis and to repigment the skin of people with vitiligo. Patients are administered psoralens either topically or orally and are then exposed to controlled doses of UVA as photochemotherapy. Psoralens in combination with UVA increase the risk of development of NMSC. Therefore it is important to protect patients with UVB- and UVAprotecting sunscreens after PUVA (psoralen plus UVA) phototherapy sessions. Photoallergy reaction Photoallergy involves interaction of the immune system and solar radiation. Photoallergic reactions are rare and are usually triggered by UVA exposure. Individuals with these disorders have previously been exposed to the responsible agent, and, after reexposure to it and UV radiation, develop the dermatitis. Because UVA is most often responsible, it is important to use an effective UVA sunscreen product [6]. Photosensitivity skin disorders Photodermatoses include several disorders. Since afflicted persons are extremely sensitive to the sun, it is essential to provide them with efficacious sunscreens and sun-protective clothing. Polymorphous light eruption (290 365 nm) Polymorphous light eruption (PMLE) is a common, idiopathic skin eruption that occurs in susceptible individuals on exposure to solar irradiation that is more intense than usual. It affects 10% to 14% of the white population, most of them female, with onset usually in the first three decades of life. Typically, PMLE manifests as some combination of pruritic papules, mascules, vesicles, plaques, or confluent erythema 1 2 days (2 hours to 5 days) after sun exposure on areas of unprotected skin. It is seen most commonly at the beginning of summer or during a visit to a geographic clime with a higher solar flux. The reaction resolves over 7 10 days if additional sun

Drug-photosensitive skin reactions Here there is a special need for photoprotective measures, including broad spectrum sunscreens and sun-protective clothing. Because the action spectra for many photosensitive drug reactions or photosensitive disease lie within the UVA, sunscreens are needed that efficiently protect individuals from these UV wavelengths. Phototoxicity reactions Phototoxicity can occur in any individual exposed to photosensitive agents and radiant energy of sufficient intensity. The action spectra usually involve UVA, and it is wise to use a broad-spectrum

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exposure is avoided. As the name suggests, the reaction is polymorphic, although, in a given individual, it is usually a single morphology that remains constant. Investigators have variously implicated UVA, UVB, UVC, visible radiation, x-rays, and even a-particles in the action spectrum. Often, PMLE flares can be prevented by using newer broad-spectrum sunscreens (eg, Mexoryl SX and Tinosorb S). Sunscreens that provide modest UVA protection (eg, benzophenones) are poorly effective for those with PMLE. More efficient UVA-protective sunscreens containing agents such as avobenzone, terephtalylidene dicamphor sulfonic acid, and bisethylhexyloxyphenol methoxyphenyl triazene are more effective. Some patients benefit from prophylactic PUVA photochemotherapy, whereas others respond to oral agents, including antimalarials and systemic coticosteroids. For some, it may be necessary to reduce their sun exposure and to wear effective sun-protective clothing. Porphyrias (400 410 nm) Porphyrias are caused by an inherited or acquired abnormality in the heme metabolic pathway. Substrates for the effected enzyme accumulate, leading to the clinical manifestations. There are a wide variety of porphyrias because of the complexity of heme biosynthesis. Photosensitivity begins in childhood on sunexposed areas, with the acute development of vesicles, bulae, and hyperpigmentation or hypopigmentation. The skin is also more sensitive to trauma than is normal. Chronically, the skin scars atrophically, with mutilating deformities of exposed areas, including cicatrizing alopecia [21]. The action spectrum is in the visible range from 400 to 410 nm (Soret band), and thus these unfortunate individuals must be protected by a physical blocking agent or by adequate clothing. Some sufferers do respond to oral b-carotene. Solar urticaria (290 515 nm) Solar urticaria is a rare, rapidly developing reaction to sun or UV exposure. Minutes after exposure, sensitive individuals develop pruritus, followed by the urticaria and erythema. The reaction quickly runs its course, rarely lasting longer than 24 hours. Persons with this syndrome encompass different subsets. Some produce a serum factor that, after inoculation into a normal subject, transiently permits induction of solar urticaria in the recipient. This group appears to generate an immunoglobulin of the IgE class, which causes the reaction. These patients

can be classified among those with photoallergies. Others cannot transfer the reaction passively, and the mechanism for the development of solar urticaria is unknown. Antihistamines are effective at high doses in a few patients. Maintenance solar exposure and PUVA therapy have also been used successfully in some. Patients should be phototested to determine the wavelengths that promote their reaction and then provided with a protective sunscreen. Alternatively, or additionally, they may be instructed to avoid the sun whenever possible. Chronic actinic dermatitis (290 nm visible) Chronic actinic dermatitis encompasses the gamut of disease described previously as chronic photosensitivity dermatosis and manifests initially as erythematous macules and plaques in sun-exposed areas, including the face, exposed areas of scalp, rim of the ears, back of the neck, forearms, and back of the hands. Over time, this leads to superimposed areas of edema and vesiculation during acute flares. Clinical evaluation in these patients should be conducted by phototesting across a broad portion of the UV and visible spectrum. Histologically, the skin initially resembles a contact dermatitis, but can progress with actinic reticuloid to the pattern of a cutaneous T-cell lymphoma. The portion of the spectrum causing the reaction varies from one person to another. Therefore phototesting and careful selection of sunscreens or avoidance of the sun are mandated in the management of these patients. Treatment options include oral azathioprine, PUVA, with or without prednisone, etretinate, and cyclosporin [22]. Persistent light reaction (290 400 nm) Most patients who develop a chemical photosensitivity dermatitis note that their reaction resolves within a week or two if the offending agent is eliminated. A subset of individuals continues to overreact to the sun in spite of careful avoidance of the putative photosensitizer. This condition is called persistent light reaction, and sometimes resolves in months, although it may persist indefinitely. For some people, the reaction is so severe that it results in a generalized exfoliate dermatitis. Histologically, the tissue shows a dense perivascular round cell infiltrate. In some cases, the mechanism of this reaction is ongoing exposure to some chemical that is not correctly identified and eliminated. In other instances, the offending agent has bonded to dermal proteins in

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such a way that it cannot be eliminated. Often the reaction is idiopathic. The action spectrum may be in the UVB, and UVA is common. Phototesting to determine appropriate protective sunscreens and avoidance of the sun are usually effective in minimizing flares. Lupus erythematosus (290 330 nm) Cutaneous lupus erythematosus (LE) occurs in two broad forms: discoid LE and subacute cutaneous LE. The lesions of discoid LE are typically found on the head and neck and are well-defined, variably sized scaly patches that heal leaving atrophy, scarring, and pigmentary changes. Subacute cutaneous LE manifests as papulosquamous or polycyclic lesions around the neck, the outer aspects of the arms, and the trunk. These lesions are milder than discoid LE and heal without scarring or atrophy. Although UVB appears to be more prominent in LE, UVA also plays a role in some individuals [23]. Interestingly, exacerbations of noncutaneous lupus (eg, nephritis) are sometimes seen after sun exposure. Therefore it is necessary to provide these patients with broad-spectrum sunblock and encourage them to avoid the sun. Oral antimalarials, such as chloroquine, have been used with limited success. Recently, an open-label trial of a broad-spectrum sunscreen containing padimate O and avobenzone reduced the clinical severity of cutaneous LE over a 4-week period [23]. Xeroderma pigmentosum (290 340 nm) The autosomal recessive disorder xerodermic pigmentosum (XP) stems from a genetic defect in the ability to repair DNA. Patients are subject to premature development of skin neoplasms, including malignant melanoma as well as basal cell and squamous cell carcinoma. Patients should aim for careful protection against the sun and vigilant detection of skin cancer. Eye protection should also be emphasized. Albinism Oculocutaneous albinism is an autosomal recessive defect in the formation of melanosomes. Although melanocytes are present, these individuals are either hypomelanotic or amelanotic in the skin and hair. Patients living in areas of high solar flux uniformly develop premalignant (ie, actinic keratoses) or malignant (ie, nonmelanoma skin cancer) skin lesions by early adulthood if they are not careful to apply sunscreen and avoid unnecessary sun exposure.

Melanoma is rare, although the reason for this is unclear.

Summary A relation between UVB exposure and the development of basal cell and squamous cell carcinoma has been documented. It appears likely that high-dose exposure to UV radiation increases the risk of development of malignant melanoma. Prolonged exposure to either UVA or UVB increases the rate of skin aging. Development continues of new, more effective sunscreen filters that will improve photoprotection. Meanwhile, physicians may benefit their patients most by discouraging excessive sun exposure, and encouraging prudent regular use of sunscreens and other sun-protective measures.

References
[1] Scotto J, Fears TR, Fraumeni JF. Incidence of nonmelanoma skin cancer in the United States. Washington, DC7 US Department of Health and Human Services Publication; 1983. p. 82 2433. [2] Sayre RM, Lowe NJ. Scientific poster presentation at the American Academy of Dermatology Meeting. Washington, DC, February 2002. [3] Stern RS. Sunscreen use and non-melanoma skin cancer. In: Lowe NJ, Shaath N, editors. Sunscreens, development, evaluation and regulatory aspects. New York7 Marcel Dekker; 1990. p. 85 92. [4] Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993;329:1147 51. [5] Shaath NA. Evolution of modern sunscreen chemicals. In: Lowe NJ, Pathak M, Shaath N, editors. Sunscreens, development, evaluation and regulatory aspects. 2nd edition. New York7 Marcel Dekker; 1997. p. 3 35. [6] Lowe NJ, Dromgoole SH, Sefton J, et al. Indoor and outdoor efficacy testing of a broad spectrum sunscreen against ultraviolet. A radiation in psoralen-sensitized subjects. J Am Acad Dermatol 1987;17:224 30. [7] Lowe NJ. USA photoprotection. In: Lowe NJ, Shaath N, editors. Sunscreens, development, evaluation and regulatory aspects. New York7 Marcel Dekker; 1990. p. 459 68. [8] Chatelain E, Gabard B. Photostabilization of Avobenzone and ethythexyl methoxycinnamate by ethythexyloxyphenol methoxyphenytriazine (Tinasorb S) a new broadband filter. Photoderm Photobiol 2001; 74(3):401 6. [9] Jing-Yi L, Selim A, Shea CR. UV photoprotection by combination topical antioxidants vitamin C and vitamin E. J Am Acad Derm 2003;48:866 87.

uv radiation, sunscreens, [10] Griffin ME, Bourget TD, Lowe NJ. Sunprotection factor determination in the United States. In: Lowe NJ, Pathak M, Shaath N, editors. Sunscreens, development, evaluation and regulatory aspects. 2nd edition. New York7 Marcel Dekker; 1997. p. 499 512. [11] Gotlieb A, Borget T, Lowe NJ. Sunscreens: effects of amounts of application of sun protection factors. In: Lowe NJ, Pathak M, Shaath N, editors. Sunscreens, development, evaluation and regulatory aspects. 2nd edition. New York7 Marcel Dekker; 1997. p. 583 600. [12] Lowe NJ. Ultraviolet A claims and testing procedures for OTC sunscreen. In: Lowe NJ, Pathak M, Shaath N, editors. Sunscreens, development, evaluation and regulatory aspects. 2nd edition. New York7 Marcel Dekker; 1997. p. 527 36. [13] Cole C, VanFossen R. Measurement of sunscreen USA protection; an unsensitized human model. J Am Acad Dermatol 1992;26:178 84. [14] Kaidbey KH, Barnes A. Determination of USA protection factors by means of immediate pigment darkening in normal skin. J Am Acad Dermatol 1991;25:262 6. [15] Agin PP, Stanfield JW. Letter. J Am Acad Dermatol 1992;27:136 7. [16] Chardon A, Moyal D, Houseau C. Persistent pigment darkening response. In: Lowe NJ, Pathak M, Shaath N, editors. Sunscreens, development, evaluation and regulatory aspects. 2nd edition. New York7 Marcel Dekker; 1997. p. 559 82. [17] Diffey BL, Robson JJ. A new substrate to measure sunscreen protection factors throughout the ultraviolet spectrum. Soc Cosmet Chem 1989;40:127 33.

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[18] Dromgoole SH, Maibach HI. Contact sensitization and photocontact sensitization of sunscreening agents. In: Lowe NJ, Shaath N, editors. Sunscreens, development, evaluation and regulatory aspects. New York7 Marcel Dekker; 1990. p. 313 40. [19] Dromgoole SH, Maibach HI. Sunscreening agent intolerance: contact and photocontact sensitization and contact urticaria. J Am Acad Dermatol 1990;22: 1068 78. [20] Diffey BI, Stokes RP, Forestier S, et al. Suncare product photostability. Eur J Dermatol 1997;7:226 8. [21] Bickers DB, Pathak MA. The porphyrias. In: Fitzpatrick TB, et al, editors. Dermatology in general medicine. 3rd edition. New York7 McGraw-Hill; 1987. p. 1660 715. [22] Roelands RJ. Chronic actinic dermatitis. J Am Acad Dermatol 1993;28:290 4. [23] Callen JP, Roth DE, McGrath MA, Dromgoole SH. Safety and efficacy of a broad spectrum sunscreen in patients with dixcoid or subacute cutaneous lupus erythematosus. Cutis 1991;47:130 6.

Further reading
Mosher DB, Fitzpatrick TB, Ortonne JP, et al. Disorders of pigmentation. In: Fitzpatrick TB, et al, editors. Dermatology in general medicine. 3rd edition. New York: McGraw-Hill, 1987. p. 739.

Dermatol Clin 24 (2006) 19 25

Ultraviolet Immunosuppression: Mechanisms and Consequences

Kaija K. Hanneman, DOa, Kevin D. Cooper, MDa,b, Elma D. Baron, MDa,b,T
a

Department of Dermatology, University Hospitals of Cleveland/Case Western Reserve University, Cleveland, OH, USA b Louis Stokes Veterans Affairs Medical Center, Cleveland, OH, USA

Sun exposure and its effects on cutaneous immunity integrate a complex network of biologic processes. An immune response, such as contact hypersensitivity (CHS), requires a coordinated series of molecular and cellular events in multiple organs. Sun damage alters many of the key pathways involved in generating an appropriate immune response to an antigen. These modifications take place at various points from the absorption of ultraviolet (UV) radiation by specific chromophores in the skin to the generation and action of effector cells that lead to the observed clinical CHS response. Evaluation of skin immune responsiveness is therefore an excellent short-term surrogate for long-term consequences of sun exposure, such as immune suppression and skin cancer risk. Moreover, intervention strategies such as the use of sunscreens, aimed at preventing these adverse effects of solar radiation, may be tested via their effects on cutaneous immunity (Fig. 1).

Key elements of utraviolet immune suppression Antigen-presenting cells Epidermal Langerhans cells (LCs) are the principal antigen-presenting cells (APCs) in the skin. They

T Corresponding author. Department of Dermatology, University Hospitals of Cleveland, 11100 Euclid Avenue, Lakeside 3500, Cleveland, OH 44106. E-mail address: elma.baron@case.edu (E.D. Baron).

have an extensive network of dendrites reaching up to the stratum corneum to detect and recognize foreign antigens that contact the epidermal surface. They comprise the major immune surveillance network of the skin. Often described as sentinels of the cutaneous immune system, these cells first encounter antigens, whether in the form of infectious agents, contact allergens, or tumor antigens. LCs take up and process the antigen, recoil their dendrites, and migrate through the skin and afferent lymphatics to the regional draining lymph node. Through antigen processing, LCs gain functional maturity marked by expression of class II major histocompatibility complex (MHC) and costimulatory molecules (B7-1 and -2) on their surface. In the lymph node, mature LCs efficiently present antigen on class II MHC to CD4+ T lymphocytes. On re-exposure, the activated T cells are then capable of producing an antigenspecific immune response. Cutaneous immunity depends on proper functioning of LCs. Exposure to UVB radiation (280 320 nm) has been shown to alter LC number, morphology, and antigen-presenting function [1]. Within hours of UV exposure, LCs begin migrating from the irradiated epidermis, without the functional maturity to mount an immune response. In response to foreign antigen, UV-irradiated LCs fail to stimulate T-helper (Th)1 cells but preferentially activate Th2 cells, resulting in increased generation of suppressor T cells [2]. Thus migration of LCs coupled with differential activation of Th subsets after antigen exposure translates to a decreased or absent ability to mount an appropriate immune response. Consequently, microbial antigens may be tolerated, and tumor growth rather than re-

0733-8635/06/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2005.08.003

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Fig. 1. (A ) A negative contact sensitivity response was observed when the allergen dinitrochlorobenzene (DNCB) was applied over skin that has been previously irradiated with a suberythemogenic dose of ultraviolet (UV). Even at a suberythemogenic UV dose, immune suppression may be observed in vivo. (B ) In contrast, a positive contact hypersensitivity response was demonstrated when DNCB was applied over skin that was UV-irradiated in the presence of a broad-spectrum SPF 15 sunscreen.

jection occurs. Similar to UVB, UVA radiation (320 to 400 nm) also causes a reduction in LC number and disruption of their functional capacity [3]. These effects of UVA may partially explain its suppressive effects on in vivo contact sensitivity that have been observed in both animal and human studies [4,5]. Cytokines UV-induced immune suppression is modulated through the participation of a number of cytokines including but not limited to interleukin (IL)-1b, tumor necrosis factor (TNF)-a, IL-10, and IL-12 [1,6]. After UV exposure, immunosuppressive cytokines TNF-a and IL-10 are released from damaged keratinocytes. TNF-a is a proinflammatory cytokine that causes the upregulation of intercellular adhesion molecule (ICAM) and MHC class I and class II [7]. TNF-a and IL-1b have been implicated in directing LC migration after UV radiation [8,9]. In vivo studies have implicated TNF-a in UV-induced CHS suppression, but not delayed-type hypersensitivity (DTH) suppression or tolerance [10]. When irradiated mice were pretreated with anti TNF-a antibodies, there was significant reduction of LC migration and CHS suppression [8]. This effect has been mediated via the TNF-a receptor 2 (p75) [10]. IL-10 was first proposed as an important mediator of UV immune suppression when in vitro studies demonstrated its production by keratinocytes in culture after UVB or UVAI irradiation [7,11]. When neutralizing antibodies (Abs) against IL-10 were added to the supernatant from UV-irradiated keratinocytes, the suppressive activity of UV was diminished. Addi-

tionally, the injection of anti IL-10 antibodies to UV-treated mice blocked the in vivo induction of immune suppression [11,12]. Other studies have shown that IL-10 plays a role in the UV-induced suppression of DTH but not CHS. This implies that UV-induced suppression of DTH and CHS are mediated through different pathways. In addition to its role in DTH suppression, IL-10 plays a critical role in the induction and transfer of hapten-specific tolerance. After injection of T lymphocytes from UV-irradiated mice, the neutralization of IL-10 in vivo to recipient mice was associated with a loss of hapten-specific tolerance. The mechanism by which IL-10 suppresses the immune response also involves modulation of antigen presentation by LC. IL-10 inhibits costimulatory molecules such as class II MHC and B7 expression. IL-10 release by UVirradiated keratinocytes preferentially activates Th2 cells. A study by Ullrich [13] demonstrated that spleen cells from UV-treated mice do not effectively present antigen to Th1 cell clones and that injection of anti IL-10 antibody to the mice restored this ability. However, UV exposure enhanced presentation to Th2 cells, and this effect is inhibited by injection of anti IL-10 antibody. The induction of T suppressor cells then leads to release of additional suppressive cytokines, such as IL-4 and IL-10. These studies indicate that the IL-10 released by UVirradiated keratinocytes modulates antigen presentation by LCs such that there is preferential activation of Th2 cells that then secrete additional immune suppressive cytokines and suppress cell-mediated immune responses [12,13]. This supports existing data indicating that UV radiation results in sup-

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pressed Th1 cell function with preferential Th2 activation, resulting in a shift to a Th2-like phenotype [14]. The release of cytokines by UV comes not only from damaged keratinocytes but also from additional sources as well. UVB-induced damage to cutaneous nerves induces the release of neuropeptides such as calcitonin gene-related peptide and substance P from nerve endings, which causes dermal mast cell degranulation and thus the release of additional IL-10 and TNF-a [1]. Infiltrating CD11b+ macrophages after UVB exposure are yet another large source of IL-10 [6,14]. IL-12 is a cytokine produced by polymorphonuclear cells, keratinocytes, and APCs [7]. It is one of the crucial cytokines involved in activation of Th1 lymphocytes and blockade of Th2 activity. Because of this capacity, it has been speculated that IL-12 could neutralize the effects of IL-10 and thus overcome UV-induced immune suppression. A study by Schmitt and colleagues [12] confirmed that injection of IL-12 to UV-irradiated mice prevented UVinduced immune suppression of both DTH and CHS. Treatment of mice with IL-12 also prevented UVinduced generation of suppressor T cells and also counteracted preformed T-suppressor cells in vivo [14]. The mechanisms by which IL-12 exerts these effects are not entirely clear, although an important link has been established between IL-12 and DNA repair [15,16]. It is well documented that UVinduced DNA damage is an important upstream molecular event inducing UV immune suppression. Indeed, IL-12 has been shown to prevent apoptosis of UV-irradiated keratinocytes both in vitro and in vivo. It caused a reduction in UV-induced DNA lesions via induction of specific DNA repair mechanisms, specifically nucleotide excision repair [15]. Schwarz and coworkers [16] demonstrated that the ability of IL-12 to prevent UV immune suppression depends on DNA repair. In their work, IL-12 prevented UV-induced LC depletion and suppression of CHS in wild-type mice but not in mice with deficient DNA repair. IL-12 could not prevent induction of regulatory T cells in mice with deficient DNA repair but was able to overcome UV-induced tolerance and prevent activity of regulatory T cell independent of DNA repair. After UV exposure, IL12 is downregulated, likely due in part to increased levels of Prostaglandin E2. Decreased IL-12 further contributes to UV-induced immune suppression [6,7,17]. Based on data demonstrating that IL-12 can interfere with UV-induced T-suppressor cells and counteract the effects of IL-10, it may have significant therapeutic potential to block UV-induced immune suppression.

T lymphocytes T-suppressor cells play a critical role in UV immune suppression and induction of tolerance, thereby preventing rejection of UV radiation-induced tumors. More than 20 years ago, Kripke [18] first demonstrated that hapten sensitization through UVexposed skin induces hapten-specific tolerance that can be transferred to na ve recipients by injecting donor T lymphocytes. Since this initial discovery, several studies have confirmed that T cells with suppressor or regulatory function are indeed a major component in the process of UV immune suppression and tolerance induction. They have been shown to originate from the draining lymph nodes of UVirradiated mice and have been associated with increased production of IL-10, TGF-b, and inhibition of IL-12 [19]. Phenotypic and cell surface marker characterization of these lymphocytes is far from complete. They are commonly referred to as CD4+ CD25+ T cells. Schwarz and colleagues [20] have demonstrated that after in vitro expansion of these T cells, they secreted a Tr-1 like cytokine pattern, characterized by high levels of IL-10, TGF-b, IFN- g, low levels of IL-2, and no IL-4. Neutralization of IL-10 in vivo in recipient mice was associated with a loss of hapten-specific tolerance in this setting. It was also demonstrated that the T cells responsible for transferring tolerance express the CTLA-4 cell surface marker [20]. CTLA-4 (CD152) is a surface marker expressed on activated T lymphocytes that cross links the B7-2 molecule on APCs [21]. This leads to downregulation of IL-2 and inhibition of a variety of immune responses. Hence when CTLA-4 blocking Abs were injected in vivo, the transfer of suppression was completely lost [20]. Regulatory T cells may interact with Dectin-2, a C-type lectin receptor expressed on APCs, via a still unidentified ligand [22]. Another group of immune effector cells, known as natural killer (NK) T cells, has also been reported to mediate UV-immune suppression and skin tumor development [23]. NK T cells express intermediate amounts of T-cell receptor molecules on their surface and coexpress surface antigens normally found on NK cells. These cells compose only 2% to 3% of the splenic T-cell population and are believed to exert their suppressive function via secretion of high levels of IL-4, similar to Th2 cells, within hours of primary CD3 stimulation. Chromophores: DNA and urocanic acid For immune suppression to occur, UV energy must be converted into a biologic signal. Photo-

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receptors in the skin, such as DNA, urocanic acid, membrane lipids, and proteins, are believed to perform this function [24]. As mentioned previously, there is a strong correlation between DNA damage and certain cytokines involved in modifying immune responses. DNA repair enzymes in the form of bacterial T4 endonuclease V liposomes prevent UVinduced upregulation of the immunosuppressive cytokines IL-10 and TNF-a in vivo [25]. Investigators have shown that topical application of DNA repair enzymes from Micrococcus luteus partially prevented simulated solar radiation (SSR)-induced suppression of CHS to dinitrochlorobenzene in human subjects, indicating that damage to DNA by SSR contributes to UV immune suppression [26]. Trans -UCA is a natural substance formed from deamination of histidine during keratinization, which leads to its accumulation in the stratum corneum [6,7,27]. Exposure to UV causes photoisomerization of trans-UCA to cis-UCA, which exerts immune-suppressive properties [1,6, 7,27]. In the early 1980s, the first suggestion that UCA might be involved in UV immune suppression came with the discovery that trans-UCA has a maximal absorption spectra of 270 nm and thus could be a natural sunscreen [6,7,28]. It was later discovered, using a mouse model, that inhibition of CHS has a similar absorption peak at 270 nm. These identical absorption spectra then strongly implicated UCA as a chromophore for UV immune suppression. Furthermore, when tape stripping was performed to remove stratum corneum, UV immune suppression was prevented [28]. Although evidence exists that both DNA and UCA could act as chromophore and trigger the initial events leading to UV immune suppression, it is unclear what determines which photoreceptor pathway is activated. A study by Kim and colleagues [29] addressed this question and found that neither the dose of UV light nor the light source had any influence on which photoreceptor pathway was activated. They reported that the antigen viability (ie, live versus formalin-fixed) was the critical determinant of which photoreceptor pathway predominated after UV irradiation. Both in vitro and in vivo studies have suggested that the immune-suppressive properties of cis-UCA may be due to modulation of cytokines such as TNF-a, IL-10, and IL-12, as well as LC depletion. When spleen cells are incubated with cis -UCA, there is enhanced IL-10 production by CD4+ T lymphocytes [30]. It is also likely that cis -UCA downregulates IL-12 production as the addition of IL-12 to UV-treated LCs restored their ability to present antigen [31]. In vivo studies have shown that UV-irradiated mice treated topically with cis -UCA

have enhanced tumor growth, whereas those treated with anti cis -UCA antibodies had a decreased incidence of tumor formation [32]. Others demonstrated that treating mice with cis -UCA inhibits CHS and DTH induction, and leads to production of Agspecific T-suppressor cells. However, when mice were treated with anti TNF-a antibody after the injection of cis -UCA, CHS was maintained [10]. Two studies, however, failed to confirm the role of cis UCA as an inhibitor of CHS but did confirm its role in DTH suppression [33,34]. This was accomplished by pretreating UV-irradiated mice with anti cis UCA antibody. DTH suppression, T-suppressor cell induction, and LC depletion were prevented by the antibody, but CHS suppression was unaffected. Other possible contributory molecules Another possible mediator involved especially in UVA-induced immune suppression is nitric oxide (NO). When topical NO inhibitor was applied to UVA-irradiated dorsal skin of mice, it prevented the UVA-induced LC depletion seen in control mice. The same effects were not observed with reactive oxygen species inhibitors, suggesting that NO production may be a particularly important oxidative event causing epidermal LC depletion in response to UVA irradiation [35]. One of the supposed beneficial effects of UVB radiation is the production of vitamin D in the skin, as well as conversion of provitamin D3 (7-dehydrocholestereol) to the active vitamin D3 metabolite (1,25 dihydroxyvitamin D3) [36]. Recent studies investigating the role of vitamin D and its related analogues now demonstrate that it may be responsible for modulating at least some of the immune suppressive effects seen after UV exposure [36 41]. In vitro studies have shown that addition of a vitamin D analogue to mouse dendritic cells led to a state of DC immaturity as well as decreased expression of cell surface maturity markers like MHC class II and costimulatory ligands. Vitamin D receptor (VDR) knockout mice did not exhibit similar effects, indicating that these mechanisms depend on the VDR. DCs pretreated with vitamin D analogue also secreted significantly less IL-12 [37,38]. In vivo studies have shown that when female mice are transplanted with male mouse skin, those pretreated with vitamin D analogue-DCs had significantly prolonged graft survival compared with animals receiving no pretreatment [37]. The in vivo application of the vitamin D analogue calcipotriol to human skin for 4 days resulted in a dose-dependent depletion of CD1a+ LCs with a dendritic morphology and of the number

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of dendrites per cell [39]. Current data suggest that vitamin D and its related analogues inhibit differentiation and induce a persistant state of immaturity in DCs via alterations in surface ligands and production and release of cytokines. VDR ligands also induce generation of CD4+, CD25+ T-regulatory cells that secrete inhibitory cytokines and inhibit Ag-specific T-cell activation. All of these effects depend on the presence of the vitamin D receptor [36,37]. Because of these important immune modulatory effects of vitamin D, and the fact that the skin is an efficient producer of vitamin D after sun exposure, further studies are warranted to identify and characterize its possible contribution to UV immune suppression in humans. UV radiation also alters cellular redox equilibrium and causes reactive oxygen species formation and membrane lipid peroxidation. Oxidative damage to cellular components may likewise contribute to immune suppression. Using a murine epidermal DC line, hydrogen peroxide was shown to mediate UVB impairment of antigen presentation [42]. The ability of various antioxidants to interfere with UV-induced immune suppression and tolerance induction suggests further that UV-induced oxidative stress contributes to immune suppression [43,44].

sion compared with only 60% of age-matched individuals without a prior skin cancer history [48]. Re-sensitization of these volunteers showed that 45% of the nonmelanoma skin cancer group versus none of the healthy controls has been rendered immunologically tolerant. Studies on DNA repair in patients with Xeroderma pigmentosum, skin cancer history, and those undergoing systemic immunosuppression all suggest that skin cancer growth is facilitated not only by faulty nucleotide excision repair of UVinduced lesions in the genome but also via creation and persistence of an immunologically tolerant cytokine environment [49].

Summary In summary, cutaneous exposure to UV radiation induces a complex network of biologic events that modulate the immune equilibrium such that the balance becomes tilted toward suppression rather than activation. Although UV itself is a complete carcinogen, its immunomodulatory effects further contribute to cutaneous neoplasia, as well as to other events that rely on an intact cutaneous immune system, such as resistance to microbial infections. Measures to protect against UV immune suppression could be evaluated via use of cutaneous immune responses such as CHS. Interventions and strategies aimed at preventing skin cancer must take into consideration the various mechanisms contributing to UV immune suppression to maximize their efficacy.

Skin cancer and ultraviolet immune suppression As mentioned earlier, UV carcinogenesis studies in mice indicate an important immunologic component in tumor induction. The antigenicity of these tumors has been established decades ago [45]. Tumor transplantation experiments using syngeneic mice with and without prior UV irradiation demonstrated that rejection of highly antigenic nonmelanoma skin cancers is observed in immunocompetent mice but not in mice that received immunosuppressive but subcarcinogenic doses of UV (reviewed in [46]). Furthermore, such inability to reject skin tumors can be passively transferred to other mice through transplantation of viable lymphoid cells. The development of tolerance to cutaneous antigens, including tumor antigens, is mainly attributed to the generation of T-suppressor or T-regulatory cells. The presence of suppressor T lymphocytes precedes and affects the development of primary tumors [47]. In humans, studies have demonstrated that nonmelanoma skin cancer patients are much more susceptible to UVinduced suppression of CHS. As high as 92% of patients with a previous history of either basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) showed susceptibility to UVB-induced CHS suppres-

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[1] Granstein RD, Matsui MS. UV radiation-induced immunosuppression and skin cancer. Cutis 2004; 74(Suppl 5):4 9. [2] Shreedhar VK, Pride MW, Sun Y, et al. Origin and characteristics of ultraviolet-B radiation-induced suppressor T lymphocytes. J Immunol 1998;161: 1327 35. [3] Dumay O, Karam A, Vian L, et al. Ultraviolet AI exposure of human skin results in Langerhans cell depletion and reduction of epidermal antigen-presenting cell function: partial protection by a broad-spectrum sunscreen. Br J Dermatol 2001;144:1161 8. [4] Fourtanier A, Gueniche A, Compan D, et al. Improved protection against solar-simulated radiation-induced immunosuppression by a sunscreen with enhanced ultraviolet A protection. J Invest Dermatol 2000; 114(4):620 7. [5] Baron ED, Fourtanier A, Compan D, et al. High ultraviolet A protection affords greater immune pro-

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J Immunol 1992; 148:3072 8. Rivas JM, Ullrich SE. Systemic suppression of DTH by supernatants from UV-irradiated keratinocytes: an essential role for interleukin-10. J Immunol 1992; 149(12):3865 71. Schmitt DA, Owen-Schaub L, Ullrich SE. Effect of IL-12 on immune suppression and suppressor cell induction by ultraviolet radiation. J Immunol 1995; 154:5114 20. Ullrich S. Mechanisms involved in the systemic suppression of antigen presenting cell function by UV radiation: keratinocyte-derived IL-10 modulates antigen-presenting cell function of splenic adherent cells. J Immunol 1994;152:3410 6. Schmitt D, Walterscheid J, Ullrich S. Reversal of ultraviolet radiation induced immune suppression by recombinant interleukin-12: suppression of cytokine production. Immunology 2000;101:90 6. Schwartz A, Stander S, Berneburg M, et al. Interleukin-12 suppresses ultraviolet radiation induced apoptosis by inducing DNA repair. Nat Cell Biol 2002;4(1):26 31. Schwartz A, Maeda A, Kernebeck K, et al. Prevention of UV radiation induced immunosuppression by IL-12 is dependent on DNA repair. J Exp Med 2005; 201(2):173 9. Murphy G. The acute effects of ultraviolet radiation on the skin. Chapter 4. In: Hawk JLM, editor. Photodermatology. London7 Chapman & Hall; 1998. p. 43 52. Kripke ML. Immunological unresponsiveness induced by ultraviolet radiation. Immunol Rev 1984; 80:87 102. Shreedar V, Pride M, Sun Y, et al. Origin and characteristics of ultraviolet B radiation-induced suppressor T lymphocytes. J Immunol 1998;161:1327 35. Schwarz A, Beissert S, Grosse-Heitmeyer K, et al. Evidence for functional relevance of CTLA-4 in ultraviolet-radiation-induced tolerance. J Immunol 2000;165:1824 31. Oosterwegel M, Greenwald R, Mandelbrot D, et al. CTLA-4 and T-cell activation. Curr Opin Immunol 1999;11:294. Aragane Y, Maeda A, Schwarz A, et al. Involvement of Dectin-2 in ultraviolet radiation-induced tolerance. J Immunol 2003;171:3801 7. Moodycliffe A, Ngheim D, Clydesdale G, Ullrich S. Immune suppression and skin cancer development: regulation by NKT cells. Nat Immunol 2000;1:521. Ullrich SE. Photoimmune suppression and photocarcinogenesis. Front Biosci 2002;7:684 703. Wolf P, Maier H, Mulleger R, et al. Topical treatment with liposomes containing T4 endonuclease V protects human skin in vivo from ultraviolet-induced upregulation of interleukin-10 and tumor necrosis factoralpha. J Invest Dermatol 2000;114:149 56. Ke MS, Camouse MM, Oshtory S, et al. Effects of T4 endonuclease liposomes and RNA fragments on UVinduced DNA damage [abstract]. J Invest Dermatol 2004;122(3):A146. Young A. The molecular and genetic effects of ultraviolet radiation exposure on skin cells. Chapter 3. In: Hawk JLM, editor. Photodermatology. London7 Chapman & Hall; 1998. p. 25 42. DeFabo EC, Noonan FP. Mechanism of immune suppression by ultraviolet irradiation in vivo. In: Evidence for the existence of a unique photoreceptor in skin and its role in photoimmunology. J Exp Med 1983;158:84. Kim T, Moodycliffe A, Yarosh D, et al. Viability of the antigen determines whether DNA or urocanic acid act as initiator molecules for UV induced suppression of delayed-type hypersensitivity. Photochem Photobiol 2003;78:228 34. Holan V, Kuffova L, Zajicova A, et al. Urocanic acid enhances IL-10 production in activated CD4+ T cells. J Immunol 1998;161:3237 41. Beissert S, Schwarz T. Mechanisms involved in ultraviolet light-induced immunosuppression. J Invest Dermatol Symp Proc 1999;4:61 4. Reeve VE, Greenoak GE, Canfield PJ, et al. Topical urocanic acid enhances UV-induced tumor yield and malignancy in the hairless mouse. Photochem Photobiol 1989;49:459 64. El-Ghorr AA, Norval M. A monoclonal antibody to cis -urocanic acid prevents the ultraviolet-induced changes in Langerhans cells and delayed hypersensitivity responses in mice, although not preventing dendritic cell accumulation in lymph nodes draining the site of irradiation and contact hypersensitivity responses. J Invest Dermatol 1995;105:264 8. Moodycliffe AM, Bucana CD, Kripke MK, et al. Differential effects of a monoclonal antibody to cis urocanic acid on the suppression of delayed and contact hypersensitivity following ultraviolet irradiation. J Immunol 1996;157:2891 9. Yuen KS, Nearn MR, Halliday GM. Nitric oxide-

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uv immunosuppression: mechanisms mediated depletion of Langerhans cells from the epidermis may be involved in UVA radiation-induced immunosuppression. Nitric Oxide 2002;6:313 8. Reichrath J. Ultraviolet light (UV)-induced immunosuppression: is vitamin D the missing link? [Letter to the Editor]. J Cell Biochem 2003;89:6 8. Griffin M, Kumar R. Effects of 1a, 25(OH)2D3 and its analogs on dendritic cell function. J Cell Biochem 2003;88:323 6. Griffin M, Lutz W, Phan V, et al. Dendritic cell modulation by 1a,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci USA 2001;98:6800 5. Dam T, Mller B, Hindkjaer J, et al. The vitamin D3 analog calcipotriol suppresses the number and antigen-presenting function of Langerhans cells in normal human skin. J Inv Dermatol Symp Proc 1996;1: 72 7. Griffin M, Xing N, Kuman R. Vitamin D and its analogs as regulators of immune activation and antigen presentation. Annu Rev Nutr 2003;23:117 45. Guo A, Okamoto H, Imamura S. The effect of 1,25(OH)2-vitamin D3 on Langerhans cells and contact hypersensitivity in mice. Arch Dermatol Res 1992;284:368 70. Caceres-Dittmar C, Ariizumi K, Xu S, et al. Hydrogen peroxide mediates UV-induced impairment of antigen presentation in a murine epidermal-derived dendritic cell line. Photochem Photobiol 1995;62:176 83.

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[43] van den Broeke LT, Beijersbergen van Henegouwen GM. Topically applied N-acetylcysteine as a protector against UVB-induced systemic immunosuppression. J Photochem Photobiol B-Biol 1995;27:61 5. [44] Nakamura T, Pinnell SR, Darr D, et al. Vitamin C abrogates the deleterious effect of UVB radiation on cutaneous immunity by a mechanism that does not depend on TNF. J Invest Dermatol 1997;109:20 4. [45] Kripke M. Antigenicity of murine skin tumors induced by ultraviolet light. J Nat Canc Inst 1974;53:1333 6. [46] Strickland FM, Kripke ML. Immune response associated with nonmelanoma skin cancer. Clin Plast Surg 1997;24:637 47. [47] Fisher M, Kripke M. Suppressor T lymphocytes control the development of primary skin cancers in ultraviolet-irriadiated mice. Science 1982;216:1133 4. [48] Yoshikawa T, Rae V, Bruins-Slot W, et al. Susceptibility to effects of UVB radiation on induction of contact hypersensitivity as risk factor for skin cancer in humans. J Invest Dermatol 1990;95:530 6. [49] Yarosh DB. DNA repair, immunosuppression, and skin cancer. Cutis 2004;74(5 Suppl):10 3.

