Electromagnetic Spectrum

The sun produces a continuous spectrum of electromagnetic radiation (Figure 14-1). The most energetic rays, which are those with wavelengths that are shorter than 10 nm (i.e., cosmic rays, gamma rays, and x-rays), do not appreciably penetrate Earth’s surface. Phototrauma is primarily the result of ultraviolet radiation (UVR). UVR (10 to 400 nm) accounts for about 10% of the incident radiation at Earth’s surface; visible light (400 to 760 nm) accounts for about 50%; and infrared (IR; 760 to 1700 nm) accounts for about 40%.⁸⁴

FIGURE 14-1 The electromagnetic spectrum.

UVR has four components. Vacuum UVR (10 to 200 nm) is readily absorbed by air and does not penetrate Earth’s atmosphere. Ultraviolet C (UVC; 200 to 290 nm) is almost entirely absorbed in the stratosphere, which is 15 to 50 km (9.3 to 31.1 miles) above Earth’s surface, and by oxygen and ozone. Manmade sources of UVC (e.g., germicidal lamps, arc-welding devices) are rarely medically relevant. Ultraviolet B (UVB; 290 to 320 nm) is biologically quite active and principally responsible for tanning, burning, and nonmelanoma skin cancer (NMSC) formation.^4,147 Beneficial effects of UVB include vitamin D production from a cutaneous precursor, 7-dehydrocholesterol, to form previtamin D₃, which is quickly converted to vitamin D₃ (cholecalciferol). It is first hydroxylated in the liver into 25-hydroxyvitamin D₃ and subsequently in the kidneys into 1,25-dihydroxyvitamin D₃; this is the active metabolite, which stimulates calcium absorption from the gut.¹³¹ Approximately 90% of 25-hydroxyvitamin D₃ is formed in this manner.²³⁷ Of the UVR that reaches Earth’s surface, UVB accounts for roughly 10%, whereas ultraviolet A (UVA; 320 to 400 nm) accounts for about 90%, depending on the season and the time of day. UVA is typically subdivided into “near UVA” or UVA II (320 to 340 nm) and “far UVA” or UVA I (340 to 400 nm). Although these subdivisions are somewhat arbitrary, they are based on photobiologic responses. UVA is biologically active, and it contributes to tanning, burning, photoaging, and carcinogenesis. UVA penetrates the skin more deeply than does UVB, with less energy lost in the superficial layers of the stratum corneum and the epidermis. In addition, UVA is the principal trigger for photo-drug reactions. Longer-wavelength visible light and IR may also cause cutaneous phototrauma, albeit rarely. Solar urticaria has been reported to occur with exposure to visible wavelengths. IR alone—as well as in combination with UVR—may produce epidermal and dermal alterations.¹⁵²

Environmental Influences On UVR Exposure

Exposure to UVR is substantially affected by latitude, altitude, season, time of day, solar zenith angle, albedo (reflectivity), clouds, atmospheric pollution, ozone levels, and personal factors, including occupation and personal behaviors.* Most UVR reaches Earth around midday: 80% between 9 AM and 3 PM and 65% between 10 AM and 2 PM.⁸⁴ UVB peaks at midday, when the sun is at its zenith.¹⁷⁹ UVB is absorbed, reflected, and scattered by the atmosphere, and, at midday, it has less atmosphere to traverse. During early morning and late afternoon, when the sun nears the horizon, UVB decreases considerably. Latitude and season have similar effects: peak UVB exposure is approximately 100 times greater in June than in December.¹⁷⁹ For each degree of latitude away from the equator, UVB intensity decreases an average of 3%. UVA varies considerably less than UVB with latitude, time of day, and season, as predicted by Rayleigh’s law:

where λ is the wavelength. The shorter the wavelength, the greater is the atmospheric scattering, so UVB is scattered much more readily than is UVA. In addition, UVA (but not UVB) is transmitted through window glass, thus allowing for indoor exposure to UVA but not to UVB.

UVR may be increased by surface reflection. Surprisingly, water is a relatively poor reflector. UVR at midday penetrates water up to 60 cm (23.6 inches), so submerged skin is not necessarily protected.¹⁷⁹ Reflection from water may increase as the sun nears the horizon, but, at that time, there remains little UVB to reflect because of atmospheric attenuation. Ice and snow are considerably better reflectors. Clean snow may reflect up to 85% of UVR,¹⁷⁹ which accounts for oddly distributed sunburns in spring skiers. Grass, sand, metal, concrete, salt flats, and other surfaces reflect UVR to varying degrees. The importance of surface reflection was demonstrated in a 2010 study that was conducted in Spain, which showed that a blue-and-white painted canvas beach umbrella with a radius of 0.8 m (2.6 ft) and a height of 1.5 m (4.9 ft) effectively blocked direct UV radiation; however, sensors positioned at the base of that same beach umbrella still measured 34% of the incident horizontal irradiance found “in the open.”²⁹⁷

Clouds may attenuate UVR exposure. Absorption by clouds varies from 10% to 80% but rarely exceeds 40%.¹⁴⁷ Polluted clouds, which contain the greatest concentration of hydrocarbons, are the most effective at absorbing UVR. Clouds are more effective at absorbing heat in the form of infrared radiation, occasionally seducing hikers and bathers into excessively lengthy midday exposures.

Wind and water augment sunburn. In mice, exposure to wind plus UVR results in more erythema than does exposure to UVR alone.²²⁶ In humans, wind may reduce heat perception, thereby encouraging longer exposure. Water increases UVR exposure because moist skin reflects less UVR, thereby resulting in greater absorption of UVB. Consequently, swimmers and hikers in humid environments may be at risk for increased UVR absorption.⁸⁴

Altitude profoundly influences UVB exposure. Until recently, it was generally accepted that UVB exposure rises 4% for each 305-m (1000-foot) rise above sea level. However, Rigel and colleagues²⁴⁷ demonstrated an 8% to 10% increase in UVB for each 305-m (1000-foot) rise above sea level. Beginning at the 3353-m (11,000-foot) summit of a ski run in Vail, Colorado, these investigators measured UVB readings every 152 m (500 feet) as they skied to the base of the run at 2500 m (8200 feet). This study showed that UVB exposure readings in Vail, Colorado (latitude 39 degrees North) at 2591 m (8500 feet) approximated readings made under similar conditions—but 772 miles nearer the equator—at Orlando, Florida (latitude 28 degrees North, elevation 18 m [60 feet]).

Snow, wind, and altitude may act simultaneously to greatly augment UVB exposure for skiers and climbers. Singh and co-workers²⁷¹ reported that 36% of climbers (24 of 67) developed significant sunburns during three consecutive expeditions up to 7000 m (23,400 feet) in the western Himalayas, despite the application of sunscreen. During a year-long study of professional Alpine mountain guides with the use of continuous dosimetry monitoring, Moehrle and colleagues²¹⁰ confirmed exceedingly high cumulative UVR exposures. These data emphasize the difficulties of providing appropriate UVR protection for high-altitude outdoor enthusiasts.

Ozone Depletion and Ultraviolet Radiation Exposure

Stratospheric ozone, which lies 15 to 50 km (9.3 to 31.1 miles) above Earth’s surface, provides a thin and fragile shield against UVR. The combination of ozone and oxygen absorbs virtually the entire incidence of UVC. Ozone attenuates UVB and modestly reduces UVA II, but it allows the transmission of all UVA I.³²³ Ozone is continuously created and removed from the stratosphere by natural physicochemical processes that are in turn significantly affected by manmade pollution. Molina and Rowland²¹¹ first suggested that chlorofluorocarbons (CFCs) could cause ozone depletion. CFCs are organic chemicals that contain carbon, chlorine, and fluorine that were initially developed during the 1970s as refrigerants. Since then, CFCs have been used in several technologies and industrial processes, including air-conditioning systems, insulation, cleaning solvents, degreasing agents, and metered-dose inhalers. Related compounds known as halons contain bromine, which also depletes stratospheric ozone. Halons arise from seawater, fire extinguishers, and various industrial processes.¹²⁸ CFCs and halons belong to the group of chemicals known as halocarbons.

