National Institutes of Health Consensus Development Conference Statement

May 8-10, 1989

This statement was originally published as:

Sunlight, Ultraviolet Radiation, and the Skin. NIH Consens Statement 1989 May 8-10;7(8):1-29.

For making bibliographic reference to the statement in the electronic form displayed here, it is recommended that the following format be used:


     Sunlight, Ultraviolet Radiation, and the Skin. NIH Consens
     Statement Online 1989 May 8-10 [cited year month day];7(8):1-29.

INTRODUCTION

It is ingrained in humans to love light and, indeed, since mankind's first wanderings from the caves, worship of the sun has been a fundamental tenet that many societies hold even to the present.

The properties of the sun that have inspired such reverence include its light (visible radiation) and its warmth (infrared radiation). Additional portions of the solar spectrum that cannot be perceived directly by the senses (ultraviolet) are capable of evoking both physiologic and pathologic events in the skin.

Sunlight is the ultimate source of energy and is vitally important to life as we know it. However, absorption of incident solar energy by components of the skin can cause a variety of pathological sequelae.

Until the 20th century, the sun was the predominant source of human skin exposure to energy within the photobiologic action spectrum. More recently, artificial devices capable of mimicking the emission of some or all of the solar spectrum have been introduced, compounding the opportunities and risks of ultraviolet radiation (UVR) exposure.

Despite the undeniable importance of cutaneous exposure to ultraviolet radiation for vitamin D homeostasis, there is little evidence to indicate that there are additional beneficial effects of such exposure. Indeed, overwhelming evidence exists to support the concept that the skin is damaged in many different ways by its direct exposure to natural or artificial UVR. Some exposure is virtually unavoidable over a lifetime and is dramatically dissimilar in different populations depending upon climate, geography, occupation, and recreational activities. The consequences of this exposure are also influenced by factors such as the degree of melanin pigmentation. The effects of UVR can be divided into two general types, acute and chronic. Acute effects include sunburn, and chronic effects include, among others, the development of certain forms of skin cancer. In addition, the skin is a major site of immunologic activity, and UVR is capable of affecting the immune system via its effects on the skin. The skin is also susceptible to degenerative changes evoked by chronic UVR. These changes are a major component of the constellation of physical changes perceived as skin aging but, which in reality, are due to chronic photodamage.

It is now possible to measure the effects of solar radiation on the skin, and epidemiologic studies from around the world have provided important new knowledge concerning the risks and benefits of exposure to sunlight and UVR.

Expanding knowledge about the hazards of exposure to sunlight and UVR has been accompanied by improved approaches to photoprotection, including the development of more effective sunscreen formulations. In addition, there is increasing interest in pharmacologic agents such as the retinoids that may be capable of inhibiting the development of or possibly even reversing certain chronic effects of cutaneous sun exposure.

Considerable controversy remains concerning the specific adverse effects caused by various wavelengths of UVR, the magnitude of the adverse effects, and potential strategies for their prevention and/or treatment. A Consensus Development Conference was undertaken in an effort to define the specific interactions of sunlight, UVR, and the skin as well as to identify methods for preventing and/or treating the adverse effects of UVR. Sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Office of Medical Applications of Research, the National Cancer Institute, and the National Institute of Child Health and Human Development of the National Institutes of Health, the Food and Drug Administration, and the Environmental Protection Agency, the conference brought together physicians, scientists, and other health care professionals, along with representatives of the public on May 8-10, 1989. Following 1 1/2 days of presentations and discussions by the invited experts and the audience, members of the consensus panel drawn from the biomedical research community and the public weighed the scientific evidence in formulating a draft statement in response to several questions:

In applying the recommendations of this consensus conference, it is important to recognize that special circumstances may exist for each patient. These may include unavoidable exposures to UVR or the inability to use certain of the preventive strategies. There are clearly some areas in which final recommendations cannot yet be made due to insufficient data. In these situations, physicians must use their best clinical judgment in advising patients.

WHAT ARE THE SOURCES OF ULTRAVIOLET RADIATION, AND IS THE EXTENT OF HUMAN EXPOSURE CHANGING OVER TIME?

There are both natural and artificial sources of UVR. Although there are many artificial sources of this energy, sunlight is the only natural source.