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Cooper KD, Baron ED, Matsui MS. Implications of UV-induced inflammation and immunomodulation. Cutis 2003;72(Suppl 3):11 6.

[42]

Dermatol Clin 24 (2006) 27 33

Sunscreen Use in Photodermatoses

Vincent DeLeo, MDT
St. Lukes Roosevelt and Beth Israel Medical Centers, New York, NY, USA

Photodermatoses are a group of conditions and diseases associated with an abnormal sensitivity or reaction to nonionizing radiation. This designation excludes the normal reactions to radiation that occur in the general population such as sunburn and carcinogenicity. Photodermatoses have usually been classified into four major categories: (1) idiopathic, (2) exogenous photochemical, (3) genetic and metabolic, and (4) photoaggravated (Table 1). Although most of these conditions are relatively uncommon, with the exception of polymorphous light eruption (PMLE), most are encountered at some time in the practice of most dermatologists. It is important to correctly identify or classify the type of photosensitivity in a given patient so that the proper treatment can be instituted. The diagnosis of the photosensitive patient has been covered elsewhere [1]. Regardless of the diagnosis, however, in most cases, the management of the photosensitive patient will involve avoidance of, and protection from, sun exposure. This always includes sunscreen usage. In the case of most exogenous photochemical reactions, including phototoxic and photo-allergic contact dermatitis and photodrug reactions, correct identification of the offending agent and avoidance of that chemical will result in clearing of the eruption. Even these patients will sometimes require sunscreen usage for a short period of time until the photosensitizer is cleared from the skin completely. In addition, in some patients with photodrug reactions who are on essential drugs for which there are no

adequate alternatives, the photosensitizing agent may be maintained with photoprotection. Sunscreens are essential in these patients.

Action spectrum Theoretically, the method by which the clinician chooses the most effective sunscreen for each patient depends on identification of the wavelength of the photons that are responsible for inducing the sensitivity, the action spectrum. With this information, the clinician can choose a sunscreen with ingredients that absorb or reflect those specific photons. It is not always possible for the practicing dermatologist to determine the inciting wavelengths in a given patient, either because of lack of the necessary phototesting equipment, or because the process cannot be reproduced easily in the artificial setting. Fortunately, the action spectra for the more common photodermatoses have been identified by photobiological researchers. As noted in a recent review of the subject published by Lenane and Murphy [2], and as outlined in Table 1, most patients who suffer from photosensitivity are reacting to radiation that is, partly at least, in the longer wavelength ranges, UVA and visible light or wavelengths greater than 320 nm. As discussed in other sections of this issue, most sunscreen agents available in the United States today offer excellent protection from UVB radiation but only partial protection in the UVA and visible ranges. In addition, because there is no established method for testing and labeling of the level of long wave protection of sunscreens marketed in the United States, it is difficult for the clinician to be able to determine which sunscreens are most efficacious in individuals who need long-wave protection.

Dr. DeLeo is a consultant for Orfagen (Paris, France). T St. Lukes Roosevelt and Beth Israel Medical Centers, 1090 Amsterdam Avenue, Suite 11B, New York, NY 10019. E-mail address: vdeleo@chpnet.org

0733-8635/06/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2005.09.004

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28 Table 1 Classification and action spectrum of photosensitive skin disease Photosensitive skin disease Idiopathic Polymorphous light eruption Hydroa vacciniforme Solar urticaria Chronic actinic dermatitis Actinic prurigo Exogenous chemical Photoallergic contact dermatitis Photoirritant contact dermatitis Photodrug reactions Genetic and metabolic Porphyria Xeroderma pigmentosa Cockaynes syndrome Smith-Lemli-Opitz Photoaggravated Lupus erythematosus UVB + + + +++ ++ + +++ +++ +++ UVA ++ ++ ++ ++ ++ +++ +++ +++ +++ ++ Visible ++ + + + +++

deleo

droxyacetone and the inorganic iron oxide. Although not approved as sunscreen active ingredients, they are available in products sold in the United States. Four other agents not approved for usage in the United States but used in some products sold in other countries appear to offer much better longrange protection, and they may be available soon in products sold in this country. These include terephthalydene dicamphor sulfonic acid and drometrizole trisiloxane, both developed by LOre al, and methylene-bis-benzotriazole tetramethylbutylphenol and bis-ethylhexyloxyphenol methoxyphenol triazine, developed by Ciba Specialty Chemicals (see Box 1). Unfortunately, there is no way for the clinician to judge the amount of UVA protection in combination agents. It has been suggested that pure inorganic

Abbreviations: +, ++, and +++; relative scale. Data from Lenane P, Murphy GM. Sunscreens and the photodermatoses. J Dermatolog Treatment 2001;12:53 7.

Box 1. Sunscreen agents offering long-range protection and may be of use in photodermatoses FDA-approved agents

The clinician theoretically is limited to recommending products that contain the UVA filters that have been approved by the US Food and Drug Administration (FDA) (Box 1). In the category of organic or chemical sunscreens, this includes the benzophenones (oxybenzone, dioxybenzone, and sulisobenzone), butylmethoxydibenzoylmethane, also known as avobenzone (Parsol 1789), and methylanthralinate. All, with the exception of avobenzone, are primarily protective in the UVA 2 range; the absorption of avobenzone extends into UVA 1. The approved inorganic screens or physical blockers are titanium dioxide and zinc oxide. When these agents were used originally, they did offer protection that extended into the UVA and visible ranges but at the expense of cosmetic acceptability. To make such agents more acceptable to consumers, the particles have been micronized and coated. Although these agents still offer some protection into the longer ranges, that protection is not as good as that of the older agents. In this regard, it has been shown in in vitro studies that microfine zinc oxide should provide better protection in the UVA 1 range than the same concentration of microfine titanium dioxide [3]. There are other agents of interest that protect against longer wave radiation in the photosensitive individual. These agents include the self tanner dihy-

Chemical or organic  Oxybenzone-benzophenone 3  Sulisobenzone-benzophenone 4  Dioxybenzone-benzophenone 8  Butylmethoxydibenzoylmethaneavobenzone (Parsol 1789)  Methyl anthranilate Physical or inorganic  Titanium dioxide (TiO2)  Zinc oxide (ZnO)
Other agents available in American products  Dihydroxyacetone  Iron oxide Agents not approved for use in United States  Terephthalydene dicamphor sulfonic acid (Mesoryl SX)  Drometrizole trisiloxane (Mexoryl XL)  Methylene-bis-benzotriazole tetramethylbutylphenol (Tinosarb M)  Bis-ehtylhexyloxyphenol methoxyphenol triazine (Tinosarb S)

sunscreen use in photodermatoses

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screens with high sun protection factor (SPF) theoretically should give good long wave protection. It has been suggested that products containing high levels of titanium dioxide and zinc oxide in high SPF chemical-free sunscreens and those that contain avobenzone in combination with the two inorganic agents seem to be reasonable alternatives if the newer non FDA-approved screens cannot be obtained. In addition, dihydroxyacetone and iron oxide may be of benefit in some individuals.

Published studies There is very little published information assessing the relative protective value of various agents against long-wave radiation in people. Bissonnette and colleagues [4] examined long-wave protection of six different commercially available (in Europe) sunscreens by measuring persistent pigment darkening in human volunteers. This endpoint is one of numerous endpoints that have been used to measure UVA protection. They found that a product containing terephthalydene dicamphor sulfonic acid, avobenzone, and TiO2 was most protective. This was followed by sunscreens that contained avobenzone and the physical blockers TiO2 and ZnO. This study used products with varying concentration of the UVA filters, making it difficult to draw solid conclusions about the relative effectiveness of individual ingredients. It generally is believed, however, that terephthalydene dicamphor sulfonic acid will offer greater protection for the photosensitive patient once it becomes available in the United States. Clinical trials testing the efficacy of sunscreens for preventing development of the various photodermatoses are rare [2]. Additionally, such studies sometimes are complicated by inconsistent diagnostic terminology. The following sections summarize a small number of studies in which various agents were tested for photoprotection in patients with various photosensitive disorders.

Polymorphous light eruption The most common photosensitivity in lightskinned individuals regardless of country of origin is PMLE. The lifetime incidence of this condition in the United States has been reported to be 10% to 15%. Similar rates have been reported from other countries [2]. As a population gets closer to the equator, the incidence rate for that population de-

creases. This may be because of differences in skin color, but it also suggests that the more sun exposure a population receives, the less likely its members are to develop the sensitivity. The classic history in affected individuals is that the first episode occurs during a sunny vacation with long exposures to sunlight. The reaction classically develops after 2 or 3 days of exposure, and with sun avoidance, the reaction will resolve in a few days to 1 or 2 weeks. The most common reaction pattern is a small papular or papulo vesicular morphology. The reaction usually involves the chest, arms and legs and routinely spares the face. In most cases, an individual will have a single episode without recurrences. A rarer group of individuals will begin to develop the reaction in a more recurrent fashion, with some individuals developing the reaction with less and less exposure. These are the patients who are likely to seek medical attention. The differential diagnosis in these patients includes lupus erythematosus and photoallergic contact dermatitis, primarily to sunscreens. Although the eruption can be reproduced with artificial light sources in photoprovocation studies, the diagnosis usually can be made from the classical history with histologic confirmation. In reviewing the literature on this and many other forms of photosensitivity, it must be remembered that nomenclature may vary with investigator. In this regard, although some reports suggest that minimal erythema dose (MED) testing may reveal lowered MED in a group of these patients, most studies reveal MED testing in PMLE is normal [5]. To reproduce the eruption, large doses of radiation greater that the MED must be applied to large areas of previously exposed skin. Numerous investigators have done studies to define the action spectrum of PMLE. Although there is variation among reports, overall, it would appear that most patients with PMLE react at least partially to UVA. There are some individuals who are sensitive to UVB alone; however, most patients react to UVA alone or to a combination of both UVB and UVA radiation [5 8]. It is likely that those patients who develop reactions to UVB alone get adequate protection from sunscreens and therefore rarely seek medical care (authors personal observation). Although most authors suggest that UVB/UVA sunscreens offer some protection against development of reactions, they usually suggest that prophylactic phototherapy and photochemotherapy are most efficacious [5 10]. Holzle and colleagues [6] showed that 4-isopropyl dibenzoyl methane and methylbenzylidene camphor were capable of preventing photoprovocation of lesions with UVA radiation in the

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laboratory setting. More recently Allas and colleagues [11,12] reported prevention of induction of the lesions of PMLE in 23 patients by a combination sunscreen containing terephthalydene dicamphor sulfonic acid using a UVA/UVB photoprovocation source. A control sunscreen containing UVB blockers and oxybenzone for UVA protection prevented the reactions in only three patients. This product and others like it likely will prove to be important for preventing PMLE and many other types of photosensitivity where longer wavelength radiation plays and etiologic role. A promising new area of research is the use of a combination of new UVA protective sunscreens and potent antioxidants that appear in early studies to protect against development of PMLE in affected patients [13,14].

until a visible tan develops. It then should be applied 2 to 3 nights per week to maintain the color and photoprotection.

Hydroa vacciniforme Hydroa vacciniforme (HV) is a rare nonfamilial photodermatosis that routinely occurs before puberty. Along with actinic prurigo (AP), it represents the two idiopathic photodermatoses of childhood. The age of onset in a recent review [15] was about 8 years of age. Males and females were affected equally. With sun exposure, affected individuals develop macules that evolve into papules and finally into vesicles that heal with variola-form scarring. The face is affected particularly. First episodes may resemble primary herpes simplex but will be culture-negative. The disease in most individuals is self-limited, with 60% resolving within 4 to 7 years. The action spectrum of the disease seems to be broad, with reproduction by both UVB and UVA [2,15,16]. There are cases of severe hydroa vacciniformelike eruptions associated with lymphoproliferative disease and Epstein-Barr virus infection. The skin manifestation in these individuals is much more severe and not related to sun exposure [17]. There should be no problem in differentiating this malignant disease from HV on clinical and histologic grounds. Purely UVB sunscreens may not prevent the HV reaction. These patients need rigorous avoidance and protection with broad-spectrum screens to prevent eruption and permanent scarring.

Solar urticaria Solar urticaria (SU) is diagnosed easily by history. The patient describes an immediate response to sunlight with the development of pruritus, erythema, and sometimes but not always edema or discrete hives. The reaction rarely persists for longer than minutes to hours. Occasionally, systemic reactions including anaphylaxis are possible but exceedingly rare. Patients vary widely in the action spectrum of their reactivity. Usually UVA or even visible radiation is involved. In most, but not all affected individuals, the eruption can be reproduced with artificial sources. It is useful to perform such phototesting to choose the proper screens for protection. Treatment other than avoidance usually consists of antihistamines as for other physical urticarias. Plasmapheresis, phototherapy, and photochemotherapy also have been used [11]. For patients who have UVB sensitivity, high-SPF sunscreens should be helpful. The new agents with UVA activity should be useful in those individuals who have UVA sensitivity. Protection in the visible range may be more difficult to achieve. The physical blockerstitanium and zinc oxidesmay offer some protection into the lower visible range. Iron oxide, which is not approved as a sunscreen by the FDA but which is contained in some products (RYPaque) as a tinting agent, has been reported to offer some protection against visible radiation [11]. The more protective these agents are, however, the less cosmetically acceptable they may be. Dihydroxyacetone is the sunless tanning ingredient. Although its SPF is low, it does protect in the UVA and visible ranges and may be useful in SU [3]. This agent should be applied before bed for 2 to 3 nights (follow manufacturers instructions)

Actinic prurigo AP is also known as familial PMLE of Amerindians. In Europe, this condition has been described in non-Indian people. In the United States, the term is used to describe a photodermatosis that develops in childhood in Amerindians from Canada through the United States and into Central and South America. Although it is an inherited disorder, it generally is classified as an idiopathic photosensitivity rather than a genodermatosis. Eighty percent of affected individuals have onset before puberty. The classic lesions are prurigenous papules developing on sun-exposed skin, although the eruption may spread to involve covered areas. It usually is accompanied by a cheilitis and eye involvement. The eruption tends to be chronic rather than recurrent with sun exposure during the sunny months and clearing in the winter. The action spectrum includes UVB and UVA radiation [2].

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Thalidomide appears to be the drug of choice when such therapy is possible. Avoidance and broadspectrum sunscreens with avobenzone have been shown to be effective in some patients [18], and narrow band UVB phototherapy has been reported to be of benefit if screening is not effective [19].

Genodermatoses As outlined in the Lenane and Murphy publication [2], the genodermatoses can be divided into those with DNA repair deficiency, pigmentary deficiencies, the porphyrias, and deficiency of cholesterol biosynthetic pathway. The DNA repair deficiencies include in individuals with Xeroderma pigmentosum, trichothiodystrophy, Rothmund Thomson syndrome, and Cockaynes syndrome. In all of these individuals, rigorous sun avoidance must be practiced. Although broad-spectrum sunscreens may be recommended, high SPF for good UVB protection is most important [20]. Photosensitivity recently has been reported in the Smith-Lemli-Opitz syndrome. Patients with this deficiency of the enzyme 7-dehydrocholesterol reductase have a high mortality rate and exhibit congenital heart disease and mental retardation. Affected individuals have the onset of a sunburn-like erythema within minutes of exposure, and this persists for 1 to 2 days. Phototesting has revealed sensitivity in the UVA range [21]. Avoidance and broad-spectrum sunscreens are therefore necessary. The porphyrias are a group of inherited and acquired diseases that represent deficiencies in the activity of enzymes of the heme biosynthetic pathway. Erythropoietic protoporphyria (EPP), congenital erythropoietic porphyria (CEP), and hepatoerythropoietic porphyria (HEP) have their onset in childhood. These individuals develop burning and stinging on exposure to sunlight. People who have CEP and HEP have much more severe photosensitivity, compared with people who have EEP, which is a relatively mild disease. In all of these individuals, sun avoidance and protection are important. In the relatively common porphyria cutanea tarda (PCT), patients complain more of easy bruisability and blistering of the exposed skin, primarily the hands. This is treatable by phlebotomies or antimalarial therapy, with reduction of porphyrin abnormalities and resolution of symptoms. Patients with the mixed porphyries, variegate porphyria (VP), and hereditary coproporphyria (HC), may have similar skin findings to patients who have PCT, but they also may have neurologic symptoms. Treatment of the skin lesions in these patients is based primarily on avoidance and photoprotection. Because the skin lesions in all of the porphyrias are caused by Soret band radiation (400 410 nm), screens that protect in the visible range are optimal for affected individuals. Such protection, however, is difficult to achieve. Broad-spectrum sunscreens usually are recommended, but the use of dihydroxyace-

Chronic actinic dermatitis Chronic actinic dermatitis (CAD) represents an idiopathic photodermatosis of adults. It is rare, and in many cases, a very debilitating disease. The term is used to describe individuals who react to radiation with an eczematous response clinically and histologically. The eruption is confined to sun-exposed areas in early stages, but may spread to involve unexposed skin also. The reaction becomes chronic, probably because very small quantities of radiation induce the pathology. The morphology in severe cases may evolve into a reticuloid appearance with lionine facies and almost tumor-like plaques. Histology also may evolve into that suggestive of cutaneous T-cell lymphoma. The latter cases are sometimes referred to as actinic reticuloid. Some patients even progress to exfoliative erythroderma. The reaction usually is reproduced easily with a lowered MED and an eczematous response to UVB radiation in most patients, with extension into the UVA and even the visible ranges in some [1]. This photodermatosis is considered an end-stage reaction triggered by numerous diverse immunologic events. Some people begin with a contact dermatitis to various allergens, including airborne compositiae reactions from plants and workplace antigens like chromates in cement, and then for unexplained reasons they develop reactions to radiation. Others begin with a photoallergic contact dermatitis and evolve into CAD after the offending agent is removed. In these cases, the reactions have been referred to as persistent light reactivity. Some patients with atopic eczema develop photosensitivity and fit into this classification. Rarely patients with photodrug reactions will continue to react to light alone when the drug is discontinued, and finally patients who have HIV also have been reported to develop this type of photosensitivity [1]. Treatment options include extensive patch and photopatch testing so that all inciting allergens can be avoided. Phototherapy and photochemotherapy have been used with varying success. Broadspectrum sunscreens as outlined in Box 1 should be used but only after patch and photopatch testing to rule out sunscreen allergy.

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tone [22] and iron oxide in combination with the more traditional UVB/UVA screens should be beneficial. Patients with various forms of albinism require broad-spectrum protection to prevent the deleterious effect of lack of natural melanin protection in their skin. Photoaggravated diseases Although there are large numbers of diseases where radiation may aggravate pathology in the skin, the two most important and common of these are lupus erythematosus (LE) and dermatomyositis (DM). Although photosensitivity in DM has not been investigated extensively, studies of the action spectra for various forms of LE have been described. Lehmann [23] studied 128 patients who had LE. The skin lesions of LE were reproducible with artificial light in 64% of patients with subacute cutaneous LE, 42% of patients with discoid LE, and 25% of patients with systemic LE. In those patients with reproducible lesions, the action spectrum was in both the UVB and UVA ranges in 53%, in the UVB range alone in 33%, and in the UVA range alone in 14%. Stege and colleagues [24] studied the effect of three different sunscreen products for preventing artificially produced LE lesions in 11 patients. A screen containing terephthalydene dicamphor sulfonic acid and drometrizole trisoloxane, Parsol 1789, and titanium dioxide was the most protective, preventing lesion development in all 11 patients. Two products with titanium dioxide and Parsol 1789 as UVA screens and different UVB screens were effective in five and three patients only. Callen and colleagues [25] studied sunscreen protection in an open-label study using a screen with Padimate O and Parsol 1789 and found good to excellent protection in 54% of patients. Johnson and Fusaro [26] suggested that dihydroxyacetone would be beneficial in LE patients who have long wave-induced disease.

References
[1] Marks J, Elsner P, DeLeo V. Contact and occupational dermatology. 3rd edition. St. Louis (MO)7 Mosby; 2002. [2] Lenane P, Murphy GM. Sunscreens and the photodermatoses. J Dermatolog Treatment 2001;12:53 7. [3] Mitchnick MA, Fairhurst D, Pinnell SP. Microfine zinc oxide as a photostable UV-A/UV-B sunblock agent. J Am Acad Dermatol 1999;40:85 90. [4] Bissonnette R, Allas S, Moyal D, et al. Comparison of UVA protection afforded by high sun protection factor sunscreens. J Am Acad Dermatol 2000;43: 1036 8. [5] Boonstra HE, van Weelden H, Toonstra J, et al. Polymorphous light eruption: a clinical, photobiologic, and follow-up study of 110 patients. J Am Acad Dermatol 2000;42:199 207. [6] Holze E, Plewig G, Hofmann C, et al. Polymorphous light eruption. Experimental reproduction of skin lesions. J Am Acad Dermatol 1982;7:111 25. [7] Ortel B, Tanew A, Wolf K, et al. Polymorphous light eruption: action spectrum and photoprotection. J Am Acad Dermatol 1986;14:748 53. [8] Holzle E, Plewig G, von Dries R, et al. Polymorphous light eruption. J Invest Dermatol 1987;88:32s 8s. [9] Honigsmann H. Effect of therapeutic sunscreen cream on phototest reaction in polymorphous light dermatosis. Z Hautkr 1989;64:1065 8. [10] McFadden N. UVA sensitivity and topical photoprotection in polymorphic light eruption. Photodermatol 1984;1:76 8. [11] Bissonnette R. Prevention of polymorphous light eruption and solar urticaria. Skin Therapy Letter 2002; 7:3 5. [12] Allas S, Lui H, Moyal D, et al. Comparison of the ability of 2 sunscreens to protect against polymorphous light eruption induced by a UV-A/UV-B metal halide lamp. Arch Dermatol 1999;135:1421 2. [13] Rippke F, Wendt G, Bohnsack K, et al. Results of photoprovocation and field studies on the efficacy of a novel topically applied antioxidant in polymorphous light eruption. J Dermatolog Treat 2001;12:3 8. [14] Hadshiew IM, Treder-Conrad C, v Bulow R, et al. Polymorphous light eruption and a new potent antioxidant and UVA-protective formulation as prophylaxis. Photodermatol Photoimmunol Photomed 2004; 20:200 4. [15] Gupta G, Man I, Kemmett D. Hydroa vacciniforme: a clinical and follow-up study of 17 cases. J Am Acad Dermatol 2000;42:208 13. [16] Sonnex TS, Hawk JL. Hydroa vacciniforme: a review of ten cases. Br J Dermatol 1998;118:101 8. [17] Cho KH, Lee SH, Kim CW, et al. Epstein-Barr virusassociated lymphoproliferative lesions presenting as a hydroa vacciniforme-like eruption: and analysis of six cases. Br J Dermatol 2004;151:372 80. [18] Fusaro RM, Johanso JA. Topical photoprotection for hereditary polymorphous light eruption of American Indians. J Am Acad Dermatol 1991;24:744 6.

Summary Most of the photodermatoses are induced by long wave radiation. Sunscreens must be used as part of the treatment of affected individuals. Currently, sunscreens that provide complete photoprotection against UVA and visible radiation and therefore provide protection for affected individuals are not available in the United States. It is hoped that such agents will be available soon.

sunscreen use in photodermatoses [19] Gambichler T, Breuckmann F, Boms S, et al. Narrowband UV-B phototherapy in the skin conditions beyond psoriasis. J Am Acad Dermatol 2005;52: 660 70. [20] Liardet S, Scaletta C, Panizzon R, et al. protection against pyrimidine dimmers, p53, and 8-hydroxy-2deoxyguanine expression in ultraviolet-irradiated human skin by sunscreens: difference between UV-B + UV-A and UV-B alone sunscreens. J Invest Dermatol 2001;117:1437 41. [21] Anstey AV, Ryan A, Rhodes LE, et al. Characterization of photosensitivity in the Smith-Lemli-Opitz syndrome: a new congenital photosensitivity syndrome. Br J Dermatol 1999;141:406 14. [22] Asawanonds P, Oberlender S, Taylor C. The use of dihydroxyacetone for photoprotection in variegate porphyries. Int J Dermatol 1999;38:916 8.

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[23] Lehmann P, Holzle E, Kind P, et al. Experimental reproduction of skin lesions in lupus erythematosus by UV-A and UV-B radiation. J Am Acad Dermatol 1990; 22:181 7. [24] Stege H, Budde MA, Grether-Beck S, et al. Evaluation of the capacity of sunscreens to photoprotect lupus erythematosus patients by employing the photoprovocation test. Photodermatol Photoimmunol Photomed 2000;16:256 9. [25] Callen JP, Roth DE, McGrath C, et al. Safety and efficacy of a broad-spectrum sunscreen in patients with discoid or subacute cutaneous lupus erythematosus. Cutis 1991;47:130 2. [26] Johnson JA, Fusaro RM. Broad-spectrum photoprotection: the roles of tinted auto windows, sunscreens and browning agents in the diagnosis and treatment of photosensitivity. Dermatology 1992;185(4):237 41.

Dermatol Clin 24 (2006) 35 51

Human Safety and Efficacy of Ultraviolet Filters and Sunscreen Products

J F. Nash, PhDT
Central Product Safety, The Procter & Gamble Company, Cincinnati, OH, USA

Sun protection is not a modern occurrence. For centuries, people have used various means to protect themselves from solar ultraviolet (UV) radiation exposure. Early on, such protection was largely achieved by clothing and wide-brim hats. The development of modern sunscreens, according to a review by Urbach [1] began in earnest during the 1930s. Through the course of the 20th century, numerous UV filters having unique characteristics were introduced with the common property of reducing solar UV, principally short wavelengths (ie, UVB [290 320 nm]). More recently, much effort has been devoted to the development of UV filters that absorb at longer wavelengths of UV or UVA (ie, 320 400 nm). There are positive or approved lists of UV filters in most countries. For example, in the United States, the US Food and Drug Administration (FDA) Sunscreen Monograph Final Rule [2] lists 16 active ingredients as category 1 ingredients (ie, safe and effective) that may be used alone or in combination (Table 1). Based on the authors 2003 survey as illustrated in Fig. 1, 9 of 16 UV filters are used in more than 98% of products marketed in the United States [3]. In other areas of the world, sunscreen products are made using UV filters from positive lists. Whereas the positive list of UV filters in regions like Europe are more extensive compared with the

United States [4], the same ones listed in the FDA monograph appear on these positive lists and in some cases are quite popular. This is reflected when considering that the same group/combination of UV filters appears in many products marketed globally (ie, ethylhexyl methoxycinnamate, benzophenone-3, butyl methoxydibenzoylmethane, octyl salicylate, octocrylene, titanium dioxide [TiO2]). The net effect is that nearly all UV filters in currently marketed products have been evaluated for safety and efficacy in some capacity. This article presents an overview of human safety and efficacy of the most commonly used UV filters. Because this subject matter is broad, and the UV filters comprise multiple classes and chemicals, a comprehensive evaluation is beyond the scope of this article. There are several papers, however, in which these subjects have been evaluated in detail [5 9]. Moreover, the list of citations provides data for each specific UV filter.

Overview of efficacy and safety Efficacy The most recognized and arguably relevant measure of sunscreen product efficacy is the sun protection factor (SPF) test. Overexposure to solar UV radiation produces a recognizable response in the skin, namely redness or erythema, and blocking this clinical response provides a meaningful endpoint for evaluation of sunscreen product efficacy. Conceptually, the SPF test is the ratio of the time for artificial

T Central Product Safety, The Procter & Gamble Company, Sharon Woods Technical Center, 11511 Reed Hartman Highway, Cincinnati, OH 45241. E-mail address: nash.jf@pg.com

0733-8635/06/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2005.09.006

derm.theclinics.com

36 Table 1 List of approved ultraviolet filters UV filter Aminobenzoic acid Avobenzone Cinoxate Dioxybenzone Homosalate Menthyl anthranilate Octocrylene Octyl methoxycinnamate Octyl salicylate Oxybenzone Octyl dimethyl PABA Phenylbenzimidazole sulfonic acid Sulisobenzone Titanium dioxide Trolamine salicylate Zinc oxide Up to % concentration 15 3 3 3 15 5 10 7.5 5 6 8 4 10 25 12 25

nash

Two or more sunscreen active ingredients may be combined with each other in a single product when used at or below the listed concentrations established for each ingredient. The concentration of each active ingredient must be sufficient to contribute a minimum SPF of not less than 2 to the finished product. Data from Sunscreen drug products for over-the-counter human use; final monograph. Food and Drug Administration, HHS. Final rule. Fed Regist 1999;64(98):27666 93.

solar UV radiation to produce a barely perceptible, uniform erythema in protected and unprotected skin 16 to 24 hours after exposure. Thus, if it takes 10 seconds to produce a barely perceptible uniform erythema in unprotected skin and 100 seconds to produce an identical response in skin where 2 mg/cm2 of sunscreen had been applied, the SPF is 10 (100/10). The erythema action spectrum is weighted for shorter more energetic wavelengths of UV radiation [10]. As such, the SPF is reflective of efficacy of sunscreen products against UVB (290 320 nm) and short wavelength UVA radiation (320 340 nm). Because there are no acute endpoints that are surrogates for long wavelength (ie, 340 400 nm) UVA damage, the development of clinical efficacy tests, while available, have not been accepted widely. At best, measures of the breadth of UVA protection using in vitro substrate spectrophotometric methods have been proposed and provide a complementary measure of sunscreen efficacy when considered in relation to SPF [7,11]. In summary, sunscreen products are unique in that efficacy as measured by SPF is assured provided proper use. Beyond efficacy, the SPF is a check of product safety/performance versus a well-recognized endpoint, erythema or sunburn, which results from solar exposure. By design, the SPF test is also a partial measure of functional photostability, again

100

UVB

UVA II

UVA I

80
Yr. 1997 Yr. 2003

% Product

60

40

20

0
OMC OSA HSA PSA OPBA OXY OCTO MAN AVO TiO2 ZNO

Fig. 1. Percentage of products containing UV filter: 1997 and 2003. (Data from Diffey BL, Tanner PR, Matts PJ, et al. In vitro assessment of the broad-spectrum ultraviolet protection of sunscreen products. J Am Acad Dermatol 2000;43(6):1024 35; and Nash JF, Tanner P, Grosick T, et al. Sunscreen market analysis: the evolution and use of UVA-1 actives. J Am Acad Dermatol 2004;50:34.) AVO, avobenzone; HSA, homosalate; MAN, methyl anthanilate; OCTO, octocrylene; OMC, octyl methoxycinnamate; OPBA, octyl dimethyl-p-aminobenzoate; OSA, octyl salicylate; OXY, benzophenone-3; PSA, 2-phenylbenzimidazole5-sulfonic acid; TiO2, titanium dioxide; ZNO, zinc oxide.

uv filters

&

sunscreens: human safety

&

efficacy

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weighted for shorter more energetic wavelengths of UV. Finally, sunscreen products should provide protection against the solar UV spectrum (290 to 400 nm). Efforts are underway to devise an acceptable method that will provide such complementary information using an in vitro test.

Issues of efficacy and safety for sunscreen products Before considering the classes of UV filters, there are several recurring concerns that deserve mention. They have more to do with the use of sunscreen products than any particular chemical. Although most of these theoretical constructs are without supportive human data, it is important to present these concerns to more openly weigh their merits. The full attention to these topics is beyond the scope of this article. What follows is a limited view of their breadth and depth. Endocrine disruption In the past several years, reports of estrogenic effects of UV filters has given rise to the concern that exposure may prove a risk to human health. Several in vitro and in vivo studies suggest weak estrogenic activity of several UV filters [15 18]. This weak endocrine-like activity does not appear to have an effect in people [19]. In a careful assessment for the most potent of these UV filters with estrogen-like activity, 3-(4-methyl benzylidene) camphor, the Scientific Committee on Consumer Products (SCCP) concluded that there was no risk to humans [163]. Still, endocrine disruption even for weakly active chemicals continues to generate much attention. Photoactivation/degradation Some UV filters and sunscreen products are thought to become photoactive upon exposure to UV radiation. The most notable one is TiO2. The photocatalytic properties of TiO2 have been used commercially in products ranging from self-cleaning surfaces [20] to treatment of pollutants in lakes or ponds [21]. Naturally, such photocatalytic activity would not be a desirable feature of any sunscreen. Fortunately, there is no evidence of a human safety or efficacy concern attributed to the photocatalytic activity of TiO2 in sunscreen products. Besides TiO2, photoactivation/degradation of other UV filters has been reported with the greatest attention given to butyl methoxydibenzoylmethane or avobenzone. The implications of avobenzone photodegradation have been applied to efficacy, or failure to protect, and safety (ie, formation of photoproducts with uncharacterized human safety). Approaches to reduce or eliminate photodegradation of UV filters are an ongoing process. To date, however, the consequences of UV-mediated activation/degradation of

Safety Human safety assessment for topically applied sunscreens is the product of hazard identification and exposure evaluation. Hazard or objective safety is the classical endpoint assessment of a test material found in textbooks and published literature [12 14]. For topical exposure, the focus is on skin effects (eg, irritation and sensitization) and dermal penetration. Based on the assessment of the latter, systemic toxicity may need to be evaluated, including reproductive and developmental toxicity. Repeat exposure data based on empirical, experimental or bridging studies are expectations for UV filters. A unique consideration for UV filters is the phototoxicologic assessment. This has two components: (1) acute/subchronic effects such as phototoxicity or photoirritation in the older literature and photoallergenicity, and (2) chronic effects as characterized by photogenotoxicity or photo cocarcinogenicity or both. Whereas phototoxicologic assessment is a subset of the objective safety evaluation, it warrants special consideration given the functional nature of UV filters. In addition to the objective safety evaluation, the exposure assessment makes up part of the human risk assessment equation. For sunscreens, exposure or use is dominated by two patterns. The recreational use of sunscreens is a full-body, intermittent application of product with anticipated high-intensity UV exposure. This is the classical view of sunscreens being used at the beach. The second use pattern is daily application of, for example, facial moisturizers containing UV filters that are limited primarily to the face and hands. This scenario is for low-dose UV exposure over the course of a day. Each exposure scenario, together with the objective safety evaluation for a given UV filter, is used to calculate a margin of safety or exposure as part of the human safety assessment. As stated, the most frequently used UV filters appear on approved or positive lists in all parts of the world. Although such lists are no guarantee or substitute for individual product efficacy and human safety evaluations, they do provide some assurance that there is general support of their human safety and efficacy.

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UV filters or sunscreen products have not revealed a frank human health result. Vitamin D deficiency Sunlight produces vitamin D3 in the skin of people. This UV-mediated event is a source of this fat-soluble vitamin. It has been suggested that current sun avoidance practices including the use of sunscreen products may or will contribute to a widespread vitamin D deficiency [22]. This is supported by clinical studies showing application of sunscreen product will reduce artificial UV-induced vitamin D in people [23]. Studies examining vitamin D status in clinical or population-based prospective human studies of sunscreen product use have not found deficiencies in vitamin D or clinical evidence of such a deficiency [24 28]. Certainly, understanding the difference between experimental results and outcomes from population-based or long-term clinical studies will require additional work. It seems prudent, however, to adhere to the safe sun strategy that includes the use of sunscreens, because consequences (ie, skin cancers) are real, and reducing UV exposure can lessen such adverse effects. Sunscreen use and melanoma It has been hypothesized that use of sunscreens may prolong time spent in the sun, thereby increasing the risk for skin cancers, particularly melanoma [29,30]. This hypothetical construct suggests that use of sunscreens has changed the UV spectrum skin
Table 2 Characteristics of classes of ultraviolet filters Chemical class Aminobenzoate Benzophenone Cinnamate Dibenzoylmethane Metal oxide Name OPBA OXY OMC AVO TiO2 ZnO OSAL PBSA Octocrylene Physical form Organic Crystalline solid, soluble polar oils Thin oily liquid Crystalline solid soluble polar oils Insoluble, nano particle Thin, oily liquid Thin, oily liquid Water soluble Thick, oily liquid

is exposed to by reducing short-wavelength UV or UVB and preventing the acute signal of sunlight overexposure (ie, sunburn) while having little impact on longer wavelengths or UVA and allowing for longer exposures [31]. As such, higher doses of UVA are a contributing factor to the increase in the incidence of melanoma. Moreover, it is argued that this explains why epidemiology studies have shown in some cases that sunscreen use increases the odds ratio for melanoma risk [32]. This is not a straightforward consideration, and proof for or against would be exceedingly difficult to establish. Weinstock [33] has dubbed this the compensation hypothesis and suggested that sunscreen use may reduce the risk of melanoma [34,35]. This opinion is shared by others [36]. The preceding concerns related to the use of sunscreens have parties of advocates and defenders. The simple truth is that sunscreen products and the UV filters they contain are intended to reduce the dose of solar UV radiation. It is individual behavior factored over many years that makes such a simple paradigm so complex. If reducing solar UV radiation is a real benefit, as supported by the weight of evidence, then the risk/benefit ratio may be in favor of continued use of sunscreens as a public health policy.

Efficacy and safety review of classes of ultraviolet filters Six chemical classes and a miscellaneous category of UV filters are reviewed. Within each group, the

Absorptiona UVB UVB and UVA II UVB UVA UVB and UVA UVB and UVA UVB UVB UVB UVB and UVA II

Comments Not widely used Can be slightly irritating to skin particular face Most commonly used UV filter globally Not photostable; negative interaction with OMC White/blue on skin, especially if it blocks UVA Cationic, slightly white on skin Weak absorber, solvent for other UV filters Weak absorber, FDA SPF 4 standard Very efficient Photstabilizes avobenzone

Salicylate Miscellaneous

Abbreviations: AVO, avobenzone; OMC, octyl methoxycinnamate; OPBA, ocytl dimethyl-p-aminobenzoate; OSAL, octyl salicylate; OXY, benzophenone-3; TiO2, titanium dioxide; ZnO, zinc oxide. a Broad range of where these UV filters absorb: UVB (290 320 nm); UVAII (320 340 nm); and UVA (320 400 nm).

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focus is on the most common UV filter used in commercial products sold in the United States. The information presented is not comprehensive but illustrative of the data that exist for these most popular UV filters. Table 2 presents some general information for these UV filters, including the waveband for which they are most efficacious. Aminobenzoates The aminobenzoates, including para-aminobenzoic acid (PABA) and octyl dimethyl-p-aminobenzoate, are important primarily from a historical perspective [37]. Whereas the use of PABA is virtually nonexistent and octyl dimethyl-p-aminobenzoate quite limited (Fig. 1), there are several key elements of their history that serve as examples for other UV filters. PABA and octyl dimethyl-p-aminobenzoate are organic filters with an absorption range in the UVB spectrum (see Table 2). The structure for PABA and octyl dimethyl-p-aminobenzoate are shown in Figs. 2 and 3. PABA has a checkered history. It was one of the first widely used UV filters. PABA was found to be a photoallergen in the guinea pig model [38]. These animal data have been confirmed through human case studies and reports of photodermatitis attributed to PABA [39 41]. It stands to reason that the photoallergenicity of PABA is, in part, the result of its photoactivation [42,43] or photodegradation [44,45]. Regardless, this adverse effect of PABA was the primary reason it was discontinued and even prompted sunscreen manufactures to claim PABA-free on their label, a claim that even persists today. Beyond photoallergy, given PABAs photoreactivity and production of oxygen-free radicals following exposure to UV radiation, the long-term health consequences would seem uncertain at best. In fact, this was studied extensively by Flindt-Hansen in a series experiments using hairless mice [46 49]. The out-

H3C

Fig. 3. Octyl dimethyl-P-aminobenzoate.