The remarkable stability of CFCs allows them to rise into the stratosphere, where, when catalyzed by solar radiation, they release chlorine (Cl⁻) and chlorine monoxide (ClO⁻), which in turn degrade ozone. One prominent chemical pathway by which CFCs deplete ozone is as follows:¹²⁸

Note that Cl⁻ is preserved in this reaction. The half-life of Cl⁻ is approximately 75 years,³⁰⁹ although CFCs may reside in the stratosphere for 50 to 200 years.¹²⁸ During that time, each Cl⁻ ion may destroy 100,000 molecules of ozone.³⁰⁹ Over Antarctica, additional and augmented ozone-depleting mechanisms may be operative; molecular halogens coat the surface of ice clouds, thereby making them even more reactive and able to degrade ozone.¹²⁸

Ozone losses were first reported over Antarctica in 1985⁷⁶ by the British Antarctic survey. Ozone showed large declines in the austral springtime (September/October), and it decreased a total of 35% during the springtimes that occurred from 1975 to 1984.¹²⁸ Ozone depletion is now documented at all latitudes except the equator. This depletion is uneven, with more loss at the poles and less at the middle latitudes.³⁰⁹ There is also a well-documented “waxing and waning” that occurs with the seasons. With the use of its total ozone mapping spectrometer in satellite orbit, the National Aeronautics and Space Administration has documented ozone depletion over continental Europe, North and South America, South Africa, New Zealand, and Australia.¹⁶⁹

Significant increases in UVB have been documented, even near the middle latitudes, because of ozone depletion. In Toronto from 1989 to 1993, Kerr and McElroy¹⁵¹ documented surface UVB increases of 35% per year in winter and 7% per year in summer, which corresponded with ozone decreases of 4% per year and 1.8% per year, respectively. Their experimental design allowed for assignment of all of the UVB increase to ozone depletion rather than to cloud coverage or pollution. Similar increases in ground-level UVB that parallel decreases in stratospheric ozone have been documented in Scotland.²¹⁵ Typically, in the northern hemisphere’s middle latitudes, ozone losses are greater during winter (i.e., about 6% per decade) than during summer (i.e., about 3% per decade).¹²⁸ Ironically, pollution (e.g., smog, particulates) may mitigate UVR increases by absorbing UVB.³⁰⁹

The effects of ozone depletion on the biosphere and human skin cancer rates have been estimated. Although these estimates vary, data suggest that, for every 1% decrease in ozone, there is a corresponding 2% increase in the incidence of basal cell carcinoma (BCCa) and 3% increase in the incidence of squamous cell cancer (SCCa).⁵⁹ Melanoma incidence may increase by 1%.³⁰⁹ However, even if UVB triples near the poles, as is suggested in worst-case scenarios, polar areas will still receive less UVB than current equatorial levels.³⁰⁹ Ozone depletion may have its greatest effects on nonhuman biosystems. Plant and plankton yields may be diminished significantly, causing an uncertain and potentially severe detriment to terrestrial and marine life.³²³

To prevent ecologic disturbances and to restore ozone levels, international agreements have been negotiated. The Vienna Convention in 1985 and subsequent Montreal Protocol in 1987 were among the first and most notable. The Montreal Protocol, which has now been signed by 184 of the 191 United Nations member nations,²⁹⁹ agreed to limit and then reduce CFC production, which led to a 50% reduction by 1998.¹²⁸ Three later amendments were made to accelerate progress in response to increasing awareness of ozone depletion in the middle latitudes. The London Amendment in 1990 required the complete phaseout of halocarbon production. The Copenhagen Amendment in 1992 accelerated the timetable for complete phaseout, stopping production in developed countries by 1996 and in undeveloped nations within 10 years; it also extended the protocol to include hydrochlorofluorocarbons. The Vienna Amendment in 1995 revised the phaseout schedule of hydrochlorofluorocarbons.^128,273

Although the Montreal Protocol is working—CFC production has been decreased by 90%²⁹⁹—its modest limitations would allow elevated stratospheric chlorine levels through most of the 21st century.¹²⁸ By contrast, the stricter limitations of the Copenhagen Amendment will result in ozone levels rising again within the first decade of the 21st century.²⁷³ Among the remaining sources of CFC production are metered-dose inhalers and cleaning agents for rocket motor manufacturers.¹²⁸ American factories could produce 53,500 tons of CFCs annually for export until 2005.²³ CFC substitutes are more costly, with an estimated 22,000 tons being produced in 1994.²³ This led to an international black market in CFCs. A significant portion of this black market is in Freon that is smuggled to automobile air-conditioner rechargers. In 1996, an estimated 10,000 tons of CFCs were smuggled into the United States from Mexico and elsewhere.⁸³ Despite these black-market sources, initial projections suggested that atmospheric chlorine would begin to fall in this decade, with resultant UVB levels gradually falling by 2050 to levels that were recorded during the 1950s. Unfortunately, recent data suggest that current global warming trends exacerbate ozone depletion and may delay the recovery of the ozone layer.²⁹⁹

Ultraviolet C Radiation

UVC has no appreciable impact on human health, as it is effectively screened from Earth’s surface by stratospheric ozone and oxygen. Even with continued ozone depletion, levels of UVC are not expected to rise. As mentioned, manmade sources of UVC such as germicidal lamps and arc-welding devices have been only rarely associated with cutaneous pathology as might be predicted, because UVC is effectively absorbed by the stratum corneum, which is the outermost cutaneous layer.⁸⁴

Ultraviolet B Radiation

UVB acutely induces a cutaneous inflammatory response that is at least partially definable clinically, histologically, and biochemically.¹³⁷ Clinically, erythema or sunburn is the hallmark of acute overexposure to UVB. The action spectrum for erythema peaks with UVB.²¹⁷ Generally, UVB is considered to be 1000-fold more effective than UVA for induction of erythema. In a human model, 300-nm UVB is 1280-fold more effective at inducing erythema than 360-nm UVA.³²⁴ Erythemogenic doses are usually defined as multiples of the minimal erythema dose (MED), which is the lowest dose that elicits perceptible erythema. In a typical fair-skinned individual, the MED might range from 15 to 70 mJ/cm² for UVB and from 20 to 80 J/cm² for UVA.