The sun emits a wide variety of electromagnetic radiation, including infrared, visible, ultraviolet A (UVA; 320 to 400 nm), ultraviolet B (UVB; 290 to 320 nm), and ultraviolet C (UVC; 10 to 290 nm). The only UVR wavelengths that reach the Earth's surface are UVA and UVB. UVA radiation is 1,000-fold less effective than UVB in producing skin redness. However, its predominance in the solar energy reaching the Earth's surface (tenfold to one hundredfold more than UVB) permits UVA to play a far more important role in contributing to the harmful effects of sun exposure than previously suspected.

Sunlight is the greatest source of human UVR exposure, affecting virtually everyone. The extent of an individual's exposure, however, varies widely depending on a multiplicity of factors such as clothing, occupation, lifestyle, age, and geographic factors such as altitude and latitude. There is greater UVR exposure with decreasing latitude. Residing at higher altitude results in a greater UVR exposure such that for every 1,000 feet above sea level, there is a compounded 4 percent increase in UVR exposure. UVR exposure increases with decreased stratospheric ozone. Other factors that influence exposure to UVR include heat, wind, humidity, pollutants, cloud cover, snow, season, and time of day.

Solar flares (sunspots) also alter the amount of UVR reaching the Earth. Solar flares increase ozone concentration in the stratosphere (above 50 km) thereby reducing the amount of surface UVB. This 11-year cycle of solar flares causes as much as a 400-percent variation in UVB at 300 nm reaching the earth. When solar flares are inactive, there is a decrease in the ozone concentration, allowing increased UVB to penetrate to the Earth's surface.

There is also serious concern about depletion of stratospheric ozone by manmade chlorofluorocarbons (CFC). These extraordinarily inert chemicals are used in numerous commercial products, including aerosols and refrigerants. The U.S. Environmental Protection Agency has been charged with estimating the effects on health associated with changes in stratospheric ozone levels. In a recent risk assessment document, the Agency predicted that without controls on CFC production, there would be a 40 percent depletion of ozone by the year 2075. The Agency further concluded that for every 1 percent decrease in ozone, there will be a compounded 2 percent increase in the more damaging shorter UVB wavelengths reaching the Earth's surface. Such an increase in UVB penetration to the earth is predicted to result in an additional 1 to 3 percent increase per year in nonmelanoma skin cancer (NMSC).

Recent satellite measurements already indicate a worldwide decrease in stratospheric ozone over the last decade. Both satellite- and land-based measurements have revealed a seasonal hole in the ozone layer over the Antarctic secondary to its destruction by CFC's. Although increased surface UVB has been measured in the Antarctic, there has not yet been a measurable change in UVB as a consequence of CFC's in the stratosphere in the United States.

Over the past several decades, the average American's exposure to UVB has increased considerably due to changing lifestyles--more outdoor recreational activities, more emphasis on tanning, scantier clothing, and a population shift to the sunbelt.

The most common sources of artificial UVR exposure are various kinds of lamps that emit this form of energy. These lamps are used primarily for recreational tanning and phototherapy of skin diseases (e.g., psoriasis and cutaneous T-cell lymphoma (mycosis fungoides). UVR lamps can emit UVA, UVB, and/or UVC. Those lamps currently used for recreational tanning emit UVA primarily or exclusively. Some UVA lamps generate greater than 5 times more UVA per unit time than solar UVA radiation reaching the Earth's surface at the Equator. At these doses, "pure UVA" is likely to have adverse biologic effects. However, UVB remains a potential problem with most of these sources. Even 1 percent UVB emission from a UVA source can cause a significant increase in the potential for skin cancer.

The tanning industry is rapidly growing in the United States. Currently, more than 1 million Americans use commercial tanning facilities every day. The biggest categories of users are adolescents and young adults, especially women.

The use of artificial ultraviolet sources for the phototherapy of dermatologic diseases has increased substantially in recent years and has exposed a group of people to markedly increased doses of UVR. Epidemiologic studies of these patients have shown an unequivocal dose- dependent increase in the incidence of NMSC, especially squamous cell carcinoma (SCC).