HO

come of these investigations was that PABA, even photodegradated PABA, significantly reduced solarsimulated UV-induced skin tumors in hairless mice. Thus, based on these data, the apparent long-term benefits of PABA would outweigh the risk associated with its photoreactivity/photodegradation. Among several PABA analogs, the 2-octyl dimethyl derivative with the common name of octyl dimethyl-p-aminobenzoate is used, but in a very small percentage of products (Fig. 1). Whereas photoreactions (ie, photoallergy) to octyl dimethyl-p-aminobenzoate have been reported, the frequency is less than that of PABA [50]. Like PABA, results from in vitro studies with octyl dimethyl-p-aminobenzoate have raised concerns. Most notably is the work of Knowland and colleagues [51 53] reporting the damage to DNA from in vitro studies, including human keratinocytes, produced by octyl dimethyl-p-aminobenzoate exposed to UV radiation. From these data, it is logical to suggest that repeated exposure to UV in the presence of octyl dimethyl-p-aminobenzoate would accelerate the genotoxic damage leading to the appearance of skin tumors. In vivo studies conducted with SKH hairless mice, however, have found that topical application of octyl dimethyl-p-aminobenzoate reduces the number of and delays the appearance of UV-induced skin tumors [54 57]. In sum, the aminobenzoate, PABA, was one of the first organic sunscreen agents used. Despite evidence of photogenotoxicity, studies conducted in vivo with hairless mice do not support the long-term predicted outcome of the in vitro experiments. The decline in the use of PABA and to a lesser extent octyl dimethyl-p-aminobenzoate has to do with the acute reaction (ie, photodermatitis). Perhaps the important lesson is that real events such as photoallergy/ phototoxicity and not theoretical or experimental concerns are the drivers of consumer product marketing. Benzophenones

NH2

Fig. 2. Para-aminobenzoic acid.

There are several substituted benzophenones that are used as UV filters, the most popular of which is benzophenone-3 (Fig. 4) or oxybenzone. The benzo-

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CH3 O

nash

OH

Fig. 4. Benzopehnone-3.

phenones have been reviewed by Cosmetic Ingredient Review (CIR) [58], and they have been found to be slightly irritating, nonsensitizing, and nonphototoxic in animal and human studies. Of the currently marketed UV filters, benzophenone-3 has the highest reported incidence of photodermatitis [59 63]. Still, benzophenone-3 remains one of the most common sunscreen ingredients, appearing in nearly 60% of products marketed in the United States in 2003 (see Fig. 1). Numerous studies have examined the absorption, distribution, metabolism, and excretion of benzophenone-3. It has been measured in the blood and urine of people [64 66] and rats [67] following topical application. Estimates of dermal penetration of benzophenone-3 using human skin explants have been up to 10% of the applied dose [68]. Studies with rodents have found that benzophenone-3 is absorbed after dermal or oral exposure, metabolized (conjugated) and excreted in urine and feces [69 72]. Thus, topical application of benzophenone-3 results in systemic exposure. Compared with other UV filters, benzophenone-3 is the most bioavailable following topical application. The bioavailability of benzophenone-3 is, in and of itself, not a toxicologic concern, but it warrants some attention to systemic toxicologic endpoints [73]. Issues of concern involving benzophenone-3 beyond skin effects include developmental and reproductive toxicity and repeat dose toxicity. These effects have been of interest to several groups [72] including the National Toxicology Program (NTP) testing program [164]. Benzophenone, the parent compound, has been evaluated in oral 13-week studies in rats [74]. As indicated, benzophenone-3 has been tested by NTP, where similar effects following topical and oral administration to rats and mice were noted [164]. Benzophenone-3 also has been tested in photocarcinogenicity studies in combination with octyl dimethyl-p-aminobenzoate, with protective effects [54]. More recently, estrogen-like effects of benzophenones have been reported [15,75]. Ma and colleagues

[76] found antiandrogen effects. These effects are based largely on in vitro screening assays and are suggestive of weak activity. Moreover, at least some of the in vivo results [163] show very weak [77] or no adverse effects in rodents [78] or people [64]. In summary, benzophenone-3 can be slightly irritating when applied topically. It is absorbed following dermal application and results in measurable concentrations in blood and urine. Benzophenone-3 is metabolized rapidly and has a favorable toxicity profile based on repeat exposure studies in rodents. The market experience with benzophenones is favorable, although skin reactions are the highest compared with other UV filters. Cinnamates Octyl methoxycinnamate or ethylhexyl-p-methoxycinnamate (OMC) (Fig. 5) is used in many sunscreen products marketed globally. Upon exposure to UV, OMC undergoes a trans-to-cis conformation change, which is the most common photo-mediated change observed [79]. Although some have suggested that OMC is photolabile, this photoisomerization is very predictable and well characterized. There are numerous studies that have been conducted using OMC as the test material. Because of the widespread use of OMC, it has been wellcharacterized rapidly toxicologically speaking. Beyond the published literature, which contains studies of OMC alone and in combination with other UV filters, the Scientific Committee on Cosmetology and Non-Food Products (SCCNFP) opinion [80] and FDA Drug Master Files (DMF), the latter available through freedom of information (FOI) inquiry, detail numerous toxicologic studies conducted to support the human safety of OMC. Topical application of OMC is tolerated well. The incidence of photocontact dermatitis associated with OMC is very low [81 83]. Similarly, skin irritation in response to OMC is negligible. Dermal penetration of OMC has been measured in vitro using human and pig skin explants [84 86]. Values have ranged from 0.2% to 4.5% of the ap-

O H3C O H3C CH3 O

Fig. 5. Ethylhexyl-p-methooxycinnamate.

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plied dose, depending on the experimental conditions. These in vitro determinations are most likely overestimates of systemic absorption. For example, in the study of Janjua [64], a cream containing 10% OMC was applied to the entire body (40 g product corresponding to 4 g OMC). Following application, blood concentration of OMC was measured, and at the maximum, the amount of OMC was 20 ng/mL. Assuming 4.7 L of blood, this would correspond to systemic absorption of 0.002% of the applied dose. OMC has been the most frequently studied UV filter in photo-cocarcinogenicity studies. Whether alone or in combination with other filters, the outcome of the studies has been the same, namely that topical application of OMC significantly reduces the number of tumors and increases time before tumors appear [57,87 92]. As is the case with other UV filters, OMC has been reported to have estrogen-like activity in vitro [15] and in vivo using screening assays [93]. Again, like the other UV filters, the estrogenicity of OMC is not observed in people [64]. Most conclusive is the two-generation reproductive toxicity study of Schneider and colleagues [94]. The no observed adverse effect level (NOAEL) in this study was 450 mg/kg/d for fertility and reproductive performance and for systemic parental and developmental toxicity. OMC is the most common UV filter used globally. It has a favorable human safety profile based on acute and repeat dose toxicity studies. This is arguably the UV filter with the least number of concerns, real or perceived. Dibenzoylmethane The structure of butyl methoxydibenzoylmethane (ie, Parsol 1789) or avobenzone is presented in Fig. 6. In 1996, the FDA published the notice of proposed rulemaking, amending the tentative final monograph, and establishing the conditions under which products containing avobenzone are recog-

CH3 H3C H3C

CH3

Fig. 6. Butyl methoxydibenzolymethane or avobenzone.

nized as safe and effective [95]. The enforcement of this rulemaking was published in 1997 [96]. This regulatory rulemaking changed the sunscreen market substantially. Before 1997, less than 1% of marketed sunscreen products contained avobenzone. In 2003, this had increased to greater than 25% or 1 in 4 products (see Fig. 1). Because avobenzone is the only organic sunscreen with absorption in long wavelength UVA (Table 2), the regulatory decision to add avobenzone to the monograph has been of great benefit to consumers by allowing manufacturers to make sunscreen products that reduce solar UV across the spectrum (290 400 nm). The 1996 FDA proposed rulemaking provides an overview of the human safety of avobenzone alone and in combination with other UV filters [95]. Some of the results of studies conducted by the supplier of avobenzone include skin penetration, in vitro and human in vivo, acute toxicity, skin sensitization and irritation, 21- and 28-day repeat dose dermal toxicity, 90-day oral toxicity, genotoxicity, reproductive toxicity, photogenotoxicity [97], and photococarcinogenicity studies (DMF). One of the points of discussion for avobenzone is photostability. It has been known for several years that exposure to UV will cause avobenzone to break down. Initial studies used extreme exposures [98]. Nonetheless, the photolability of avobenzone has been demonstrated using various experimental conditions [99,100]. Formulation, however, can reduce this photodegradation with the inclusion of stabilizers such as other UV filters [101,102]. For avobenzone, the most noted skin-related effect is photoallergy [103 106]. Structurally related dibenzoylmethanes [106 108] have established photoallergenic potential. It appears slightly misleading, however, to group avobenzone with its structural cousins, because the incidence of photodermatitis in longitudinal studies suggests that it is lower than that of other UV filters [109,110]. The systemic bioavailability of avobenzone is limited based on in vitro and in vivo studies of skin penetration. As with other lipophilic UV filters, the dermal penetration of avobenzone is less than or equal to 1% of the applied dose [111,112]. As such, systemic bioavailability is considered to be very low. In summary, the introduction of avobenzone into the United States market has changed the sunscreen market and provided consumers with superior products. Avobenzone has been evaluated extensively in toxicologic studies with a favorable profile. Marketing history also is acceptable. Issues of photostability have improved with increasing formulation experience.

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Salicylate The structures of the two most commonly used salicylates, octyl salicylate and homosalate, are shown in Figs. 7 and 8. Octyl and 3,3,5-trimethylcyclohexyl substituted salicylates are oil-soluble, short wavelength (UVB) filters, which are considered weak absorbers (see Table 2). They are photostable, and in the case of octyl salicylate, employed as a solvent for other UV filters, namely avobenzone. Rarely, if ever, do these UV filters appear in sunscreen products alone, the exception being the current FDA standard for SPF testing, which contains 8% homosalate. The human safety of salicylates in general, and octyl salicylate specifically, has been reviewed extensively by the CIR panel of experts [113]. In general, the salicylate UV filters are tolerated well. Skin sensitization and photocontact sensitization reactions to topical application of octyl salicylate or homosalate are rare [50,114]. Likewise, skin irritation is low order [115]. The market experience is consistent with studies conducted in animal models that demonstrate low irritation and contact/photocontact potential of salicylate UV filters [38,116]. Topical application of octyl salicylate or homosalate results in limited skin penetration [86,117,118], which agrees with results from skin penetration studies of other lipophilic UV filters. The study of Walters and colleagues is the most thorough investigation of the dermal penetration of octyl salicylate. Walters and colleagues [117] is the most thorough investigation of the dermal penetration of ocytl salicylate. In this study [117], the authors report that less than 1% of the applied dose of octyl salicylate penetrates through the human skin. This is similar to dermal penetration of homosalate. It is expected that both compounds would be subject to metabolism by cleavage of the ester linkage, resulting in salicylic acid and the octyl and trimethylcyclohexyl moieties. As such, any systemic effects would be limited and consistent with toxicity attributed to salicylic acid. The salicylate UV filters have been evaluated for endocrine-like effects. Homosalate was reported to bind to the estrogen receptor in vitro, but it was inactive using the in vivo uterotrophic assay [119]. Octyl salicylate is without any effect [120]. These
O H3C H3C O OH O OH O CH3 CH3 CH3

Fig. 8. Homosalate.

results are in line with most lipophilic UV filters in that in vitro some weak endocrine effects are observed, but the in vivo manifestation in screening assays is either not present or very weak. Topical application of salicylic acid has been shown to decrease UV-induced skin tumors in mice [121]. Considering that octyl salicylate and homosalate are likely converted to salicylic acid, these data have some relevance, albeit limited. In sum, the salicylate UV filters, octyl salicylate and homosalate, are weak UVB filters with favorable toxicologic profiles and market experience. Metal oxides The metal oxides, TiO2 and zinc oxide (ZnO), often are referred to as physical sunscreens. The physical sunscreens are described in the older sunscreen literature as agents that reflect and scatter UV. Technologic advances in manufacturing have led to the availability of microfine or nanoparticles (size range 20 100 nm) of TiO2 and ZnO. These nanoparticles absorb and reflect/scatter UV, and they are transparent on the skin, thereby reducing any whiteness (reflectance of longer wavelengths of light) on the skin. Microfine TiO2, particularly, has an absorption profile greater in UVB but extends into the long wavelength UVA. Microfine ZnO particles have a flat absorption profile that spans UVB and UVA (see Table 2). Until recently, TiO2 and ZnO were promoted as safe alternatives to organic UV filters based largely on their inertness. Concerns regarding potential skin penetration of microfine TiO2 and ZnO, however, have led to a re-evaluation of their toxicity. If these microfine metal oxides do not penetrate into or through the skin, then there is limited or no concern regarding systemic exposure to such materials from the topical applied products. There are several studies that have examined the dermal penetration of pigmentary (ie, particles > 100 nm) and microfine or TiO2 and ZnO. In general, these data support the view that these metal oxides, pigmentary or micro-

Fig. 7. Octyl salicylate.

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fine, do not penetrate through the skin but remain on the top layer (ie, stratum corneum). This and other toxicologic properties of TiO2 and ZnO will be considered. Titanium dioxide TiO2 has a very low if not negligible irritation and sensitization potential. There is no evidence of sensitization to TiO2. Most studies supportive of the safety of TiO2 can be found in the SCCNFP 2000 opinion [165]. The studies evaluating the irritation and sensitization potential of TiO2 provide a singular conclusion that there is no evidence of either event after single or repeated topical application in multiple species [165]. The study of Tan and colleagues[122] reported preliminary findings on the penetration of microfine TiO2. There was no statistically significant (P = .14) difference in the concentration of TiO2 in the epidermis and dermis of subjects who applied microfine TiO2 compared with controls. The authors suggest, however, that the amount of TiO2 is higher in the treatment group compared with controls, even though the results were not statistically significant. The results of this study should be considered either inconclusive or to demonstrate that microfine TiO2 does not penetrate the skin. Dussert and colleagues [123] used scanning and transmission electron microscopy (TEM) to determine the distribution of TiO2 on human skin. Neither intercellular nor intracellular penetration of TiO2 was observed in this study using explants of human skin. The particles appeared to be confined to the stratum corneum. Similarly, in a carefully conducted in vitro pig skin penetration study, Pflu cker and colleagues [124] found that there was no penetration of microfine TiO2 beyond the outermost stratum corneum. Again, TEM revealed no penetration of TiO2 beyond the stratum corneum. Whereas traces of TiO2 particles were seen at the hair follicle, there was no evidence of penetration into the skin. Lademann and colleagues [125] found no evidence of penetration of microfine TiO2 into human skin based on tape strips and biopsy samples. Puccetti and Leblanc [126] used photoacoustic spectroscopy to measure the depth of penetration of TiO2 particles (average diameter 80 nm) in human skin samples from cadavers. The three-dimensional depth profiles were unchanged up to 15 hours after application of TiO2. Additionally, the UV light absorption profile seen ex vivo was unchanged compared with the absorption profile of an oil-based emulsion containing microfine TiO2, suggesting no interaction between the TiO2 particles and skin. Schulz and colleagues [127] examined the skin pene-

tration of three types of micronized TiO2 into the skin of human volunteers. The TiO2 pigments were located exclusively on the outermost layer of the human stratum corneum regardless of the type of coating, formulation, or particle dimensions. Finally, Menzel and colleagues [128] found that particles of TiO2 with a diameter of 15 nm penetrated through the stratum corneum into the stratum granulosum but no further (ie, no particles in stratum spinosum). The hair follicle was not an important route for penetration. Based on these data using in vitro pig skin and in vivo human and pig skin, there is no evidence of penetration of TiO2 regardless of the particle size or coating. The absence of dermal penetration of TiO2 is supportive of the view that systemic toxicity is not present following topical exposure to TiO2. The phototoxicologic properties of TiO2, pigmentary, and microfine, have been evaluated. There has been some concern regarding the use of such a photocatalytic agent in sunscreen products, but there is no evidence of phototoxicity associated with pigment-grade or microfine TiO2. The most likely explanation for the absence of phototoxicity associated with topical application of TiO2 is the coating and formulation of such products [129 131]. Several investigators have evaluated the photogenotoxicity potential of microfine TiO2 inspired in part by its photocatalytic potential. For example, Hidaka and colleagues [132] reported that solutions of TiO2 (P25) incubated with pyrimidine and purine bases, together with DNA and RNA and exposed to a artificial mercury light source, could produce damage. In separate single-cell and chromosome aberration studies, microfine TiO2 particles exposed to artificial UV induced DNA damage and structural chromosome aberrations. No gene mutations were observed in microbial or mammalian cell systems. Based on these studies, the authors conclude that TiO2 particles are photogenotoxic [133]. The conditions of this study make any extrapolation to in vivo very difficult. Other investigators have reported no effect of TiO2 in single-cell photo-Comet assay using V79 cultures [134]. Finally, mechanistically, the DNA strand-breaking activity of irradiated TiO2 is caused by active oxygen species (ie, photocatalytic, especially hydroxyl radicals) [135 137]. In summary, studies examining the photogenotoxicity of TiO2 particles have found evidence for, and, to a lesser extent, against such activity. The interpretation of the human relevance of such results is limited and negligible in light of the in vivo data. Based on the hypothesis that microfine TiO2 could be photoactivated leading to the formation of free radicals that cause biologic damage, it follows that

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such a mechanism would exacerbate UV-induced skin tumors. The evidence does not support this hypothesis. In two studies examining the effect of microfine TiO2 on UV-induced skin tumor formation, topical application was protective [92,138]. Thus, the in vitro demonstration of photogenotoxicity is, perhaps, an artifact of the experimental conditions, as the opposite effect is observed in vivo.

Zinc oxide In 1998, the FDA issued a notice of proposed rulemaking that established conditions under which products containing zinc oxide (ZnO) as a sunscreen active ingredient are recognized as safe and effective and not misbranded [139]. This, together with the earlier approval of avobenzone, significantly changed the sunscreen market (see Fig. 1) and provided consumers with products that offered true broadspectrum UV protection. The absorbance profile for microfine ZnO is flat throughout the UV spectrum [140]. It is not as efficient as organic UV filters but provides a broader range of coverage throughout the UV spectrum. Microfine ZnO is photostable, and the photocatalytic properties are virtually nonexistent [141]. The human safety profile of ZnO is based on an extraordinary volume of studies conducted during the past century. Much experience with topical treatments containing ZnO (eg, calamine lotion) exists given that such therapies were some of the first recorded treatments of dermatologic conditions. ZnO creams, ointments, and salves have been applied to human skin with therapeutic benefits, and very little in the way of adverse or toxicologic consequences has been reported. This is even more remarkable when considering studies of wound healing benefits of ZnO where it has been applied to damaged skin, in some cases covering large portions of the body (ie, burn victims). ZnO is nonirritating and without sensitization potential [142]. As is the case with microfine TiO2, concerns related to the penetration of microfine ZnO have been discussed. The major difference is that ZnO is slightly soluble, forming zinc ions. Of course, zinc is an essential element, with dietary requirements of 10 to 15 mg. Studies of ZnO skin penetration have demonstrated some penetration using pigmentary grade ZnO [143 146]. In one study, however, whole-body application of ZnO did not change serum concentrations of zinc, suggesting that systemic absorption was limited [147]. Most recently, an in vitro study using pig skin found that microfine ZnO did not penetrate beyond the stratum corneum (Dr. Leibold,

personal communication, 2005). These results are consistent with studies of microfine TiO2. Photoprotection by ZnO against UV-induced DNA damage has been reported in hairless mice [148] in vitro and in situ in human skin [149]. This photoprotective effect of ZnO occurs over the breadth of UV (ie, UVB/UVA) [150] as demonstrated in studies with hairless mice. The absence of skin effects, irritation, and sensitization or photo-related effects (ie, phototoxicity or photoallergy) of microfine TiO2 or ZnO is testament to their inherent inert properties. The absence of demonstrable dermal penetration greatly diminishes any concerns related to systemic toxicity. Miscellaneous In contrast to the preceding sections where there were multiple structurally-related compounds that were UV filters in a chemical class, the miscellaneous category consists of two materials that have no structural relatives that are UV filters. This has the net effect of reducing the available information regarding toxicity. Still, there is evidence supporting human safety for these materials. 2-Phenyl-benzimidazole-5-sulphonic acid The structure for the water soluble, UVB filter, 2-phenyl-benzimidazole-5-sulphonic acid (PBSA), is shown in Fig. 9. Marketed sunscreen products containing PBSA comprised less than 10% of the market in 2003 (see Fig. 1). PBSA absorbs most efficiently in the UVB portion of the spectrum (see Table 2). It is included as a category 1 sunscreen in the FDA monograph and as part of the positive list in Europe. In fact, PBSA has been marketed in Europe since 1933, and, for Germany, it is reported to be in more that 20% of sunscreen products. Even so, the number of skin effects (ie, irritation, sensitization, phototoxicity, or photoallergy) is rare [50,109,151]. PBSA is considered as photostable. Recent studies, however, have shown that under laboratory conditions, solutions of PBSA irradiated with UV can produce free radicals [152,153]. The implications of these in vitro studies are unknown. Common sense
H N O N O S OH

Fig. 9. 2-Pheny-benzimidazole-5-sulfonic acid.

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material. Collectively, the data available for octocrylene support the human safety of this UV filter.
O O H3C CH3

Summary Despite concerns spanning from photoactivation/ degradation to interfering with key hormones, for the nine UV filters that make up over 98% of sunscreen products sold in the United States, there is largely supportive evidence of their efficacy and safety. It is not surprising that concerns are much more newsworthy than the simple fact that sunscreen products and the UV filters they contain provide a convenient and practical means to reduce solar UV exposure, thereby protecting human skin from deleterious effects. Perhaps there is no greater testament to the potential benefits of sunscreens than the relatively short term human trials that by and large have demonstrated the reduction of risk of solar damage [158 162]. As the saying goes, only time will tell, and for sunscreens, it would seem that the benefit to public health outweighs the risk such that global healthcare providers should continue to promote the proper use of sunscreen products.

Fig. 10. Octocrylene.

would suggest that like other UV filters, the potential to form free radicals in vitro using solution photochemistry may not have biologic relevance. Few studies have examined the dermal penetration of PBSA. In one study, PBSA was shown to penetrate through hairless rat skin explants [154]. These data were verified, in part, by studies measuring PBSA in the urine following topical application of a sunscreen containing this UV filter [155]. Thus, it would seem a small amount of PBSA penetrates through the skin and enters the systemic circulation. The amount of available information supporting the human safety of PBSA is not as great compared with other UV filters. Data contained in SCCP and FDA files from suppliers of this material support the human safety. Moreover, given the extensive and favorable market history, absence of current data is less concerning. Still, the SCCP in Europe has asked the industry to update the human safety dossier for PBSA. Octocrylene The structure of octocrylene is presented in Fig. 10. Since the approval of avobenzone, the number of products containing octocrylene has increased (see Fig. 1). This is not surprising, because this UV filter has been used successfully to help photostabilize avobenzone. There is no evidence of contact sensitization to octocrylene except in rare case reports [156]. Octocrylene is not irritating to skin and lacks phototoxicity and photoallergenicity potential. No evidence of photogenotoxicity has been reported.1 The most comprehensive evaluation of the human safety of octocrylene is presented in the study of Odio and colleagues[157]. These involve subchronic (28 and 91 days) repeat dose application. Overall lack of systemic organ histopathologic, hematologic, and clinical chemistry effect in octocrylene-treated rabbits substantiates the favorable toxicity profile of this
1 Opinion of the S.C.C. concerning octocrylene Colipa no S 32, adopted by the plenary session of the S.C.C. on 21 October 1994.

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nash [150] Gelis C, Girard S, Mavon A, et al. Assessment of the skin photoprotective capacities of an organo-mineral broad-spectrum sunblock on two ex vivo skin models. Photodermatol Photoimmunol Photomed 2003;19(5): 242 53. [151] Funk JO, Dromgoole SH, Maibach HI. Sunscreen intolerance. Contact sensitization, photocontact sensitization, and irritancy of sunscreen agents. Dermatol Clin 1995;13(2):473 81. [152] Inbaraj JJ, Bilski P, Chignell CF. Photophysical and photochemical studies of 2-phenylbenzimidazole and UVB sunscreen 2-phenylbenzimidazole-5-sulfonic acid. Photochem Photobiol 2002;75(2):107 16. [153] Scalia S, Molinari A, Casolari A, et al. Complexation of the sunscreen agent, phenylbenzimidazole sulphonic acid with cyclodextrins: effect on stability and photo-induced free radical formation. Eur J Pharm Sci 2004;22(4):241 9. [154] Aghazarian V, Tchiakpe L, Reynier JP, et al. Release of benzimidazole and benzylidene camphor from topical sunscreen formulations. Drug Dev Ind Pharm 1999;25(12):1277 82. [155] Vidal MT, Chisvert A, Salvador A. Sensitive sequential injection system for the determination of 2-phenylbenzimidazole-5-sulphonic acid in human urine samples using on-line solid-phase extraction coupled with fluorimetric detection. Talanta 2003; 59(3):591 9. [156] Carrotte-Lefebvre I, Bonnevalle A, Segard M, et al. Contact allergy to octocrylene. Contact Dermatitis 2003;48(1):46 7. [157] Odio MR, zri-Meehan S, Robison SH, et al. Evaluation of subchronic (13-week), reproductive, and in vitro genetic toxicity potential of 2-ethylhexyl2-cyano-3,3-diphenyl acrylate (Octocrylene). Fundam Appl Toxicol 1994;22(3):355 68. [158] Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993;329(16):1147 51. [159] Naylor MF, Boyd A, Smith DW, et al. High sun protection factor sunscreens in the suppression of actinic neoplasia. Arch Dermatol 1995;131(2):170 5. [160] Boyd AS, Naylor M, Cameron GS, et al. The effects of chronic sunscreen use on the histologic changes of dermatoheliosis. J Am Acad Dermatol 1995;33(6): 941 6. [161] Green A, Williams G, Neale R, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999;354(9180):723 9. [162] Darlington S, Williams G, Neale R, et al. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Arch Dermatol 2003;139(4):451 5. [163] Europa, European Commission, Public Health. Opinion on the Evaluation of Potentially Estrogenic Effects of UV-filters adopted by the SCCNFP during the 17th Plenary meeting of 12 June 2001. Available

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[135]

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[139]

[140]

[141]

[142]

[143]

[144]

[145]

[146]

[147]

[148] [149]

uv filters

&

sunscreens: human safety

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efficacy

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at http://europa.eu.int/comm/health/ph_risk/commit tees/sccp/docshtml/sccp_out145_en.htm. [164] US Department of Health and Human Services. National Toxicology Program. Available at: http:// ntp. niehs.nih.gov:8080/query.html?col=005 main&qt=2-hydroxy-4-methoxybenzophenone.

[165] Europa, European Commission, Public Health. Opinion concerning Titanium Dioxide, Colipa n S75 adopted by the SCCNFP during the 14th plenary meeting of 24 October. Available at: http://europa. eu.int/comm/health/ph_risk/committees/sccp/ docshtml/sccp_out135_en.htm.

Dermatol Clin 24 (2006) 53 62

Sunscreen Product Formulation

Paul R. Tanner, BST
Skin Care, The Procter & Gamble Company, Cincinnati, OH, USA

With the growing awareness of the damaging effects of solar ultraviolet (UV) rays over the past 10 years, sunscreen products are becoming more and more a part of everyday life, showing up in the form of daily moisturizers, antiaging products, and even cosmetics, in addition to the traditional beach or recreational sunscreen products. As a consequence of this growth, however, a brief walk through a typical large grocery or drug store will reveal a bewildering array of sunscreen products in various forms that make a wide range of product claims. This article provides a general overview of the technology behind sunscreen product formulation, including perspective around the choice of sunscreen actives and the design of the product vehicle, and will thus allow readers to better navigate their way through the plethora of sunscreen products on the market. The focus will be limited to sunscreen products, with no discussion of related products such as after-sun products or sunless tanning products. Further, it should be emphasized that sunscreens are only one of the tools for protecting skin from the damaging effects of UV rays. Reducing exposure to the sun during its most intense hours of the day and wearing protective clothing are also critical elements in a sound safe sun strategy.

Overview: what are sunscreen products, and how do they work? The primary function of a sunscreen product is to protect the skin from the damaging effects of solar UV radiation. To provide this protection, sunscreen products contain sunscreen active ingredients. These materials absorb, reflect, or scatter UV radiation that is incident on the skin, thus intercepting the UV radiation before it can penetrate into the skin and damage key skin components such as DNA, collagen, elastin, and lipids. Thus, much like an umbrella shields people from the unwanted effects of rain, sunscreen products shield people from the unwanted effects of solar UV light. To be highly effective in this function, however, requires more than the right levels and combinations of sunscreen actives. A sunscreen product must coat the skin surface uniformly. Although this sounds like a relatively simple task, in reality, achieving a uniform coating on the skin is quite a challenge, because the topography of the skin is very uneven, commonly being described as consisting of a series of peaks and valleys. Additionally, the layer of applied sunscreen is very thin, less than 0.001 inches thick. Specifically, as can be seen from the illustrations in Fig. 1, application of sunscreen product to the skin can result in accumulation of excess product in the valleys, with very poor coating of the peaks. The end result of this uneven coverage is that even for a product with a high level of effective sunscreen actives, the peaks of the skin are not protected well, and hence the overall measured product UV efficacy will be poor [1,2].

T Skin Care, The Procter & Gamble Company, Sharon Woods Technical Center, 11520 Reed Hartman Highway, Cincinnati, OH 45241. E-mail address: tanner.pr@pg.com

0733-8635/06/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2005.09.002

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Skin Surface

Skin Surface

Fig. 1. Sunscreen product applied to the skin surface. (A ) Poor film formation. (B ) Ideal film formation on the skin.

In contrast, uniformly coating the skin surface including both the peaks and valleys, as shown in Fig. 1, maximizes the UV efficacy of a sunscreen product. In practice, to achieve this more uniform coating on the skin, the sunscreen formulation typically is designed to have a very specific rheological profile [3]. The viscosity of the product should decrease significantly during the high shear process of spreading the product on the skin so the product can cover the skin surface evenly. Additionally, the product should recover its viscosity quickly immediately after the rub-in process is complete (shear is removed), so the product stays in place (does not pool in the valleys). The previous discussion involves coating the surface of the skin. In general, penetration of sunscreen active ingredients from a sunscreen product into the skin should be minimized [4]. In this way, the sunscreen actives reside on the outer surface of the skin and can intercept UV rays before they can reach and damage viable skin components. The first key principle for formulating highly effective sunscreen products is providing a uniform film of sunscreen active on the skin surface.

Formulating sunscreen products: a step-by-step review The best way to learn about the many facets of sunscreen product formulation is to go through the typical steps in formulating a new sunscreen product. This knowledge also should help in understanding more about marketed sunscreen products, including the differences between the many available product forms and the reasons for the use of particular sunscreen active combinations. In general, formulating a new sunscreen product can be described as a series of four key steps: (1) setting product design targets, (2) selecting the sunscreen active system, (3) selecting/formulating the product vehicle, and (4) optimizing the product. The end result of this four-step process is an optimized sunscreen product that people will use

regularly and properly. This is a critical point, because while the labeled product UV efficacy is certainly important, perhaps more important is the true UV performance that people will achieve when they use the product. Specifically, labeled product UV performance is based on carefully controlled clinical testing, uniform application of 2 mg/cm2 of product to a small, flat area on the back typically followed by a controlled drying period. Real-world UV performance, however, depends not only on sunscreen product clinical efficacy, but also on compliance, another key principle of sunscreen product formulation. Compliance encompasses both how regularly the product is used (frequency) and how much product is applied at each use (dose). Why is compliance so important? The only way for a sunscreen product to protect skin from solar UV rays is for the product to be applied at an adequate dose. Numerous factors are believed to impact sunscreen product compliance, including product skin feel, fragrance, appearance, packaging, and cost. Specifically, if a sun protection factor (SPF) 30 sunscreen product feels greasy or sticky, people will tend to use less of it or use it less often, and hence the product will provide much less protection than its SPF 30 label. For example, one study showed that daily application of an SPF 15 product provided greater protection of the skin from numerous biological effects of UV rays than intermittent application of an SPF 29 product [5]. Additionally, a 3-week ad-lib study showed significant differences in usage amounts between two commercial daily facial UV moisturizer products, with the average dose per use of an SPF 15 product being about twice that of an SPF 30 product [6]. Importantly, given that SPF is not a linear function of dose, the SPF 15 product in this study actually provided significantly greater SPF protection in actual use than the SPF 30 product did. Thus, compliance is the key to effective realworld sunscreen protection, and hence compliance should be a key overall goal of sunscreen product formulation. This principle should be kept in mind as the four-step process of formulating a sunscreen product is discussed in detail.

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Step 1: setting product design targets The first step in formulating a new sunscreen product is to decide just what should be formulated. Although some product requirements are universal, like the product being safe to use, having adequate microbial preservation, and being physically stable under typical storage conditions, there are many unique choices that must be made in designing a sunscreen product, including:
 Type of product: Will the product be a beach

 

sunscreen, a moisturizer, a foundation, or an antiaging product, and which part of the body will it be used on? Product form: Will the product be a lotion, cream, spray, stick, gel, or wipe? UV efficacy targets: What is the desired SPF? Will the product provide UVA or broad spectrum claims, and will the product need to be water resistant? Nonsunscreen claims: These claims could include, for example, moisturization, fragrancefree, noncomedogenic, and even insect-repellant. Cost constraints: Specifically, how much money is available per unit for the product formulation and packaging? Where the product will be marketed: This is very important, because sunscreen product regulations vary considerably around the world [7]. Aesthetic targets: These include numerous product attributes, including fragrance, color/ appearance, and skin feel.

All of these choices are very important, given they will have an impact on the options available for steps 2 and 3, selecting the sunscreen active system and selecting/formulating the product vehicle, respectively. For example, if it is desired to make water-resistant claims, water-soluble sunscreen active ingredients are generally not good options. Alternatively, if the product is targeted for beach use, an aerosol spray in a metal container may not be ideal given the high temperatures and direct sunlight to which the product likely will be exposed. Thus, it is important to consider the full range of product design features before actually embarking on the formulation of a new sunscreen product.

Step 2: selecting the sunscreen active system Once the design targets have been set, the focus then becomes how to formulate the best product to meet those targets. Typically, the best sunscreen product is the one that most effectively manages factors such as skin feel, skin compatibility/irritation, and cost. Importantly, from a formula ingredient standpoint, the sunscreen active ingredients by far have the single greatest impact on all of these factors, and hence the selection of a sunscreen active system is often the starting point in formulating a new sunscreen product. To understand why the sunscreen active ingredients have such a big impact, it is necessary to first understand a bit more about the globally available sunscreen active ingredients. Sunscreen active in-

Fig. 2. Data from a 2003 survey of 88 marketed sunscreen products in the United States, showing the variation in labeled sunscreen product active level with labeled product SPF and measured product broad spectrum efficacy based on critical wavelength measurements [7]. Products with critical wavelengths less than 370 nm were classified as not broad spectrum.

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gredients work by attenuating solar UV light by absorbing, reflecting, or scattering. This UV light attenuation by sunscreen active ingredients can be quantified by both the magnitude and the wavelength range or breadth of the attenuation [8]. The magnitude and breadth of UV attenuation vary widely between the different sunscreen active ingredients, with some active ingredients attenuating predominantly UVB rays with wavelengths of 290 to 320 nm. Others attenuate shorter UVA rays with wavelengths from 320 to 340 nm, and still others attenuating longer UVA rays with wavelengths from 340 to 400 nm. Further, higher levels of sunscreen active ingredients generally increase the magnitude of UV light attenuation. Importantly, while sunscreen regulations vary around the world, each country generally imposes a maximum level of each specific sunscreen active ingredient that can be used in a sunscreen product [7]. Thus, to formulate a sunscreen product that provides both a high SPF and protection against a broad spectrum of UV wavelengths (UVA in addition to UVB) requires the use of multiple sunscreen active ingredients in combination to achieve the necessary magnitude and breadth of UV attenuation. To demonstrate these points, Fig. 2 shows the results of a 2003 survey of 88 marketed sunscreen products in the United States [9]. Average sunscreen active levels in marketed sunscreen products range from about 5% to about 35%, and as the labeled product SPF increases, the level of sunscreen active ingredients in the formula also greatly increases. For example, the average sunscreen active ingredient level almost triples in going from SPF 15 products to SPF 40 to 50 products. Further, to achieve broad spectrum protection against all wavelengths of UVA and UVB at any given SPF requires on average 3.5% more sunscreen active ingredients, demonstrating the additional challenge of adding long-wavelength UVA efficacy to a sunscreen product. Thus, at levels of 5% to 35% and more, sunscreen active ingredients comprise a very large portion of a sunscreen product formulation. This is an extremely important point, especially given that these sunscreen active ingredients carry various general and individual tradeoffs that inevitably become the focal point of selecting a sunscreen active system [10]. To better understand these sunscreen active tradeoffs, it is first necessary to understand more about the physical characteristics of the sunscreen active ingredients. From a formulation perspective, sunscreen active ingredients can be categorized into four groups based on their physical properties: polar oils, oilsoluble crystalline solids, water-soluble salts, and in-

soluble particulates. All possess significant skin feel or skin appearance tradeoffs, particularly at higher levels. 1. Polar oils, such as octinoxate and octisalate, represent the most common type of sunscreen actives. These oily materials, however, tend to make products feel greasy and oily, especially at high levels. 2. Oil-soluble crystalline solids, such as oxybenzone and avobenzone, require relatively high levels of oily solvents/emollients to dissolve them and keep them from crystallizing in the product over time. Because of this solvent/ emollient requirement, use of these crystalline actives also tends to make products feel greasy and oily. 3. Water-soluble salts, such as ensulizole, tend to reduce the thickening ability of most of the commonly used aqueous polymeric thickeners. This leads to the use of much higher polymer levels to achieve a target product thickness, and these high polymer levels can make the product feel heavy or sticky on the skin. 4. Insoluble particulates, such as zinc oxide and titanium dioxide, can make products feel dry and draggy, and often also lead to an undesirable white appearance on the skin. Additionally, beyond these specific individual sunscreen active aesthetic effects, there is an added general negative skin feel effect that comes from putting high levels of sunscreen actives in a product, higher coated feel on the skin. Specifically, the largest single component of most marketed sunscreen products is a volatile carrier material, typically water. Thus, when a layer of a sunscreen product is applied to the skin, most of the product (water) evaporates, leaving behind a thinner layer of nonvolatile material consisting of the sunscreen active ingredients together with product vehicle components. As the product SPF is increased, however, the sunscreen active ingredient level is increased greatly. As a result, much more of the applied product is left behind on the skin, and the skin feels more heavy and coated. Thus, even if significant work is done to try to mitigate the greasy, draggy, or sticky effects of the specific sunscreen active ingredients, the skin will still be left with an overall unpleasant coated feeling given the high level of nonvolatile materials left behind from the sunscreen product. This effect is illustrated in Fig. 3. On top of the general and specific skin feel tradeoffs with the use of high levels of sunscreen

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Fig. 3. Impact of sunscreen product SPF level on the amount of nonvolatile left coating the skin after application of sunscreen product to the skin.

photo-unstable sunscreen actives is because of a change in the sunscreen molecular structure, such as isomerization, degradation, or even chemical reaction with other ingredients in the product. Any level of photo-instability reduces the ultimate UV performance of a sunscreen system. Thus for optimal efficiency, sunscreen active systems with good photostability should be selected, either by avoiding photo-unstable sunscreen actives, or including additional ingredients capable of photostabilizing the inherently photo-unstable actives. For example, there are numerous approaches to improve the photostability of avobenzone, including using specific photostabilizing solvents [11] and additives [12], and using combinations of avobenzone with specific levels of certain other sunscreen active ingredients like octocrylene [13]. Adequately disperse particulate sunscreen active ingredients The effectiveness of particulate sunscreen actives, most notably titanium dioxide and zinc oxide, varies significantly with their degree of dispersion in the sunscreen product and ultimately on the skin [14]. Thus, for maximum UV efficiency, it is recommended to use a combination of chemical (dispersing aids) and mechanical (high shear equipment) energy to achieve and maintain adequate dispersion of these particulate sunscreen active ingredients. Include sunscreen active ingredients in all of the product phases As will be discussed in the section on vehicle formulation, most marketed sunscreen products are emulsion systems consisting of both water and oil phases [15]. By formulating sunscreen actives into each of these two phases, all areas of the product film on the skin include active ingredients; hence superior sunscreen efficiency often results. Finally, given the increasing interest in the deleterious effects of UVA rays on the skin, it should be noted that most modern sunscreen products are designed to be broad spectrum, providing significant long wavelength UVA efficacy in addition to delivering their target SPF (which is primarily a function of a products ability to attenuate UVB and shorter UVA wavelengths). Importantly, as noted earlier, delivering broad-spectrum UVA efficacy at a given SPF adds an additional burden on the choice of sunscreen systems, generally requiring the use of higher sunscreen active levels. As a potential approach to remedy this use of higher sunscreen active ingredient levels in broad-spectrum products, it is noteworthy that two of the tricks for increasing sunscreen effi-

active ingredients, there are two additional tradeoffs generally associated with sunscreen active ingredients. First, sunscreen active ingredients are some of the most expensive materials in a sunscreen formulation, often collectively accounting for over half of the total cost of the formula. Second, some sunscreen actives are known to elicit slight irritant responses in subjects predisposed toward these types of reactions. All three of these factors related to sunscreen activesskin feel, cost, and skin compatibility influence sunscreen product compliance, directly affecting whether people will use the sunscreen product regularly and properly (ie, at an appropriate dose), and whether they repurchase the product. Thus, the third key principle of sunscreen product formulation is efficiency, minimizing the amount of sunscreen active ingredients needed to achieve a given efficacy target, and hence delivering lower cost, less irritating, and better feeling sunscreen products that people will use more regularly. Although there are several ways to increase sunscreen efficiency by manipulating the product vehicle, from strictly a sunscreen active ingredient standpoint there are also a few known approaches. Use photostable sunscreen active systems Although many sunscreen actives are photostable, meaning that they retain their ability to attenuate UV rays over time as they are exposed to UV (for example, on the skin), there are a few sunscreen active ingredients, most notably the UVA sunscreen avobenzone, whose UV efficacy decreases as they are exposed to UV [10]. This loss in UV efficacy for

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Silicones Hydrocarbon Emollients (Mineral Oil) (less polar) Ester Emollients

Oily or Oil Soluble Sunscreen Actives

Glycerin Ethanol Glycols Water

(more polar)

Fig. 4. Sunscreen product ingredient classification by polarity, ranging from low polarity oily or hydrophobic materials to high polarity or hydrophilic materials.

ciency center around the only three currently globally approved sunscreen active ingredients capable of attenuating long wavelength UVA: avobenzone, titanium dioxide, and zinc oxide. Thus, the selection of a sunscreen active system involves selecting an efficient sunscreen active ingredient combination to minimize general and specific sunscreen active ingredient tradeoffs related to cost, skin feel, and skin compatibility, while meeting the desired UV efficacy targets. Step 3: selecting/formulating the product vehicle Having identified the product design targets and the starting sunscreen active system, the next step is to design the product vehicle. The key to understanding the range of vehicle choices that are possible, how they are formulated, and their respective pros and cons is to first understand the key concept of ingredient polarity. In its simplest sense, materials

can be grouped based on how polar they are, with very nonpolar or hydrophobic materials like mineral oil and silicones at one end of the scale and very polar or hydrophilic materials such as water, glycerin, and glycols at the other end of the scale as is shown in Fig. 4. All of the ingredients used in sunscreen products can then be placed on this scale, with materials with similar polarity generally being mutually soluble (likes dissolve likes), and materials with very different polarity generally not being compatible with each other. There are technical parameters that more quantitatively describe ingredient polarity, for example the Hansen solubility parameter [16]. For the purposes of this discussion of sunscreen product formulation, however, the general polarity concept will suffice. With this background, the broad range of sunscreen product forms can be described by a combination of their polarity and their viscosity or thickness, as is illustrated in Fig. 5. Thus, products can be cate-

Oil Based
(thicker)

Ethanol / Oil Based

Emulsion Based With Both Water And Oil Phases

Water Based

Sticks Creams Ointments Product Viscosity Oily Gels Oils

(thinner)

Gels

Lotions

Aqueous Gels

Sprays

Sprays

Mousses Sprays

(less polar)

(more polar)

Polarity

Fig. 5. Range of sunscreen product formulation types by overall formula polarity and product viscosity.