For example, 1 MED of UVB for a typical fair-skinned individual would require 20 minutes of midsummer exposure in San Diego, whereas 1 MED of UVA would require 2 to 3 hours of exposure. In a day’s time, a person can receive 15 MEDs of UVB but only 2 to 4 MEDs of UVA.²⁰⁰ Consequently, although people are exposed to 10-fold to 100-fold more UVA than UVB, more than 90% of sunlight-induced erythema is attributable to UVB. The erythema action spectrum, which peaks in UVB, is remarkably similar to the absorption spectrum of DNA,²¹⁷ which suggests that DNA is a principal target chromophore for UVB-induced erythema³²⁵ and pyrimidine dimer formation. Supporting this is the finding that pyrimidine dimer yields correlate with erythema.¹¹⁶

Sunburn reflects a local vascular reaction. The causes are multifactorial: DNA damage, prostaglandin activation, cytotoxicity, and other mechanisms are implicated. UVB erythema has its onset 2 to 6 hours after exposure; it peaks at around 12 to 36 hours and fades after 72 to 120 hours.^84,137,147 Acute histologic changes that accompany UVB exposure include edema with vasodilation of the upper dermal vasculature¹³⁷ and endothelial cell swelling, most likely as a result of vasoactive mediators being released.¹¹² Delayed histologic changes include the appearance of sunburn cells in as little as 30 minutes after exposure. These dyskeratotic cells have enlarged nuclei and vacuolated cytoplasm. Initially, sunburn cells are localized in the lower one-half of the epidermis; however, after 24 hours, they are also found in the upper half. These sunburn cells may represent actively cycling and proliferating basal cells that cannot adequately repair UVR-induced DNA lysosomal damage.⁵⁵ Beginning 1 hour after exposure, stainable Langerhans’ cells (i.e., cutaneous antigen-presenting cells) are reduced by 25%; by 72 hours after exposure, only 10% remain.¹³⁷ In mice that are exposed to repetitive suberythemogenic doses of UVB, normal numbers of Langerhans’ cells return by 8 days after exposure.¹³⁷ Vacuolization of melanocytes is seen after 1 hour and returns to normal 4 to 24 hours after exposure.¹³⁷ Mast cells decrease in number and granularity within 1 hour, returning to normal after 12 to 72 hours.¹³⁷ By 24 to 48 hours after exposure, there is increased melanin synthesis, epidermal proliferation, and thickening of the stratum corneum. Functionally, the epidermal permeability barrier diminishes after UVB exposure because of the altered kinetics of lamellar-body–containing cells in the exposed epidermis.¹³³

Biochemical changes that accompany sunburn include increased levels of histamine,¹³⁷ which return to normal within 74 hours. However, histamine is unlikely to be the sole or even the principal mediator of vasodilation and erythema, because antihistamines are ineffective in preventing sunburn. UVR induces increased phospholipase activity, with accompanying increases in prostaglandins (PGs). PGD₂, PGE₂, PGF, and 12-hydroxyeicosatetraenoic acid are increased in suctioned blister aspirates immediately after UVB exposure, and peak after 18 to 24 hours.¹³⁷ Topical and intradermal indomethacin, which is a prostaglandin inhibitor, blocks UVB-induced erythema for 24 hours after exposure,²⁷⁵ thus supporting the thesis that eicosanoids (PGs and leukotrienes) are significant mediators of UVR-induced inflammation.¹⁶⁰ UVB stimulates induction of proinflammatory and mutagenic cytokines: tumor necrosis factor-α and interleukins 6 and 12.¹³³ UVR generates free radicals in the skin that probably contribute to the sunburn reaction¹⁹³ by causing peroxidative chromosomal, membrane, and protein damage.¹⁶ Topical antioxidants may mitigate sunburn when they are applied before but not after exposure. Melatonin¹⁶ and vitamin C⁵⁷ act protectively by scavenging UVR-generated free radicals; however, neither absorbs UVR.

Ultraviolet a Radiation

UVA penetrates more deeply into the skin than does UVB. Whereas 95% of incident UVB is reflected or absorbed by the epidermis, nearly 50% of UVA reaches the dermis.⁷⁵ UVA contributes modestly to sunburn and may cause clinical erythema. Prolonged daily UVA exposure can approach 125 J/cm², which significantly exceeds the threshold erythema dose of 20 to 80 J/cm².²⁷⁸ Clinically, UVA erythema has an onset within 4 to 6 hours; it peaks after 8 to 12 hours and fades after 24 to 48 hours.^137,147 Erythema that results from UVA may have a distinct pathophysiologic mechanism. UVA-induced erythema may be caused by keratinocyte cytotoxicity.¹³⁷ Histologically, UVA erythema displays more epidermal spongiosis, fewer sunburn cells, and more dermal changes than does UVB-induced erythema, with a denser and deeper mononuclear cell infiltrate and more vascular damage.¹³⁷

Infrared Radiation

IR radiation plays a less well-defined role in photodamage. Near-IR preirradiation prevents UVR-induced cytotoxicity,²⁰⁰ which suggests that a possible evolutionary protective mechanism for IR is the daily preparation of skin cells to resist UVR-induced damage. However, no data indicate whether IR protects against UVR’s mutagenic and carcinogenic effects.

Sunburn Treatment

Sunburn is self-limited, and its treatment is largely symptomatic, involving local skin care, pain control, and antiinflammatory agents (Box 14-1).¹⁵ Studies that have assessed the treatment of sunburn can be divided into those that evaluated the agents used immediately after UV exposure (i.e., before symptoms have manifested) and those that evaluated the agents for the actual treatment of acute sunburn reactions.¹²¹

Cool-water soaks or compresses may provide immediate relief, and topical anesthetics are sometimes useful. It is generally preferable to use the nonsensitizing anesthetics menthol, camphor, pramoxine, and lidocaine rather than the potentially sensitizing anesthetics that contain benzocaine and diphenhydramine. Refrigerating topical anesthetics before application provides added relief. A legion of topical remedies have been suggested anecdotally. These include aloe, baking soda, and oatmeal, but controlled studies are lacking. Topical steroids, with their vasoconstrictive effects, are often considered “first-line” treatment for acute sunburn; however, their efficacy remains controversial. A randomized, double-blind clinical trial of 20 patients with Fitzpatrick skin types I, II, and III compared erythema reactions in areas that were treated with either topical moderate-potency corticosteroid (hydrocortisone-17-butyrate) or high-potency corticosteroid (clobetasol propionate) 30 minutes before and 6 or 23 hours after exposure to UVB (i.e., a bank of TL12 fluorescent tubes); only the areas that had been treated with high-potency corticosteroid 30 minutes before UVB exposure demonstrated clinically significant results.⁷⁸ Diclofenac gel, which is a topical nonsteroidal antiinflammatory drug, alleviates pain, erythema, and edema for up to 48 hours when it is applied after exposure.¹⁵² Oral nonsteroidal antiinflammatory drugs provide analgesia and may reduce sunburn erythema.⁸⁴ According to a recent Medical Letter, the combined use of topical steroids and oral nonsteroidal antiinflammatory drugs slightly decreases erythema during the first 24 hours if these drugs are administered before exposure or shortly after exposure, before sunburn becomes clinically apparent.²³⁸ Few published studies support the value of systemic steroids, but they enjoy considerable anecdotal support. In a metastudy of all published articles related to sunburn treatment from 1966 to 2001, Han and Maibach¹²¹ found no therapy to be unequivocally or consistently effective and no consensus for the treatment of sunburn. Moreover, education for acutely sunburned patients is lacking. Warnings regarding skin cancer are rarely given to sunburned patients when they are seen in the emergency department.¹⁵

Tanning

Tanning, like sunburning, is caused by UVR. Consequently, persons who are seeking a tan risk sunburn. Tanning is biphasic. After sun exposure, there is immediate pigment darkening within minutes, followed by delayed pigment darkening (DPD) in 3 days. Immediate pigment darkening is predominantly the result of the action of UVA on preformed melanin precursors; it occurs in as little as 5 minutes after exposure, peaks in 60 to 90 minutes, and then fades quickly. However, DPD represents new melanin synthesis within melanocytes and the subsequent spread of the richly melanized melanosomes into surrounding keratinocytes. After UVB exposure, DPD is notable by 72 hours, peaks after 5 to 10 days, and then slowly fades. DPD is primarily a response to UVB. Most tanning studies have been performed with erythemal doses of UVR. However, multiple suberythemal exposures to UVA are significantly more melanogenic than is similarly dosed UVB.²⁰ The mechanism of DPD is uncertain, but it is likely to be multifactorial. UVB stimulates tyrosinase release and arachidonic acid metabolites, and it releases α-melanocyte-stimulating hormone from keratinocytes.⁷ It also increases the binding affinity of melanocytes for melanocyte-stimulating hormone, thereby resulting in increased melanocyte proliferation, melanization, and arborization.²⁹ UVB increases melanocytes in both exposed and protected human skin,²⁸² which suggests the possibility of a UVR-stimulated circulating factor that promotes melanocyte proliferation.