Another potential but as yet unexplored source of artificial UVR is unshielded fluorescent bulbs used for illumination. An unresolved issue is the amount of UVA emitted by such sources and the long-term effects of this exposure. More research is needed to clarify these problems.

WHAT ARE THE EFFECTS OF SUNLIGHT ON THE SKIN?

Marked morphologic changes in all parts of the skin, except perhaps the subcutaneous tissue, are recognized as consequences of exposure to UVR. These changes underlie the clinically observed sagging, wrinkling, leathery texture, and blotchy discoloration of skin typically associated with actinic damage. It is unclear how much exposure and how much time is required to effect these changes, although it is evident that clinically normal appearing skin can show pathologic signs of sun damage upon histologic and ultrastructural examination. It is known that individuals with fair complexions are more susceptible to this damage.

In the epidermis UVR-induced changes include aberrant tissue architecture and alterations in keratinocytes and melanocytes and functional changes in Langerhans cells. Sun-exposed epidermis becomes thickened as much as twofold compared to sun-protected skin and is disorganized, showing evidence of hyperkeratosis, parakeratosis, and acanthosis. Keratinocytes lose their typical alignment and progressive flattening, show inclusions in the nucleus, and accumulate excessive amounts of melanosome complexes above the nucleus (capping). At the ultrastructural level, clumped keratin filaments and alterations in electron density of some basal cells are characteristic. Keratinocytes of the more differentiated epidermal layers (upper spinous, granular, and cornified) show few, if any, cytologic changes.

In spite of evidence for morphologic change, there are no data indicating altered keratinocyte differentiation as a result of sun exposure. Furthermore, it is not known how UVR interactions with light- absorbing molecules within the keratinocytes (e.g., DNA, keratins, lipids) correlate with the changes in morphology. Two other cells of the epidermis are also affected by UVR. The melanocyte, with its melanin pigment-containing melanosomes, is the primary cell involved in photoprotection of the skin. In sun-damaged epidermis, these cells enlarge, increase in number, and migrate to higher levels of the epidermis. UVR also affects Langerhans cells in both animal and human skin by altering their immunologic function. Even low doses of UVB can reduce their antigen-presenting capability, block the normal effector pathway, and evoke an inappropriate response by activating T suppressor networks. It is unclear whether UVR affects Langerhans cells both directly and indirectly through soluble factors released by damaged keratinocytes.

The dermal-epidermal junction loses its rete ridges forming a flattened interface between the epidermis and dermis. This kind of abutment is more susceptible to shearing forces than the normal interlocked system of epidermal rete ridges and dermal papillae. At the ultrastructural level, regions of reduplicated lamina densa are evident. This change is not unique to photodamage but is characteristic of trauma to the epidermis by wounding and/or by disease.

UVR causes unique dermal damage such as alterations in architecture, matrix composition, vascular structure and function, and cellular activities. The connective tissue immediately beneath the epidermis (Grenz Zone) contains large bundles of densely packed, normal-appearing collagen fibrils. Beneath this region, a broad zone of electron-dense elastotic material is evident. There are no data that demonstrate how newly synthesized or degraded, previously existing elastic fibers contribute to this material. Abnormal collagen fibrils can be admixed with the elastotic substance. Other studies show changes in the type III:I collagen ratio and an increase in glycosaminoglycans. Fibroblasts appear to be metabolically active. It is not clear whether this is a transient response to the UVR or whether there is a change in cell phenotype that can be retained in vitro. The mechanisms for the altered connective tissue responses are not understood. Dermal vessels become dilated, leaky, and accumulate excessive basement membrane-like material. Inflammatory cells collect around the vessels; mast cells are increased and may show evidence of degranulation and apparent physical associations with fibroblasts. Although the nature of this relationship is unknown, it is a common observation in other disorders in which fibrosis occurs.

Sunburn is UVR-induced erythema of the skin caused by vasodilatation of dermal vessels. This may be mediated through cyclo-oxygenase and lipoxygenase products of arachidonic acid. Generation of the prostaglandins associated with UVB erythema produced within the first 6 to 12 hours can be blocked by topical nonsteroidal anti-inflammatory agents such as indomethacin. These anti-inflammatory agents, however, cannot inhibit the delayed, post 24-hour erythema that is modulated by lipoxygenase products. The time-dependent release of varying mediators during the UV-induced inflammatory process underscores the need for further exploration into selective inhibitors of both the cyclo- oxygenase and lipoxygenase pathways in the prevention and treatment of sunburn erythema.