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gorized by whether they are water-based, oil-based, ethanol/oil-based, or emulsions that contain both water and oil phases, as well as by whether they are thin, thick, or even solids. The following is a detailed discussion of each type of sunscreen product form. Oil-based products As is shown in Fig. 5, oil-based sunscreen products range from thin oils and oily sprays to thick gels and ointments, to solid stick formulations, with the only difference between these various oil-based product forms being the amount of thickening agent. Generally, these oil-based sunscreen products are relatively easy to make, because most sunscreen active ingredients are either oils or oil-soluble crystalline solids. For example, combining oily sunscreen active ingredients with emollient oils yields a clear sunscreen oil or oily spray product. Adding various levels of thickeners such as waxes, particulates like silica and clays, and oil-soluble polymers yields more viscous oily gels and ointments, though heating to above the wax melting point is required when waxes are used in these systems. Finally, adding even higher levels of waxes then leads to the stick form, similar to most lipstick formulations on the market. Unfortunately, although oily formulations are relatively easy to make, they suffer from numerous significant disadvantages, including heavy, greasy skin feel, relatively poor package compatibility, high cost, and generally low SPF on skin because of their poor film-forming ability (the oils tend to not stay in place on skin). Hence, these oily forms have found only limited use as sunscreen vehicles in recent years, with most of the marketed oily products in the form of sticks for application to relatively small areas of the body (ie, lips or noses). Water-based products Water-based products are virtually nonexistent in the market, primarily because of the limited number of water soluble sunscreen active ingredients and the poor water and sweat resistance of these formulations. In principle, however, formulating water-based sunscreens is also fairly simple; combine water with water-soluble sunscreen active ingredients and then thicken the mixture by adding one of many commercially available water-soluble polymers to yield a clear or translucent gel. Ethanol/oil-based products Because of the unique solvency and volatility properties of ethanol, ethanol-based sunscreen products can overcome many of the issues associated with the oil-based and water-based sunscreen formula-

tions. Specifically, unlike water, ethanol is miscible with most of the oily or oil-soluble sunscreen actives. Further, while oily vehicles are typically nonvolatile and hence leave large amounts of greasy residue on the skin after product application, ethanol quickly evaporates, thus reducing the amount of residual material left on the skin and improving product skin feel. Additionally, by adding various commercially available polymeric thickeners, a range of product viscosities can be prepared, ranging from thin sprays and liquids to thick, easy-to-handle gels. Other advantages of these ethanol-based sunscreens that have led to their relatively common use in the market are their clarity, fast drying nature, and pleasant cooling sensation upon application. However, in spite of these advantages, there are several potential issues. For example, ethanol-based products can be drying and slightly irritating (stinging) to the skin. Additionally, rapid evaporation of ethanol from the product upon application to the skin can lead to an uneven product film and hence lower SPF performance [15]. Further, like oil-based systems, ethanol-based sunscreen gels can show incompatibilities with some packages, and hence particular attention to this should be given when qualifying these products. Finally, depending on their ethanol content, ethanol-based sunscreens may present a fire hazard during making, storing, or shipping.

Emulsion-based products Sunscreen lotions and creams are the most common product form on the market [3,15]. In terms of formula composition, these lotions and creams are emulsions, or stabilized dispersions of one liquid in another liquid, with the key difference being viscosity. Generally thinner emulsions are called lotions, while thicker emulsions are called creams. Although various different emulsion types are possible, for example oil-in-water, water-in-oil, and water-in-oilin-water emulsions, most emulsion-based sunscreen lotions and creams are oil-in-water emulsions in which microscopic drops of various oily materials are dispersed in a continuous water phase that also typically contains other polar ingredients like glycerin or glycols. Thus, these emulsion-based systems include materials spanning the full range of polarity, and they can incorporate any of the four physical forms of sunscreen active ingredients. This allows maximum flexibility to select the most efficient sunscreen active system, thus providing cost, skin feel, and irritation benefits. Beyond the ability to incorporate any type of sunscreen active ingredients, these emulsion vehicles

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have other important attributes that contribute to their popularity. First, one of their main components is water, which not only greatly reduces formula costs, but also improves skin feel, because it is volatile and reduces the amount of residual material left on the skin after product application. Further, because these emulsions contain both oil and water phases, they can incorporate just about any other desired ingredient, such as emollients, moisturizing agents, and antiaging active ingredients. Additionally, because of their composition and structure, is it relatively easy to control the rheology and film formation behavior of emulsions systems. Hence emulsion systems tend to be very efficient sunscreen vehicles. Finally, because oil-in-water emulsions have water as the continuous phase, these emulsion-based products tend to have much better compatibility with a range of package materials and types. What is the price of all of this formulation flexibility? The key tradeoffs with emulsions relative to the other product forms are that they are more difficult to stabilize and manufacture. The two main challenges in stabilizing emulsions are to keep the dispersed phase drops from combining, also called coalescence, and to prevent the vertical movement of the dispersed drops under the influence of gravity because of the difference in densities of the emulsion phases, a process called creaming. To reduce/prevent coalescence, materials called emulsifiers generally are added to the formulation. These emulsifiers are molecules that contain a nonpolar or oil-like part and a polar or water-like part. Because of this, in an emulsion, these emulsifiers typically reside at the interface around the dispersed drops, with the polar part of the emulsifier residing in the water phase and the nonpolar part of the emulsifier residing in the oil phase. Thus these emulsifiers can be regarded as forming a protective coating around each dispersed phase drop, preventing the combining or coalescence of two drops if they should come in close contact or collide. There is a range of different types of emulsifiers, including polymeric emulsifiers and those that help to form special structures called liquid crystals and gel networks to provide even greater stability to emulsions. The details of these materials are beyond the scope of this text. To protect against the forces of gravity and prevent creaming, there are three general approaches: match the densities of the two phases so there is no tendency for the dispersed phase to settle or rise, reduce the particle size of the dispersed phase to reduce the driving force for settle/rising, or increase the viscosity or structure of the external phase to limit the mobility of the dispersed phase. The lat-

ter approach is employed most commonly, with low levels of various polymeric thickeners being effective in stabilizing emulsions against the forces of gravity. Manufacturing sunscreen emulsions typically involves two separate mixing vessels, one for the water phase into which water and the polar emulsion components are added, and one for the oil phase into which the nonpolar or oily emulsion components are added. Each phase is mixed until uniform, heating each phase if necessary to melt any waxy materials present. The dispersed phase then is added to the continuous phase, which for the case of the common oil-in-water emulsions means that the oil phase is added to the water phase. After combining the phases, the resulting emulsion typically is subjected to high shear to reduce the particle size of the dispersed phase droplets. There is a great amount of expertise around making and stabilizing emulsions today; hence these two emulsion tradeoffs typically are not seen as significant limitations within the industry. Beyond the general discussion of water-, oil-, ethanol/oil-, and emulsion-based sunscreen formulations, a few comments should be made concerning sunscreen sprays and wipes. For sprays, the sunscreen formulation is forced through a special orifice under the pressure created by either a mechanical pump or moderate levels of aerosol propellants, thus being atomized into small drops that travel to the intended surface (skin). Generally, to achieve small, aesthetically pleasing drops requires low product viscosity, and hence only thin versions of water-, oil-, ethanol/oil-, or emulsion-based sunscreen formulations are useful in spray products. Spray products allow the user to apply product onto hardto-reach places, although many sunscreen spray products still need to be rubbed into the skin for uniform coverage. Related to sprays, certain thin oilin-water emulsion-based sunscreens also can be made into mousse products by adding low levels of aerosol propellants and packing the product into an appropriate mousse package. Sunscreen wipes consist of sunscreen formulations absorbed onto a nonwoven substrate, and these formulations also need to be thin to adequately absorb into/onto the substrate. Thus, similar thin sunscreen formulations are used for sunscreen sprays and wipes. The sunscreen wipe substrate provides a convenient applicator for easy coating of the skin with a uniform film of product. One potential issue unique to these types of products, however, is that the substrates are often not inert, but rather can interact with the sunscreen active ingredients and other components of the formulation (preservative, for exam-

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ple). Thus, careful stability testing is necessary with sunscreen wipe formulations.

 Safety testing, although this typically is con-

ducted only on the final optimized formulation. Although this optimization in theory could go on indefinitely, in practice, companies have a finite amount of time and money, and this often dictates when in the iterative optimization process a final formula is selected to take to the market. If the key principles are followed, the end result of this fourstep formulation effort is an optimized product that best meets the product design targets and that will achieve a high level of compliance among consumers who buy the product.

Step 4: optimizing the product Once the initial sunscreen active system and initial product vehicle have been selected based on the product design targets, arriving at a final formula that meets all of the various design targets often involves an iterative process of testing, modifying the formulation, and retesting. Some of the key types of testing often involved in this iterative optimization process are:
 UV efficacy testing, typically using fast and in-

expensive in-vitro UV efficacy testing to evaluate and optimize the SPF and UVA performance of early prototypes. This optimization often involves trying to maximize sunscreen efficiency in meeting the product UV efficacy targets by means of the modification of the sunscreen active system and adjusting the product vehicle to improve product film formation on the skin. Optimized formulations are placed into in-vivo clinical tests to confirm their SPF, and water resistance or in-vivo UVA efficacy, if appropriate. Skin feel assessments, either by expert panels or actual consumers to confirm that the product has acceptable in-use aesthetics, especially important given the importance of compliance to realworld product UV performance. Stability testing, including physical and chemical stability assessments, and microbial testing to ensure adequate product preservation. Ideally, this testing should be done in the final package, given that there can be significant interactions between packages and sunscreen formulations. Migration testing for facial products, which involves measuring the spreading rate of the sunscreen product after it is applied to skin, typically by monitoring the movement of the sunscreen active ingredients on the skin by means of fluorescence techniques. If the sunscreen active ingredients spread too readily, there is a greater chance of eye irritation from the product migrating into the eye from the surrounding skin (not to mention that UV performance is likely to suffer because of poorer film formation). Typically, sunscreen migration is reduced by using either film-forming polymers or absorbent particulates. Non-UV claims testing, for example moisturization or noncomedogenicity claims.

Summary Much of the effort involved in the formulation of a new sunscreen product is focused on managing the tradeoffs associated with current sunscreen active ingredients and the many potential product vehicles. By keeping in mind, however, the key principles of film formation on the skin, sunscreen efficiency, material polarity, and compliance, one can design a sunscreen product that best addresses the myriad of sunscreen product performance and in-use parameters. This optimized sunscreen product will be more likely to be used regularly and properly by people, and hence deliver real-world efficacy against the damaging acute and chronic effects of solar UV radiation on skin.

References
[1] ONeill JJ. Effect of film irregularities on sunscreen efficacy. J Pharm Sci 1984;73(7):888 91. [2] Ferrero L, Pissavini M, Marguerie S, et al. Efficiency of a continuous height distribution model of sunscreen film geometry to predict a realistic sun protection factor. J Cosmet Sci 2003;54(5):463 81. [3] Anderson MW, Hewitt JP, Spruce SR. Broad-spectrum physical sunscreens: titanium dioxide and zinc oxide. In: Lowe NJ, Shaath NA, Pathak MA, editors. Sunscreens development, evaluation, and regulatory aspects. 2nd edition. New York: Marcel Dekker; 1997. p. 353 97. [4] Wilkinson MA, Moore RJ. Sunscreen, suntan and antisunburn products. In: Godwin G, editor. Harrys cosmeticology. 7th edition. London7 Logman House; 1982. p. 222 63. [5] Phillips TJ, Bhawan J, Yaar M, et al. Effect of daily versus intermittent sunscreen application on solar simulated UV radiation-induced skin response in humans. J Am Acad Dermatol 2000;43(4):610 8.

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tanner [12] Chaudhuri RK. Photo stable organic sunscreen compositions. US Patent 2004/0247536; 2004. [13] Gonzenbach HU, Pittet G. US Patent 6,033,649, Light screening agents; 2000. [14] Georgalas A, Kasprzyk E, Jung A. Inorganic sunscreen dispersions: experience with development and evaluation for efficacy and aesthetics. J Cosmet Sci 2004; 55(4):414 20. [15] Klein K. Sunscreen products: formulation and regulatory considerations. In: Lowe NJ, Shaath NA, Pathak MA, editors. Sunscreens development, evaluation, and regulatory aspects. 2nd edition. New York: Marcel Dekker; 1997. p. 285 311. [16] Vaughan CD. The solubility parameter: what is it? Cosmetics & Toiletries 1991;106(11):69 73.

[6] Grosick TL, Tanner P. Efficacy as used, not as tested, is true measure of sunscreen performance. J Am Acad Dermatol 2004;50(3):31. [7] Klein K. Encyclopedia of UV absorbers for sunscreen products. Cosmetics & Toiletries 1992;107(10): 45 64. [8] Diffey BL. A method for broad-spectrum classification of sunscreens. Int J Cosmet Sci 1994;16:47 52. [9] Nash JF, Tanner P, Grosick TL, et al. Sunscreen market analysis: the evolution and use of UVA-I actives. J Am Acad Dermatol 2004;50(3):34. [10] Johncock W. Sunscreen interactions in formulations. Cosmetics & Toiletries 1999;114(9):75 82. [11] Bonda C. Solvent polarity and sunscreen photostability. J Cosmet Sci 2003;54(1):87 9.

Dermatol Clin 24 (2006) 63 74

Ultraviolet A Radiation: Testing and Labeling for Sunscreen Products

J F. Nash, PhDa,T, Paul R. Tanner, BSb, Paul J. Matts, PhDc
a

Central Product Safety, The Procter & Gamble Company, Cincinnati, OH, USA b Skin Care, The Procter & Gamble Company, Cincinnati, OH, USA c Skin Care, The Procter & Gamble Company, Egham, Surrey, UK

Conceptually, sunscreen products are quite simple. The ultraviolet (UV) filter or filters in these topically applied products absorb, reflect, or scatter sunlight, thereby reducing the amount or dose of energy to which the target organ (ie, skin) might otherwise be exposed. Underlying this empirical notion are many complexities including approaches used to reproducibly evaluate product efficacy and how best to communicate such product performance to consumers. The sun protection factor (SPF) test measuring prevention of UV-induced erythema is the singular in vivo method used to evaluate sunscreens. In addition, thin-layer substrate spectrophotometric measure of absorbance and the calculation of the summary statistic, such as the critical wavelength (ie, kc), should be used as a means of evaluating broad-spectrum protection (ie, UVA protection). Collectively, a combination of in vivo SPF and a singular in vitro metric, like the critical wavelength, provides a complete description of a products inherent photoprotective characteristicsSPF describes the amplitude of protection (at a given application or dose) and critical wavelength provides a reliable measure of the breadth of a products spectral absorption capability. Ideally, the photoprotective efficacy of sunscreen products will be communicated to consumers as an SPF value no greater than 50 and a single designation of broad-spectrum to indicate long-wavelength UVA protection.
T Corresponding author. Central Product Safety, The Procter & Gamble Company, Sharon Woods Technical Center, 11511 Reed Hartman Highway, Cincinnati, OH 45241. E-mail address: nash.jf@pg.com (J.F. Nash).

The solar spectrum Sunlight reaching the surface of the earth includes: (1) ultraviolet (UV), wavelengths (k) > 290 and < 400 nm, (2) visible, k between 400 and 760 nm, and (3) infrared, k > 760 nm, radiation. Experimental and observational evidence supports the view that solar UV has a pronounced impact on biologic systems. To simplify the discussion of solar UV, it has become the practice of many to divide wavebands of the terrestrial UV spectrum into UVB (290 320 nm) and UVA (320 400 nm). In addition, the UVA waveband is often subdivided into UVA II (320 340 nm) and UVA I (340 400 nm), generally reflecting the higher erythemogenic efficiency of shorter UVA wavelengths. The division between these UV wavebands is arbitrary, and humans are exposed to all UV wavebands from the sun. This point cannot be overemphasized because the evaluation of sunscreen products depends on an artificial light source that, by definition, makes any experimentally derived measure of a protection factor subjective. Sunscreen products and consumer expectations Consumers purchase and dermatologists recommend sunscreens with the presumed understanding that such products will reduce skin damage produced by sunlight or the entire UV spectrum (ie, 290 400 nm). To date, the driving force behind the choice of sunscreen product is the sun protection factor (SPF). SPF provides a clinically meaningful, comparative product index of protection against UVinduced erythema or sunburn. As the erythema

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endpoint is weighted disproportionately to wavelengths < 340 nm, SPF alone cannot meet the na ve expectation of the consumer. Thus, much work has been done to educate consumers regarding the need for broad-spectrum protection. The evaluation of products and communication of this information has been an ongoing process involving academics, industry, and regulatory authorities. In sum, human skin is exposed to solar UV composed of wavelengths between 290 and 400 nm. As part of a strategy to reduce skin damage produced by sunlight, consumers purchase and apply sunscreen products. Such products infer a protective benefit that presently is weighted for short wavelength UV. The remainder of this article is devoted to the discussion of measures of sunscreen product efficacy and labeling.

Sun protection factor test: the gold standard Ultraviolet-induced erythema The most recognizable human skin response to acute exposure from sunlight or artificial sources of UV is erythema (ie, sunburn). This clinically meaningful response has been used as the cornerstone for evaluating sunscreen product efficacy for the past 30 years. To successfully use erythema or any other measure as an endpoint for efficacy testing, knowledge of the action spectrum [1] (ie, relative biologic response versus wavelength of UV) is critical. This view is clearly understood by considering what is

known about erythema. The action spectrum for UV-induced erythema is well established in human skin [2] and illustrated in Fig. 1. UV-induced erythema may be produced in all Fitzpatrick skin types with a peak response around 24 hours in most subjects. Although erythema arises primarily from short wavelengths of UV (ie, UVB 290 320 nm) radiation, UVA, particularly 320 to 340 nm (ie, UVAII), contributes to this response as well. Whereas the precise mechanism for UV-induced erythema is not known, it seems to share an identical action spectrum with DNA damage [3 5] and animal models of UV-induced skin carcinogenesis [6]. Numerous endpoints that are responsive to UV, ranging from functional (eg, immunosuppressant) to biochemical and molecular (eg, p53 expression), have been evaluated. In many if not most instances, these acute responses have not been evaluated with respect to their action spectra. Nonetheless, what is known about many such biologic responses to UV exposure is that they are weighted significantly such that shorter, more energetic wavelengths between 290 and 335 nm produce the greatest effects, indeed between 100 to 1000 times that of longwave UV (ie, k > 340 nm). It is clear, therefore, that a thorough understanding of the action spectrum for any endpoint measure is essential before it can or should be used in the evaluation of sunscreen products. Methodologic aspects of the sun protection factor test Based on the preceding discussion, it should not be surprising that erythema continues to be the most

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universally recognized endpoint in sunscreen photobiology. Clinically, erythema appears as a faint redness, which may proceed to a darker red with increasing exposure to UV. By measuring the threshold or lowest dose of UV energy that produces a minimal, uniform redness in human skin in the presence and absence of a fixed dose of sunscreen product (2 mg/cm2), a ratio of protection is determined. For example, if it takes 20 mJ/cm2 of UV from a 150-W xenon arc solar-simulator to produce a well-defined erythema in unprotected human skin, this would be the minimal erythema dose (MED) for this subject. If a sunscreen product is applied to the skin at a fixed dose of 2 mg/cm2, and the dose of UV needed to produce the MED was 100 mJ/cm2, then the SPF for the product would be 5 (ie, 100 mJ/cm2 MED in sunscreen-protected skin divided by 20 mJ/cm2 MED unprotected skin which equals 5). Thus, considering its widespread appeal (ie, a noninvasive threshold endpoint, relative reproducibility, UV-dose reciprocity, and short duration of exposure), it has become the standard for evaluating sunscreens. For all practical purposes, the SPF test method is a global standard used to measure sunscreen product efficacy. However, the precise details and protocols differ from one region to another, resulting in slight dissimilarities, particularly when high SPF products (eg, SPF > 30) are compared from region to region (eg, the United States, Japan, and Europe). Industry trade organizations, spearheaded by the European Cosmetics, Toiletry and Perfumery Association (COLIPA), are working to establish a singular SPF test method that would be accepted and recognized by authorities throughout the world such as the US Food and Drug Administration (FDA). This is challenging but will be a clear benefit to consumers if a single SPF test method could be adopted.

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Fig. 2. Relationship between sun protection factor label and percent reduction in erythemally-weighted UV.

More importantly, the endpoint of erythema is biologically meaningful and a likely surrogate for chronic effects of UV exposure (eg, nonmelanoma skin cancer) over the short wavelength UVB region. Because SPF is weighted toward shorter UV wavelengths, some standard measure of protection against long wavelength UV is needed since consumers are of the na ve, though wholly logical, view that the sunscreen product they purchased will reduce skin damage from sunlight which, of course, includes the entire UV spectrum.

The need for ultraviolet A photoprotection Presently, there is no global consensus for testing or labeling long wavelength UVA protection of sunscreen products. Before considering the test methods that do exist, it is important to consider what is known about the harmful effects of long wavelength UV on human skin. Beyond erythema, it has been demonstrated that long wavelengths of solar UV (> 340 nm) can contribute to acute and chronic skin damage. This assertion is based on both clinical evidence and theoretical considerations. The studies by Lavker and colleagues [7 9] and Lowe and associates [10] provide evidence that repeated exposure to an artificial source of long wavelength UVA produces morphologic changes in human skin indicative of photodamage. These data corroborate studies in animals where exposure to UVA was reported to accelerate photodamage [11] and the induction of skin tumors [12,13]. Since the overwhelming majority of sunscreen products available in the United States to consumers

Sun protection factor label The SPF value is currently the single most important piece of information used by consumers to select a sunscreen product. However, this numeric value should not be viewed as a quantitative value but rather as a relative measure to compare products. This is true, particularly as the SPF exceeds 30, because the relationship between absorption of erythemogenic energy versus SPF is nonlinear, as illustrated in Fig. 2. Despite several shortcomings of the SPF test method and labeling, it remains the most consumerrecognized efficacy measure of sunscreen products.

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provide protection primarily limited to UVB and short wavelength UVA II (320 340 nm), controversial hypotheses have been put forward, even postulating whether the use of UVB-weighted sunscreen products may paradoxically (1) increase exposure to long wavelength UVA I (340 400 nm) [14] by selectively changing the spectrum of solar sunlight received by the skin [15], while (2) suppressing the natural consumer warning signal of erythema. Repeated exposure to long wavelength UV from sunlight can cause damage to human skin. In the world of sunscreens, the logical manifestation of this belief is the development of products that reduce the dose of all wavelengths of solar UV. Aside from the inclusion of known long-wavelength UV filters such as avobenzone or zinc oxide, there is a pressing need for a test to reproducibly evaluate the ability of sunscreen products to protect against UVA. Perhaps of equal importance is the form in which such protection is communicated to consumers.

are used to label sunscreen products. In contrast, in Japan, UVA protection is determined using in vivo UVA-protection factor based on the persistent pigment darkening (PPD) method. These data are used to label products with a PA+, PA++, or PA+++ designation.

Overview of in vivo ultraviolet A test methods Given the need for long wavelength UVA protection and the parallel absence of relevant information on currently marketed sunscreen products, there is an urgent demand for a reliable, versatile, and universally applicable method that provides purposeful, SPF-independent information regarding UVA photoprotection. Quite naturally, a test analogous to the SPF wherein sunscreen product is evaluated on human skin and a protection factor is obtained would be desirable. Several such in vivo methods using human subjects have been proposed [16 20], but none are accepted widely. Although there are several reasons for this, which are summarized in Box 1, the single fundamental limitation of all proposed human studies of UVA photoprotection is the absence of an endpoint measure that is a true surrogate marker for long wavelength (ie, > 340 nm) UVA-induced skin damage (ie, skin cancer or photoaging). From a more practical perspective, the existing human studies use endpoints that are redundant with SPF testing (ie, erythema and pigmentation) that depend on oxygen tension, flux, skintype, and may require extraordinary exposures to an artificial UVA source, the human health consequences of which are unknown. All the in vivo methods, including immediate pigment darkening (IPD), PPD, developed by LOre ` al [21], and protection factor UVA (PFA), developed by Johnson & Johnson [22], are modeled after the SPF test. The difference between the SPF test and the in vivo UVA tests is the spectrum of the light source and, for IPD, the endpoint measured. The PPD and PFA tests, although originally developed as independent tests methods, are without question the same, measuring erythema/pigmentation, often referred to simply as skin color change. Although an in vivo test might be desired, as stated, the currently available methods are of no relevance to consumers since the information obtained depends on the experimental conditions, particularly the light source, and has no known biologic meaning. To highlight one of the concerns associated with the in vivo tests, the effect of exposure to full spectrum (290 400 nm) solar-simulated UV and filtered solar-

Ultraviolet A test methods The purpose of any standardized method is to perform operator or laboratory-independent, reproducible measurements on multiple product types. For labeling and claims based on the result of a standard measurement, it is absolutely essential that the method is: (1) reproducible, not only in one laboratory, but also when different institutes in different geographies measure the same product; (2) relevant with respect to real-life conditions and consumer expectations, and (3) noninvasive and free from ethical concerns. At this time, there is no one universally accepted UVA test method, in vivo or in vitro. There are numerous reasons for the absence of a single test method, some of which are reviewed here. From a regulatory perspective, regions have adopted standards for testing and labeling products for UVA protection. For example, in the United Kingdom, the absorbance of a sunscreen product measured by in vitro substrate spectrophotometry is used to calculate the ratio of UVA (k = 320 400 nm) absorbance to UVB (k = 290 320 nm) absorbance and calculate a Boots Star Rating. Likewise, Australia has a UVA test method (AS/NZS 2604: 1998) using in vitro absorbance measures that have been used in Germany as well; the FDA and the European Union Commission have not adopted any method officially. In both the United Kingdom and Australia, results obtained using these in vitro test methods

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Box 1. Advantages and disadvantages of in vivo ultraviolet A test methods Advantages  Distinguish different UVA protection factors  Biologic response in humans  Photo-instability tested  Water resistance  Support from some dermatologists Disadvantages  Endpoints determined using filtered, artificial light, UVA of 320 to 400 nm, are meaningless with respect to solar UV exposure (ie, 290 400 nm)  Expensive, time-consuming and and labor-intensive  High operator expertise  UVA protection factors are non-linear  Subjective, artificial UV spectrum and intensity  Large variability, uncertain reproducibility  Response potentially influenced by non UV filters  Human health consequences following exposure to high doses of UVA radiation are unknown; significant ethical considerations

simulated UVA (320 400 nm) light on the absorbance profile of the most widely used UVA filter avobenzone was studied. In this example, the longwave UVA filter, avobenzone, was prepared at 3% w/w in a simple oil/ water emulsion and applied at 1 mg/cm2 to a collagen substrate (ie, Vitro-Skin). The attenuation (absorbance) profile of this thin film was obtained without preirradiation (0 J/cm2). Separately, the product was preirradiated with 30 J/cm2 of either full spectrum UV or the same light source filtered to produce a UVA spectrum (ie, 320 400 nm). After this preirradiation, the attenuation profile was once again obtained. As illustrated in Fig. 3A, exposure to 30 J/cm2 full spectrum UV results in near complete attenuation of absorbance compared with the baseline or no preirradiation 0 J/cm2. In stark contrast, using the same light source filtered to yield UVA 320 to 400 nm, exposure to 30 J/cm2, considered to be the top end of the minimal pigmenting dose [21], did not

substantially change the absorbance (Fig. 3B). Thus, artificially eliminating the UVB portion of the UV spectrum significantly altered the absorbance profile of this UV filter. Even though the contribution of wavelengths between 290 and 320 nm to the total dose of 30 J/cm2 of full spectrum UV (ie, 290 400 nm) is quite small, the impact of eliminating this part of the solar spectrum is dramatic. Clearly, the attenuation of UV by avobenzone changes depending on the source of light. The consequences of this are significant. For example, protection factors such as PPD or PFA, which are determined using a filtered light source, could be misleading since the change in absorption/ attenuation is not observed with only UVA exposure (see Fig. 3B). In sum, the absorption profile of a UV filter may be affected differently by the artificial light source. This change in absorption/attenuation is most likely due to a photochemical change in the molecule based on the spectrum of energy to which it is exposed. Regardless, exposure to a UVA-only light source results in a different absorption profile compared with full spectrum UV (290 400 nm), which is most relevant to product evaluation and consumer use. In vivo testing cannot be conducted using full spectrum solar-simulated (290 400 nm) radiation because highly energetic UVB wavelengths overwhelm the UVA-induced erythema and pigment responses. Thus, the example provided raises many questions regarding the applicability and conduct of in vivo tests using UV light filtered to exclude UVB or short wavelengths < 320 nm. Beyond the experimental results described previously, there are additional concerns with the current in vivo UVA test methods. With regard to the consumer using sunscreen products, it is important to keep in mind that exposure to a UVA-only source is never encountered in nature (ie, the division between these UV wavebands is arbitrary); human skin is exposed to sunlight, which includes all UV wavebands. Finally, the in vivo studies require exposure to an artificial UVA source, in some cases at extraordinarily high doses (ie, if the minimal threshold for PPD is assumed to be between 8-30 J/cm2 [22], then a protection value of 10 would be detected after exposure to doses greater than 80 to 300 J/cm2). Thus, it is conceivable that subjects or sunscreen products would be exposed to UVA radiation at doses where (1) the human health consequences are unknown and (2) UV filters are stressed to an utterly unrealistic extent. Any one of these numerous concerns might be sufficient to question the results obtained in current

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Fig. 3. Effect of exposure to solar-simulated full spectrum UV or UVA on absorption of avobenzone. In (A ), a 3% avobenzone lotion was exposed to 30 J full-spectrum UV from a xenon arc solar simulator. The blue line is the product with no preirradiation and the red line is the absorption curve after preirradiation with 30 J full-spectrum UV. In (B ), the same product exposed to 30 J filtered to yield a UVA spectrum (320 400 nm). The blue line is the product with no preirradiation and the red line is the absorption curve after preirradiation with 30 J UVA.

in vivo UVA tests. When considered collectively, however, the information derived from such studies is of dubious value. Thus, although it might be considered desirable to have an in vivo method to measure protection against long-wavelength UV, the selection of a test that is clinically irrelevant could prove harmful, arguably unethical to test subjects, and could subject UV filters to levels of stress they were never designed to endure.

In vitro absorbance, transmittance, and monochromatic protection factor: mathematicallyrelated terms To appreciate the utility of in vitro methods, it is necessary to review a few simple properties. Diffey and Robson [23] described a method to assess

sunscreens using a substrate, Transpore tape, measuring transmission of UV through the substrate in the presence and absence of a sunscreen. Before this, the in vitro absorption profile of UV filters or sunscreen products was determined by using dilute solutions of sunscreen agents or determination of the transmission spectrum of thin films on glass surfaces, neither of which were very accurate in predicting in vivo SPFs. Although substrate spectrophotometry has provided much information regarding sunscreen products, there is an understanding that this method cannot precisely determine in vivo protection factors. The ability of a sunscreen product to attenuate radiation as measured spectroradiometrically can be expressed as absorbance, transmittance, or a monochromatic protection factor. These three mathematically related terms are derived from the ratio of the amount of energy delivered by a constant UV source

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through a substrate without product and the amount of energy delivered through a substrate with product. The relationship among the different terms can be expressed as in Eqs. 1 3: mPF 1=T T 1=10A Log mPF A 1 2 3

absorption spectrum of a sunscreen product, which is obtained using thin-film substrate spectrophotometry. The shape of the absorption spectrum is reduced to a single index termed critical wavelength, defined as the wavelength where the integral of the spectral absorbance curve reaches 90% of the integral from 290 to 400 nm. The critical wavelength, often abbreviated kc, is calculated using Eq. 4: Z
kC

Akdk 0:9

400

Akdk
290

290

where mPF is the monochromatic protection factor, T represents transmittance, A represents absorbance. Using substrate spectrophotometry, absorbance /transmittance of UV can be measured and UV attenuation curves can be constructed with these mathematically related terms (ie, mPF, T, or A ) at specific wavelengths. Overview of in vitro ultraviolet A test methods Several in vitro methods to evaluate UVA photoprotection have been designed, obviating the need for human subjects and clinical endpoints with indeterminate value in relation to protection from sunlight [24 27]. One such method proposed by Diffey [24] makes no assumptions regarding the action spectra for UVA-induced acute or chronic skin damage. This proposed in vitro method is based on the shape of the

Graphically, the critical wavelength is illustrated in Fig. 4. The critical wavelength value is based on the inherent shape of the absorbance curve, not its amplitude and, therefore, is independent of application thickness and other undesirable variables characteristic of in vitro calculations of absolute protection factors. The critical wavelength determination does not promote the false notion of UVB and UVA as separate entities but rather as part of a continuous electromagnetic spectrum. Finally, as the critical wavelength increases, so too must the breadth of protection against long wavelength UV. As is the case with in vivo UVA test methods, in vitro approaches including the critical wavelength have advantages and disadvantages, which are presented in Box 2. There are many advantages of in vitro methods including their low expense, low training burden,

Critical Wavelength

Absorbance

90% AUC
Amplitude

Breadth

290

300

310

320

330

340

350

360

370

380

390

400

Wavelength (nm)
Fig. 4. Hypothetical absorbance curve obtained from substrate spectrophotometric measurement. The summary statistic, critical wavelength, is the wavelength at which 90% of the absorption is equal or less than.

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Box 2. Advantages and disadvantages of in vitro ultraviolet A methods Advantages  Inexpensive  Quick  Relevant UV spectrum and intensity  Simple to perform  Reproducible  Distinguishes breadth of UV protection  Support from some dermatologists  Photo-instability tested  No risk to human volunteers Disadvantages  Not a human test  No clinical endpoint  Poor agreement with absolute UVAPF value  Product/substrate interactions  Water resistance

then there must be a corresponding increase in UVA absorbance to maintain the shape of the curve and obtain the same critical wavelength. In short, a combination of in vivo SPF and critical wavelength provides a complete description of a products inherent photoprotective characteristics. SPF describes the amplitude of protection (at a given application rate) and critical wavelength provides a reliable measure of the products spectral absorption capability. No other efficacy measures are needed.