Natural Defenses and Skin Type

Absence of erythema does not preclude cutaneous photoreactions. Chronic exposure to UVR is accompanied by insidious cumulative biologic and clinical changes. Although some of these changes are the result of broadband UVR, UVA and UVB often have distinct and different effects on the epidermis, dermis, extracellular matrix, cytokines, and immune response.³¹¹ In response to UVB, the stratum corneum thickens¹¹⁰ and melanin increases; both of these are protective mechanisms to mitigate further UVB photodamage. The stratum corneum, which is the outermost layer of skin, is composed of flattened anucleate keratinocytes. It reflects, scatters, or absorbs up to 95% of incident UVB, depending largely on its thickness.¹²³ With repeated exposure to UVB, the stratum corneum can increase its thickness up to sixfold.⁸⁴ As a consequence, the stratum corneum is the main photoprotective factor in whites.¹¹⁰ Repeated UVA exposures may cause some thickening,¹⁷⁸ but to a much lesser degree. Consequently, UVA tans are not as photoprotective as are UVB tans.

Melanin reflects, scatters, and absorbs throughout the UVR spectrum; it acts as an antioxidant, and it reduces UVR-induced photoproducts.¹⁵⁷ Consequently, constitutive (racial) skin color is a principal determinant of an individual’s erythemal response to UVR. Although blacks and whites have similar numbers of melanocytes, these pigment-forming cells are differently melanized and distributed in black and white skin. Increased melanin in blacks can decrease the dermal penetration of UVR up to fivefold⁵³ and increase the MED up to 30-fold. By contrast, tanning is much less protective. After an entire summer of tanning, the MED in whites increased only 2.3-fold.⁵³ Clinically, these racial differences in melanization are reflected in lower rates of burning, photoaging, and skin cancer in blacks.

Susceptibility to photodamage is typically defined by six distinct skin types (Box 14-2). Racial pigmentation alone does not account for differences in skin type. Some redheads tan easily, whereas some blacks burn readily. Reporting errors (typically involving the overstating of sun tolerance) are common, thus further complicating the interpretation of skin types.²³⁹

Skin type correlates well with MED. Additional factors that influence MED include age and anatomic site. Lower MEDs are recorded in the very young and the very old.¹⁴⁷ Differences in stratum corneum thickness and melanocyte concentration may account for body-site–specific differences in MED. For example, the MED of the back is typically less than the MED of the lower leg.

Chronic suberythemal UVA exposures also cause photodamage. Repetitive low-dose exposures to UVA result in histologic changes,^170,178 including the thickening of the stratum corneum and of the granular and stratified cell layers, decreased elastin, vascular dilation, and inflammation.

Aside from the thickened stratum corneum and increased pigmentation, intrinsic mechanisms of photoprotection include antioxidants, such as the glutathione peroxidase-reductase system, that mitigate damage from UVR-induced reactive oxygen species. DNA repair enzymes correct most UVR-induced mutations. Carotenoids stabilize biologic membranes from singlet oxygen attack. Urocanic acid absorbs some of the UVR that penetrates the stratum corneum.⁵⁸

Photoaging

Long-term repetitive exposures to sunlight result in photoaging.⁸⁰ This process, known as dermatoheliosis, is distinctive clinically and histologically from chronologic aging; it is not merely accelerated chronoaging. Photoaged skin is characterized by dryness, roughness, mottling, wrinkling, atrophy, and pebbling, and it may be studded with precancers (actinic keratoses) or cancers (Figure 14-2). Most of what we consider “old-looking” skin is in fact the result of photoaging rather than chronoaging. Although age can be estimated from observing sun-exposed sites, it cannot be estimated from photoprotected sites.³⁰⁷ The action spectrum for photoaging includes UVB, UVA, and IR.¹⁷⁸

FIGURE 14-2 Phototrauma. A, Tan and peeling after sunburn. B to D, Dry, mottled, wrinkled, and pebbled skin with photoaging.

Chronically sun-exposed sites have fewer Langerhans’ cells. Keratinocytes and fibroblasts from sun-damaged skin have diminished life spans in culture.¹⁰⁴ The most notable histologic change with chronic UVB exposure is deposition of thickened amorphous elastic fibers high in the dermis, which is demonstrable in photoexposed white skin by the age of 30 years. In a transgenic mouse model, UVB but not UVA produces this solar elastosis.²⁹⁴ Another mouse model suggests that the action spectrum for “photosagging” peaks in UVA at 340 nm¹²² and that this action spectrum is remarkably similar to that of the generation of singlet oxygen by the excitation of transurocanic acid. The authors of that study concluded that UVA causes photoaging because of its interaction with transurocanic acid, which releases reactive oxygen species.

With photoaging, elastin gene expression appears to be activated, although data are conflicting. Tropoelastin and fibrillin synthesis actually diminish with chronic UVB exposure,³¹⁰ whereas transcription of other extracellular matrix genes is enhanced. In particular, photoaged skin demonstrates increased matrix metalloproteinases, which are potent mediators of connective tissue damage.⁸⁰ These arise within hours of UVB exposure and even after suberythemal exposure.⁷⁹ Interestingly, tretinoin inhibits induction of these UVB-induced proteinases,^79,80 perhaps explaining in part its clinical usefulness against photoaging.^223,308 Tretinoin also normalizes photoaltered epidermal differentiation and deposits new type I collagen in the upper dermis.¹¹⁵

Ocular Effects

Acute overexposure to UVB may cause photokeratitis (snowblindness), especially in skiers and climbers,³²⁶ whereas chronic exposure to UVR may cause or contribute to pterygia, cataracts, and macular degeneration. A full discussion is presented in Chapter 28.

Sun and Skin Cancer

Actinic keratoses (solar keratoses) are considered by many dermatologists to represent in situ dysplasias that result from exposure to solar irradiation. The majority of these lesions are characterized clinically as being 0.3 to 2 cm (0.12 to 0.79 inch) in size, multiple, sharply bordered, irregularly shaped pink papules with adherent scale. It is often easier to appreciate actinic keratoses as “rough spots” via direct palpation than by visual detection alone. A hypertrophic type exists and may lead to cutaneous horn formation, especially on the dorsal surfaces of the hands and the extensor forearms. Actinic keratoses may be tender when rubbed or shaved over with a razor. They are predominantly located in chronically sun-exposed areas. Actinic keratoses tend to be more common in lighter skin, and they typically appear in people who are more than 50 years old, although fair-skinned patients who live in areas of high solar irradiation may develop them much earlier (i.e., at the age of 20 to 40 years). Actinic keratoses may be prevented by sun avoidance and a diet that is low in fats. Treatment strategies range from cryosurgery and topical chemotherapy with 5-fluorouacil or imiquimod to chemical peels, laser resurfacing, and photodynamic therapy. The consideration of skin biopsy is warranted when the lesion is larger than 0.6 cm (0.24 inch), if there is a palpable dermal component, or when the lesion persists despite appropriate therapy.

Like precancerous actinic keratoses, true skin cancers (Figure 14-3) are believed by most dermatologists to be overwhelmingly caused by UVR exposure. In particular, UVR is the principal cause of NMSC (i.e., BCCa and SCCa), which is the most common of all cancers. UVR also contributes significantly to melanoma, but it is not a sine qua non. The incidence of skin cancer is staggering. One in five Americans²⁴⁷ and two-thirds of all Australians¹³ born today will develop skin cancer. In addition, the incidences of both NMSC¹⁰⁸ and melanoma continue to increase.²⁴⁶ Three causative factors seem to predominate:

FIGURE 14-3 A, Actinic keratoses: thin, vague, and scaly papules. B, Basal cell carcinoma: smooth, pearly papule. C, Squamous cell carcinoma: keratotic red and tan papule. D, Melanoma: note the asymmetry, border irregularity, color variegation, and diameter of more than 6 mm (0.24 inch).