Also associated with UVR irradiation of human skin is the appearance of dyskeratotic keratinocytes, known as sunburn cells, in the superficial layers of the epidermis. The mechanisms of the development of these cells are still unclear and warrant further exploration.

Tanning is the term applied to the increase in melanin pigmentation following UVR exposure. It is mediated by a combination of immediate pigment darkening (IPD) and delayed pigment darkening (DPD). IPD is caused by UVA and is due to photo-oxidation of preformed melanin. It is not protective against UVB erythema. DPD occurs about 72 hours after UVR exposure and does not afford much protection against UVB erythema and pyrimidine dimer formation. It is accompanied by an increase in the number of DOPA-positive melanocytes, an increase in the number and melanization of melanosomes, and an increase in dendricity of melanocytes. The degree of protection afforded by melanin is unclear. Individuals with dark complexions are still susceptible to UVR-induced photodamage. UVR also increases the transfer of melanosomes from melanocytes to keratinocytes. Following UVR melanosomes diffusely distributed within keratinocytes collect above the nucleus, forming a "cap" over it. DPD occurs with either UVB or UVA. DPD induced by UVB is more protective against UVB erythema than is DPD induced by UVA. Both UVB- and UVA-induced DPD protect equally well against UVB dimer formation.

In addition to certain genetic and metabolic disorders that are precipitated by UVR, there are many photosensitive diseases of unknown cause. These include lupus erythematosus and polymorphous light eruption, which are elicited by certain wavelengths of the UVR spectrum. Photosensitivity disorders may also occur due to the interaction of UVR with many commonly used drugs, as well as chemicals used in industry and consumer products.

UVR modifies local and systemic immune responses, functionally alters Langerhans cells, and activates the T cell suppressor pathway. Soluble factors released from UV-irradiated epidermal cells also may be responsible for this altered immune response. In certain experimental systems, UVR-induced tumors transplanted into genetically identical animals are normally rejected. If these host animals are UV-irradiated before transplantation, the tumor will be accepted. These conclusions are based on animal studies. The role of UVR in the immunobiology of human skin cancer and, particularly, in susceptibility against certain cutaneous infectious diseases is unclear. More studies on the effect of UVR on human neoplastic and infectious disease are warranted.

There is extensive epidemiological evidence supporting the direct role sunlight plays in human skin cancer. Basal cell carcinomas (BCC), the most common skin cancers in Caucasians, are found primarily on sun- exposed areas such as the head and neck where a dose-response relationship exists. Furthermore, patients with skin cancer generally have decreased melanin pigmentation and associated photo-protection; people with light complexion and who sunburn easily have a higher incidence of tumors. There is even stronger evidence for the role of sunlight in causing SCC's. Although both BCC's and SCC's are more prevalent in geographic areas of high sun exposure, there is a much greater increase in SCC with decreasing latitude and increasing sun exposure. A reasonable correlation exists between sunlight exposure and melanoma, but the relationship is not as clear as with NMSC. It should be emphasized that the incidence of NMSC and melanomas has been steadily increasing. Unlike NMSC, melanomas occur most frequently on the upper back in males and lower extremities in females. Melanoma incidence does not follow a pattern of increased risk with cumulative UVR exposure whereas the incidence of NMSC does.

Extensive data also exist concerning UVR-induced skin cancer in experimental animals. In mice and guinea pigs, UVR induces mainly SCC whereas in rats both SCC and BCC are produced by repeated doses of UVR. In general, UVR induces SCC's in mice somewhat more effectively in young animals than in older ones. The cancer response is preceded by photodamage to the epidermal DNA, inflammation, epidermal hyperplasia, and dysplasia. Although there are several animal models in which chemical carcinogens can induce melanomas, the induction of melanomas by UVR has been very difficult if not impossible. Recent studies suggest that the opossum may be a reasonable model for UVR-induced melanomas.