Beyond critical wavelength: mathematical calculations using absorbance data Raw data (in this case, absorbance/transmittance) obtained using substrate spectrophotometry are then mathematically manipulated to generate a metric, which is used to express long wavelength photoprotection. Thus, beyond critical wavelength, there are a number of other ways to express the same data. For example, Wendel and colleagues [25] have proposed a new metric for in vitro substrate spectrophotometric data to assess UVA protection of sunscreen products. The investigators suggest that this method combines the reproducibility and other advantages of in vitro with in vivo by using the SPF obtained in humans to correct (ie, adjust the height of the absorbance curve) the in vitro absorbance curves from which protection factors can be calculated. In other words, this approach can calculate in vitro PPD or PFA from absorbance curves that have been adjusted using in vivo data (ie, SPF), while avoiding the problems associated with the in vivo aspect of these methodologies, described earlier. Various calculations have been compared for sunscreen products [26,27].

high reproducibility, high transferability, and lack of risk to human subjects. Perhaps the most frequent criticism of in vitro methods is the fact that the sunscreen product is not evaluated on human skin and, as such, no protection factor can be accurately determined. This, of course, is without question. However, as stated previously, in the absence of any known biologic marker for UVA damage, protection factors generated in any test are meaningless, particularly to the consumer. Moreover, an in vitro test based on a measure of absorbance/transmittance from substrate spectrophotometry is not and should not be proposed as a singular means of evaluating sunscreens but rather in conjunction with the in vivo SPF test. The critical wavelength value or any other metric derived from substrate spectrophotometric absorbance data must always be considered in conjunction with its corresponding in vivo SPF. To be explicit, if two products (A and B) share the same critical wavelength but exhibit differing in vivo SPF values (15 and 30, respectively), then according to the critical wavelength calculation, Product B must have been formulated with significantly more long wavelength UVA protection than Product A (ie, commensurate with SPF). In other words, if the SPF of a product is increased by the addition of a UVB filter,

Sunscreen product labeling Arguably, the single most important consideration related to sunscreen product protection remains how to communicate such information to consumers, most of whom believe they have been receiving such protection with their existing products. The guiding principle in this consideration is to keep SPF as the most important indicator of sunscreen product efficacy because most UV-induced skin damage is produced by short wavelength UVB. Based on the studies presented in the next section, products labeled with SPF and a single designation such as broad spectrum are the easiest to understand by con-

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sumers. The reasons for this simple broad spectrum designation to denote UVA protection are that
 it provides consumers with clear, simple, and

relevant information that does not interfere with or otherwise obfuscate the SPF, which remains the primary criteria for selection and recommendation of a sunscreen product;  any multilevel or numeric system used to denote UVA protection would invariably lead to a claims race for the highest level, which would detract from SPF; and  it results in a seamless, transparent public health message (ie, as part of a sun avoidance strategy, wear an SPF 15 broad-spectrum sunscreen). Presently, around the globe, all sunscreen products are labeled with an SPF number. In the United States, more than 80% of marketed sunscreen products claim UVA protection (eg, label: UVA Protection or Broad Spectrum or Extra UVA Protection) even though only 56% have a recognized UVA-I filter (ie, avobenzone or zinc oxide) [28]. Thus, the present system, at least in the United States, is not optimal because there is no method for evaluating UVA protection nor is there a system to label for such protection.

the product cell). Each respondent received one product cell and was instructed to examine the cell as if they were at the store shelf with the intent to purchase a sunscreen product. Then, the panelist completed a questionnaire, which gathered information regarding the choice of a product appropriate for their needs, ease of selection, why the specific product was chosen, current SPF product purchase habits, and key demographic information.

Labeling information The three label options were described verbally as pass/fail system, 3-tier scaleverbal descriptor, and 3-tier scalegraphonumeric. The pass/ fail or hurdle label indicates the presence or absence of UVA protection. In this scheme, if a product did not qualify for UVA protection, it would be labeled with the SPF and nothing more or, if it passed the criteria for UVA protection, it would have SPF and a label such as broad spectrum protection. The 3-tier scales provide three levels of UVA protection along with the SPF. For example, the graphonumeric label might say SPF 15, UVA-PF 3 or SPF 8 UVA-PF 5, and so on. All products in cells were labeled as XYZ SunscreenSPF A, where the A is either 4, 8, 15, or 30. Box 3 outlines how UVA efficacy was communicated on the products within each options cell (Note: all products had SPF on the label).

Consumer labeling study: how best to communicate ultraviolet A protection? This summarizes the results of two identical, independent studies evaluating three methods of sunscreen product labeling for UVA protection. These studies were conducted among representative male and female consumers 18 and older. The objectives of the studies were (1) to evaluate three sunscreen product labeling schemes of SPF and UVA efficacy among representative male and female consumers and (2) to identify the best means to communicate a products UVA efficacy to consumers while maintaining the importance of SPF protection. Test design This methodology was designed to closely imitate a representative male or female consumers experience of selecting a sunscreen product from a typical store shelf, regardless of the geography. Each labeling option (ie, store shelf representation) was depicted visually on an 8.5 11-inch sheet of paper (called

Box 3. Ultraviolet A efficacy as communicated on test products Pass/fail system Blank bottle (ie, no UVA protection claimed) Broad spectrum UVA and UVB protection 3-Tier scaleverbal descriptor Blank bottle (ie, no UVA protection claimed) UVA and UVA protection UVB plus extended UVA protection 3-Tier scalegraphonumeric Bar graph with level 4 UVA protection Bar graph with level 8 UVA protection Bar graph with level 12 UVA protection

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Summary of results A thorough analysis of the data from both studies resulted in the following conclusions and key findings:
 A total of 2238 individuals completed ques-

options selected low SPF products. Reasons for selection of low SPF products appeared to be based on personal preference (eg, wanted low level of SPF to achieve a suntan). This test design represents a suitable method to realistically imitate a consumers experience of purchasing a sunscreen product from a store shelf. This is supported by: (1) the SPF levels selected by the panelist via the test cells were consistent with the SPF levels that the panelists are currently purchasing for facial moisturizers or recreational beach sunscreens, and (2) the conclusion and findings were consistent between both tests. Based on these independent studies evaluating UVA label options, the pass/fail label was significantly superior to the other labels with respect to ease of product selection, selection of the higher level of protection, and SPF remained the primary indicator of sunscreen product efficacy.

tionnaires (1082 in the spring and 1156 in the fall). The data from both tests indicate that the pass/ fail label allowed consumers to most easily choose the sunscreen product appropriate for their personal use. Ease of choice for the pass/fail leg was significantly (P < .05) higher versus both 3-tier scales among representative males and females in both studies, including specific target groups within the tests populations, such as SPF product purchasers and those consumers with a history of skin cancer. The graphonumeric approach had significantly ( P < .05) fewer panelists indicating their selection was easy. This option appears to place an undue emphasis on UVA efficacy features and diminishes the SPF focus. This is supported by the inflated number of want highest level of UVA voluntary comments as a reason for product choice. Additionally, the number of UVB protection comments as the reason for product choice is consistently lower across both studies versus the pass/fail and verbal descriptor options. The verbal descriptor options ease of selection was the lowest of the three options. Additionally, it also had the lowest percentage of panelists selecting maximum UVA versus both the pass/fail and graphonumeric approaches. Of equal importance, this system may mislead consumers into thinking that extended protection translates to staying in the sun for longer than normal and could potentially misguide those seeking maximum UVA/UVB combination protection. This is supported by inflated voluntary comments for extended protection from sun/UV/UVB rays and extended/longer UVA protection for this option, which suggests that consumers are inferring an extended time element. Clearly, this confusion leads to the potential for long- and short-term adverse health effects (sunburn, skin cancer) to the consumer and should be avoided. The SPF levels chosen were consistent among the three labeling options. The majority of panelists chose products with either SPF 15 or 30. A small percentage in each of the three

Other ultraviolet A labels Certain regions have adopted standards for testing and labeling products for UVA protection. For example, in the United Kingdom, the absorbance of a sunscreen product measured by in vitro substrate spectrophotometer is used to evaluate the ratio of UVA to UVB and calculate a Boots Star Rating. The Boots Star Rating in the United Kingdom has been in existence since the early 1990s. There are currently 5 stars and since its introduction, nearly all currently marketed sunscreen products achieve a 3- to 5-star rating. Thus, an in vitro method has substantially changed the sunscreen market, providing consumers with greater UVA protection. However, the labeling options (ie, multiple star ratings) have over time become more consistent with a pass/ fail approach. In Australia, as well, a UVA test method (AS/ NZS 2604: 1998) uses in vitro absorbance measures. The labeling is a pass/fail system in which only ! SPF 15 products that pass the UVA test method can be labeled broad spectrum. This label is identical to the proposed pass/fail label described previously. Finally, it is noteworthy that in Japan, the PPD method is used to classify sunscreen products according to PA+, PA++, and PA+++. This quasigraphonumeric scale was implemented to avoid a UVA-protection factor number that might confuse consumers. However, a study conducted by Dr. Kawada at the Kinki University School of Medicine, Osaka, reported at the 60th Annual Meeting of the

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American Academy of Dermatology (2002), revealed lack of understanding about the PA+/++/+++ system among a Japanese cohort. In the study survey of 740 medical students conducted between September to November 2000, 87% (n = 642) reported use of sunscreens. When asked about the meaning of PA, only 7% (n = 52) of the students were familiar with the term and only 10 out of 740 (1.4%) correctly defined it. The remaining 42 subjects who stated familiarity with the term either misunderstood it or could not define it. These results suggest that even though the PA label has been in existence for some time, it is of limited value. Perhaps, a revision of the Japanese system should be considered.

product selection without misleading consumers. SPF should remain the primary indicator for sunscreen efficacy and broad-spectrum should be used to reflect UVA protection.

References
[1] de Gruijl FR. Biological action spectra. Radiat Prot Dosimetry 2000;91:57 63. [2] McKinlay AF, Diffey BL. A reference action spectrum for ultraviolet induced erythema in human skin. CIE J 1987;66:17 22. [3] Hacham H, Freeman SE, Gange RW, et al. Do pyrimidine diimer yields correlate with erythema induction in human skin irradiated in situ with ultraviolet light (275 365 nm)? Photochem Photobiol 1991;53:559 63. [4] Young AR, Chadwick CA, Harrison GI, et al. The similarity of action spectra for thymine dimers in human epidermis and erythema suggests that DNA is the chromophore for erythema. J Invest Dermatol 1998; 111:982 8. [5] Young AR, Sheehan JM, Chadwick CA, Potten CS. Protection by ultraviolet A and B sunscreens against in situ dipyrimidine photolesions in human epidermis is comparable to protection against sunburn. J Invest Dermatol 2000;115:37 41. [6] De Gruijl FR, Fobes PD. UV-induced skin cancer in a hairless mouse model. Bioessays 1995;17:651 60. [7] Lavker RM, Gerberick GF, Veres D, et al. Cumulative effects from repeated exposures to suberythemal doses of UVB and UVA in human skin. J Am Acad Dermatol 1995;32:53 62. [8] Lavker RM, Veres DA, Irwin CJ, Kaidbey KH. Quantitative assessment of cumulatvie damage from repetitive exposures to suberythemogenic doses of UVA in human skin. Photochem Photobiol 1995;62: 348 52. [9] Lavker R, Kaidbey K. The spectral dependence for UVA-induced cumulative damage in human skin. J Invest Dermatol 1997;108:17 21. [10] Lowe NJ, Meyers DP, Wieder JM, et al. Low doses of repetitive ultraviolet A induced morphologic changes in human skin. J Invest Dermatol 1995;105:739 43. [11] Bissett DL, Hannon DP, Orr TV. Wavelength dependence of histological, physical and visible changes in chronically UV-irradiated hairless mouse skin. Photochem Photobiol 1989;50:763 9. [12] Harrison JA, Walker SL, Plastow SR, et al. Sunscreens with low sun protection factor inhibit ultraviolet B and A photoaging in the skin of the hairless albino mouse. Photodermatol Photoimmunol Photomed 1991; 8:12 20. [13] Sterenborg HJCM, van der Leun JC. Tumorigenesis by a long wavelength UV-A source. Photochem Photobiol 1990;51:325 30. [14] Autier P, Dore J-F, Ne grier S, et al. Sunscreen use and

Summary This article discusses the current in vivo and in vitro UVA test methods, the science behind them, and how sunscreen protection should be communicated to consumers. Sunscreen protection over the entire solar spectra, not arbitrarily defined UVB or UVA regions only, is a fundamental consumer need and expectation. Given the up-to-date understanding of human skin damage produced by long wavelength UVA radiation, the following quote from Diffey [29] from a UVA workshop sponsored by the American Society for Photobiology held in 1991 still holds true today:
We do not yet know the importance of UVA with regard to photoaging . . .and . . .skin cancer. . . .It would seem prudent, therefore, to encourage the development of sunscreens which absorb more or less uniformly throughout the UV spectrum.

This reflects the lack of a true surrogate marker for measuring UVA protection in vivo, a fundamental limitation that has not yet been resolved. One metric calculated from data obtained using thin-layer substrate spectrophotometry, critical wavelength, measures the breath of the absorbance of sunscreen in relationship to SPF. This summary statistic could be adopted as a single reproducible test to establish UVA protection of sunscreen products. Researchers have recommended a critical wavelength of ! 370 nm would ensure sunscreen products broad protection against UV. Of equal, if not more importance, is the label communicating UVA efficacy. Studies on labeling sunscreen efficacy have shown that SPF number, in combination with broad spectrum (qualified with critical wavelength ! 370 nm or an equivalent metric), represents a simple and sensible way for

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nash et al duration of sun exposure: a double blind randomized trial. J Natl Cancer Inst 1999;91:1304 9. Diffey BL. The need for sunscreens with broadspectrum protection. In: Urbach F, editor. Biological responses to ultraviolet A radiation. Overland Park, Kansas7 Valdenmar Publishing; 1992. p. 321 8. Kaidbey K, Gange RW. Comparison of methods for assessing photoprotection against ultraviolet A in vivo. J Am Acad Dermatol 1987;16:346 53. Roelandts R. Evaluating the UVA protection of sunscreens. J Am Acad Dermatol 1989;21:56 62. Roelandts R. Shedding light on sunscreens. Clin Exp Dermatol 1998;23:147 57. Standfield JW, Feldt PA, Csortan ES, Krochmal L. Ultraviolet A sunscreen evaluations in normal subjects. J Am Acad Dermatol 1989;20:744 8. Cole C. Sunscreen protection in the ultraviolet A region: how to measure the effectiveness. Photodermatol Photoimmunol Photomed 2001;17:2 10. Chardon A, Moyal D, Hourseau C. Persistant pigmentdarkening response as a method for evaluation of ultraviolet A protection assays. In: Lowe NJ, Shaath MA, Pathak MA, editors. Sunscreens development, evaluation and regulatory aspects. 2nd edition. New York7 Marcel Dekker; 1997. p. 559 82. Cole C, VanFossen R. Measurement of sunscreen UVA protection: an unsensitized human model. J Am Acad Dermatol 1992;26:174 84. [23] Diffey BL, Robson J. A new substrate to measure sunscreen protection factors throughout the ultraviolet spectrum. J Soc Cosmet Chem 1989;40:127 33. [24] Diffey BL. A method for broad-spectrum classification of sunscreens. Int J Cosmet Sci 1994;16:47 52. [25] Wendel V, Klette E, Gers-Barlag H. A new in vitro test method to assess the UVA protection performance of sun care products. SOFW 2001;127:12 31. [26] Heinrich U, Tronnier H, Kockott D, et al. Comparison of sun protection factors determined by an in vivo and different in vitro methodologies: a study with 58 different commercially available sunscreen products. Int J Cosmet Sci 2004;26:79 89. [27] Dippe R, Klette E, Mann T, et al. Comparison of four different in vitro test methods to assess the UVA protection performance of sunscreen products. SOFW J 2005;131:1 7. [28] Nash JF, Tanner PR, Grosick TL, et al. Sunscreen market analysis: the evolution and use of UVA-1 actives. 62nd Annual Meeting of the American Academy of Dermatology. Washington, DC, February 6 11, 2004. [29] Diffey BL. The need for sunscreens with broad spectrum protection. In: Urbach F, editor. Biological responses to ultraviolet A radiation. A symposium on UVA radiation. San Antonio, TX, June 1991. Overland Park, KS7 Valdenmar Publishing Co.; 1992. p. 321 8.

[15]

[16]

[17] [18] [19]

[20]

[21]

[22]

Dermatol Clin 24 (2006) 75 79

Water Resistance and Extended Wear Sunscreens

Patricia Poh Agin, PhDT
Product Safety and Performance, Schering-Plough HealthCare Products, Memphis, TN, USA

The effectiveness of a sunscreen product can be reduced by sweating, friction, water immersion, or any other force that has the potential to remove the product from the surface of the skin. Resistance to removal by water, sweat, and physical activity is an important aspect of sunscreen performance along with the basic protection provided against sunburn and other skin damage. The ability of a sunscreen to bind to the skin and resist removal during swimming SPF Value

tection factor (SPF) is defined as the dose of UV radiation (UVR) required to produce 1 minimal erythema dose (MED; minimally perceptible redness) on protected skin after the application of 2 mg/cm2 of product divided by the dose of UVR required to produce 1 MED on unprotected skin. To determine the SPF for a product label, a panel of at least 20 but no more than 25 valid SPF results must be obtained. A simple equation for this ratio is:

Exposure Interval MED on protected skin Exposure Interval MED on unprotected skin To determine how well a sunscreen product will remain on the skin, however, additional testing is required beyond an assessment of basic sun protection.

or sweating is known as substantivity. Standards for measuring substantivity are available in regulations or guidelines around the world, but these regulations vary concerning the labeling and communication of product performance to consumers due to differing regulatory environments. For example, in Europe and Japan, sunscreen products are regarded as cosmetics, whereas in Australia, Canada, and the United States, they are regulated as therapeutic (drug) products. In the United States, the Food and Drug Administration (FDA) regulates sunscreen products as over-the-counter (OTC) drugs [1]. The 1999 Final Monograph on Sunscreens established the current conditions for safety, efficacy, and labeling of sunscreen products, but it is expected to be revised to address ultraviolet A range (UVA) testing and labeling [1]. According to the monograph, the sun pro-

Water resistance In addition to providing a basic test method for the determination of the inherent efficacy of a sunscreen product, the FDA sunscreen monograph also outlines the procedures for measuring the capacity of a sunscreen product to resist removal by water. Methods for determining water resistance require the SPF to be measured after a defined water immersion procedure. Hot tubs, spa-pools, or similar tubs may be used, as long as the water quality (fresh water, chlorinated, or brominated as required), temperature, and circulation comply with published requirements. A water resistant SPF claim means that a sunscreens photoprotective effect remains after 40 minutes of water exposure; very water resistant means that the SPF of the sunscreen product can withstand at least

T Product Safety and Performance, Schering-Plough HealthCare Products, 3030 Jackson Avenue, Memphis, TN 38151. E-mail address: patty.agin@spcorp.com

0733-8635/06/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2005.08.002

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80 minutes of water immersion. The water resistant and very water resistant tests consist of cycles of 20-minute immersion intervals, each followed by a 20-minute rest/air dry period until the total water exposure time is reached. The test sites are air dried without toweling at the completion of the last water immersion period. In the United States, the SPF value on the label of a water resistant or very water resistant sunscreen product is the SPF value determined after water exposure. Some formulations have been shown to maintain their SPF for up to 6 or 8 hours of total water exposure, using an extended version of the water resistance test. In the 1999 Sunscreen Final Monograph, the FDA noted that several comments had been submitted in support of modifying the water resistance test procedures to allow for continuation of the water exposure regimen beyond the 80-minute total for products exhibiting longer substantive performance [1]. Other comments submitted to FDA proposed a testing protocol for an additional claim of rubproof or abrasion proof. Although the FDA did not agree with any expansion of the very water resistant claim, it recognized that data submitted confirmed that under extended testing conditions, products may retain their SPF values for up to 270 minutes of water exposure. Nevertheless, the agency felt that for consumers to compare products with multiple performance characteristics, a labeling claim of very water resistant is best supported by a uniform testing standard. For similar reasons, FDA also determined that extended wear claims concerning a specific number of hours of protection (or similar terminology) or an absolute claim such as all-day protection would be considered nonmonograph because they might encourage consumers to extend their time in the sun inappropriately. Because UV radiation can penetrate through water, the protective capacity of a product in water and its resistance to water removal is important. Water resistance, however, is not an indication of how friction will affect the substantivity or durability of a product. Abrasion of the product film on the skin, for example from toweling, can remove up to 85% of a sunscreen, leaving it on the towel [2]. Therefore, even a waterproof sunscreen should be reapplied after toweling, prolonged swimming, or vigorous activity to help ensure adequate protection. In Europe, the most recent guideline for measuring and labeling water resistance was published by The European Cosmetic, Toiletry and Perfumery Association (Colipa) in 2005 [3]. For this test, the SPF after a period of immersion in water is compared with the original SPF before water exposure (also

termed the static SPF), which is determined according to the proposed International Sun Protection Factor (static SPF) test method [3]. Whereas the Colipa substantivity method recommends the use of a spa tub or hot tub, an alternative procedure using a swimming pool is also acceptable. A product is considered water resistant if the SPF data after 40 minutes of water exposure meet certain statistical requirements and the percentage of the original static SPF value remaining after water immersion is greater than or equal to 50%. A product is considered extra water resistant if the SPF data after 80 minutes of water exposure meet certain statistical requirements and the percentage of the original static SPF value remaining after water immersion is greater than or equal to 50%. Thus, the SPF number on the product label for European sunscreen products is the prewater exposure (static) SPF whether the product is water-resistant or not, as shown in Table 1. Standard methods have also been published in Australia/New Zealand [4]. In Australia, SPF ratings begin at SPF 4. SPFs of 8 15 are considered moderate, SPFs 15 30 are high, and SPF 30+ is very high. Before March 1997, the maximum SPF allowed on a sunscreen label in Australia was 15+ ; currently the maximum SPF that can be claimed for a sunscreen in Australia is 30+ . Any skin care product that claims an SPF has therapeutic (drug) status in Australia and is classified as a primary sunscreen. A secondary sunscreen is a cosmetic (like a moisturizer) that has some unspecified sun protective capability. Secondary sunscreen products carry limited labeling such as: contains sunscreen (no SPF value is shown on the label). The water resistance capacity of Australian sunscreens differs according to SPF level (Table 2). The term water resistant must be

Table 1 Sun protection factor labeling after water immersion SPF value on label SPF test type US/Canada EU (COLIPA) Static SPF

Static SPF Static SPF (no water exposure) Water-resistant SPF after 40-min (40 min total water immersion water immersion) Very water resistant/ extra water resistant/waterproof (80 min total water immersion)

Static SPF (SPF before the 40-min water exposure) SPF after 80-min Static SPF water immersion (SPF before the 80-min water exposure)

water resistance

&

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Table 2 Water resistance claims for Australian sunscreen products SPF after water immersion ! 2, but < 4 ! 4, but < 8 ! 8, but < 15 ! 15, but < 20 ! 20, but < 25 ! 25 Maximum water resistance claim No water resistance claim allowed 40 min 80 min 2h 3h 4h

Durability: resistance to removal by wear Sunscreens have now been incorporated into a broad range of consumer products, including daily use cosmetics. A study of product migration on the face showed that makeup tends to collect in facial lines not long after application [6]. A study of 12 women who wore various types of foundation for 8 hours in an indoor, controlled environment found that the foundation makeup migrated or degraded on the faces of women with oily skin in 2 hours or less. The same was true for all the women by 4 hours after application. Consumers should be aware that if they are going to be in the sun for an extended period, they should only rely on a foundation makeup with SPF to protect them from the sun for a few hours due to the propensity for makeup to migrate on the skin. In these situations, it would be advisable to use a sunscreen product with an SPF of 15 or higher underneath the makeup. Selection of a sunscreen and the frequency of reapplication should be based on the knowledge of individual sun sensitivity, the type of outdoor activity, the geographical location, time of the year and time of day, along with the anticipated time in the sun. For more long-lasting protection, a sunscreen that is water or sweat-resistant may prove more durable than a makeup or moisturizer with SPF for an extended period of sun exposure. Ideally, a sunscreen should maintain its original efficacy on the skin for several hours after it is applied. To assess the relationship between SPF and durability after application, a study was conducted that investigated the time dependence of sunscreen effectiveness on human skin in vivo for up to 8 hours after application [7]. Products of both high and low SPF were applied at 2 mg/cm2 to the lower back. Subjects were monitored during the time between product application and subsequent exposure to UV radiation during the SPF test to ensure that the product was not physically removed. Between product applications and SPF testing, subjects were free to perform normal activities that did not affect the test sites. Products tested included foundation make-up with SPF 4, a non-waterproof SPF 4 cream, a non-waterproof SPF 15 lotion and a waterproof SPF 25 lotion. The protection provided by two SPF 4 products and the SPF 25 waterproof product remained virtually unchanged over time, while the protection provided by the non-waterproof SPF 15 lotion was found to be slightly lower at 8 hours postapplication. These results demonstrated that products of both high and low SPF, in different vehicle types, can maintain their efficacy for several hours on the skin if not physically removed or absorbed. Of

followed by a maximum time period ranging from 40 minutes for an SPF 4 up to 4 hours for a product with an SPF of 25 or higher. Importantly, when a sunscreen is labeled water resistant in Australia, the SPF number refers to the SPF remaining after the specified period of water resistance. The protection time on the label relates only to the water resistance claim and does not indicate the degree or time extent of basic protection against sunburn offered by the product. The Australian water resistance test may be performed in a spa pool or swimming pool. In South America, the MERCOSUR trade alliance has published guidelines for SPF testing that recognize either the US FDA method or the Colipa method for determining the basic static SPF. However, to label a product as water resistant or very water resistant, the MERCOSUR guidelines specify that testing for substantivity is to be conducted by the US FDA procedures [5].

Sweat resistance In the United States, a product that has been shown to be water resistant or very water resistant can also be labeled as sweat resistant [1]. In addition, some products tested under supplementary performance protocols demonstrate the capacity for the product to resist removal by sweat during exercise or after extended exposure to a hot and humid environment. This type of sweat resistance could be demonstrated by a static SPF test or by other means of substantiating the ability of the product to remain on the skin such as Woods lamp evaluation or by analyzing swabs or tape-strips of the skin preand post-exercise. Another property that can be tested is the ability of a formulation to not migrate or run into the eyes to cause stinging while in use. There are no specific performance standards for sweat resistance published in Europe, Japan, South America, or Australia.

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course, these data do not reflect use outdoors in the sun and do not include water exposure or other environmental influences such as wind or heat. Therefore, it remains important to apply sunscreen properly to all sun exposed areas and to reapply after swimming, excessive perspiration, vigorous activity, or anytime after toweling. Diffey and Grice [8] have suggested that the first reapplication should be made about 20 minutes after the initial application, to boost protection and ensure good coverage.

Other product performance considerations Sunscreens begin to work as sun protectants to absorb or block UV radiation immediately after application to the skin, so that although it is an excellent practice to apply sunscreen in advance of planned sun exposure, it is not too late to apply when first exposed to the sun if an earlier application has not been made. For some types of formulations, there may be a need to wait for the product to dry to form a film that will resist removal by water. For other products, however, the vehicle itself may be substantive immediately on application, thus providing immediate water resistance. This type of performance has been confirmed by omitting the 15-minute waiting period used in the standard water resistant or waterproof SPF tests; subjects enter the water immediately after product application and continue the regular water exposure periods until the 40-minute or 80-minute immersion total has been reached before conducting the UV exposures. Therefore, it is always important to read and follow labeled use directions for each sunscreen product. The durability and water-resistance properties of a sunscreen product depend on the type of vehicle in which it is formulated as well as the choice of sunscreen active ingredients. Vehicle type is critical both to sunscreen efficacy and to skinfeel. Inactive ingredients such as solvents and emollients play a role not only as carriers for the active ingredients but also can affect the wavelengths at which they absorb. Film formers and emulsifiers provide the foundation of the film that covers and protects the skin surface. To deliver a high SPF, a uniform and homogeneous film of the active ingredients must be created on the skin [9]. Due to their film-forming properties, dimethicone crosspolymers or other co-polymers can be used as substantivity aids for active ingredients that are oil soluble. Silicone elastomers can also be used with sunscreen active ingredients to enhance product performance.

Durability and water resistance are related characteristics of sunscreen vehicle systems. Oil-in-water and water-in-oil emulsion systems can both be used for sunscreen lotion formulations and allow for a variety of aesthetics and performance attributes in a formulation [10]. Both oil-in-water and water-in-oil formulations have been shown to deliver immediate water resistance, for example. Many sunscreen active ingredients are oil soluble; very high SPF products may contain >20% sunscreen active ingredients. Drier feeling sport lotions and oil-free formulations may rely on inactive ingredients such as silicas, starches, or other materials to provide a product with a low amount of residue and a smooth and sheer skinfeel after application and during exercise. Stick products based on waxy vehicles can be useful because they are anhydrous, very substantive to skin, and resistant to removal by water and sweat. Unfortunately, sticks are generally not appropriate for use over wide areas of the body due to their limited spreadability once applied to the skin. Alcohol-based sunscreen products can also deliver durable, substantive performance but present their own formulation hurdles in maintaining clarity and skin aesthetics. Because most outdoor activities include some physical exertion and sweating, creating durable sunscreens with high-performance waterand sweat-resistant properties in a variety of forms provides an important consumer benefit.

Summary Sunscreen use alone, no matter how substantive or durable the product, should not be relied on to prevent all of the possible harmful effects of sun exposure and should be used as an important part of an overall sun safety program. Variation between individuals, substantivity of sunscreen products, and exposure conditions all play a role in the real-world performance and durability of sunscreens. These factors must be considered when choosing a sunscreen product. Above all, it is important to read and follow label directions.

References
[1] US Food and Drug Administration. Final Monograph on Sunscreens. Fed Regist 1999;64:27666 93. [2] Stokes RP, Diffey BL. A novel ex vivo technique to assess the sand/rub resistance of sunscreen products. International J Cos Sci 2000;22(5):329 34.

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[3] The European Cosmetic, Toiletry and Perfumery Association (COLIPA). COLIPA recommendation no. 16. Brussels: COLIPA; April 7, 2005. [4] Australian Standard 2604:1998. Sunscreen productsevaluation and classification. Sydney7 Standards Association Australia; 1998. [5] MERCOSUR Group Common Market. Service manual Mercosur on solar cosmetic products. Res. No. 26/02, Annex 1. Buenos Aires: 2002. [6] Draelos ZD. Degradation and migration of facial foundations. J Am Acad Dermatol 2001;45(4):542 3. [7] Agin PP, Levine DJ. Sunscreens retain their efficacy on human skin for up to 8 h after application. J Photochem Photobiol B 1992;15(4):371 4. [8] Diffey BL, Grice J. The influence of sunscreen type on photoprotection. Br J Dermatol 1997;137(1):103 5. [9] Anderson MW, Hewitt JP, Spruce SR. Broad-spectrum physical sunscreens: titanium dioxide and zinc oxide.

In: Lowe NJ, Shaath NA, Pathak MA, editors. Sunscreens: development, evaluation and regulatory aspects. New York7 Marcel Dekker; 1997. p. 369 70. [10] Klein K. Sunscreen products: formulation and regulatory considerations. In: Lowe NJ, Shaath NA, Pathak MA, editors. Sunscreens: development, evaluation and regulatory aspects. New York7 Marcel Dekker; 1997. p. 285 311.

Further reading
The European Cosmetic, Toiletry and Perfumery Association (Colipa), The Japanese Cosmetic Industry Association (JCIA) and the Cosmetic, Toiletry and Fragrance Association of South Africa (CTFA-SA). International sun protection factor (SPF) test method. Brussels, February 2003.

Dermatol Clin 24 (2006) 81 84

Sunscreens and Hair Photoprotection

Zoe Diana Draelos, MDT
Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Photoprotection as it pertains to hair is not a common topic addressed by the dermatologist. Hair is nonliving and requires no protection from ultraviolet (UV) radiation because carcinogenesis of the hair shaft itself is not possible. If hair proteins are altered by sun exposure, damaged hair can be removed and replaced by new growth. Thus, at first glance, the whole issue of photoprotection for the hair might seem irrelevant; however, patients frequently consult the dermatologist for advice on hair growth and appearance problems. Hair photoprotection is an important part of maintaining the cosmetic value of the hair shaft. This article focuses on the chemical effects of UV radiation on the hair shaft, hair photoaging, intrinsic hair UV photoprotective mechanisms, and the use of hair sunscreens. The whole science of hair and photoprotection is currently in its infancy and an area of focused research within the hair care product and salon industries.

melanin, is found in unprocessed human hair that has been exposed to sunlight. Oxymelanin is an oxidative photodegradation product [1]. While the presence of this photodegraded melanin decreases the cosmetic value of the hair, it also chemically affects hair dye and permanent wave solution interaction with the hair shaft [2]. Most importantly, the amount of oxymelanin present equates with the degree of hair shaft photoaging. UV radiation also damages the hair lipids, so photodamaged hair is dull and dry. Intact hair lipids are required to coat the hair shaft imparting shine and manageability. Manageability is the ease with which the hair shaft can be styled. Hair that is devoid of intact lipids is subject to static electricity, fractures easily with combing friction, and appears frizzy.

Hair photoaging and endogenous protection To understand hair photoaging, it is necessary to understand how UV radiation interacts with the proteins of the hair shaft. Hair is a complex nonliving structure with an outer cuticle that provides a hard protective barrier for the inner cortex. The cortex is composed of fibrillar proteins, which are responsible for the mechanical strength of the hair shaft. Melanin pigments are contained in the cortex embedded in an amorphous protein matrix. Sometimes the hair shaft may contain a medulla, but the function of this inner structure is largely unknown and is found less frequently in mature hair shafts. Sunlight damages the strength of the hair shaft by increasing the scission of the cystine disulfide bonds. The hair disulfide bonds prevent the hair shaft from fracturing with minimal trauma. Thus, the primary photoaging effect of sunlight on hair is physical weakening of the shaft.

Hair and ultraviolet radiation Much of the understanding regarding hair and how it interacts with UV radiation has come from the textile industry. Natural fibers, such as wool, cotton, silk, and rayon, discolor when exposed to sunlight. White fabrics tend to take on a light brown/yellow color, a process known as photoyellowing. The same chemical process of photoyellowing also can occur in natural unprocessed human hair. Human hair contains two pigments, eumelanin and pheomelanin, accounting for the brown and red hues seen in hair, respectively. A third melanin pigment, known as oxyT 2444 North Main Street, High Point, NC 27262. E-mail address: zdraelos@northstate.net

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The second major effect of sunlight on the hair shaft is oxymelanin production, previously mentioned [3]. While oxymelanin leads to pigment dilution and lightening of hair color, it is the pigments within the hair shaft that provide the only source of endogenous photoprotection. The natural pigments actually prevent disulfide bond disruption, preserving the strength of the hair shaft, even though a hair color change occurs. In other words, chemical alterations in the hair pigment function to protect the protein structural backbone of the hair [4]. Hair contains the original pigment sunscreen, which is an area of rapid technical development in the commercial skin sunscreen industry.

Topical hair photoprotection Until recently, the main approach to topical exogenous hair photoprotection was no different than skin photoprotection. UV-B and UV-A sunscreens were added to formulations designed for hair use, such as instant conditioners, styling gels, and hair sprays. The main problem with this topical approach to hair photoprotection was the failure to create an even film protecting the entire surface area of every hair on the head, This topical approach is impossible to achieve because the collective surface area of the hair on a human head is huge. Another challenge is creating a sunscreen formulation that adheres to the hair cuticle. Furthermore, coating each and every hair shaft with an equal thickness of sunscreen without making the hair seem limp or greasy is a cosmetic challenge no hair care product has yet overcome. This dilemma led cosmetic researchers to question whether photoprotection could be imparted to the hair shaft through another means, perhaps through the internal structure of the hair shaft.

a brown hue. This loss of pigment and the resultant amino acid changes seem to predispose the hair shaft to more accelerated photoaging. This result led the cosmetics industry to question whether alterations in hair color could be used to enhance intrinsic hair photoprotection. Industry hair researchers have demonstrated that unpigmented hair is more susceptible to UV-induced damage than pigmented hair, meaning that the color granules are providing some protection from oxidative damage [5]. The rate of cystine disulfide bond breakage caused by environmental exposure is greater for unpigmented than pigmented hair. Thus, white hair and advanced gray hair are more susceptible to the damaging effects of UV radiation than youthful pigmented hair. Even though hair dyes are damaging to the hair shaft, the photoprotective effects of replacing hair shaft pigments may offset some of this damage.

Methods of enhancing intrinsic photoprotection If natural pigments within the hair shaft provide photoprotection, preserving the hair cosmetic value with synthetic pigments deposited on the cuticle and within the cortex by way of hair dyes may be possible. Two types of hair dyes exist that can artificially increase the hair shaft pigments: semipermanent and permanent. Semipermanent hair dyes are composed of a combination of dyes, such as nitrophenylenediamines, nitroaminophenols, and amionanthraquinones. These dyes are left on the hair 25 minutes and are used in combination to arrive at the final desired color. Damage occurs to the hair fibers on dyeing; however, as the hair is exposed to longer periods of UV radiation, the initial damaging effect of the dyeing procedure is outweighed by antioxidant effect of the color deposited on and in the hair shaft. Thus, white hair that is undyed exhibits more mechanical strength damage from UV radiation than semipermanently dyed hair after 4 days of exposure. The darker the hair dye color, therefore, the more photoprotection provided. The semipermanent hair colors are a mixture of dyes designed to create the desired final color. Usually, a mixture of reds and blues are used to create brown. The red pigments produce better photoprotection than the blue pigments. The red dyes likely are absorbing the more energetic part of the UV spectrum than the blue dyes. This same effect was also observed with permanent hair dyes. Permanent hair dyes penetrate more deeply into the hair shaft creating color because of an

Intrinsic hair photoprotection An analysis of the internal structure of the hair shaft led to some interesting insight into possible mechanisms of photoprotection. The natural color of the hair shaft results from a combination of visible light absorption and light-scattering abilities of the pigment granules distributed within the cortex. Exposure of the hair to sunlight leads to lightening of the hair color, known as bleaching, and ultimately damage to the fiber itself, as discussed earlier. The pigment lightening is obvious when looking at a woman with long brown hair. The distal hair tips have a reddish hue, whereas the proximal hair shafts have

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oxidation/reduction reaction. They too act as photoprotectants; however, the permanent hair dyes are more damaging as a result of the hydrogen peroxide and ammonia used to allow the chemicals to penetrate the hair shaft. Paradoxically, alkaline dyes, which produce more cuticule and structural hair shaft damage, provide better photoprotection, a result of the ability of permanent hair dyes to act as passive photofilters by reducing hair fiber protein damage through incident light attenuation. The dye molecule absorbs light energy, which promotes it to a more excited stated, followed by a return to ground state by way of radiative and nonradiative pathways. These pathways is the mechanism by which hair dyes can function as antioxidants to prevent hair weakening through disulfide bond dissolution.

Sunscreen containing hair care products Various hair care products exist, in addition to hair dyes, which can provide some hair photoprotection. These products include shampoos, instant conditioners, deep conditioners, and hairstyling products. Some of the higher priced prestige shampoos are incorporating sunscreens into their formulations designed for dyed hair. As discussed earlier, because UVA radiation alters the color of dyed hair, these shampoos are marketed as products that extend the life of the hair dye. The products may prevent dyed blonde hair and dyed brunette hair from developing red hues or brassy overtones. Certainly, the delivery of photoprotection from a shampoo is challenging, because the surfactant must be rinsed completely from the hair before styling. These products, in the authors opinion, contain added chemical sunscreens, such as oxybenzone or octylmethoxycinnamate, but their ability to coat and protect the hair is limited. A better approach to hair photoprotection is through the use of conditioners. Some of the newer conditioners based on silicones, such as dimethicone, can indeed deposit a thin film of conditioner and sunscreen on the hair shaft. While it is likely that the film will not evenly coat each hair shaft, sunscreens have better substantitivity when applied in this manner. Instant conditioners that are applied immediately following shampooing and rinsed before towel drying are not as effective as deep conditioners that remain on the hair for 15 to 30 minutes. The longer the conditioner remains on the hair shaft, the more likely the added sunscreen ingredient adheres to the hair. Thus, the contact time of the conditioner with the hair determines, to some extent, the degree of photoprotection obtained.

Styling products that are applied following drying of the hair are probably the most effective in delivering photoprotection. These products include blowdrying conditioners, styling gels, and hair sprays. Blow-drying conditioners are massaged through the hair when wet just before drying to act as a protectant against heat damage. If these conditioners are massaged thoroughly through the hair, they may provide excellent photoprotection. Styling gels applied to only certain areas of the hair, such as the hair shaft roots or tips, may not provide much protection because of limited contact. Hair sprays that are applied as a thin film to a finished hairstyle have the same limited effect. The degree of photoprotection offered by a hair care products is minimal at best. A more thorough, thicker application will result in better photoprotection, but this is difficult given the massive surface area of a head of hair. Many currently available sunscreen actives are not substantive to hair, meaning that they do not stick or adhere to the hair well, preventing sunscreen deposition and facilitating removal. A better approach to hair photoprotection may be the use of clothing, such as a hat, scarf, or umbrella. Much research and development remains in the realm of hair photoprotection.