Since the 1890s, epidemiologic evidence has accumulated that links sun exposure with NMSC in humans. The incidence of skin cancer increases with increasing proximity to the equator.⁵⁴ NMSC has a far greater incidence in whites than in blacks, and occurs primarily on sun-exposed areas. Risk for NMSC increases with increasing sun exposure, and repeated sunburn is an independent risk factor.¹⁶⁴ Adopting a sun-protected lifestyle is associated with decreased risk.¹³⁰ Patients with xeroderma pigmentosum (XP), which involves a deficient ability to repair UVR-induced DNA damage, have a 1000-fold greater risk of developing NMSC, typically at a very early age.¹⁶⁰

During the 1920s, laboratory data confirmed that UVR induces and promotes NMSC in mammalian animal models.^147,287 UVC and UVB are effective inducers of SCCa in mice.¹³⁷ Although UVB is primarily implicated, UVA augments UVB-induced carcinogenesis,²⁸⁷ and can be a carcinogen on its own.

Development of NMSC in humans is related to the time and intensity of exposure. Sun exposure during childhood and adolescence is more predictive of later BCCa.⁸⁸ British immigrants to Australia assume the much higher Australian risk of NMSC only if they emigrate before the age of 18 years; after that time, these immigrants retain the lower British risk.¹⁸⁹ A separate study suggests that risk decreases after the age of 10 years.¹⁶³ Gallagher and co-workers⁸⁸ found that BCCa is associated with sun exposure up to the age of 19 years but that it is not associated with mean annual cumulative summer sun exposure. In this study, risk for BCCa was also associated with fair complexion and freckling. Kricker and colleagues¹⁶⁴ suggest that intermittent (rather than continuous) sun exposure in poor tanners is the most important factor in development of BCCa.

Clinically, BCCa includes a heterogeneous group of low-grade malignant cutaneous tumors that are characterized by differentiation markers that are usually associated with hair-follicle development. BCCa is the most common cancer in the United States, and, although it can be locally aggressive, it is almost never metastatic. These lesions are most commonly found on the head and neck (Figure 14-4), but any part of the body may be involved. Interestingly, in contrast with SCCa, BCCa is relatively uncommon on the dorsal surface of the hand, where solar radiation exposure is high. Several clinical morphologies of BCCa exist, and the diagnosis depends on the astute clinician recognizing the many forms that are taken by this cancer. Nodular BCCa, which comprises the majority of BCCa, may manifest as one or a few small, pearly papules with a central depression and “rolled borders” (Figure 14-5). Telangiectasias may be seen coursing through the lesion; the lesions are usually friable, and they frequently bleed when rubbed with a cotton-tipped swab. Pigmented BCCa is similar to nodular BCCa, but this morphologic type appears brown or black because of the presence of pigment. Cystic BCCa manifests as bluish-grey, dome-shaped cystic papules or nodules that are similar in appearance to hidrocystomas. Morpheaform BCCa manifests as a white sclerotic plaque, usually without the characteristic findings of a pearly, “rolled” border; for this reason, it is often missed or misdiagnosed as a scar. Superficial BCCa, which is the most common pattern seen in patients with human immunodeficiency virus, is another common form of BCCa that favors the trunk and distal extremities; it usually manifests as a superficial, dry, scaly lesion that can resemble patches of slow-growing eczema or psoriasis, although close examination reveals the raised border. Rodent ulcer is a neglected BCCa that has ulcerated; consequently, the “rolled” border of the lesion may not be present or recognizable.

FIGURE 14-4 Pink, pearly papule with a rolled border and overlying telangiectasias located on the right pectoral area of a 55-year-old surfer from San Diego; biopsy revealed a basal cell carcinoma.

FIGURE 14-5 Basal cell carcinoma demonstrating characteristic “rolled” borders and central ulceration.

SCCa, which is the second most common form of skin cancer, manifests clinically as dull-red, superficial, indurated, well-demarcated plaques that arise on sun-exposed areas such as the face and dorsal surfaces of the hands. Lower-lip lesions may develop with actinic cheilitis; in these cases, a history of repeated sunburns and smoking are predisposing factors. As the lesions grow over the course of months, they become deeply nodular and ulcerate (Figure 14-6, A and B). The ulcer may be hidden by an overlying crust that, when removed, reveals a discrete, indurated, and elevated base. Careful examination of regional lymph nodes is warranted in suspected cases. The rate of metastasis from all skin sites ranges from 0.5% to about 5%; risk factors that can increase this rate include a location that involves the temples, scalp, ear, or lip; recurrence after prior treatment; size and depth of the primary lesion; histologic findings; and host immunosuppression. The relationship of photoexposure and SCCa is distinct and different from that of the sun and BCCa. There is a significantly increased risk of SCCa with chronic occupational exposure, especially during the 10 years before diagnosis.⁸⁹ Although cumulative lifetime photoexposure and SCCa are not associated, risk factors include periodic recreational exposure, pale complexion, and red hair. Persons who develop SCCa seem to be phenotypically sensitive to UVR, with chronic exposure as adults. Household and office exposure to nonsolar UVR does not increase the risk of BCCa and SCCa.¹⁴ In select mouse models, suberythemal UVR has caused SCCa.²¹⁷ In these models, gradual suberythemal exposures to UVR may actually be more carcinogenic than are erythemal doses.⁸⁷ This may be relevant to humans, and it may explain why persons without any prior sunburns may develop SCCa.

FIGURE 14-6 Squamous cell carcinoma. A, Neglected squamous cell carcinoma on lateral and posterior shoulder. B, Closer image of the same carcinoma.

Melanoma

Melanoma includes a number of different clinicopathologic types. Nodular melanomas are typically smooth, dome-shaped, and friable lesions that most commonly occur on sun-exposed areas of the head, neck, and trunk. They are twice as common in men as in women. Lentigo maligna manifests as a tan macule on sun-damaged skin, typically among older patients who live in sunny climates; this type of melanoma may darken and spread so slowly that patients are often unaware of changes (Figure 14-7). Superficial spreading melanoma has no known preference for sun-damaged skin, and affects adults of all ages. Color variegation (i.e., dark brown, black, red, white, blue) is common with this type of melanoma (Figure 14-8). These lesions may arise de novo or in association with a preexisting nevus; a new papule or nodule may develop as the vertical growth phase develops. Acral lentiginous melanoma, which is the most common type of melanoma in dark-skinned and Asian populations, may begin as a light brown and uniformly pigmented macule or patch that gradually darkens, thickens, and ulcerates with time. Subungual or plantar lesions are often present, and Hutchinson’s sign (i.e., a black discoloration of the proximal nail fold at the end of a hyperpigmented linear streak) portends melanoma in the matrix of the nail. Amelanotic melanoma is difficult to discern clinically, because it lacks pigment and may mimic a benign inflammatory papule or BCCa. Other types include ocular, mucosal, polypoid, desmoplastic, and soft-tissue melanomas.

FIGURE 14-7 Melanoma on the posterior helix, which made early self-detection difficult.

FIGURE 14-8 “Yin-yang”–shaped melanoma on back demonstrating asymmetry, color variegation, and a diameter of more than 6 mm (0.24 inch). The location made early self-detection difficult.

Melanoma has a less well-defined relationship with sun exposure; clearly, however, sun exposure plays a significant role in its development.⁶ The ultraviolet action spectrum for melanoma remains uncertain, with different results in different animal models. In Monodelphis domestica, a South American marsupial, both UVA and UVB are implicated⁶³; in Xiphophorus (platyfish and swordtails), UVA, UVB, and visible (blue) light are causative⁶³; and in transgenic mice Tyr-SV40E (C57BL/6 strain), UVB is the etiologic waveband.¹⁵³ In humans with XP, the 1000-fold increased incidence of melanoma strongly supports UVB as a causative agent.¹⁶¹ A unique and elegant laboratory experiment documented that UVB induces melanocytic hyperplasia, atypia, and melanoma in newborn human foreskin xenografts on RAG-1 (immunodeficient) mice.⁷

Melanoma incidence increases with proximity to the equator in white populations¹⁴⁹ in the United States, Australia, and Scandinavia as well as in the nonwhite population of India.¹⁶⁷ In the U.S. Surveillance, Epidemiology, and End Results Program from 1992 to 2001, the incidence of melanoma increased with lower latitudes in non-Hispanic whites; no association was noted in Hispanics or blacks.⁶⁹ In contrast, Hu and co-workers¹³⁸ noted a positive association of lower latitude and UVR exposure with melanoma in blacks and Hispanics in the United States, although statistical significance was reached for black men only. Intermittent intense exposures pose a particularly high risk for melanoma.⁷¹ A meta-analysis of 57 studies published before September 2002 supports a significantly increased risk of melanoma with a history of intermittent sun exposure and sunburn.⁹¹ In contrast, there is only a small increased risk for total sun exposure, and there is decreased risk with heavy occupational exposure.^73,91 Patients with melanoma are twice as likely to relate a history of a prior sunburn than are age-matched controls, and they are three times as likely to relate a history of multiple prior sunburns.⁷³ Persons who tan poorly and burn readily are at higher risk for melanoma.¹⁸⁰ The distribution of melanomas on the trunk (in both sexes) and the lower legs (in women) is consistent with the hypothesis that intermittent sun exposure is provocative. However, melanomas also arise in sun-protected sites, especially in nonwhite populations, which suggests an additional cause that is separate from sun exposure.

A high level of outdoor activity during college is associated with a fourfold risk of later melanoma.⁷² Servicemen who served in the Pacific theater during World War II have a higher risk of melanoma than do those who served in Europe.³⁹ The incidence of melanoma is increased in indoor workers with higher socioeconomic status, again reflecting the role of intermittent intense sun exposure.¹⁴⁹ Fluorescent lights raise some concern,³⁰⁵ but they do not significantly increase melanoma risk, especially when these lights have covers or diffusers.¹³⁵

Sunburns in childhood may be particularly relevant to the later development of melanoma. Celtic migrants to Australia who arrived before the age of 10 years assume the high melanoma risk of native Australians; migrants who are more than 15 years old on arrival have only one-fourth that risk.²⁵⁵ Europeans who live more than 1 year in a sunny climate have an increased relative risk (i.e., 2.7) of melanoma, and the risk increases substantially (i.e., 4.3) if they arrive before the age of 10 years.¹⁰ However, one study suggests that childhood sun exposure contributes a serious risk only if there is subsequent and significant sun exposure as an adult.⁸

This association of increased melanoma risk with sun exposure during youth may be in part attributable to the effect of sun on the development of melanocytic nevi (moles) in children. Several studies confirm that the number of nevi in children increases with increasing acute and chronic sun exposure.* In Australia, the number of nevi up to the age of 12 years increases with increasing proximity to the equator.¹⁵⁰ Increased nevus counts with sun exposure are demonstrable at early ages. In Queensland preschoolers between the ages of 0 and 35 months, increased nevus counts are associated with more time spent outdoors and a history of sunburn.¹²⁵ These children have the highest number of nevi in the world, and, not surprisingly, Queensland has the highest incidence of melanoma in the world¹²⁶ at 55.8 per 100,000 for males and 42.9 per 100,000 for females.^13,25 The number of nevi is a strong predictor of melanoma risk. Melanoma increases with increasing numbers of benign acquired nevi. In a large European case-controlled study, the most important risk factors for melanoma are the number of nevi and the number of atypical nevi.⁹³ Established nevi may develop histologic changes transiently, thus simulating melanoma after a single UVR exposure;²⁹¹ some data suggest that sunburn can induce malignant transformation in benign nevi.⁴⁷

In the United States, melanoma incidence has increased since records were first kept in the 1930s, rising 121% in the 20 years between 1973 and 1994.¹¹⁷ An estimated 68,130 Americans (29,260 women and 38,870 men) will have developed new cases of invasive cutaneous melanoma in 2010; an additional 46,770 cases of melanoma in situ will have been diagnosed that year as well.¹⁴³ Today, the lifetime risk of melanoma for a male child born in the United States is 1 in 57; for a female child, the risk is 1 in 81.⁴ Similarly, large increases in melanoma incidence have been noted in Europe, Australia, and even Japan.¹⁴⁹ However, melanoma incidence and death rates show signs of stabilizing and perhaps decreasing for younger cohorts,^106,117,149 probably as a result of improved sun-protective behaviors.

Significant national efforts have been made to educate and protect populations at risk. In Australia, taxes have been removed from sunscreen sales, hats are typically required for children when they are playing outdoor sports, and artificial shade is increasingly available in public parks. In addition to improved photoprotection, early detection has been widely promoted. The Skin Cancer Foundation encourages monthly self-examinations, with special attention to pigmented lesions that display atypical clinical features, which are the so-called ABCDEs of melanoma:²³⁵ asymmetry; border irregularity; color variegation; diameter of more than 6 mm (0.24 inch); and evolving features (Figure 14-9). Nevi with these clinical features, symptomatic nevi, or nevi that bleed should be evaluated by a dermatologist.

FIGURE 14-9 Melanoma on the back demonstrating the ABCDEs: asymmetry, border irregularity, color variegation, diameter of more than 6 mm (0.24 inch), and evolving features (i.e., the patient’s wife had noticed that the area at 9 o’clock was “growing out from the rest of it”).

Molecular Basis of Photocarcinogenesis

Several photomolecular events are associated with NMSC. UVR causes characteristic photoinsults at sites of adjacent pyrimidines on DNA.^36,213,324 UVR photons are absorbed at the 5-5 double bonds, which results in cyclobutane dimers if both bonds open and 6-4 (pyrimidine-pyrimidone) photoproducts if a single bond opens.³⁶ Cyclobutane dimers predominate 3:1, with thymine (T-T) dimers being the most common.¹⁶⁰ Suberythemal and erythemal doses of UVR can induce T-T dimers.³²⁵ High-performance liquid chromatography can quantitatively measure these UVB photoproducts.⁴² Such measurements indicate 30-fold interindividual variation in photoproduct yields.⁴²

Resultant UVR-induced mutations have a distinctive signature: two-thirds display cytosine → thymine (C → T) substitutions at dipyrimidine sites, and 10% show CC → TT substitutions.³⁶ These mutations are relatively unique to UVR damage and allow UVR-induced mutations to be distinguished from chemical mutations.³⁶

Data suggest that cyclobutane dimers and 6-4 photoproducts are primarily responsible for the mutagenic¹⁷¹ and carcinogenic¹⁶⁰ properties of UVR. Many genes, including genes that are involved in tumor suppression and promotion, may be targets for UVR mutations. Tumor-suppressor genes (TSGs) that are known to play a role in photocarcinogenesis include p53, p16, and PTCH.^35,134 A mutation of p53, which is the most common genetic alteration identified in human cancers,¹³⁴ is found in nearly 50% of all cancers.^36,160 Approximately 50% of BCCa, 60% of actinic keratoses, and 90% of SCCa contain p53 mutations.^36,328 Although p53 mutations may be found in non–sun-damaged skin at a low frequency, 10⁻² to 10⁻³, mutations are much more common in sun-exposed sites.³⁶