Summary New insights into semipermanent and permanent dyes as a means of hair photoprotection are intriguing. Many women who present to the dermatologist for suggestions regarding hair growth are mature with gray hair. The temptation is to bleach the hair, thus removing any remaining pigment granules to produce lightening of hair color. Hair that is gray or bleached possesses fewer pigment granules than brown hair and is thus more susceptible to photoaging. Darker hair colors are more resistant to photodegradation. Mature women who enjoy the outdoors may find it more beneficial, therefore, to dye their hair a darker color to prevent hair shaft weakening from UV-A exposure. Currently, hair dye is the best sunscreen available. Sunscreen-containing shampoos and conditioners offer limited photoprotection at best.

References
[1] Hoting E, Zimmerman M. Sunlight-induced modifications in bleached, permed, or dyed human hair. J Soc Cosmet Chem 1997;48:79 91.

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draelos chemical alterations in human hair: I. Artificial irradiation and investigation of hair proteins. J Soc Cosmet Chem 1995;46:85 99. [5] Tolgyesi E. Weathering of hair. Cosmet Toilet 1983;98: 29 33.

[2] Pande CM, Albrecht L. Hair photoprotection by dyes. J Soc Cosmet Chem 2001;52:377 89. [3] Jachowicz J. Hair damage and attempts at its repair. J Soc Cosmet Chem 1987;38:263 86. [4] Hoting E, Zimmerman M, Hilterhaus-Bong S. Photo-

Dermatol Clin 24 (2006) 85 100

Garments As Solar Ultraviolet Radiation Screening Materials

Kathryn L. Hatch, PhDa, Uli Osterwalder, MSb,T
a

Agricultural and Biosystems Engineering, University of Arizona, Tucson, AZ, USA b Ciba Specialty Chemicals, Basel, Switzerland

Although wearing clothing to protect ones skin from the harmful rays of the sun is not new practice, this practice is of recent increasing interest. This article discusses 1) three types of protection (sunburn, precancerous skin lesion development, and photoaging) that can be realized by covering the skin with fabric, 2) the process by which some garmets come to be labeled with information about ultraviolet (UV) radiation protection advantage, 3) the meaning of the information provided on product labels, 4) practical guidelines that can be used to decide which summertime garments having no stated sun protection information are the best for wearing out-of-doors, and 5) the pros and cons of using fabric and sunscreen lotions for sun protection. Although this article covers information that has been reviewed previously [1 4], it also conveys new information and takes a different approach to explaining about how garments act as solar radiation screening materials. This should provide clear answers to questions most frequently asked. This article covers four main topics. The first topic is about the types of sun protectionsunburn protection, precancerous skin lesion development protection, and photoaging protectionthat can be realized by covering the skin with fabric. New unpublished information is provided about photoaging protection to fabric-covered skin. The second topic centers on the process by which some garments come to be labeled with information about ultraviolet
T Corresponding author. Ciba Specialty Chemicals, Klybeckstrasse 141, R-1045.2.12, CH4002, Basel, Switzerland. E-mail address: uli.osterwalder@cibasc.com (U. Osterwalder).

radiation protection advantage and about the meaning of the information provided on the product label. These are the garments that form a special classification of garments called sun-protective or UVprotective garments. By definition, sun-protective clothing is an item of personal apparel (including garments, hats, shoes, and fabric intended to be made into personal apparel) for which a claim of protective advantage against solar ultraviolet radiation is made [5]. A UV-protective textile is any textile whose manufacturer or seller claims that it protects from sunlight, including harmful UV light, claims the reduction of risk of skin injury associated with UV exposure, or uses a rating system that quantifies the amount of sun protection afforded [6]. There is no wording in these definitions that delineates/specifies a specific skin injury associated with UV radiation. The definitions are clear, however, that the claims are for UV radiation from the sun, not from other sources. Claims currently being made are for sunburn protection, but that wording rarely is used on product labels. The third topic is about guidelines individuals can use to assist in deciding which garments (that have no stated sun protection performance) would be the best selection for a summer day out-of-doors activity. The fourth topic compares and contrasts the use of fabric and sunscreen lotions for sun protection effectiveness. Finally, the article summarizes the concepts.

Types of protection This section describes test methods used to quantity the sunburn protection provided to skin by covering it with fabric. It also describes results of

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experiments in which fabrics differing in sunburn protection capability were used to investigate the capability of fabric to prevent or slow the occurrence of precancerous skin lesions or skin photoaging. Sunburn protection The fundamental evidence that fabric protects against erythema is the condition called farmers tan. The areas of skin not covered by fabric, often the lower arms and the neck, are the first to tan (darken) or burn (redden). There are two major methods to assess the amount/degree of sunburn protection provided by various fabrics: the in vivo method and the in vitro method. In vivo method The in vivo method is one that closely parallels the method used to assess the effectiveness of sunscreen lotions, that is to determine the sun protection factor (SPF) of the lotion. The major difference is that fabric is placed on the skin surface rather than spreading sunscreen lotion over the skin surface. Fabric SPF can be determined with Eq. 1: Radiation dose to produce just perceptible erythema under fabric covered skin SPF Radiation dose to produce just perceptible erythema of uncovered skin

of several swatches of the same fabric to take into account variation in fabric uniformity), they are used to calculate percent transmittance values (percent UVA, percent UVB, or a total percent transmittance value), a fabric ultraviolet protection factor (UPF) value, or a percent penetration value (1/UPF). Percent transmittance The calculation of total UV percent transmittance for a fabric is the ratio of the amount of radiation transmitted to the amount of radiation directed perpendicular to the fabric swatch surface. The calculation of the percentage of UVB transmitted through the fabric is the same, except only the data from the UV rays in the UVB region are used. Likewise, the calculation of the percentage of UVA transmitted involves only the data when UVA was directed at the fabric surface. Percent transmittance data do not take into account that certain wavelengths in the UV range are more responsible for skin damage than others. A fabric that allows a high proportion of UVA may be quite effective in preventing sunburn, as sunburning is linked to UVB radiation. Fabric ultraviolet protection factor value. The calculation of a UPF value is accomplished by combining the transmittance data with data collected that established the relative power of UV wavelengths to cause the skin to redden. These latter data, data collected using human subjects, are given in the erythemal action spectra [7]. The importance of using the erythemal action spectra data in a protection calculation is that fabrics that allow a greater portion of the most powerful skin reddening rays to be transmitted will receive a numerical value lower than a fabric that allows less of the powerful skin reddening rays through, even when both fabrics transmit the same amount of radiation. UPF can be calculated as in Eq. 2:
400 P

In vitro method The in vitro method is also called the instrumental method, because a spectrophotometer is used. This method has an in vivo component to it. The two major steps in this procedure are transmittance testing and calculations based on the transmittance data collected. To obtain transmittance data, a fabric swatch is placed in a spectrophotometer equipped with an integrating sphere. The procedure is to direct a beam of radiation composed of one wavelength in the UV light and of known quantity perpendicular to the surface of the fabric swatch and to measure the amount of radiation transmitted through the fabric. The sending of beams of radiation continues until all wavelengths in the UV range (or in some tests the wavelengths at 2 or 5 nm intervals) have been directed to the fabric face and transmittance data collected. Once the transmittance data have been collected (usually by measuring the UV transmittance

E k S k Dk 2

UPF

k290 400 P k290

Ek T k S k Dk

where E(k) is the relative erythemal spectral effectiveness, S(k) is the solar spectral irradiance (W m2 nm1), Dk is measured wavelength interval (nm), and T(k) is average spectral transmittance of the specimen. The definition of UPF is that it is the ratio of average effective UV radiation irradiance transmitted and calculated through air to the average effective

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UVR irradiance transmitted and calculated through fabric. The UPF value calculated therefore indicates how much longer a person can stay in the sun when fabric covers the skin as compared with the length of time in the sun without fabric covering to obtain same erythemal response. The endpoint is generally just perceptible skin reddening. Specific details on how to conduct transmittance testing, and use the transmittance data to calculate a UPF value for the fabric tested can be found in the following standard documents developed by committees within national, regional, or international standard setting organizations:
 AS/NZS 4399 (1996): Sun protective clothing Fig. 1. Regression correlation curve between UPF and SPF. (Data from Osterwalder U, Rohwer H. Improving UV protection by clothingrecent developments. Recent Results Cancer Res 2002;160:62 9.)

evaluation and classification [5]

 American Association of Textile Chemists and

Colorists 183-2000: Transmittance or blocking of erythemally weighted ultraviolet radiation through fabrics [8]  BS 7914 (1998): Method of test for penetration of erythemally weighted solar ultraviolet radiation through clothing fabrics [9]  EN 13758-1 (2001): Textilessolar UV protective properties. Part 1: method of test for apparel fabrics [10] Penetration/weighted transmittance. Another expression of sunburn protection is penetration or erythema weighted transmittance. It is calculated as the inverse of UPF (1/UPF). The significance of 1/UPF is that the resulting value lies between 1 and 0 (or 100% and 0%). The interpretation is that the lower the percent or the closer to zero the value is, the greater the sunburn protection provided by the fabric. In contrast, the UPF value has virtually no upper limit to indicate the protection provided. Comparison of sun protection factor and ultraviolet protection factor values Theoretically, the UPF and SPF value for any fabric should be the same, given the same incident spectral distribution on the fabric specimens used. As Menter and Hatch [3] concluded after reviewing studies in which swatches of the same fabrics were used in in vivo and in vitro tests, however, statistically identical results do not result. It is possible, however, that the development of a standard in vivo procedure that takes into account the results of UPF/SPF comparison studies might lead to a procedure in which in vivo results would be correlated more perfectly with in vitro results. Additionally, it has been shown (Fig. 1) that a good correlation between the UPF and SPF values can be achieved, provided the garment is covering the skin uniformly [11].

Precancerous skin lesion protection Two dermatologists [12,13] have reported cases in which either the appearance of or number of skin tumors on the patients body seemed directly related to type of clothing worn. In 1991, Bech-Thomson and colleagues [12] reported that their xeroderma pigmentosum patient had marked improvement in skin condition after she started and continued to wear leather and denim skirts that transmitted little UV. In 1998, OQuinn and Wagner [13] observed that their male patient (Fig. 2), who worked outside almost every day, had markedly fewer skin cancers under the yoke areas of his shirt than under other areas of his shirt. They concluded that the skin was more protected by the double layer of fabric forming the yoke (front and back) than by the single layer of fabric forming the body of the shirt. It was Menter and his research team [14,15] who conducted two studies to determine the ability of fabric to reduce the production of skin tumors. In other studies, hairless albino mice were used. In the study described here, the skins of the mice were not photosensitized. In the other study they were. Sk-1 hairless albino micewhose skins either were covered with a fabric with an SPF of greater than 30, a fabric with an SPF of 6.5, or not covered (the control)were irradiated with UV radiation using a dose regimen seven-fold higher than that used to produce squamous cell cancer in unprotected hairless mice. The outcome of the experiment illustrated by photographing one of the mice in each group and presented in Fig. 3, was that the fabric with an SPF of greater than 30 protected against premalignant lesions better than the fabric with an SPF of 6.5. There was no protection improvement, however, by the fabric with

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origin were protected by two different fabrics or left bare. Specifically, the fabrics were: 1. Non UV-enhanced fabric: Cotton T-shirt fabric TF 437W, tubular, 124 g/m2 (Test Fabrics Incorporated, Middlesex, New Jersey) 2. UV-enhanced fabric: Cotton T-shirt fabric TF437W treated with three washes in household washing machine (Miele Deluxe Electronic W724) at 40C (cotton program) with a common laundry detergent containing 0.25% of the UV-cutting agent (UVCA) Tinosorb FD (Ciba Specialty Chemicals Incorporated, Basel Switzerland) The UPF values of the unwashed and UVCAwashed fabrics were determined as UPF 4 and UPF 13 respectively, using the Australian standard [5]. Biophysical parameters of skin color, skin moisture content, skin wrinkling, and skin elasticity were determined as a function of exposure to UV radiation. Irradiation was performed three times a week for 12 weeks with less than one mean effective dose monthly adjusted (effective dose UVA 320 400 nm [24 26 J/cm2], UVB 280 320 nm [0.04 0.06 J/cm2]) using a Multiport 601 150W Solar Light Simulator (Solar Light Company, Philadelphia, Pennsylvania).

Fig. 2. Precancerous skin lesions under various sections of a shirt. (From OQuinn RP, Wagner RF. Unusual patterns of chronic photodamage through clothing. Cutis 1998;61: 269 71; with permission. n 1998, Quadrant HeathCom, Inc.)

an SPF of 6.5 compared with the control. One would expect that fabrics with higher SPF/UPF values to provide more protection against the development of precancerous tumors, because it is primarily UVB radiation that is involved in skin cancer development. Photoaging protection The possible reduction of photoaging of skin by covering it with fabric was just recently studied [16]. Over a 3-month period, skin of volunteers of Asian

Skin-darkening protection Darkness of skin was assessed using a Minolta CM-508i Chromameter (Konica Minolta, Hannover, Germany) yielding the color in L-a-b coordinates. As shown in Fig. 4, fabrics can efficiently prevent tan-

Fig. 3. Clinical appearance at 24 weeks of Sk-1 hairless mice irradiated with solar-simulating (SSR) for 12 weeks. (From Menter JM, Hollins TD, Sayre RM, et al. Protection against UV photocarcinogenesis by fabric materials. J Am Acad Dermatol 1994;31:711 6; with permission.) (A ) A mouse from the group irradiated with 5960 J/cm2 SSR in absence of fabric, with squamous cell carcinoma (SCC). (B ) A mouse from the group irradiated with 3460 J/cm2 SSR through typical fabric (SPF 6.5 1.0). Note development of SCC. (C ) A mouse from the group irradiated with 3460 J/cm2. (D ) Normal unradiated control mouse.

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Fig. 4. Pigmentation of fabric-covered and -uncovered skin over a 3-month period of sun exposure.

ning. Tanning can be seen as a surrogate for various other kinds of photodamage. There is significantly better protection by the UPF-13 fabric as compared with the UPF-4 fabric. As can be seen in the figure, there was also adequate (ie, balanced) UVA protection in these studies. With inferior UVA protection as is the case with some types of sunscreens, one would expect more tanning. To completely avoid any sign of tanning (skin pigmentation), UPF greater than 15 is required under the regime of irradiation used in the study. Skin moisture retention protection Skin exposed to sun has reduced moisture content. To determine whether skin covered with fabric reduced the degree of skin moisture loss, skin moisture content was determined before and after irradiation using a Corneometer (Courage + Khazaka Electronic GmbH, Ko ln, Germany) skin conductivity/ capacitance instrument. The results in Fig. 5 show that the skin moisture content drops considerably with UV irradiation. With fabric protection, the degree of skin moisture loss was reduced to some extent, but not entirely. Again, the UPF-13 fabric had a significantly better protection effect than the UPF-4 fabric. To avoid moisture loss or even increase the moisture content of the skin, however, a protective cream has to be applied. Wrinkle protection Wrinkles are an important sign of photoaging. In this phase of the study, wrinkling was measured

by surface profilometry (ie, analysis of the shadow patterns). As seen in Fig. 6, a significant increase in wrinkling occurred on the uncovered site over the 3 months of UV exposure used in this study. When fabric covered the skin during UV exposure, the formation of wrinkles was avoided. In the case of the protection by the UPF 13 fabric, a slight but significant reduction of the wrinkles was detected after 3 months. Skin-elasticity protection Skin elasticity was determined by a cutometer. A tube with integrated light barrier measures by means of repetitive suction skin extension and rebound time

Fig. 5. Change in skin moisture content of skin covered and not covered by fabric over a 3-month period of sun exposure.

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ments for protection against erythemally weighted solar ultraviolet radiation [17]  EN 13758-2 (2003): Solar UV protective propertiesclassification and marking of apparel [18] Labeling standards Labeling standards differ from those that define a process for determining the UPF/SPF for the swatches (fabrics), because they direct the conversion of the fabric UPF values generated in in vitro testing to a single label UPF value, which in turn determines a classification category of the fabric/product. Labeling standards provide different directions for determining label information including the state of the fabric (eg, new or laundered) at the time of transmittance testing, so it is important to look for the standard number on the product label. Differences in basis of claims One of the active debates about classifying garments as UV-protective is whether classification should include:
 only those garments made of fabrics having or

Fig. 6. Formation of wrinkles as a result of sun exposure over a 3-month period.

of the skin. As seen in Fig. 7, without protection skin elasticity drops significantly over the irradiation regime of 3 months. This effect was reduced to some extent when fabric covered the skin. Again, the UPF 13 fabric protected significantly better than the UPF-4 fabric, but some loss in skin elasticity occurred. This can be avoided completely or even be improved with a protective cream. Conclusions In all of these experiments, covering the skin with fabric was beneficial to reducing skin photoaging. The skin was less changed in color, had fewer wrinkles, was more elastic, and more hydrated. Repeating these experiments with fabrics with identical UPF values, however, may not give the same results. Identical results would be obtained only if the absorption spectra of the fabrics were identical, or the absorption in the UVA was identical. The higher UPF value fabric in the study was one containing a compound known to have excellent UVA absorption and possibly was one that absorbs the most harmful of the photoaging rays.

exceeding an agreed to minimal level of sunburn protection and covering at least an agreed to minimum skin surface area; and  those garments made of fabric having or exceeding an agreed-to minimal level of sunburn protection with no requirement for area of garment skin coverage Both bases for making a claim have been adopted. AS/NZS 4399:1996 was issued by Standard Australia/

Garments sold with a sunburn-protective claim The labeling of sunburn protective fabrics usually is accomplished using one of the following labeling standards developed by a committee within a national, regional, or international standard setting organization:
 AS/NZS 4399 (1996): Sun protective clothing

evaluation and classification [5]

 ASTM D6603-00: Standard guide for labeling

of UV-protective textiles [6]

Fig. 7. Changes in skin elasticity as a result of sunlight exposure over a 3-month period.

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New Zealand and titled Sun protective clothing evaluation and classification [5]. ASTM D6603-00 was issued by ASTM International and titled Standard guide for labeling of UV-protective textiles [6], require only that the fabric meet minimum protection levels. The BS 7914 (1999) standard issued by the British Standards Institute and titled Childrens clothing, [17] and EN 13758-2 issued by the European Committee for Standardization under the title Solar UV protective propertiesclassification and marking of apparel [18] require garment classification and minimum fabric UV-protective levels. Another critical difference in basis of claims that a garment/fabric is sunburn protective lies in the condition of the fabric swatches of the fabric at the time of testing. The ASTM 6603 labeling document [6] specifies that the fabric swatches must be prepared for testing. What this means is that fabric is subjected to 40 launderings and many hours of UV radiation exposure. If the fabric will be used in swimwear, it also must be subjected to chlorinated pool water. Procedures for these exposures are specified in ASTM 6544the preparation of textiles before ultraviolet transmittance testing [19]. The rationale for this swatch preparation step is to ensure that the lowest amount of protection during a normal life of the fabric is used in making the sunburn protection claim. In other words, the wearer of the garment is assured that the label amount is the least to be expected. Garment skin coverage and label UPF minimums BS 7914 applies to childrens garments [17] and EN 13758-2 [18] applies to garments for individuals of all ages. Both standards require that clothing designed to offer protection to the upper body will at least completely cover the upper body, clothing designed to offer protection to the lower body will completely cover at least the lower body, and clothing designed to offer protection to both the upper and lower body will at least completely cover the upper and lower body. Definitions of upper and lower body in these standards include garments with elbow-length sleeves, pants, and skirts extending to the knees to be classed as solar UV-protective. The two standards differ in setting the garment fabrics sunburn protection level. EN 13758-2 requires more than UPF 40 and BS 7914 a penetration of 2.5% or less. According to both AS/NZS 4399 [5] and ASTM D 6603 [6], the fabric comprising the garment must have a label-UPF rating of 15 for it to be classed as solar UV-protective. An important phrase here is label UPF. This is different than swatch UPF value . As outlined earlier, transmittance testing of swatches

gives the amount of each wavelength of radiation that passes through the fabric, that is, is transmitted. These values are combined with weights, numbers that reflect relative differences among the wavelengths to cause skin reddening. The multiplication and addition in the equation lead to a single UPF value, a value for the swatch of fabric that was tested. The labeling documents instruct that the amount of variation in the swatch UPF values can alter the UPF value, which is a straight average of the swatch UPF values. High variations lead to a lowering of the label UPF value. Classification categories UPF garments/fabrics are placed into classes based on the calculated label UPF value [5,6]. The good protection class is composed of fabrics with label UPF values of 15 to 24, the very good protection class is composed of fabrics with label UPF values of 25 to 39, and the excellent protection class of fabrics with label UPF values of 40 to 50 and 50 + (the highest value permitted on a label). Manufacturers and certifiers Fabric and garment manufacturers who wish to label their garments or a line of their garments as being sun protective tend to do so using a label (hangtag) of a certifier. For example, in Australia/ New Zealand, the certifier is the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA). In the United States, the major certifier for some years was the American Sun Protection Association (ASPA). In Europe, a certifier is the International Testing Association for Applied UV Protection. Another certifier is the Skin Cancer Foundation, which provides a certification seal for those products that meet its certification requirements. Certifiers may use the standards produced by national and international standard-setting organizations. Often they set their own testing and labeling procedures and standards. The certifiers name usually appears on the garment label. Garment choice Garments include swimwear (styled with at least elbow-length sleeves and knee-length shorts), longsleeved shirts (often pastel or white) usually with collars, long skirts, driving sleeves, and pants. The fiber content of the fabric of many of these garments is 100% nylon or 100% polyester. Because fiber content is required as marketplace information, individuals can determine if the sun protective

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garment is made from these fibers [20]. Nylon and polyester, especially the latter, have high UV absorbance [21] that can be enhanced with the addition of titanium dioxide (TiO2) particles [22,23]. Often the styling of garments made with polyester or nylon fabric includes vents so that the garment is cooler to wear, the vents permitting insensible perspiration to have a way to escape (because water vapor has a difficult time diffusing through the fabric itself) and thus for body cooling to take place. Two factors prevent the diffusion of moisture through the fabric. First, there is insufficient space between the yarns in the fabric, because the straight smooth filament yarns pack closely together leaving insufficient void space for water molecules to diffuse. Second, moisture cannot diffuse through the fibers (these are hydrophobic fibers). The feeling can be likened to wearing plastic wrap. Worthy of note is a recently developed nylon fabric made with BASF fibers that is cottonlike by touch and has high UPF value because of the inclusion of finely dispersed TiO2 particles within the fibers [24]. Other garments for which a claim of UV protection is made are those made with cotton fiber or rayon fiber (both fibers are composed of cellulosic polymers). Again, fabric fiber composition is required product information [20]. These fibers have poor UV absorbance [21], but their UV absorbance can be improved significantly by finishing the fabric with optical whitener and UV-absorbing compounds so that UPF ratings of 15 to 50+ can be obtained. These UPF values qualify the fabric as UV-protective and allow the manufacturer to make a claim in the marketplace. The most used commercial modification to date for cotton fiber is the addition of a UVabsorbing compound, a compound specifically developed to enhance UV absorption [25 29]. The compound does not interfere with moisture transport through the fiber or fabric. The most used modification for rayon fibers is to incorporate TiO2 in the fiber, with best improvement in UV absorption when the new microsized TiO2 particles are incorporated [22,23]. Two recent experimental treatments [30,31] hold promise for enhancing the UV protection of cotton fabrics. One treatment is applying a thin layer of titanium using a sol gel application method [30], and the second is applying nano-scale titanium hydrosol in combination with fluorescent whitening agent [31]. Purchasers Purchasers of garments sold with a UV protective claim know the level of sunburn protection provided

in the fabric at the time of purchase and during a reasonable length of use. The garments tend to be more expensive than similar styled garments for which a sunburn protection claim is not made. The higher cost covers expenses for transmittance testing, product labeling, and development of the chemical compounds to enhance the UV-absorbance of the fabric. Individuals who become sunburned with short periods of sunlight exposure are encouraged to purchase and wear sunburn protective clothing. This group includes fair skinned, red-headed individuals. Individuals who sunburn slowly but spend long periods of time in the mid-day sun (working, gardening, and playing sports for example) also are encouraged to wear labeled sunburn protective clothing mainly because they know the degree of built-in protection. Individuals who have other photosensitive conditions may be helped by wearing sunburn protective clothing, but this clothing would need to have ability to highly absorb UVA and also certain visible wavelengths. UPF values do not reveal that this is the case. As Menter and Hatch point out [3], exposure to UVB radiation has a relatively minor role in triggering the skin response of photosensitive individuals. It is exposure to UVA and visible rays that are responsible for their photosensitivity condition.

Garments sold without a claim Most, if not all, summertime outerwear garments in a persons closet probably were purchased without consideration of how UV protective they are. Some of these garments, if transmittance tested, would show UPF values of at least 15. In fact, the results of four studies undertaken during the 1990s [32 35] show that 50% to 80% of summertime fabrics have UPF values of 15 or greater (Fig. 8). Between 20% and 40% of the garments in these studies had UPF values of 40 or greater. The question is How can individuals make best choices for UV protection among garments they own or among garments they are considering as additions to their own or childrens wardrobe? Or rephrased, What fabric features (selection criteria) likely place a fabric in the 15 UPF classification or higher? This section discusses the answer by first discussing useful selection factors and then often recommended but not practical selection factors. Useful selection factors Useful selection factors are those that are visually obvious, whether there is product information

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required to be stated on a textile product label, and fibers are known to differ in UV-absorbing ability. Crews and colleagues [21] determined how fibers ranked relative to each other in regard to UV absorbance. This approach is in contrast to earlier studies in which fabrics of various fiber compositions were ranked and fabrics that differed in other important characteristics such as thickness (eg, wool fabrics are much thicker than cotton fabrics). The results of the experiment [21] established fibers could be classified in three distinct groups: Group 1: polyester, which is the best UV absorber Group 2: wool, silk, and nylon Group 3: cotton and rayon (cellulosic fibers), which are the poorest UV absorbers What is discouraging about these results is that the favorite fibers, cotton, rayon and flax (linen) for summer wear, are at the bottom of the list. What is encouraging is that garments one has in his/her possession, perhaps the favorite ones having this fiber composition may be excellent choices. This is because of the presence of optical whitening compounds on these fabrics. Laundering history of cellulosic fiber fabrics Knowing the number of times a garment made from 100% cotton, 100% rayon, 100% flax (linen), or from blends of these fibers with each other or with polyester have been laundered is helpful information in making a good choice of garment to wear out in the sun. Garments with these fiber compositions that have been laundered most are most likely the better choices. There are two major reasons; optical whitener is being deposited, and the fabric is shrinking with each wash. Optical whitener accumulation Optical whitening agents (OWAs), also known as florescent whitening agents and as brighteners, are included in almost every heavy-duty detergent product sold in the United States and in Europe. These OWAs are included, because they whiten and brighten fabrics. Compounds in this classification convert a portion of incident UV radiation to the visible blue wavelength and reflect the visible blue wavelength. More specifically, OWAs absorb UV radiation near 360 nm and re-emit it at about 430 nm. More visible light reaches an observers eye from the surface of a fabric containing OWA than from an identical fabric without OWA. White fabrics containing OWA are said to be whiter and colored fabrics to be brighter compared with the same fabric without the OWA.

Fig. 8. Fraction of summertime fabrics having various UPF values. (Data from Refs. [32 35].)

that assists, or if the garment owner knows the laundering history of his/her garments or his/her childrens garments. Garment style Garments that cover or shade the greatest skin area are better choices. These include hats with wide all-around brims, shirts with collars and long sleeves, trousers with long legs, and skirts that are knee length or longer. For many individuals, this is just too much fabric, too confining and not appropriate to the occasion. This is the time to complement garment selection with sunscreen lotion. Double fabric layers and fabric thickness Shirts that have a yoke, as do cowboy-style shirts, can be constructed with a single or double layer of fabric in the yoke area. For UV protection to the shoulder and upper torso, purchasing and wearing a double yoke garment would be the better choice. This is illustrated in Fig. 2, which shows the skin condition of a man who wore shirts with a double layer of fabric in the yoke area. Note that the dark area on the mans back is where there was a single layer of fabric and the lighter areas where the double layer of a fabric in the shirt yoke reduced the penetration of UV radiation [13]. Fabric thickness, a reflection of the amount of fiber in a given fabric area, is one concentration measure. Given two fabrics differing from each other only in thickness, the thicker fabric would have the higher UV-absorbing ability. Fabric fiber composition Fabrics may be composed of just one fiber (eg, 100% cotton, 100% polyester, 100% wool, or 100% silk). Other fabrics are blends of fibers (eg, 65% polyester and 35% cotton). Fiber composition is

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Secondarily, the presence of OWAs on fabric enhances UPF value, because they absorb UV. Specifically, they absorb better in the UVA region than in the UVB region (where most compounds in the classification absorb poorly). Most compounds in this classification have an absorption weakness at about 308 nm, a wavelength that is a powerful producer of erythema. Zhou and Crews [36] found after laundering cotton sheeting and cotton broadcloth 20 times in home laundering equipment using detergent containing OWA, that the 100% cotton sheeting showed a tenfold increase in mean UPF (initial fabric UPF 5.5 and after 20 washings UPF 57.1). The 100% cotton broadcloth showed about sixfold increase (after 20 washing UPF of 22). At 20 launderings, UPF still had not leveled off; more laundering may lead to even greater improvement, but not only because of the OWA. They noted that some of the UPF increase was because of shrinkage in the fabric. UPF values increased when the test fabrics were laundered under identical conditions except for the presence of OWA. Zhou and Crews [36] did not observe enhanced UPF values for the polyester or nylon fabrics they laundered 20 times with detergent containing OWA. Reinehr and colleagues [37] compared whiteness values and UPF values of white and colored cotton fabrics before and after laundering the fabrics with a traditional OWA compound and with an OWA compound with improved absorption in the UV. Some fabrics had been prewhitened, so they could determine whether the addition of OWA in laundry had a detrimental effect on whiteness, which it did not. Finally, Reinehr and colleagues [37] softened and added OWA to cotton fabric using two-rinse cycle fabric-softening products: one containing a cationicOWA (OWA-4) and the other OWA-2. Two formulations were used; 0.3% and 2.7% on weight of after-rinse product of softening compound. The fabric swatches laundered with the higher concentration cationic-OWA softener had higher SPF values than the swatches laundered with the lower concentration (SPF of 30 compared with 12). The comparison treatment (OWA-2) resulted in an SPF of 5 at both concentrations.

Ultraviolet-absorber accumulation UV-absorber compounds are available in select detergents and in a dedicated laundry product (a dedicated product whose sole intent is to enhance the UPF values of cotton and cotton blend fabrics). The name of the dedicated product is Rit SunGuard, manufactured by Phoenix Brands (Indianapolis,

Indiana). It is distributed primarily to grocery stores in the United States. Laundry detergents containing UV absorbers are available in Europe, Asia, and Australia. Rinse-cycle fabric softeners (conditioners) containing UV absorber are available in Switzerland and Japan. Consumers should look for the Skin Cancer Foundation Certification Seal and Ciba Specialty Chemical companys butterfly logo on laundry product packages and wording such as UV cut detergent , UV Shield , UPF 30+ , and Sun Care on the package to determine which products contain UV absorbers. The classification of compounds called the UVCA class or UV-absorbing class is composed of compounds having chromophore systems that absorb very effectively in the UV region, enabling them to maximize the absorption of UVR while in situ on textiles. These compounds also contribute to fabric whiteness and brightness. Compounds within this class enhance the UPF values of cellulosic fabrics, cellulosic blended fabrics, 100% polyester fabrics, and 100% nylon fabrics when added to the fabric during mill finishing [25 29]. Such mill-finished fabrics usually are made into garments for which a claim of UV protection will be made. Their presence on those fabrics often is not revealed in labeling. Compounds in the UVCA class should not be confused with UV-absorbing compounds whose purpose is to slow the solar degradation of PA (polyamide/nylon) fiber or enhance light fastness of dyes on automotive PES (polyester/polyethylene terephthalate) fibers/fabrics. Scientists working on the development of laundry products that include UV-absorbing compounds have shown that these products lead to significant improvement in UPF values of cotton fabrics that initially have little sunburn protection capability [38 43]. Of particular interest are two studies conducted by researchers outside the product development arena to determine differences in the amount of UPF enhancement that would result by home laundering the same fabrics with different laundry products. Wang and colleagues [44] laundered a jersey fabric (initial UPF 4.7) and a print cloth fabric (initial UPF 3.1). They found that after five cycles of laundering in water only, the UPF of their jersey fabric increased to 7.1 and UPF of their print cloth increased to 4.2, which they attributed to fabric shrinkage. After five cycles of washing in American Association of Textile Chemists and Colorists detergent with OWA, the UPF value was 6.0 for jersey and 4.4 for print cloth. After washing the swatches once with detergent containing UVCA, the UPF for jersey was 11 and 7 for print cloth. By the fifth wash cycle, the jersey fabric had a UPF value of 23, and the print cloth had a value of about 12.

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Kim and colleagues [45] laundered two white knit fabrics: a 100% cotton jersey (initial UPF of 14.2) and a 60% cotton 40% polyester pique (initial UPF of 23.4). After one laundering cycle with the Rit SunGuard product, UPF values were 81.4 23.0 (jersey) and 39.6 8.3 (pique). With Rit Whitener and Brightener product values were 30.5 6.1 (jersey) and 36.6 6.1 (pique). UPF values above 30 were obtained by the conclusion of the fifth laundering with Tide (Procter & Gamble, Cincinnati, Ohio) and with Wisk (Unilever, Englewood Cliffs, New Jersey). Specifically, the UPF values at this point were 43.3 8.5 (jersey) and 39.7 10.4 (pique fabric). There were statistically significant differences in UPF values for fabric type and for laundry product used in the wash. Adding just the Rit SunGuard product to laundry water resulted in the most rapid achievement of a UPF of 30+. Fabric shrinkage Cotton fabrics are subject to shrinkage when they are laundered, knit cotton fabrics tending to shrink more than woven cotton fabrics. Small amounts of shrinkage can lead to significant improvement in the UPF value of the fabric. This is because a fabric parameter textile scientists call fabric cover factor has a tremendous influence on UV transmission, that is directed transmission, rays that do directly through the fabric. They are not scattered as they go through the fabric, because they never interact with the fibers [46,47]. Fabric cover factor is discussed in the next section. Often recommended, but not practical selection factors Fabric cover factor, fabric depth of shade, and fabric hue are three selection criteria that can have a significant influence on the sun protection provided to fabric-covered skin. Dermatologists and others providing advice about UV protection by means of garments should not recommend that individuals

use these selection factors, however. An explanation follows. Fabric cover factor Fabric cover factor is the proportion of a fabric surface area filled with fiber/yarn to the total fabric surface area. Scientists [21,26,27,48 51] quantify the cover factor of fabrics using either image analysis (the more commonly used method and that used to determine the cover factor of the fabrics in Fig. 9) or direct transmittance data. When a fabric is placed on a white surface and the surface is magnified, as is the case in the photographs of the cotton fabric shown in Fig. 9, one sees that a portion of the white underlying surface is visible. The amount of white showing decreases from left to right. The measured fabric cover factors are 86%, 95%, and 98% [48]. The complementary relationship is called fabric porosity (or fabric optical porosity) and provides data about the percent of fabric surface area not filled by fiber. The porosity of the fabrics in Fig. 9 is therefore 14%, 5%, and 2%, respectively. Cover factor is a highly important fabric parameter, because it determines the probability of a UV ray striking a fiber. The greater the probability that UV radiation directed at the fabric surface will strike a fiber and therefore be reflected or absorbed by the surface fiber or other fibers as it continues its journey through the maze of fibers comprising the yarn leads to decreased transmittance (higher UPF). Conversely, the higher the percent porosity of the fabric, the greater the probability that rays directed perpendicular to the fabric surface (as is the case in transmittance testing) will pass directly through the pores in the fabric (where there is no UVabsorbing material. If one had a set of fabrics composed of fibers that absorbed all the radiation that struck them, but each fabric had a different cover factor, then the relationship between percent cover factor and SPF/ UPF value would be as shown in Table 1 [33]. These

Fig. 9. Comparison of cover factor of three cotton fabrics having identical yarn structures. (From Algaba I, Riva A, Crews PC. Influence of fiber type and fabric porosity on the UPF of summer fabrics. AATCC Review 2004;4(2):26 31; with permission.)

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Table 1 Relationship between cover factor/porosity and sun and ultraviolet protection factor values Cover factor (%) 80 90 93.4 95 97.5 98 99 99.5 Porosity (%) 20 10 6.6 5 2.5 2 1 0.5 Max theoretical fabric SPF/UPF 5 10 15 20 40 50 100 200

black fabric is being absorbed while the visible light striking the fibrous portion of the white fabric scatters and is transmitted through the fabric. The transmitted scattered light blurs the impression of the amount of light coming directly through the pores of the white fabric. Although they used two extremes (a white and black fabric), the same conclusions are reached under other scenarios. Fabric depth of shade The description of a fabrics color may be specified, in a nonscientific way, by its hue (eg, red, orange, yellow, blue, or green) and its depth of shade. This discussion begins with the wisdom of using fabric depth of shade to estimate fabric UPF. Fabric depth of shade is related to the lightness or darkness of the color (hue) of a fabric. For example, a red dye can be used to make fabrics ranging in shade from light pink to dark red, the shade differing because of the concentration of the dye in the fabric. Similarly, a black dye can be used to make fabrics ranging in shade from light gray to intense black. Although it is true that the darker the shade of fabrics dyed with the same dye, the higher the UPF of the fabric (provided the dye used has capability of absorbing in the UV region of the electromagnetic spectrum) [52], fabric depth of shade is an impractical selection factor for consumers to use, because the comparison probably will not be between or among fabrics that were dyed with the same dye. Because dyes, even those that dye the fabric to the same hue, differ in ability to absorb UV radiation, fabrics of the same hue and depth of shade will have different UPF values, sometimes dramatically different values. Srinivasan and Gatewood [52] conducted a study showing how unreliable using hue and depth of shade comparison can be to estimate the UPF value of fabrics or attempt to rank fabrics on the basis of UPF values. It was not their intent to show this relationship, however. They chose a 100%-cotton bleached print cloth fabric (initial UPF 4.1) and a series of commonly used direct dyes, and then dyed swatches of the fabric with each dye to a pale shade and a dark shade. The amount of dye added to the pale shade swatches was ~ 0.5% OWF and ~ 1.0% OWF to the dark shade fabrics. When the UPF values for each swatch were determined, it was obvious that the fabrics containing more dye (dark shades) had higher UPF values than swatches containing less of the same dye (pale shades). Fabric color: hue Hue is the color of the fabric (eg, red, yellow, or blue). The question is whether one can relate fabric

data show that UPF increases rapidly as percent cover factor increases in small increments. Again, the fibers in this set of fabrics absorb all the UV that strikes them. This is not usually the case. What if one had a set of cotton fabrics (or rayon fabrics) that were identical except for percent cover factor? Algaba and colleagues [48] prepared such a set (see Fig. 9) and determined the cover factor of each; the values are 86%, 95%, and 98% from left to right. What would the UPF values of the fabrics be? The UPF of these fabrics (all below 15 UPF) does not reflect the numbers shown in the figure. The reason is that the fibers allow UV radiation to pass through them, so the effect of fabric cover factor is diminished. None of the fabrics would provide even minimum protection (at least as defined in the UV labeling standards). Another reason not to recommend visual comparison of fabrics to determine relative cover factor, even when the fabrics may be made from fibers more UV-absorbing than cotton and rayon (the least UVabsorbing fibers), is because the comparison fabrics likely will differ in color; shade, even if the same hue; and thickness, all of which will effect the conclusion (ranking). The visual comparison method is to hold fabrics up to a light source, estimate the relative quantity of light passing through the fabric, and select the fabric letting the least amount of visible light through. Osterwalder and colleagues [1] provide an explanation about why this is not a reliable procedure by showing diagrams of two fabrics with cover factors of 1.0%. One fabric was white (UPF 3.7) and the other black (UPF 48.2). Using the visual comparison method leads to subjects saying that the black fabric would be far less ultraviolet protective than the white fabric. The reason for this erroneous conclusion is that the eye sees more distinct spots of visible light coming through the black fabric than the white one because the light striking the fibrous area of the

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color (hue) to UPF. The answer is no. Consider the data in Table 2, columns 1 and 4. The UPF data in column 4 were calculated using the data in column 3 and knowing exactly the amount of dye that was added to the swatches. Note that the UPF values in column 4 are in descending order. Then note that fabrics of the same hue do not cluster together. For example, red fabrics with identical concentration of dye have UPF values of 51, 31, and 20. Of note is that the black fabric in this study did not have the highest UPF value, even though advice has been given to consumers that black fabrics are the best UV protection choices. Also to be noted is that most fabrics in the marketplace are not dyed with a single dye but a carefully chosen set of dyes to produce the fashion color, a situation that further complicates any chance of estimating the UPF values of colored fabrics, even those of like fiber composition or cover factor. Other data about the relationship of dye type and dye concentration on fabric to UPF values that support the previous conclusions and add additional knowledge about dyes and UPF can be found elsewhere [53,54].