Normal p53 protein is a transcription factor that regulates the cell cycle. DNA damage stimulates p53 protein production, which leads to cell-cycle arrest in G₁ (a premitotic phase), thereby allowing time for DNA repair.³⁶ Irreparable damage leads to apoptosis or programmed cell death. Sunburn cells are examples of apoptotic cells.³²⁸ Cells with mutated p53 are more resistant to apoptosis with subsequent UVR exposures, which explains why p53 inactivation reduces sunburn cells in irradiated mouse skin.³²⁸

Within the p53 gene there are “hot spots:” these are codons where mutations frequently occur.^36,43 Most p53 mutations result in a single amino-acid substitution, typically cytosine to thymine (C → T).³²⁸ Although normal, wild-type p53 has a short half-life and is generally unstable and unstainable, mutated p53 is significantly more stable and consequently stainable by immunohistochemical techniques.^43,247 Both UVA and UVB upregulate p53 expression in human skin.⁴⁶ After a single UVR exposure to the forearms, p53 protein expression peaks in 24 hours and returns to baseline after 360 hours.¹¹⁹

Mutations in p53 occur as an early initiating event in photocarcinogenesis.¹⁶⁰ In actinic keratoses, unique p53 mutations are present throughout the lesion,³²⁸ which confirms that they occur before (rather than after) lesion formation. Different actinic keratoses display different p53 mutations, again supporting the role of p53 mutations as initial causative events that are followed by the clonal expansion of mutated cells to form clinically visible lesions of precancerous actinic keratosis.³²⁸ Altered p53 provides a survival advantage to mutated cells. In response to chronic UVR, neighboring nonmutated cells become apoptotic and die, thereby allowing space for the further expansion of the mutated clone with ongoing UVR exposure³⁶ and ultimately resulting in development of actinic keratosis or SCCa.

However, p53 mutations alone may be insufficient to produce NMSC. Patients with Li-Fraumeni syndrome, who inherit a mutated form of the p53 gene, have increased incidence of sarcomas, adenocarcinomas, and melanomas, but not NMSC.¹⁶⁰ Consequently, other factors, such as decreased DNA repair and UVR-induced immunosuppression, must play a permissive role. For example, in patients with XP, there are increased numbers of p53 mutations³⁶ and defective gene repair mechanisms as well as greatly increased numbers of NMSC. DNA repair may also be defective in normal patients who do not have the syndrome who develop BCCa at an early age³⁰⁶ as well as in older adult patients,²¹³ who have a higher incidence of NMSC.

Cutaneous lymphomas may also show a higher frequency of UVR signature p53 mutations.¹⁹⁷ In mycosis fungoides, these mutations are found in the tumor stage but not the plaque stage,¹⁹⁷ which suggests that UVR promotes the clinical progression of this lymphoma. These findings are particularly interesting in the light of epidemiologic data that demonstrate increased incidence of non-Hodgkin’s lymphoma among those who live closer to the equator.¹

Other TSGs are less well studied but have increasingly defined roles in photocarcinogenesis. In melanoma, p16 is frequently inactivated¹³⁹ and increasingly downregulated as melanoma progresses.²⁷⁷ Another TSG, PTCH, which is also located on chromosome 9, is frequently mutated in both familial and sporadic BCCa. Mutations of PTCH are especially notable in patients with XP and multiple BCCa.¹³⁹

In addition to downregulating TSGs, UVR can activate proto-oncogenes to form functional oncogenes.¹³⁹ Included in this group are the proto-oncogenes bcl-2, c-fos, and ras. In response to UVR, the bcl-2 protein is overexpressed, with resultant suppression of apoptosis and consequent permissive expansion of malignant clones. In addition, UVR alters c-fos, thereby disrupting transcription of nuclear proteins that are involved in cell proliferation. UVB also causes mutations in ras, thereby disrupting mitogenic signaling pathways. In particular, mutations in BRAF, which is a critical component of the ras protein kinase pathway, are found in a large percentage of nevi¹⁶⁸ and melanomas,²³¹ especially melanomas that arise on intermittently sun-exposed skin.¹⁸⁶ However, BRAF mutations occur only rarely in melanomas that arise in chronically sun-exposed or completely sun-protected skin,¹⁸⁶ which suggests multiple genetic pathways for melanoma induction. Moreover, mutations of BRAF and p53 may interact to form melanoma.²³¹

Oxidative damage is another mechanism, in addition to mutation, by which UVR contributes to photocarcinogenesis. Although UVA is less directly mutagenic than is UVB, it is more potent with regard to causing cellular oxidative damage by producing reactive molecular oxygen and nitrogen species that in turn damage DNA, proteins, and lipids. This damage contributes to carcinogenesis via inflammation, immunosuppression, and, ultimately, mutation.¹²⁰ In addition, a group of zinc-dependent enzymes, known as matrix metalloproteinases, increase in response to UVR by altering the cutaneous extracellular environment to favor tumor invasion and spread.^38,139

Photoimmunology

UVR produces local and systemic immunosuppression.²¹⁹ Locally, UVB depletes Langerhans’ cells, which are immunocompetent antigen-processing cells, for up to 2 weeks after exposure.²⁰⁸ In addition, UVB functionally alters Langerhans’ cells by interfering with their presentation of antigens to T cells,¹¹¹ thereby diminishing helper T cell 1 responses (which promote contact hypersensitivity) while preserving helper T cell 2 responses²⁵⁷ (which suppress contact hypersensitivity), thereby effectively converting Langerhans’ cells from immunogenic to tolerogenic. Antigen-specific suppressor T cells arise; their appearance is possibly mediated by the UVR-induced synthesis of interleukin 10 from keratinocytes.²⁵⁷ As a consequence, contact hypersensitivity and mixed lymphocyte reactions are diminished with UVR exposure. This may at least partially explain why UVR-induced skin cancers, which are antigenic, progress to clinical lesions. In mice, this UVR-induced immunosuppression can be transferred with irradiated T lymphocytes.²¹⁹ Other proposed mediators of UVR-induced immunosuppression include cis-urocanic acid,⁵⁴ tumor necrosis factor-α, prostaglandins,²¹⁷ and DNA photoproducts.²⁰⁹

Immunoregulatory failure contributes to formation of skin cancer.¹⁶⁵ Skin cancer is often more aggressive and occurs at an earlier age among immunosuppressed patients.^74,224 In Australia, 45% of kidney transplant patients develop skin cancer within 11 years, and 70% develop it within 20 years.³² For heart transplant patients in Australia, the incidence of skin cancer is 31% at 5 years and 43% at 10 years; skin cancer accounts for 27% of patient deaths in this group after the fourth post-transplant year.²²⁴ In these patients, the ratio of SCCa to BCCa is 3:1, which is the precise opposite of the ratio that is present in nonimmunosuppressed patients. These figures are unusual only because most studies suggest that the risk of skin cancer is higher after heart transplant than after kidney transplant because of higher doses of immunosuppressive drugs with the former. Chronic sun exposure and fair complexion further increase risk of skin cancer in transplant patients,²²⁴ possibly as a result of the overexpression of p53.⁹⁹

Sunscreens

Chemical sunscreens were discovered in 1926. By 1928, the first commercial sunscreen, which contained benzyl salicylate and benzyl cinnamate, was marketed in the United States.⁸² Subsequent sunscreen evolution was primarily directed toward UVB protection to mitigate development of sunburn from overexposure to the sun. Para-aminobenzoic acid (PABA) was first advocated as a sunscreen in 1942; it was patented in 1943 and made commercially available in 1960. By then, national advertisements for sunscreens were promoting the message that people would be able to tan without burning. Sun protection factor (SPF) 15 formulations became available around 1980. More recently, as UVA photodamage has been increasingly appreciated, UVA sunscreening agents such as avobenzone have been introduced. Micronized preparations of titanium dioxide (TiO₂) and zinc oxide (ZnO) have become popular, and they provide broad-spectrum protection throughout the UVR range. Previously considered “physical” (reflective) as opposed to “chemical” (absorptive) sunscreens, these micronized preparations blur the traditional distinctions. Micronized TiO₂ and ZnO are largely transparent and absorb, reflect, and scatter UVR.¹⁵⁹ Consequently, chemical and physical labels for sunscreens are of diminishing value and perhaps should be dropped.

In the United States, sunscreens are regulated over-the-counter drugs. The U.S. Food and Drug Administration’s (FDA) Final Over-the-Counter Drug Products Monograph on Sunscreens, which was published in the Federal Register on May 21, 1999, established the allowable sunscreening agents, testing procedures, and labeling claims for efficacy, water resistance, and safety.²⁹⁵ On June 17, 2011, the FDA published a final rule that updated the labeling claims and testing procedures of the 1999 Final Monograph.²⁹⁶

The current FDA-approved sunscreening ingredients are listed in Table 14-1. Two names are sometimes given for the same agent, because the U.S. Pharmacopeia changed the names of several sunscreening agents (effective September 1, 2002) to better conform to international standards.²⁹⁷ PABA is an effective UVB absorber that has fallen out of favor. Poorly water soluble, PABA must be formulated in an alcohol vehicle. On the skin, it binds epidermal proteins, thus enhancing its resistance to water removal (substantivity) but provoking contact and photocontact dermatitis in approximately 4% of exposed subjects. Further limiting its acceptability, PABA can permanently stain fabrics a dull yellow color. As a consequence, PABA has been largely replaced by PABA esters such as amyl dimethyl PABA (padimate A) and octyl dimethyl PABA (padimate O). These absorb well in the UVB range, are easier to formulate in nonalcoholic vehicles, and are less staining and less allergenic.

TABLE 14-1 Sunscreening Agents Approved in the United States

* Approved by the U.S. Food and Drug Administration on July 21, 2006.

Cinnamates are the next most potent UVB absorbers. They often replace PABA in PABA-free sunscreens, but octyl methoxycinnamate (octinoxate; Parsol MCX) is an order-of-magnitude less potent than padimate O.¹⁷⁵ Octocrylene, which is a cinnamate derivative, is a weak UVB absorber that also absorbs UVA modestly up to 360 nm. Cinnamates are poorly bound to the stratum corneum and may cause contact dermatitis. Cinoxate is the most frequent contact sensitizer, with cross-sensitization to related cinnamates in coca leaves, balsam of Peru, and cinnamon oil.⁶⁵

Salicylates, including homosalate and octyl salicylate (octisalate), are relatively weak absorbers of UVB, and they are consequently most often used in combination with other sunscreening agents. They have the advantages of being nonsensitizing and water insoluble, and they help to solubilize benzophenones in commercial products.⁸⁴

Anthranilates are similarly weak UVB absorbers that also filter UVA. They display peak absorption at 340 nm.¹⁷⁵ The single commercially available agent from this class is methyl anthranilate (meradimate).

Phenylbenzimidazole sulfonic acid (ensulizole) is a unique UVB absorber. Unlike other chemical absorbers, which solubilize in the oil phase of emulsion formulations, phenylbenzimidazole sulfonic acid is water soluble. This physiochemical property has resulted in its increasing use in oil-free cosmetic sunscreens.¹⁷⁵

Benzophenones are broader-spectrum sunscreening agents, with good absorption in the UVB and UVA ranges up to 360 nm.¹⁷⁵ The three benzophenones available in the U.S. market are oxybenzone, dioxybenzone, and sulisobenzone.

In the United States, dibenzoylmethanes are represented by a single agent: avobenzone (Parsol 1789, butyl methoxydibenzoylmethane). It is a potent UVA absorber, with little or no absorption in the UVB range.¹⁷⁵ Its absorption peak at 358 nm falls nearly to zero at 400 nm.²⁵² Concerns have been raised that photodegradation may limit its effectiveness. Under simulated solar light, avobenzone can be degraded 36% in as little as 15 minutes.²⁶¹ However, these data are disputed, and there is debate regarding whether any significant decrease occurs with typical use, especially given the mitigating effect of combined sunscreening agents in commercially available preparations.²⁶¹ For example, a patented complex known as Helioplex—a combination of avobenzone, oxybenzone, and diethyl 2,6-naphthalate—is remarkably photostable.⁵¹ In addition, select stabilizing compounds such as vitamin C, vitamin E, and iron chelators may retard photodegradation.¹⁹⁹ Ecamsule (Mexoryl SX) is the newest sunscreening agent to be approved by the FDA, although it has been available in Europe and elsewhere for several years. It is an excellent UVA filter, with maximal absorbance at 345 nm and with modest absorption in the UVB range as well. Ecamsule is distinguished by being highly photostable and thermostable. It effectively protects skin from repeated exposures to UVA, thereby preventing the histologic changes associated with photoaging.²⁶⁷

Physical sunscreens traditionally refer to opaque agents that primarily reflect, scatter, and, to a lesser extent, absorb UVR. These include calamine, ichthammol, iron oxide, kaolin, red veterinary petroleum, starch, talc, TiO₂, and ZnO. In the wilderness, extemporaneous physical blockers can be made from ashes, mud, and leaves. A sunscreen with a physical filter typically protects throughout the UVR and visible spectra and may even protect against IR-induced erythema.²²⁷ However, classic physical blockers are messy, uncomfortable, and cosmetically undesirable.

Preparations of TiO₂ and ZnO with a submicron (i.e., nano) particle size are now widely available. In contrast, with normal TiO₂ and ZnO size ranges (150-300 nm for TiO₂ and 200-400 nm for ZnO), in which the larger size permits these particles to reflect and scatter light, the submicron dimensions (typically 20-150 nm for TiO₂ and 40-100 for ZnO) make these particles more soluble in their vehicle base and minimally reflective of visible light. Cosmetically, this is an advantage, because it makes them more transparent (or nearly so) in thin coats. The lower refractive index of ZnO in the visible range makes it less white and more transparent than TiO₂.²⁰⁷ However, submicron-sized preparations significantly absorb UVR, thereby providing broad-spectrum protection from UVB and UVA and blurring the distinction between chemical and physical sunscreens, as mentioned previously.^64,175,260 TiO₂ and ZnO are sometimes marketed as “chemical-free” sunscreens, which is clearly a misnomer. In addition, products that contain “physical” sunscreening agents are often marketed as “sunblocks,” which is a misleading term that was eliminated in the 1999 FDA Final Monograph.²⁹⁵ Of note is that metal oxide nanoparticles, with their potential to be absorbed through the skin, have received a great deal of media attention in recent years but have not been comprehensively evaluated with regard to their potential long-term effects on human health. Likewise, the ecologic impact of product use and disposal and the fate and toxicity of nanoparticles in the environment will most likely be influenced by a number of factors (e.g., aggregation, stability, transport, sedimentation, biouptake) that remain to be rigorously studied.²²⁵

New sunscreens are on the horizon, with imaginative observation leading to future sources of sunscreening agents. For example, Saikawa and colleagues²⁵⁸ determined that the viscous “red sweat” of the hippopotamus is an excellent broad-spectrum sunscreen, with absorption in the 200 to 600 nm range.²⁵⁸

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