Fig. 10. Transmission of UV through unfinished and UVCA-treated fabric when dry and wet. (Data from Osterwalder U, Schlenker W, Rohwer H, et al. Facts and fiction on ultraviolet protection by clothing. Radiat Prot Dosimetry 2000;91:255 60.)

Cautions Sun protection afforded by covering ones skin with fabrics can be reduced during wearing. Of major concern is a reduction in UPF when the fabric becomes saturated with water. This would be of the most concern for swimwear and garments worn by heavily sweating individuals. The amount of reduction can be minimal or substantial depending on the fiber content of the fabric and whether the fabric has been finished with UV-absorbing compounds or laundered with products containing these compounds [3,55 58]. In general, the UPF of white and pastel colored 100% cotton fabric decreases as the moisture content of the fabric increases. As these fabrics get wet, scattering is reduced, leading to an increase of UVR penetration/transmittance. In contrast, fabrics containing UV absorbers or dyestuff compounds do not have reduced UPF, because UV protection is provided almost exclusively by absorbance (Fig. 10). Although this has been said before, ranking fabrics for sun protection performance is not done easily and often will lead to mistakes in judgment about how much sun protection is a being provided.

Table 2 Direct dyes ranked for effectiveness in improving the ultraviolet protection factor of 4.1-UPF cotton fabric Direct dye used to dye cotton fabric Red 28 Black 38 Red 24 Green 26 Yellow 44 Blue 1 Yellow 106 Brown 154 Blue 86 Violet 9 Yellow 28 Red 80 Yellow 12 Blue 218 None
a

Fabric UPF shade Palea 39 30 28 22 18 22 19 23 16 21 20 17 13 13 4.1 Darkb 51.7 40 37 29 29 30 28 31 19 29 29 25 19 19 4.1

Fabric UPF value when each fabric had the same dye concentration 41 34 31 26 25 26 25 25 24 24 22 20 18 17 4.1

Each fabric contains about 0.5% dye on weight of fiber. b Each fabric contains about 1.0% dye on weight of fiber. Data from Srinivasan M, Gatewood BM. Relationship of dye characteristics to UV protection provided by cotton fabric. Textile Chem Colorist Am Dyestuff Reporter 2000; 32:36 43.

Comparison of fabric with sunscreen lotions Fabric can be a highly effective sun (ultraviolet radiation) screening material. Fabric SPF/UPF values can be as high as for sunscreen lotions. The major disadvantage of using garments as sunscreening materials is probably that most garments do not

98 Table 3 Comparison of garments and sunscreens Comparison factor of garments vs. sunscreen Cost

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osterwalder

Comment Sunscreen costs ! $1 per one full body application. Garments labeled as UV-protective are costly. Use of regular garments does not have an additional cost unless dedicated UV absorber is purchased and applied. Sunscreen lotion needs replacement more frequently. Protective garments are long-lasting. Sunscreen is costly to test because it must be performed in vivo. Fabrics are easily tested. Sunscreen is temporary and must be reapplied. Garments keep their protective property over the whole day. Lotions require an even application to avoid having areas of inadequate protection. Individuals tend to underuse lotion so the protection stated on the product may not be achieved. Garments protect the area they cover. Sunscreens must be applied 30 minutes prior to sun exposure. Garments may be donned at the last minute. Sunscreen must be reapplied. Does not apply to normal textiles Protection may be lessened when white fabrics are wetted, but not if protection effect is mainly due to absorption by dyestuff or UV absorber. There are known reactions to certain ingredients in lotions. No known skin reactions from UV-absorbing compounds on fabrics. UVA protection by lotions often insufficient and not photostable; no UVA issue with garments. As a rule-of-thumb, sunscreens only provide ~1/3 of the labeled protection value [59] due to the lack of proper compliance. Protection is much more reliable in fabrics (compliance is not a factor). Sunscreens are advantageous because of their active influence on hydration of the skin. Sunscreens preferred to covering the skin with fabric.

Replacement frequency Simplicity in testing Long-lasting and photostable Even and sufficient application

Timing of application Waterproof-staying power on the skin Affected by wetting Skin tolerance UVA protection Sunburn protection

Photoaging Transparency

come labeled with a UPF value. But consumers can make reasonable judgments about relative sun protection performance and now have laundering options that lead to known levels of sun protection performance. Application of sunscreen lotions and garment selection lead to a good sun screening strategy. Each option has its advantages and disadvantages as outlined in Table 3.

Summary Fabric serves as a UV radiation filtering material, because it is made from fibers that all have some UV reflecting and absorption ability, and because fabric often is colored, meaning it contains colorants (dyes and pigments) that likewise have varying degrees of UV-absorbing ability. Further, cotton and cotton blend fabrics (eg, cotton and polyester blends) and rayon (viscose) fabrics and rayon blend fabrics

acquire a UV-absorbing compound, OWA (also known as a florescent whitener), or they many be finished in the mill with these compounds. The introduction of UVCA, compounds that increase the absorption of UV radiation of the fabrics to which they are applied, especially the absorption of the wavelengths most responsible for skin reddening (sunburning), has increased the ability of cotton and cotton blend fabrics to protect against UV radiation. Manufactured fibers can be enhanced by adding TiO2. Other compounds recently studied may be applied to commercially available fabrics in the near future. Fabrics can protect against sun burning, development of precancerous skin lesions, and solar aging of the skin. UV protection labeling is about sunburn protection. New procedures will need to be developed for labeling fabrics intended to protect against other deleterious effects of the sun. Another major point was that most cover-up garments, garments that cover the arms, legs and

solar uv radiation screening garments

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torso are UV protective, because the fabric from which they are made provides some UV protection to the skin. When a manufacturer decides to make a claim that a garment is UV protective, that manufacturer usually tests and labels the garment using a standard procedure, often one developed by a committee within a national, regional, or international standard setting organization. Individuals who are sun-sensitive are urged to purchase and wear garments for which a claim of UV protection is made. Using cover-up garments and sunscreen lotions is an effective combination for protection of the skin while outdoors on sunny and cloudy days.

References
[1] Osterwalder U, Schlenker W, Rohwer H, et al. Facts and fiction on ultraviolet protection by clothing. Radiat Prot Dosimetry 2000;91:255 60. [2] Rupp J, Bo hringer A, Yonenaga A, et al. Textiles for protection against harmful ultraviolet radiation. International Textiles Bulletin 2001;47(6):8 20. [3] Menter JM, Hatch KL. Clothing as solar radiation protection. Curr Probl Dermatol 2003;31:50 63. [4] Hatch KL. Fabrics as UV radiation filters. In: Shaath NA, editor. Sunscreens: regulations and commercial development. 3rd edition. New York7 Karger Publishing; 2004. p. 557 72. [5] Standards Association of Australia. Standard AS/NZS 4399: sun protective clothing: evaluation and classification. Homebush, Australia7 Australian/New Zealand Standards; 1996. Available at: http://www.standards. com.au. Accessed October 28, 2005. [6] American Society for Testing and Materials (ASTM International). Standard D 6603 00, Standard guide for labeling of UV-protective textiles. In: Bailey SJ, Baldwin NC, McElrone EK, et al, editors. ASTM standards, Vol. 7:03. 2004. p. 1187 91. Available at: http://www.astm.org. Accessed October 28, 2005. [7] Commission Internationale de lEclairage. Research note. A reference action spectrum for ultravioletinduced erythema in human skin. CIE J 1987;6:17 22. [8] American Association of Textile Chemists and Colorists. Test method 183-2000: transmittance or blocking of erythemally weighted ultraviolet radiation through fabrics. In: AATCC technical manual. Research Triangle Park (NC): AATCC; 2004. p. 341 3. [9] British Standards Institute. Standard 7914 1998: method of test for penetration of erythemally weighted solar ultraviolet radiation through clothing fabrics. Available at: http://www.bsi.org.uk. Accessed October 28, 2005. [10] European Committee for Standardization. Standard EN 13758 1: textilessolar UV-protective properties. Part 1: method of test for apparel fabrics. Available at: http://www.cenorm.be. Accessed October 28, 2005.

[11] Osterwalder U, Rohwer H. Improving UV protection by clothingrecent developments. Recent Results Cancer Res 2002;160:62 9. [12] Bech-Thomson M, Wuld HC, Ullman S. Xeroderma pigmentosum lesions related to ultraviolet transmittance by clothes. J Am Acad Dermatol 1991;24:365 8. [13] OQuinn RP, Wagner RF. Unusual patterns of chronic photodamage through clothing. Cutis 1998;61:269 71. [14] Menter JM, Hollins TD, Sayre RM, et al. Protection against UV photocarcinogenesis by fabric materials. J Am Acad Dermatol 1994;31:711 6. [15] Menter JM, Hollins TD, Sayre RM, et al. Protection against photodynamic therapy (PDT)-induced photosensitivity by fabric material. Photodermatol Photoimmunol Photomed 1998;4:154 9. [16] Baschong W, Artmann C, Schaumann M, et al. Sun protection beyond sunburnUV-protection in nonCaucasians. Presented at the American Academy of Dermatology 62nd Annual Meeting. Washington DC, February 6 11, 2004. [17] British Standards Institute. Standard 7949 1999: childrens clothing, requirements for protection against erythemally weighted solar ultraviolet radiation. Available at: http://www.bsi.org.uk. Accessed October 28, 2005. [18] European Committee for Standardization. Standard EN 13758 2: textilessolar UV-protective properties. Part 2: classification and marking of apparel. Available at: http://www.cenorm.be. Accessed October 28, 2005. [19] American Society for Testing and Materials. ASTM D6544 00: standard practice for preparation of textiles prior to ultraviolet (UV) transmission testing. In: Bailey SJ, Baldwin NC, McElrone EK, et al, editors. ASTM standards, Vol. 7:03. 2004. p. 1152 5. Available at: http://www.astm.org. Accessed October 28, 2005. [20] United States Federal Trade Commission. Textile Fiber Products Identification Act of 1960 and its amendments. Available at: http://www.ftc.gov. Accessed October 28, 2005. [21] Crews PC, Kachman S, Beyer AG. Influences on UVR transmission of undyed woven fabrics. Textile Chemist and Colorist 1999;31:17 26. [22] Wedler M, Hirthe B. UV-absorbing micro additives for synthetic fibers. Chem Fibers International 1999;49:72. [23] Dransfield GP. Inorganic sunscreens. Radiat Prot Dosimetry 2000;91(1 3):271 3. [24] BASF. No more sunburn! Clothing with sun protection for young and old. Available at: http://www.basf.de/ science_around-us. Accessed October 28, 2005. [25] Hilfiker R, Kaufmann W, Reinert G, et al. Improving sun protection factors of fabrics by applying UV absorbers. Textile Res J 1996;66:61 70. [26] Reinert G, Fuso F, Hilfiker R, Schmidt E. UVprotecting properties of textile fabrics and their improvement. Textile Chem Colorist 1997;29:36 43. [27] Jo llenbeck M. New UV absorbers for sun protective fabrics. In: Altmeyer P, Hoffmann K, Stu cker M, editors. Skin cancer and UV radiation. Berlin7 Springer Verlag; 1997. p. 382 7.

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osterwalder [44] Wang SQ, Kopf AW, Marx J, et al. Reduction of ultraviolet transmission through cotton t-shirt fabrics with low ultraviolet protection by various laundering methods and dyeing: clinical implications. J Am Acad Dermatol 2001;44:767 74. [45] Kim J, Stone J, Crews P, et al. Improving knit fabric UPF using consumer laundry products: a comparison of results using two instruments. Fam Consum Sci Res J 2004;33(2):141 58. [46] Stanford DG, Georgouras KE, Pailthorpe MT. The effect of laundering on the sun protection afforded by a summer weight garment. J Eur Acad Dermatol Venereol 1995;5:28 30. [47] Stanford DG, Georgouras KE, Pailthorpe MT. Sun protection afforded by a summer weight garment: the effect of wash and wear. Med J Austr 1995;162: 422 5. [48] Algaba I, Riva A, Crews PC. Influence of fiber type and fabric porosity on the UPF of summer fabrics. AATCC Review 2004;4(2):26 31. [49] Menzies SW, Lukins PB, Greenoak GE, et al. A comparative study of fabric protection against ultraviolet induced erythema determined by spectrophotometric and human skin measurements. Photodermatol Photoimmunol Photomed 1992;8:157 63. [50] Sedlacek M. Development of an optical porosity meter for the analysis of UV protective clothing [diploma thesis]. Grenzach (Germany): FH Karlsruhe; 1998. [51] Bommer B. Investigation of the UV protection factor of knit wear under stretch [diploma thesis]. Grenzach (Germany): FHBB Muttenz; 1999. [52] Srinivasan M, Gatewood BM. Relationship of dye characteristics to UV protection provided by cotton fabric. Textile Chemist and Colorist American Dyestuff Reporter 2000;32:36 43. [53] Veatch KD, Gatewood BM. Influence of light exposure on the UV protection of direct, reactive, acid, and disperse dyes on cotton and nylon fabrics. AATCC Review 2002;2(2):47 51. [54] Gorens ek M, Sluga F. Modifying the UV blocking effect of polyester fabric. Textile Research Journal 2004; 74(6):469 74. [55] Jevtic AP. The sun protective effect of clothing including beachwear. Aust J Dermatol 1990;31:5 7. [56] Gambichler T, Hatch KL, Avermaete A, et al. Influence of wetness on the ultraviolet protection factor (UPF) of textiles: in vitro and in vivo measurements. Photodermatol Photoimmunol Photomed 2002;180: 29 35. [57] Moon R, Pailthorpe M. Effect of stretch and wetting on the UPF of elastane fabrics. Australasian Textiles 1995;15:39 42. [58] Jesson N. Textiles for sun protection: wet versus dry fabric protection against UV radiation. [dissertation]. Sydney (Australia)7 University of New South Wales; 1992. [59] Diffey BL. Sunscreen isnt enough. J Photochem Photobiol 2001;64:105 8.

[28] Jo llenbeck M, Ha rri HP, Schlenker W, Osterwalder U. UV protective fabrics. In: UV-protective Fabrics. Proceedings of American Association of Textile Chemists and Colorists Functional Finishes and High Performance Textiles Symposium. Charlotte, North Carolina, January 27 28, 2000. [29] Eckhardt C, Rohwer H. UV protector for cotton fabrics. Textile Chem Colorist Am Dyestuff Reporter 2000;32:21 3. [30] Xin JH, Daoud WA, Kong YY. A new approach to UV-blocking treatment for cotton fabrics. Textile Res J 2004;72(2):97 100. [31] New Xu P, Wang W, Chen S-L. UV blocking treatment of cotton fabrics by titanium hydrosol. AATCC Review 2005;5(6):28 31. [32] Robson J, Diffey BL. Textiles and sun protection. Photodermatol Photoimmunol Photomed 1990;7:32 4. [33] Pailthorpe M. Textile parameters and sun protection factors. In: Pailthorpe M, editor. Textiles and Sun Protection Conference Proceedings. Kensington (NSW)7 The Society of Dyers and Colourists of Australia and New Zealand; 1993. p. 32 53. [34] Dummer R, Osterwalder U. UV protection factor of summer clothing in Switzerland and Germany. Dermatology 2000;200:81 2. [35] Gies HP, Roy CR, Elliott G, et al. Ultraviolet radiation protection factors for clothing. Health Phys 1994;67: 131 9. [36] Zhou Y, Crews PC. Effect of OBAs and repeated launderings on UVR transmission through fabrics. Textile Chemist and Colorist 1998;30:19 24. [37] Reinehr D, Eckhardt C, Kaufmann W. Skin protection against ultraviolet light by cotton textiles treated with optical brighteners. In: 4th World Surfactants CongressAsociacion Espanola de Productores de Sustancias para Aplicaciones Tensioactivas (Barcelona). Cambridge (UK): Royal Society of Chemistry; 1996. p. 264 76. [38] Eckhardt C, Osterwalder U. Laundering clothes to be sun protective. In: Cahn A, editor. Proceedings 4th World Conference of Detergents: strategies for the 21st century. (Montreux, 1998). Champaign (IL)7 AOCS Press; 1999. p. 317 22. [39] Rohwer H, Eckhardt C. Laundry additive for the sun FW J 1998;124:1241 4. protection of the skin. SO [40] Rohwer H, Osterwalder U, Dubini M. Enhanced textile sun protection within a few washes. 39th International Detergency Conference. Luxembourg, September 6 8, 1999. [41] Rohwer H, Kvita P. Sun protection of the skin with a FW J novel UV absorber for rinse cycle application. SO 1999;125:1 5. [42] Spillmann N. Sun protection via laundry products innovative science and creative effects to complete the circle of sun protection. In: Proceedings of the 5th World Conference on Detergents. (Montreux, 2002). Champaign (IL)7 AOCS Press; 1999. p. 42 197. [43] Schaumann M, Rohwer H. UV absorbers for fabrics. Happi 2003;36(2):59 61.

Dermatol Clin 24 (2006) 101 104

Compliance and Sunscreens

Zoe Diana Draelos, MD*
Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Some of the most hotly debated issues surrounding sunscreens deal with daily application. For the compliant person who applies his/her sunscreen to all exposed body parts on a daily basis, there is little concern; but for the person who sporadically applies sunscreen, the controversy is great. There are those who say that sunscreen prevents the body from developing a protective tan, leaving the forgetful sunscreen user open to more severe sunburns. This is true, but it reinforces the need to apply sunscreen daily in a compliant manner. Further controversy has arisen over the need to receive sunlight to maintain adequate body vitamin D levels. Although this may have been an issue years ago when milk and other common foods were not enriched with vitamin D, the incidence of vitamin D deficiency induced rickets is low. Most individuals receive enough casual sun exposure on a daily basis to manufacture adequate amounts of vitamin D in addition to normal dietary intake. Concerns over vitamin D levels should not prevent the use of sunscreen. The third controversy regarding daily sunscreen use is the concern of sunscreen penetration through the skin. It is possible for there to be some systemic absorption of topically applied sunscreens, but the levels absorbed are low. It is more likely that systemic absorption will arise through inadvertent sunscreen consumption from the hands while eating. Because sunscreens are classified as over-the-counter drugs, their safety must be established and validated by the US Food and Drug Administration. Only mono-

graphed ingredients can be used as sunscreen actives, further ensuring their safety. Although there are many possible excuses for not using sunscreen on a daily basis, most of the arguments presented only sidestep the issues regarding ultraviolet (UV) exposure and premature aging or photocarcinogenesis. It is then necessary to examine methods of improving sunscreen compliance.

Sunscreen selection and compliance There are many reasons why sunscreen remains in the bottle. Probably the most common reason quoted by patients is the fact that sunscreen is sticky. Perhaps it is important to obtain more insight into this issue. Most of the chemical sunscreen actives, which function by resonance delocalization to transform UV radiation into heat, are sticky oils, such as methyl anthranilate. Usually a sunscreen formulation will combine at least two to three different actives to get broader spectrum coverage and a higher sun protection factor (SPF). The SPF is increased as the concentration of the active ingredient is increased. Thus, higher SPF products are usually stickier. Sunscreens with an SPF of 30 or higher are usually stickier than sunscreens with an SPF of 15 or lower. Yet, an SPF of 15 blocks about 93% of the UVB radiation while an SPF of 30 blocks out 97% of the UV radiation (Fig. 1). This is only a 4% difference in UVB photoprotection that may make the difference between an aesthetically pleasing sunscreen and one that is undesirable. For this reason, dermatologists should reconsider advising patients to use the highest SPF product possible (Fig. 2). Lower SPF products generally have better aesthetics and may yield better compliance. The authors recommendation is that

T 2444 North Main Street High Point, NC 27262. E-mail address: zdraelos@northstate.net

0733-8635/06/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2005.09.001

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Fig. 1. SPF compliance relationship: SPF 15 is the standard protection; an increase in SPF is not linear to protection; and SPF rating does not indicate UVA protection level. Higher SPF products block out incrementally less UVB radiation.

patients should use an SPF 15, which provides excellent photoprotection and optimal aesthetics. Another common complaint regarding sunscreen use is that patients feel hot and sweaty while they are wearing sunscreens. Although some of this may be due to the fact that sunscreens are worn in the hot sun, chemical sunscreens, such as octylmethoxycinnamate, benzophenone, methyl anthranilate, and homosalate, actually function by transforming UV-B radiation to heat energy, as mentioned previously. This generation of heat by the sunscreen contributes to the feeling of skin warmth. This should not be a deterrent to wearing sunscreen, however, as the physical sunscreen agents, such as zinc oxide or titanium dioxide, do not produce heat. Selecting the proper sunscreen can help minimize this problem. Other common compliance problems include the perception that sunscreens cause acne. Usually the acne is in the form of inflammatory papules, not open

or closed comedones, and presents within 48 hours after initial application. This is not true acne because sufficient time has not passed since the sunscreen application for follicular rupture to occur. The acne seen with sunscreens is more of an acneiform eruption, which may be indicative of irritant contact dermatitis. Some of the more extended-wear, waterresistant sunscreens are more occlusive by nature and may cause difficulty at the follicular ostia. The solution to this problem is basically sorting through various sunscreen formulations by trial and error. Major problems can be avoided by applying the sunscreen for five consecutive nights to a small area of skin in front of the ear. The skin should be observed for the presence of inflammatory papules and pustules. Another helpful tip is avoiding long-wearing sunscreen products. For daily use, long-wearing products are not necessary, and a sunscreen-containing moisturizer may be a good alternative. If a beach-

100.0

% UVB Protection

80.0 60.0 40.0 20.0 0.0 2 4 6 8 10 12 15 30 50 100

SPF Level
Fig. 2. SPF comparison: the SPF rating scale is not linear. The curve demonstrates the relationship between SPF and protection against UVB radiation.

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wear product is desired, the vehicle of gel sunscreens, which may contain a polymer, should be avoided. Instead, a light-weight cream formulation should be selected and then applied frequently to obtain maximal protection. Some sunscreens sting when applied, and this is more common in gel sunscreen formulations with a high concentration of a volatile vehicle, such as alcohol. Creamy sunscreens are a possible solution to this problem. Sunscreens also may sting when they enter the eye. One option is to use one of the waxy stick sunscreens in the eye area that will not melt or run when combined with sweat. These sunscreens can be stroked above the eyebrows and on the upper and lower eyelid. One of the methods for improving compliance is to pick the proper sunscreen for the proper skin site. No one sunscreen formulation will work in all body areas. There are some who are skeptical of sunscreen efficacy from the start. This concern may be wellfounded, because sunscreens can fail. How does this occur? It is important to remember that sunscreens do not work unless present on the skin surface. Thus, failure to coat the entire exposed skin surface with sunscreen and sunscreen removal from rubbing or sweating are two of the most common causes of sunscreen failure. Sunscreens also may fail if the film applied to the skin is too thin. A thin film, created by failure to apply the proper amount of sunscreen, leaves the skin unprotected. Formulation issues are also important. Some sunscreens have better skin substantivity. Substantivity is a term used by the cosmetic chemist to explain the ability of the sunscreen to remain in place on the skin. Not all bottles of sunscreen with an identical SPF are equivalent. There is no substitute for the formulation knowledge of an experienced sunscreen manufacturer. By law, all products labeled with an SPF of 15 will provide consistent sun protection under optimal conditions. These optimal conditions include minimal perspiration, no water contact, low humidity, minimal activity, no wind, and thick film application. In reality, sunscreens are not worn under these conditions. The sunscreen in the bottle may be an SPF 15, but its performance on the skin may differ depending on formulation. The author encourages patients to avoid off-brand sunscreens in favor of wellestablished branded products. The last excuse patients give for failing to wear sunscreen is that they simply do not like the way it looks or feels on the skin. Many women complain that their facial foundation does not perform well when applied over sunscreen and the sunscreen makes their face look shiny and greasy. Again, care-

ful sunscreen selection is important. However, many women can get excellent sun protection by using a sunscreen-containing facial foundation. Although most sunscreen-containing facial foundations do not have an SPF higher than eight for aesthetic reasons, an SPF 8 facial foundation blocks 88% of the received UVB radiation. This is excellent protection for casual sun exposure. Applying facial powder over the sunscreen can minimize the facial shine seen with some sunscreens. This decreases facial shine, increases the SPF of the sunscreen, and improves the ability of the sunscreen to remain on the skin. This preceding discussion highlighted the need for creativity when devising methods to improve patient sunscreen compliance. This can be a challenge. The following section presents some ideas to improve compliance.

Box 1. Methods of improving sunscreen compliance

 Begin developing habits during

   

childhood for good hygiene: brush teeth, wash face, apply sunscreen Select sunscreen formulations that are appropriate for the body area of application Use sunscreen-containing moisturizers instead of plain moisturizers on face, neck, upper chest, and hands Select a sunscreen-containing facial foundation for a female face Use a sunscreen-containing lip balm or lipstick Use a gel sunscreen as an aftershave on the male face Apply a quarter-sized dab of sunscreen to the hand and use the entire amount on the face, neck, and ears Develop a routine for sunscreen application to include face, front of neck, back of neck, ears, behind the ears, and central chest Select separate products with different esthetics for daily wear and beach wear Use clothing effectively in the form of long pants, long sleeves, hats, scarves, and umbrellas as photoprotection

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Methods of improving sunscreen compliance Box 1 lists several ideas the author uses to encourage sunscreen compliance. God sunscreen habits develop during childhood as part of good general hygiene. It is also important to pick sunscreens with specific body areas in mind. For example, creams work better on the face, gels on the body, and sticks around the eyes and mouth. Exploring the use of sunscreen-containing moisturizers and facial foundations may provide good protection for casual sun exposure while increasing compliance. Lastly, patients who claim they cannot use sunscreen, for whatever reason, should be encouraged to use clothing effectively in the form of long pants, long sleeves, hats, scarves, and umbrellas as photoprotection.

Summary Compliance is more important with sunscreen than any other topical over-the-counter drug, except for possibly toothpaste. Dermatologists should em-

phasize to patients that if they want to keep their teeth, they should use toothpaste, and if they want to keep their skin, they should use sunscreen in combination with clothing. It is insightful to view the habits of people who live in very sunny climates, such as the Middle East. People who inhabit this part of the world with abundant UV radiation do not lie out in the sun to get a tan or wear skimpy clothing when engaging in outdoor activities. Both the men and women wear loose-fitting, long-sleeved gowns, shirts, and pants. Very little skin is exposed. A cloth also is wrapped around or over the head for further protection. These people know that too much sun can result in immediate health problems, such as sunburn, heat stroke, dehydration, and long-term health problems, such as skin cancer. Although the sun in North America is not nearly as strong as in the Middle East, sun protection is still a very important part of healthy living. The author is reminded of the young child who asked which teeth he had to brush, and the dentist replied, only the ones you want to keep. Patients frequently ask where they should apply sunscreen. The proper reply should be only the skin you want to be beautiful for the rest of your life.

Dermatol Clin 24 (2006) 105 117

Novel Emerging Sunscreen Technologies

Chanisada Tuchinda, MDa, Henry W. Lim, MDa,T, Uli Osterwalder, MSb, Andre Rougier, PhDc
a

Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA b Ciba Specialty Chemicals, Basel, Switzerland c La Roche-Posay Pharmaceutical Laboratories, Asnie ` res, France

Because of increases in the number of skin cancers diagnosed annually, adverse effects of ultraviolet (UV) radiation are being recognized, and major public education programs have been undertaken concerning photoprotection, including the use of sunscreen. In daily life, UV exposure is unavoidable; therefore sunscreen should be used regularly. Development in sunscreen manufacturing has grown tremendously in the last decade. Sunscreen active ingredients now are incorporated into cosmetics products to minimize photoaging changes. With the advances in technologies, many new UV filters have been developed recently. These have improved efficacy and safety. This article reviews these new filters, along with regulatory issues in the United States. The introduction of new sunscreen actives does not occur frequently. Compared with the United States, there are more new filters available in Europe. In fact, eight new organic UV filters have been approved in Europe within the past 14 years: 1. Diethylhexyl butamido triazone (DBT) 2. Benzylidene malonate polysiloxane (BMP) 3. Terephthalylidene dicamphor sulphonic acid (TDSA) 4. Disodium phenyl dibenzimidazole tetrasulfonate (DPDT)

5. Diethylamino hydroxybenzoyl hexyl benzoate (DHHB) 6. Drometrizole trisiloxane (DTS) 7. Methylene-bis-benzotriazolyl tetramethylbutylphenol (MBBT) 8. Bis-ethylhexyloxyphenol methoxyphenyl triazine (BEMT) The absorption spectra of these filters are shown in Fig. 1. TDSA, MBBT, and BEMT are at the various stages of the approval process from the US Food and Drug Administration (FDA). [1]

Ultraviolet-B filters Table 1 lists new active ingredients previously approved for sunscreens in Europe or other countries but not yet available in the United States. They are described in greater details in the following paragraphs. Ethylhexyl triazone Ethylhexyl triazone (EHT) is a UVB filter. In Europe, EHT has been available for some time; in fact, in 1996, it was listed as one of the top 10 most frequently used filters in Germany [2]. EHT obtained the status of eligible to enter the sunscreen monograph through the FDA Time and Extent Application (TEA) process in 2003 [3]. It is now eligible to continue in the process to be added to the overthe-counter (OTC) monograph of active ingredients approved for sunscreen in the United States, upon

T Corresponding author. Department of Dermatology, Henry Ford Hospital, 3031 West Grand Boulevard, Suite 800, Detroit, MI 48303. E-mail address: hlim1@hfhs.org (H.W. Lim).

0733-8635/06/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2005.09.003

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1600 1400 1200

tuchinda et al

Benzylidene malonate polysiloxane

S 71 (TDSA) S 73 (DTS) S 74 (BMP) S 78 (DBT) S 79 (MBBT) S 80 (DPDT) S 81 (BEMT)

E(1,1)*

1000 800 600 400 200 0 290 310 330 350 370 390

Wavelength (nm)
Fig. 1. Absorption spectrum of the new UV filters.

satisfactory presentation of data on safety and effectiveness to the FDA [3]. The structure of EHT is comprised of the chromophore of para-amino benzoic acid (PABA) linking it to a triazine ring. The peak absorption spectrum of EHT is 314 nm (Fig. 2). Even though solubility is limited, EHT can be incorporated in sunscreen formulations in substantial amounts [1]. Diethylhexyl butamido triazone DBT is a very efficient UVB filter. It can be regarded as an improved version of EHT, which was considered to be the most efficient UVB filter before the introduction of DBT. Besides the slight improvement in efficacy, the solubility is increased compared with EHT [4]. The structure and absorption spectrum of DBT are shown in Fig. 3.

BMP is a new UVB filter that has a structure of benzylidene malonate chromophore attached to a specific point on a polysiloxane chain (Fig. 4) [5]. The molecular weight is about 6000 Da. Because of the large molecular weight, it does not penetrate the skin surface, thus providing improvement in safety. Because the fraction of UV-absorbing moieties in the overall mass of the molecule is small, however, the efficiency in term of E 1,1 is quite low [1]. E 1,1 is the extinction efficiency, and it refers to the theoretical extinction of a 1% solution of the substance measured at an optical path length of 1 cm. BMP can be combined with nanopigments such as micronized titanium dioxide (TiO2) or zinc oxide (ZnO) for broad-spectrum UV protection. It also photostabilizes avobenzone; therefore, the combined product is photostable and provides broad UV protection.

Ultraviolet-A filters Terephthalylidene dicamphor sulphonic acid TDSA is a broad UV absorber, absorbing UV radiation between 290 and 390 nm with a peak at 345 nm (Fig. 5). It first was shown to be effective against the effect of chronic UVA irradiation in animal study in 1992 [6]. Unlike other UVA filters, such as avobenzone, which is a photo-unstable filter, and benzophenone, which has poor UVA absorption, TDSA provides broad UVA absorption with photostable properties [7].

Table 1 New ultraviolet absorbers that are not yet approved in the United States Sunscreen active COLIPA no./INCI name S69 S78 S74 S71 EHT DBT BMP TDSA Spectrum max (nm) (oil/water soluble) 314 312 312 345 (oil) (oil) (oil) (water) Molecular mass (Da) 823 766 6000 607 675 398 501 659 629

Type UVB

Trade name (supplier) Uvinul T 150 (BASF) Uvasorb HEB (3V Sigma) Parsol SLX (Roche/DSM) Mexoryl SX (LOre al) Neo Heliopan AP (Symrise) Uvinul A Plus (BASF) Mexoryl XL (LOre al) Tinosorb M (Ciba SC) Tinosorb S (Ciba SC)

Approval (status) Europe, USA (TEAa) Europe Europe Europe, Japan, USA (NDA) Europe Europe Europe, Japan Europe, Australia, USA (TEAa) Europe, USA (TEAa)

UVA

UVB and UVA

S80 DPDT DHHB S73 DTS S79 MBBT S81 BEMT

334 (water) 354 (oil) 303, 341 (oil) 305, 360 (water dispersible) 310, 343 (oil)

Abbreviations: COLIPA, European Cosmetic, Toiletry, and Perfumery Assocation; INCI, International Nomenclature Cosmetic Ingredient. a With foreign marketing data.

novel emerging sunscreen technologies

107

1500
O O

1200
NH

E(1,1)

900
N H O

N N

N H N O

600

300

0 290

310

330

350

370

390

Wavelength / nm
Fig. 2. Structure and absorption spectrum of EHT (Uvinul T150). (*) Represents the extinction in efficacy referring to the theoretical extinction of a 1% solution of the substance, measured at an optical path length of 1 cm.

Numerous studies of this agent showed promising results for preventing photoaging, UV-induced skin pigmentation, and UV-induced immunosuppression and carcinogenesis. TDSA is also beneficial in photodermatosis and photosensitivity conditions. In human study, TDSA applied before UVA exposure decreased loss of skin hydration and elasticity

and slowed UVA-induced skin pigmentation [8]. Protection against pigmentation correlated with the concentration of TDSA, and the level of protection was synergistic when TDSA was associated with DTS (a broad-spectrum UVB and UVA filter, discussed later in this section). Level of pigmentation protection essentially depends on UVA protection.

1500
NH

1200

O NH N N N H N O O O

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E(1,1)

N H O

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Wavelength / nm
Fig. 3. Structure and absorption spectrum of DBT (Uvasorb HEB).

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500
Si O Si O R Si
n

400
R = 92.1 - 92.5%

n = approx. 60 C H3 O O O O approx. 6% O O O approx. 1.5% O O O

E(1,1)

300

200

100

0 290

310

330

350

370

390

Wavelength / nm
Fig. 4. Structure and absorption spectrum of BMP (Parsol SLX).

When sunscreens with the same sun protection factor (SPF) but different level of UVA protection were compared, only those with high UVA protection provided similar levels of protection against sunburn and pigmentation [9,10]. Broad-spectrum sunscreen containing TDSA also may play a role in decreasing the degree of UVinduced immunosuppression, which was evidenced by its effect in decreasing UV-induced trans- to cisphotoisomerization of urocanic acid in human stra-

tum corneum [11]. In addition, sunscreen containing TDSA was shown to be more effective than 5% octyl methoxycinnamate at preventing photocarcinogenesis and UV suppression of contact hypersensitivity reaction to allergens in mouse model [12,13]. This UVA filter was shown to be useful for patients with photodermatoses. A 1999 study evaluated a broad-spectrum SPF 60 sunscreen containing 5% 4-methylbenzylidene camphor (MBC), 3.3% TDSA, 3.5% avobenzone, and 4.1% TiO2. This high UVA

1000
O NaO 3 S O

800

SO 3 Na

E(1,1)

600

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0 290

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390

Wavelength / nm
Fig. 5. Structure and absorption spectrum of TDSA (Mexoryl SX).

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protection sunscreen prevented the development of lesions that developed in all 23 patients with polymorphous light eruption (PMLE). Twenty patients (87%) using SPF 45 sunscreen containing 6% oxybenzone and UVB filters (8% homosalate, 7.5% octyl methoxycinnamate, 5% octyl salicylate) developed lesions on UV-tested areas [14]. Solar urticaria (SU) is a photodermatosis that has an action spectrum in the UVA and visible range. Most sunscreen products may not be sufficient to prevent the disease because of insufficient UVA protection. A broad-spectrum sunscreen containing MBC, TiO2, TDSA, and avobenzone has been shown to prevent development of SU in patients whose action spectrum was in the UVA and UVB range. This sunscreen preparation provided SU protection factors (SU-PF) 75, 56, and 133, in the long UVA, short UVA, and UVB ranges, respectively [15]. In a study of systemic absorption after topical application, it was shown that human systemic absorption of topical TDSA was less than 0.1% [16]. Disodium phenyl dibenzimidazole tetrasulfonate DPDT is a new water-soluble UVA filter, with a peak absorption spectrum at 334 nm (Fig. 6) [1,17,18]. Similar to TDSA, it shows synergistic effect when combined with filters in the oil phase. According to a formulators rule, higher SPF sunscreens are most effective (ie, use less UV filter), if both the water and the oil phases of a sunscreen emulsion contain some UV filter.

Diethylamino hydroxybenzoyl hexyl benzoate DHHB was launched as a successor of avobenzone. The UV-spectral properties are similar to avobenzone, but the photostability of DHHB is superior [1]. The structure and absorption spectrum of DHHB are demonstrated in Fig. 7. DHHB is approved in Europe.

Broad-spectrum ultraviolet-B and -A filters Drometriazole trisiloxane A new UV filter, DTS, first was introduced in the European Academy of Dermatology and Venereology in 1998. It is the first photostable broad UV filter against UVA and UVB. DTS belongs to the photostable group of the hydroxybenzotriazoles. Its structure is composed of two different chemical groups, hydroxyphenylbenzotriazol, which provides photostable UVA and UVB absorption, and short siloxane chain, which provides liposolubility of the molecule. DTS has two absorption spectra in UVB and UVA range (290 320 nm, kmax 303 nm; and 320 360 nm, kmax 344 nm) (Fig. 8). By combining the lipophilic DTS with hydrophilic TDSA, a high level of photoprotection can be achieved [9]. Since 1999, the combination of TDSA with the new filter DTS has been used in the Anthe lios product line of La Roche Posay.

1000
HO 3 S N N H SO 3 Na N N H SO 3 H SO 3 Na

800

E(1,1)

600

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0 290

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Wavelength / nm
Fig. 6. Structure and absorption spectrum of DPDT (Neo Heliopan AP).

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OH O O O

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N

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400

200

0 290

310

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Wavelength / nm
Fig. 7. Structure and absorption spectrum of DHHB (Uvinul A Plus).

Combination of TDSA and DTS was shown to be beneficial in different studies. Combination of TDSA, DTS, avobenzone, TiO2, and octocrylene completely inhibited photoprovocation-induced lesion in 100% of tested lupus erythematosus patients; in contrast, only 45% of patients were protected by a product that did not contain the two products [19]. In another study, 16 patients suffering from polymorphous light eruption were exposed under the sun during 6 days with this combination of filters TDSA,

DTS, avobenzone, TiO2 and octocrylene applied on a half body, the other half body was treated by a product affording a low UVA protection. Only four subjects developed a PMLE with the potent broadspectrum product, whereas 15 subjects developed a PMLE with the other product [20]. Moreover, it has been demonstrated that sunscreens with high and comparable SPF values but not containing TDSA and DTS were not equivalent at protecting against UVA-induced polymorphous light eruption (PLE)

500
Si N N N OH O Si O Si

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E(1,1)

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0 290

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Wavelength / nm
Fig. 8. Structure and absorption spectrum of DTS (Mexoryl XL).

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111

500

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E(1,1)

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N OH OH N N N

200

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0 290

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390

Wavelength / nm
Fig. 9. Structure and absorption spectrum of MBBT (Tinosorb M).

[21]. The same observations have been made in the protection against UVA induced phototoxicity following topical antibiotherapy [22]. Under intensive sunlight exposure and realistic application conditions, the use of the same highly protective filter combination prevented the photoinduced skin immunosuppression [23,24].
1000

Methylene-bis-benzotriazolyl tetramethylbutylphenol MBBT is a photostable UVA filter that also has a strong absorption in UVB (kmax 305 and 360 nm) (Fig. 9) [1,25]. It is the in the first class of sunscreens that combine the benefits of organic and inorganic filters. It comes as microfine organic particles with a

800

600

E(1,1)

OCH3

400
OH N N N OH

200

0 290

310

330

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370

390

Wavelength / nm
Fig. 10. Structure and absorption spectrum of BEMT (Tinosorb S).

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diameter of 100 to 200 nm; therefore it not only absorbs UV, but also scatters and reflects it [26]. MBBT is intended for use in aqueous dispersion. The microfine organic particles are dispersed in the water phase, leading to a synergistic effect with oil-soluble filters. Because MBBT is relatively large, its systemic absorption following topical application is small. Bis-ethylhexyloxyphenol methoxyphenyl triazine BEMT is a new broad-band UV filter. Because of its hydroxyphenyltriazine structure, it exhibits both UVB and UVA absorptions (kmax 310 nm and 343 nm) (Fig. 10). BEMT is oil-soluble and photostable. It has been shown to improve photostability of avobenzone, and the combination of avobenzone and octyl methoxycinnamate (OMC) [27]. Both MBBT and BEMT were reported to have no estrogenic or androgenic activities [28].

available for avobenzone or by an energy transfer from avobenzone to the stabilizing molecule. In the case of UV-absorbers, both mechanisms are possible, but with DEHN, which shows only negligible absorption in the UVB and none in the UVA, the latter one applies. Sun protection factor boosters by the use of nonabsorbing materials The technique to increase an SPF of sunscreen was introduced by adding new nonabsorbing material to sunscreen [31]. Sunspheres is a nonabsorbing material, developed by Rohm and Haas (Philadelphia, Pennsylvania). It is a styrene/acrylates copolymer manufactured by means of emulsion polymerization. The polymer itself does not absorb UV radiation; therefore is not an active sunscreen agent. It was designed to enhance the effectiveness of the active ingredients present in the formula [32]. When Sunspheres are manufactured, they are filled with water. When the product is applied to the skin, the internal water migrates out of the sphere, leaving microscopic hollow beads. When UV hits these hollow beads, the UV radiation is scattered and begins to travel sideways instead of straight down into skin. The spheres act as efficient scattering centers that increase the probability of UV radiation coming into contact with the UV active ingredients present in the sunscreen formulation. Sunspheres polymer was claimed to boost a sunscreens SPF by 50% to 70%, making it possible to reduce the amount of active ingredients in sunscreen products while providing the same level of photoprotection [32]. With a tiny external diameter of approximately 325 nm, the particle is nearly invisible and cannot be felt during the application of sunscreen on the skin. Sunspheres function well with UVB and UVA filters. Examples of products containing styrene/acrylates copolymer include facial care products of Nivea Vital, Dove, and Yves Saint Laurent. Micronization of inorganic sunscreen Because of the efficacy and safety of inorganic sunscreen, the initial purpose of its development was for the use in children and individuals with sensitive skin. Because of the whitening effect, however, it was not cosmetically acceptable to most individuals. UV attenuation performance of inorganic sunscreen is influenced by its particle size. When particle size is not sufficiently small (ie, < 100 nm), it can cause whitening of skin [33]. With the development in sunscreen technology, inorganic particle size now can be decreased into micronized form (10 50 nm), compared with 200 to 500 nm of the nonmicronized form, resulting in less scattering of visible light. This im-

Update on US Food and Drug Administration approval of new filters A United States clinical trial with TDSA has been completed; data have been submitted to the FDA as part of a new drug application (NDA) process. MBBT and BEMT have fulfilled the 5-year foreign marketing criterion; they are being submitted for FDA TEA for inclusion in the FDA sunscreen monograph.

Development of UV filters for sunscreens Some of the new technologies to improve the efficacy or safety of UV filters developed in recent years are summarized. New development with respect to conventional UV filters Stabilizing agents for butyl methoxydibenzoylmethane Avobenzone is a broad UVA absorber; however, its drawback is photoinstability. After exposed to 1 hour of sunlight, it was estimated that it would degrade by 36% [29]. Avobenzone/OMC combination is known as a photounstable formulation. The photoinstability of avobenzone can be avoided by combining it with octocrylene, MBC [30], BEMT, or with non-UV filters such as diethylhexyl 2,6 naphthalate (DEHN) [1,27]. This stabilization is either caused by a reduction of the number of photons

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proves the cosmetic acceptability and allows easier incorporation into formulations. Microfine TiO2 and microfine ZnO are used widely for daily wear sunscreen and traditional recreational products. To maximize the UV attenuation without causing whitening of skin, inorganic particle size needs to be controlled. TiO2 with particle size smaller than 100 nm will decrease scattering effects, resulting in a decrease in UVA attenuation, but an increase in UVB absorption. Therefore, by reducing the particle size, the peak of the absorption spectrum is shifted to the shorter wavelength. ZnO absorbs UV more uniformly than TiO2. UV absorption curve of ZnO has a sharp cutoff around 375 nm; similar to TiO2, as the particle size gets smaller, the UV absorption will shift to slightly shorter wavelengths [34]. Because microfine ZnO has better absorption at longer wave of UVA (340 380 nm) than TiO2, there has been a shift of sunscreen use from TiO2 to ZnO in the past few years [1,34]. Because of possible photocatalytic activity of inorganic sunscreen, inorganic particles frequently are coated with dimethicone or silica for maintenance of their efficacy [35].

cause there is no chemical interaction of these two UV filters [37,38]. Microfine organic particles Microfine organic particle is a new form of UV filters providing characters of organic and inorganic filters. Its unique property includes absorbing UV radiation similar to an organic filter, and scattering and reflecting UV similar to an inorganic filter [26]. MBBT is the first agent in this new class using microfine particle technology. Colorless UV-absorbing organic solid has been micronized to particles below 200 nm in diameter. The physical properties of microfine organic particles strongly depend on the particle size. At 160 nm particle size, about 85% of the transmitted UV is absorbed; 10% to 15% is forward scattered and 3% to 5% is backward scattered (reflected) [39]. It is inherently photostable and highly efficient because of its triple actions: UV absorption (by photostable organic molecules), scattering, and reflection (by microfine particles).

Requirements for sunscreen active ingredients New product forms Encapsulation of conventional UV absorbers By using a technique called micro-encapsulation, the organic sunscreen actives can be entrapped within a silica shell [36]. This silica glass is produced at room temperature so the sunscreen is not destroyed. The little glass spheres are only one-hundredth of the width of a human hair in diameter, extremely stable. They form a protective film on the skin. By using this technique, the organic filter does not contact with the skin directly, therefore decreasing the probability of allergic or irritant reaction. This microencapsulation technique is not limited to UV filters but is applicable to many other cosmetic ingredients. Eusolex UV-Pearls is the first sunscreen product using this technique. The first commercially available product contains octyl methoxycinnamate [36]. It is supplied as aqueous dispersions containing approximately 37% (w/w) of the UV absorber. The white liquids contain Eusolex UV-Pearls of about 1.0 mm diameter on average. They are sufficiently small to be transparent when applied to the skin and to give a pleasant skin feeling. Using this technique for encapsulation of UV filters, the incompatibility problem between sunscreen active ingredients can be solved. Photostability of the avobenzone/OMC is improved after segregate encapsulation technique, beThree basic requirements on sunscreen active ingredients must be fulfilled before they can be incorporated into a final product [1]. Efficacy The sunscreen active ingredients must demonstrate good UV absorption at least in parts of the UV range of 290 to 400 nm. Efficacy also includes good solubility. UV filters must be incorporated easily to any kind of formulation. Lastly, photostability of UV filters also influence efficacy of sunscreen active ingredients. Safety/registration In Europe, South America, Asia, and Africa, sunscreens are considered as cosmetics. Therefore, the approval is possible within 1 to 2 years of filling. Sunscreen actives should have no adverse effect on people or the environment. The toxicological studies generally required for a global registration include acute and chronic toxicity, fertility, embryofetal toxicity, and peri-/postnatal effects, in vitro and in vivo percutaneous absorption, genetic toxicity, and carcinogenicity [40]. In Australia and Japan, specific data on a complete formulation are required in addition to the European Union dossier. In the United States,

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Patent freedom Patent freedom means the free use of sunscreen active ingredient by any sunscreen manufacturer, avoiding the infringement of any third-party rights.

E(1,1)

600 400 200 0 290

Sunscreen regulation by the US Food and Drug Administration

310 330 350 370 390

Wavelength / nm
Fig. 11. Absorption spectrum of IMC (amiloxate).

Twenty-eight, 26, and 21 active ingredients are approved for UVA and UVB sunscreens in Europe,

sunscreen actives are considered as OTC drugs; as such, they need to be included in the FDA sunscreen monograph before they could be used. Starting in January 2002, there was a new procedure (TEA) introduced by the FDA. It is a two-step process. After a minimum of 5 continuous years of experience in the same countries as OTC products, new sunscreen actives can be considered for TEA approval [41]. In the next step, data on efficacy and safety have to be submitted. TEA provides an alternative to filling an NDA, which requires significantly more time and cost. Three UVB filters widely used outside the United States have received the status of eligibility to enter the sunscreen monograph in the United States [42]. These are 1. Isoamyl p-methoxycinnamate (IMC), US drug name: amiloxate (absorption spectrum is shown in Fig. 11) 2. 4-Methylbenzylidene camphor (MBC), US drug name: enzacamene (absorption spectrum is shown in Fig. 12) 3. Ethylhexyl triazone (EHT), US drug name: octyl triazone

Box 1. Sunscreens approved in European countries Benzophenone-4 (sulisobenzone) 3-Benzylidene camphor Benzylidene camphor sulfonic acid BEMT (bemotrizinol [Tinosorb S]) Bisymidazylate Butyl methoxydibenzoylmethane (avobenzone [Parsol 1789]) 7. Camphor benzalkonium methosulfate 8. DHHB 9. DBT 10. Dimethicodiethylbenzal malonate 11. DTS (silatriazole [Mexoryl XL]) 12. Ethoxylated ethyl 4-aminobenzoic acid (PEG-25 PABA) 13. Ethylhexyl methoxycinnamate (octyl methoxycinnamate and octinoxate) 14. 2-Ethylhexyl p -dimethyl amino benzoate (octyl dimethyl PABA) 15. Ethylhexyl salicylate (octyl salicylate; Octisalate) 16. Homomenthyl salicylate (homosalate) 17. IMC (Amiloxate) 18. MBC (enzacamene) 19. MBBT (bisoctrizole [Tinosorb M]) 20. Octocrylene 21. Octyl triazone 22. Oxybenzone 23. PABA 24. Phenylbenzimidazole sulfonic acid (ensulizole) 25. Polyacrylamidomethyl benzylidene camphor 26. TDSA (ecamsule [Mexoryl SX]) 27. TiO2 28. ZnO 1. 2. 3. 4. 5. 6.

1000 800

E(1,1)

600 400 200 0 290

310

330

350

370

390

Wavelength / nm
Fig. 12. Absorption spectrum of MBC (enzacamene).

novel emerging sunscreen technologies Table 2 Sixteen sunscreens approved in the United States Approved sunscreens PABA Avobenzone Cinoxate Dioxybenzone Ensulizole Homosalate Meradimate (menthyl anthranilate) Octinoxate Octisalate Octocrylene Octyl dimethyl PABA Oxybenzone Salisobenzone TiO2 Trolamine salicylate ZnO Max concentration (%) 15 3 3 3 4 15 5 7.5 5 10 8 6 10 25 12 25

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and safety of sun protective products. In the near future, new sunscreen products with even better in efficacy and safety should become available all over the world.

References
[1] Herzog B, Hueglin D, Osterwalder U. New sunscreen actives. In: Shaath NA, editor. Sunscreen: regulations and commercial development. 3rd edition. New York7 Marcel Dekker; 2005. p. 291 320. [2] Finkel P. Formulierung kosmetischer SonnenschutzmittelTrends und Tendenzen [Formulating cosmetic sun protection productstrends and tendencies]. Parf u merie Kosmetik 1999;80:10 6 [in German]. [3] BASF The Chemical Company. BASF is one of first to receive initial TEA approval from FDA. Available at: http://www.basf.com/corporate/news2003/newsinfo_ tea_approval.html. Accessed May 2005. [4] Malpede A, Fumagalli S. Diethylhexyl butamido triazone-nuovo filtro per la protezione cutanea [Diethylhexyl butamide triazonea new filter for skin protection]. Cosmet Technol 2000;3:33 8 [in Italian]. [5] Parsol SLX: a new possibility to combine with nanopigments. Available at: http://www.dsm.com/en_us/ downloads/dnp/news_rel_2004_08.pdf. Accessed October 2005. [6] Fourtanier A, Labat-Robert J, Kern P, et al. In vivo evaluation of photoprotection against chronic ultraviolet-A irradiation by a new sunscreen Mexoryl SX. Photochem Photobiol 1992;55:549 60. [7] Diffey BL, Strokes RP, Forestier S, et al. Suncare product phostability: a key for more realistic in vitro efficacy evaluation. In: Rougier A, Schaefer H, editors. Protection of the skin against ultraviolet radiation. Paris7 John Libbey; 1998. p. 137 42. [8] Seite S, Moyal D, Richard S, et al. Mexoryl SX: a broad absorption UV-A filter protects human skin from the effects of repeated suberythemal doses of UVA. J Photochem Photobiol B 1998;44:69 76. [9] Moyal D. Prevention of ultraviolet-induced skin pigmentation. Photodermatol Photoimmunol Photomed 2004;20:243 7. [10] Moyal D, Dutei L, Queille-Roussel C, et al. Comparison of UV-A protection afforded by sunscreens with a high sun protection factor. Eur J Dermatol 2002;12: 2 3. [11] Krien P, Moyal D, Rougier A. Influence of high protective sunscreens on photoisomerization of urocanic acid in human skin. In: Rougier A, Schaefer H, editors. Protection of the skin against ultraviolet radiation. Paris7 John Libbey; 1998. p. 183 8. [12] Fourtanier A. Mexoryl SX protects against solarsimulated UVR-induced photocarcinogenesis in mice. Photochem Photobiol 1996;64:688 93. [13] Gueniche A, Fourtanier A. Mexoryl SX protects against photoimmunosuppression. In: Altmeyer P, Hoff-

Australia, and Canada, respectively [26]. A list of 28 active ingredients approved in the European Union is shown in Box 1. In the United States, there are 16 filters included in the FDA sunscreen monograph (Table 2). Some of the permitted filters are not broad UVA filters; some are not photostable or are difficult to incorporate into formulations. All permitted UV filters can be used with any other permitted UV filters except avobenzone. Current FDA rules do not allow formulators to combine avobenzone with inorganic sunscreen [26]. Avobenzone is allowed to be used only with cinoxate, dioxybenzone, octinoxate, octisalate, homosalate, oxybenzone, octocrylene, sulisobenzone, and trolamine salicylate. Microfine oxides are allowed in the United States, Europe, and Australia [43]. Because of their safety, they are probably the most common choice for childrens and high SPF products.

Summary To improve the efficacy and safety of sunscreen products, UV filters and efficient photostable UVA and broadband UVB/UVA filters have been developed. Other new technologies, including a nonabsorbing material to boost SPF, coating/modifications of inorganic sunscreen, stabilizing avobenzone by photostabilizers, encapsulation of UV absorbers, and microfine organic particles also may improve efficacy

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tuchinda et al mann K, Stucker M, editors. Skin cancer and UV radiation. Berlin: Springer Verlag; 1997. p. 249 62. Allas S, Lui H, Moyal D, et al. Comparison of the ability of 2 sunscreens to protect against polymorphous light eruption induced by a UV-A/UV-B metal halide lamp. Arch Dermatol 1999;135:1421 2. Nocera T, Peyron JL, Moyal D, et al. Protection contre lurticaire solaire par les filtres : Une me thode de de termination du coefficient de photoprotection UVA [Protection of solar urticaria using broad spectrum sunscreen and determination of solar urticaria protection factor]. Les Nouvelles Dermatologiques 1998; 17(5):301 4 [in French]. Benech-Kieffer F, Meuling WJ, Leclerc C, et al. Percutaneous absorption of Mexoryl SX in human volunteer: comparison with in vitro data. Skin Pharmacol Appl Skin Physiol 2003;16:343 55. Symrise GmbH & Co. Neo heliopan AP product and brochure. Holzminden (Germany)7 Symrise; 2002. Johncock W, Langner R. Advance in UVA photoprotection via a novel water soluble UV-A absorbing bis-phenylimidazole derivative. 21st International Federation of Societies of Cosmetic Chemists Congress Congress. Berlin, Germany, September 11 14, 2000. Augsburg (Germany)7 Verlag fu r Chemische Industrie; 2000. p. 372 7. Stege H, Budde MA, Grether-Beck S, et al. Evaluation of the capacity of sunscreens to photoprotect lupus erythematosus patients by employing the photoprovocation test. Eur J Dermatol 2002;12:7 9. Moyal D, Binet O, Richard A, et al. Prevention of polymorphous light eruption by a new broad spectrum sunscreen: a need for a high UVA protecting factor. Presented at the 57th Annual Meeting of the American Academy of Dermatology. New Orleans, Louisiana, March 19 24, 1999. Stege H, Budde M, Grether-Beck S, et al. Sunscreen with high SPF values are not equivalent in protection from UV-A induced polymorphous light eruption. Eur J Dermatol 2002;12:4 6. Duteil L, Queille-Roussel C, Rougier A, et al. High protective effect of a broad-spectrum sunscreen against tetracycline toxicity. Eur J Dermatol 2002;12: 10 1. Moyal D, Duteil L, Queille-Roussel C, et al. Prevention of solar-induced immunosuppression by a new highly protective broad-spectrum sunscreen. Presented at the 57th Annual Meeting of the American Academy of Dermatology. New Orleans, Louisiana, March 19 24, 1999. Schiller M, Brzoska T, Bohm M, et al. Solar-simulated ultraviolet radiation induced upregulation of the melanocortin-1 receptor, proopiomelanocortin, and alpha-melanocyte stimulating hormone in human epidermis in vivo. J Invest Dermatol 2004;122:468 76. Ciba Specialty Chemical Inc. EC0746305. Basel (Switzerland): Ciba Specialty Chemicals. Reisch MC. New-wave sunscreens active ingredient makers are frustrated by the long list of sunscreesn and UV-A testing protocols that are still waiting FDA decisions. Chemical and Engineering News 2005; 83(15):18 22. Available at: http://pubs.acs.org/cen/ coverstory/83/print/8315sunscreens.html. Chatelain E, Gabard B. Photostabilization of butyl methoxydibenzoylmethane (Avobenzone) and ethylhexyl methoxycinnamate by bis-ethylhexyloxyphenol methoxyphenyl triazine (Tinosorb S), a new UV broadband filter. Photochem Photobiol 2001;74: 401 6. Ashby J, Tinwell H, Plautz J, et al. Lack of binding to isolated estrogen or androgen receptors, and inactivity in the immature rat uterotrophic assay, of the ultraviolet sunscreen filters Tinosorb M-active and Tinosorb S. Regul Toxicol Pharmacol 2001;34: 287 91. Deflandre A, Lang G. Photostability assessment of sunscreens: benzylidene camphor and dibenzoylmethane derivatives. Int J Cosmet Sci 1988;10:53 62. Forestier S, Mazillier C, Richard A, et al. Suncare product photostability: a key parameter for a more realistic in vitro efficacy evaluation. Part II: chromatographic analysis. In: Rougier A, Schaefer H, editors. Protection of the skin against ultraviolet radiation. Paris7 John Libbey; 1998. p. 143 7. Jones CE. A new polymeric additive for sunscreen. FW 1995;121:561 5. SO SunSpheres Hollow Sphere Technology. Available at: http://www.rhpersonalcare.com/pdf/sunspheres_personal care.pdf. Accessed October 2005. Shaath NA, Walele IL. Inorganic particulate ultraviolet filters in commerce. In: Shaath NA, editor. Sunscreen: regulations and commercial development. 3rd edition. New York7 Marcel Dekker; 2005. p. 281 90. Schlossman D, Shao Y. Inorganic sunscreens. In: Shaath NA, editor. Sunscreen: regulations and commercial development. 3rd edition. New York7 Marcel Dekker; 2005. p. 239 79. Lademann J, Weigmann H, Schafer H, et al. Investigation of the stability of coated titanium microparticles used in sunscreens. Skin Pharmacol Appl Skin Physiol 2000;13:258 64. Merck. Eusolex UV-Pearls. Available at: http://www. merck.de/servlet/PB/menu/1322070/index.html. Assessed May 2005. Schwack W, Rudolph T. Photoreaction of chemical UVA filters in cosmetics. GIT Lab J 1997;1:17 20. Chadorowski S, Quinn FX, Sanchez C, inventors. LOreal, assignee. Method for improving UV radiation stability of photosensitive sunscreen filters. US Patent 6,607,713. August 19, 2003. Mu ller S, Herzog B, Osterwalder U. Microfine organic particlesa new type of physical sunscreen actives. Presented at the 63th Annual Meeting of the American Academy of Dermatology. New Orleans, Louisiana, February 18 23, 2005. Nohynek G, Schaefer H. Benefit and risk of organic ultraviolet filters. Regul Toxicol Pharmacol 2001;33: 1 15.

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Dermatol Clin 24 (2006) 119 124

Public Health Challenges in Sun Protection

Melody J. Eide, MD, MPHa,b,T, Martin A. Weinstock, MD, PhDa,c
Departments of Dermatology and Community Health, Brown University, Providence, RI, USA b Department of Dermatology, Henry Ford Health System, Detroit, MI, USA c Dermatoepidemiology Unit, Providence Veterans Affairs Medical Center, Providence, RI, USA
a

Skin cancer, which consists mainly of keratinocyte carcinomas and melanoma, is the most common cancer and a substantial public health problem in many parts of the world. The incidence rate of melanoma, the most deadly type of skin cancer, has increased over 500% in the last fifty years, a faster increase than for any other type of cancer. The incidence rate of melanoma in the United States has climbed from 6.8 cases per 100,000 population in 1973 to almost 19 cases per 100,000 population in 2001 [1,2]. The most modifiable risk factor for skin cancer is ultraviolet radiation (UVR) exposure [3]. Because of the role of UVR exposure in skin cancer, ultraviolet (UV) light was included by the National Institute of Environmental Health Sciences (NIEHS) in their Tenth Report on Carcinogens in 2002 [4]. An individuals exposure to UVR is determined by the ambient UV flux and personal behavior. Efforts to improve sun protection have focused on reducing UV exposure by promoting sun avoidance behaviors and awareness of available barriers to UVR penetrance, including clothing and shade. Central to these efforts, the use of sunscreens in protection from UVR is a key component in public health campaigns

aimed at reducing skin cancer, especially in lightskinned populations. Sunscreen provides many health benefits, as discussed elsewhere in this issue, including reducing photoaging and providing protection from photosensitive dermatoses and skin cancers. In this article, the controversies, concerns, and challenges of sunscreen use as it relates to public health are discussed.

Use and application of sunscreens The US Department of Health and Human Services included several objectives in Healthy People 2010 targeted at the reducing outcomes associated with UV exposure and its relationship to skin cancer [5]. Included in their recommendations was the goal of increasing the number of people that used safe sun practices, including avoiding the sun during midday hours, wearing sun-protective clothing, using sunscreen with at least a sun protective factor (SPF) of 15, and avoiding artificial sources of UV light. By 2010, a target outcome is that at least 75% of adults over the age of 18 will be using at least one identified protective measure, which will be achieved in part by promoting an increase in the use of sunscreen [5]. A significant public health effort is necessary to achieve this goal, especially as past sunscreen use statistics are dismal, demonstrated by findings from a cancer control supplement to the 1992 National Health Interview Study (NHIS). That survey questioned over 10,000 white adults about their use of sunscreen, protective clothing, and shade. They found that only 41% of women and 22% of men selfreported that they would be very likely to use sunscreen, while conversely, 36% of women and 56%

Dr. Eide is supported by a Dermatology Foundation Fellowship award and a Surdna Foundation award. Dr. Weinstock is supported by grants from the Office of Research and Development (CSP 402), Department of Veterans Affairs, and the National Cancer Institute (CA 106592). T Corresponding author. Department of Dermatology, Henry Ford Health System, 3031 West Grand Boulevard, Suite 800, Detroit, MI 48202. E-mail address: meide1@hfhs.org (M.J. Eide).

0733-8635/06/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2005.08.007

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of men reported being unlikely to use sunscreen [6]. Sunscreen use in children is also inadequate, as demonstrated by another study, which found that only 53% of adults reported that their children always or usually applied sunscreen (and further decreased to 44% when discussing the reapplication of sunscreen) [7]. Furthermore, those people using sunscreen may be applying it inadequately. An American Cancer Society (ACS) study of youths ages 11 to 18 years found that 39% of adolescents who experienced at least one summer sunburn reported having used a sunscreen with an SPF of greater than or equal to 15 when they received their worst sunburn of the summer [8]. While an increase in the use of sunscreen is important and necessary, the appropriate use of sunscreen must also be encouraged. Optimal sunscreen use is necessary for sunscreen to be effective. While many people now have a better understanding of the importance of identifying a sunscreens protective effect using its SPF, evidence exists that suggests challenges in the proper application of an adequate amount of sunscreen initially and an appropriate reapplication. Because consumers typically apply less sunscreen than is used to establish the SPF on the bottle, the actual SPF received may be only 20% to 50% of that desired [9,10]. An Australian study found that the median quantity of sunscreen applied was only 0.8 mg/cm2, less than half the amount needed to achieve the labeled SPF [11]. Partly because of this issue many have recommended the use of an SPF 30 instead of an SPF 15 sunscreen in messages to the public [12]. Additionally, many people do not understand the need to reapply sunscreen, especially sunscreen labeled as waterproof or water resistant, after perspiring or swimming. The ACS advocates labeling sunscreen lotions with a reapplication time to help people improve their use of sunscreen [13]. While people are inconsistent in their reapplication of sunscreen, large sun protective benefits exist to be gained from routine sunscreen reapplication as noted by an Australian study which found a two- to three-fold increase in sun protection with reapplication compared with single application [14,15]. Another important aspect of appropriate sunscreen use is use during critical exposure periods, such as childhood. Concern exists about sun exposure during early childhood, and, hence, children have been the target population for many primary prevention campaigns [16]. The American Academy of Pediatrics Committee on Environmental Health published recommendations in 1999 urging pediatricians to promote a reduction in sun exposure during childhood

by encouraging the use of sunscreen; physical protection, such as hats, clothing, and shade; and being mindful of the UV index [17]. A wide range of public health campaigns have been implemented to encourage sun protection in childhood, including targeting mothers of newborns and school children and their parents [18,19]. While many of these childhood interventions have met with a degree of short-term success, their effect during the transition to adulthoodwhen peers may replace parental influence is unclear [20]. In a longitudinal study of Australian youth, beginning with the summer after finishing secondary school and continuing through the subsequent two summers, Schofield and colleagues [21]found that sunscreen use decreased with time, regardless of skin type, with men less likely to report frequent use than women. The 17- to 24-year-old age group were less likely than any other age group to use sunscreen (the odd ratios [OR] for using protection increased with age: the 25- to 34-year-old age group compared with the 17- to 24-year-old age group had an OR of 1.7 [95% confidence interval {CI} 1.4 2.1] while those 75 and over had an OR of 6.0 in comparison to the 17- to 24-year-old group [95% CI 4.5 7.9]) [6]. Young adults are also more likely to believe that a base tan decreases melanoma risk [18]. Better sun protective behaviors by young adults need to be encouraged.

Compensation hypothesis: sunscreen use and sun exposure Another matter that must be considered when discussing sunscreen use relates to the so-called compensation hypothesis [22]. This hypothesis has several postulates. First, the UV wavelengths that are responsible for sunburn (ie, those in the UVB range) may not be the same wavelengths responsible for inducing melanoma (ie, those in the UVA range). Because many sunscreens provide protection primarily from shorter-length UVB range wavelengths, sunscreen may protect against sunburn but not against melanoma. An additional postulate of the hypothesis is that melanoma is caused primarily by UVA exposure, as compared with UVB exposure. The final assumption of the hypothesis suggests that because sunscreen reduces the risk for sunburn, a major factor in limiting time of UV exposure, use of sunscreen could lead to longer length of time before induction of a sunburn and, thus, longer exposure to UVR, particularly longer-wavelength (UVA type) radiation. Sunscreens, therefore, may theoretically increase the risk for carcinogenesis.

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Evidence exists that supports the compensation hypothesis. Autier and colleagues [10] investigated sunscreen use and duration of sun exposure in a double-blind randomized controlled trial (RCT). Despite no baseline difference in fondness for sunbathing or report of daytime sunbathing, participants (university students on break) assigned to use a higher SPF sunscreen (SPF 30 versus SPF 15) accumulated significantly more hours of sun exposure and sunbathing. Participants using an SPF of 30 spent roughly 20% longer in the sun on average than those using the SPF-15 sunscreen [10]. Substantial evidence exists, however, against the hypothesis. Todays sunscreens, including anything with an SPF of 10 or higher, commonly use ingredients that are given a broader spectrum of UV protection, providing protection from UVA and UVB radiation [23]. Furthermore, a subsequent RCT of sunscreen use in white Canadian children did not find increased sun exposure in the sunscreen group compared with the control group [24]. The theory is further disputed by a randomized control trial in Australia that found a 25% lower incidence of squamous cell carcinoma (SCC) (rate ratio [RR] 0.74 [95% CI 0.31 1.77]) in sunscreen-use group compared with placebo (though the incidence of basal cell carcinoma (BCC) was similar between groups (RR 0.96 [95% CI 0.59 1.57]) and no evidence of significant compensation [25]. Despite the compensation hypothesis, it is clear that sunscreen provides fundamental sun protection, though sunscreen use should not be the only public health message promoted.

Alternative strategies in the primary prevention of skin cancer It is important to recognize the importance of other methods for reducing sun exposure besides sunscreen. There is a photo-protective effect from normal clothing (though less than that provided by the sun-protective clothing discussed in Chapter 18), as we are reminded almost annually by the appearance of summer tan-lines which appear at the edge of clothing-covered- (nonexposed) versus bare- (exposed) skin. Long sleeve shirts and pants provided direct protection from UVR, especially when worn in addition to sunscreen, and the public should be encouraged to wear clothing with more skin coverage, especially during summer months. Fashion trends may prove helpful in this regard, as suggested by the full-body swimwear sported by swimmers such as phenomenon Michael Phelps at the most recent

Olympic Games. Hats, especially wide-brimmed hats, are also important means of providing sun protection. Wide-brimmed hats also provide protection in one or more ways: either by shading the face and neck from sun-exposure, or especially as in the case of a person with thin or short hair or a balding or receding hairline, by providing direct coverage from the sun. The use of a hat has been strongly emphasized for children. Individuals should be encouraged to seek out shade when available outdoors, either naturally provided by trees or under constructed awnings. An assessment of 33 elementary schools in western Australia found shade to be present in only 15% of the area of an the average playground (range 3% 26%) [26]. While the sun protection provided by shade is variable, in regards to the variation in the amount of sky-coverage provided (ie, an umbrella propped in the sand at the beach does not provide the same shade protection as that found in a forest with a dense canopy of trees) or diurnal variation in protection based on angle of the sun, its value should not be neglected. With almost half of the year spent in school, a childs sun exposure is the responsibility of the schools. Schools should seek to encourage the use of shade, expand playground shade, and schedule recesses and physical education classes for hours when the ambient UVR is lower. One study estimated that up to 47% of daily UV exposure may occur when children are outdoors during school breaks, and another found that children received almost 16% of their daily UVR during the lunch break alone [26,27]. The promotion of shade should not be limited to the playground. Besides providing complimentary sunscreen, employers should be encouraged to make shade an available option for employees who desire it. Awareness of peak periods of ambient UV exposure by the public must also be emphasized. Public health campaigns have championed the reduction or rescheduling, when possible, of outdoor activities outside the critical 10 2 (10 am to 2 pm) time window. However, because of the large geographic distribution of time zones and time zone adjustments such as daylight savings time, the 10 2 window does not universally capture the critical exposure window. A better message than the 10 2 warning is the shadow rule, which warns that the sun is most intense, and sunburn more likely, when shadows are shorter than those casting them (indicating that the solar zenith is less than 45) [28]. Forecasts by the National Weather Service and the Weather Channel have helped identify specific days or time periods when more UV exposure caution is warranted. With the availability and popularity of these forecasts,

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more local network news broadcasts are incorporating beach watch segments or including the estimated UV index into their weather telecasts, institutionalizing the UV index and facilitating its transition as a norm in society. While it is unclear if the promotion of UV index awareness reduces sun exposure during particularly hazardous time periods, may it at least increase public awareness of the need to apply sunscreen that day and help schedule physical activity and exercise routines at less dangerous times. Finally, any discussion on the public health battle against skin cancer must address the importance of reducing intentional UV exposure, including tanning bed use. It has been estimated that 11% and 37% of white adolescent males and females in the United States, respectively, have used a tanning bed [29]. The large number of teenagers using tanning beds has drawn concern from public health officials and legislators alike, including state legislative proposals that would require tanning bed operators to display a warning of the cancer risk associated with UV exposure (California) and require written parental consent to indoor tan for children under 17 (Texas). The exact impact of the superfluous UV from tanning bed use on skin cancer incidence is unclear but likely will contribute significantly to the growing skin cancer pandemic if public health efforts and policy fail to limit the growing use of tanning beds, especially by youth. In a case-control study of young women with BCC, lifetime tanning bed exposure was almost double in patients with a BCC, though this finding was nonsignificant [30]. However, in another case-control study of BCC and SCC patients compared with age and sex-matched controls, Karagas and colleagues [31]found that any use of an artificial tanning device was associated with increased likelihood of SCC (OR 2.5; 95% CI [1.7 3.8]) and BCC (OR 1.5; 95% CI [1.1 2.1]), and these findings persisted after controlling for sunburns and sun exposure.

Public health messages in skin cancer prevention A successful strategy in public health efforts to improve sun protection has been to construct clever and catchy slogans with a youthful appeal. Many of these catch-phrases have originated in Australia, which has designated skin cancer as a major public health concern. One of the most popular Australianorigin sun protection messages is slip, slop, slap, a campaign which was been adopted in the United States by the ACS in 1998, and encourages children and adults alike to slip on a shirt, slop on sunscreen,

and slap on a hat to protect your skin. The slogan was implemented as part of an ACS campaign focusing on children and their parents, that encourages people to practice outdoor sun protection by wearing clothing with long sleeves and a hat that shades the face, neck, and ears; using a sunscreen with an SPF of at least 15 on bare skin; and avoiding midday outdoor activity. In Australia, another public health policy has been introduced with the catchy slogan no hat, no play [26]. The policy requires that school children wear sun-protective hats (wide-brimmed hats and Legionnaire caps, which have flaps covering the neck) when playing outdoors, and is especially encouraged from September through April (summer in the southern hemisphere) [26]. The no hat, no play policy increased the percentage of students wearing sunprotective hats at 7 out of 8 schools in an Australian study [32]. Societal norms have also been a target of public health campaigns. The public health message, the healthiest color for your skin is the color you were born with, hopes to dispel the association of a tan with beauty. Evidence exists that suggests that in the United States people continue to value the beauty of a tan, despite educational efforts. A 1996 survey found that while knowledge of the harmful effects of UVR increased compared with the 1986 study [33], report of sunburning and regular artificial tanning bed use increased. Some evidence exists, however, that suggests things may be trending away from valuing a tan, as suggested by an evaluation of leading fashion magazines. George and colleagues [34] examined fashion magazines between 1983 and 1993 and found trends toward lighter tans, more women wearing hats, more articles promoting sun awareness, and more sunscreen advertisements. Procter and Gambles product Olay raised funds to aid in the fight against skin cancer for the Skin Cancer Foundation through the sale of love the skin youre in apparel. Changing societal norms is a slow process and can be marked by periods of regression of progress. As is evident, however, from the success of another public health concern, smoking, public health campaigns can have a large-scale impact.

Impact of sunscreen on general health: societal windfall or pitfall? The benefits of sunscreen extend beyond skin cancer prevention into other aspects of health and disease prevention. Using sunscreen protects from sunburn during physical activity. Increased physical

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activity is important for combating the heavy public health burden in the US from obesity and other diseases such as diabetes mellitus, and cardiovascular diseases. Exercise is also important in preventing other diseases, including depression, osteoporosis and some cancers, including colon and breast. The Institute of Medicine has found evidence of a protective effect of physical activity for colon cancer (RR = 0.51 0.75) and for breast cancer (RR = 0.76 0.90) [35]. While many behavioral factors must be addressed to reduce inactivity-related diseases, sunscreen availability eliminates one of the excuses for a paucity of outdoor activity. One of the concerns that has arisen with the increasing use of sunscreen, especially in the northern hemisphere, is that people develop vitamin D deficiencies, an important vitamin for overall health and well-being. Vitamin D deficiencies have been linked to increase risks of many common cancers, diabetes, and most commonly, osteoporosis. In a case-control study, SPF 15 sunscreen users had no significant difference in DEXA scan bone mass noted in comparison with controls, and the authors concluded that SPF 15 sunscreen use did not seem to increase the risk for osteoporosis [36]. Minimal sun exposure (roughly 10 15 minutes of exposure to the arms and legs or hands, arms and face 2 3 times/wk) in addition to increased vitamin D consumption, especially in the winter, through supplements or dietary intake, can guarantee that adequate vitamin D is available for good health [37,38]. A final concern that should be addressed regards false security. No randomized control trials (which are capable of generating gold standard evidence) have been done that investigate the impact of the regular use of sunscreen on melanoma risk, and hence, the extent of skin cancer protection provided by optimal sunscreen use, let alone the protection obtained from actual use, is not known. Thus, it is important that patients, loved ones, and providers be encouraged to practice full-body skin examinations and vigilantly follow-up on new or changing pigmented lesions that may be skin cancers; wearing sunscreen religiously is no guarantee. The public health campaign to reduce skin cancer incidence and mortality is multifaceted and promotes primary and secondary prevention.

fore, are an important component in the public health campaign to reduce the burden of skin cancer. However, gains must still be made in proper use and application of sunscreen and alternative sunprotection measures and sun-related behaviors. Effective public health education strategies that encourage sun protection and the primary prevention of skin cancer must be promoted and developed. Health policies targeted at the individual and communitylevel are a key part to effective public health campaigns. State and federal government involvement will continue to play a role in public policy development, including addressing sun protection concerns when evaluating the licensing of daycares, developing tanning bed regulations, and perhaps even formulating tax policies (such as in Australia where sunscreen sales are exempt from sales tax). The public health battle to reduce skin cancer wages on.

Acknowledgments The authors wish to acknowledge the institutions that support their academic endeavors.

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