Experiments in animals indicate that UVB is much more effective than UVA in causing NMSC. Nevertheless, UVA can induce DNA damage, erythema, and SCC in both pigmented and albino mice and in guinea pigs. Recent evidence suggests that the longer UVA wavelengths (UVA I:340 to 400 nm) of the UVA spectrum are less damaging than the shorter UVA wavelengths (UVA II:320 to 340 nm), but further research is needed to confirm this distinction.

The exposure of skin to UVB is essential for the endogenous production of vitamin D[sub3]. In areas of the world where there are inadequate levels of nutritionally available vitamin D, UVB is the only source. The relationship of sunshine to vitamin D[sub3] and the normal growth and development of the skeleton is well known. Exposure of skin to UVR in the region of 290 to 315 nm is essential for the formation of vitamin D[sub3] in the epidermis.

There is evidence that vitamin D[sub3] synthesis is inhibited by the use of sunscreens. In the United States, this does not represent a health hazard for the pediatric population that receives adequate vitamin D supplementation in milk. In other countries this may not be the case. Deficiencies in elderly populations may exist.

WHAT FACTORS INFLUENCE SUSCEPTIBILITY TO ULTRAVIOLET RADIATION?

Susceptibility to damage by UVR may be influenced by genetic and acquired disorders, genetic traits, age-related factors, and the use of some medications.

Genetic abnormalities can increase the susceptibility to UVR damage. These include disorders manifested in utero that may be lifelong or that may appear shortly after birth. Among them are disorders of keratinization and pigmentation. Several inherited disorders in which there is marked susceptibility to UVR in early childhood include xeroderma pigmentosum, Bloom's syndrome, Rothmund-Thomson syndrome, the porphyrias, phenylketonuria, dysplastic nevus syndrome, and the basal cell nevus syndrome.

There are also numerous and diverse acquired diseases that manifest increased light susceptibility. Examples include persistent light reaction, actinic reticuloid, polymorphous light eruption, solar urticaria, hydroa aestivale, hydroa vacciniforme, actinic prurigo, lupus erythematosus, dermatomyositis, Darier's disease, and disseminated superficial actinic parakeratosis.

Significant factors that influence susceptibility to UVR damage include race, ethnicity, eye and hair color, and the tendency toward formation of freckles and nevi. One approach to categorizing humans in terms of susceptibility to UVR is typing according to history of sunburning and tanning. Six skin types have been defined. Type I individuals always burn and never tan; type VI individuals always tan and never burn. The age of an individual may be correlated with factors that influence the susceptibility to UVR. These may include age-related structural differences in the skin, behavioral differences (e.g., adolescent risk taking) and, hypothetically, age-related immunological differences.

Numerous systemic medications may augment UVR susceptibility. Increased UVR damage may occur with the use of oral antibiotics, antihypertensives, psoralens, immunosuppressive agents, nonsteroidal anti-inflammatory drugs, and numerous other agents. In addition, a number of topical medications and industrial chemicals may increase the susceptibility to damage by sunlight. These include topical psoralens, tretinoin, and other photosensitizing and depigmenting agents.

CAN ULTRAVIOLET-INDUCED CHANGES BE PREVENTED? IF SO, HOW?

Skin cancers in which UVR exposure plays an important role are the most common form of cancer. In 1978, there were more than 500,000 new cases of skin cancer. This is probably a substantial underestimate for 1989, because the number of office visits for NMSC has increased more than 50 percent in the past decade while the overall increase in office visits has only been 11 percent. Therefore, it is imperative to consider ways to minimize the deleterious effects of UVR.

What measures can be taken to diminish the risk of UVR exposure? There is considerable information that can serve as a basis for developing a policy of "low-risk" behavior.

There is a critical need to educate the public about all of these factors, consideration of which will show that the low-risk strategies described above are compatible with normal, active lives.

ARE SUNLIGHT-INDUCED ADVERSE SKIN ALTERATIONS TREATABLE AND/OR REVERSIBLE? IF SO, HOW?

Sunlight-induced adverse skin alterations include NMSC, melanoma, actinic keratoses, as well as textural and pigmentary changes characteristic of chronic photodamage. All of these cancers are treated by standard surgical techniques. Precancerous lesions such as actinic keratoses are treated by topical chemotherapy (e.g., by the use of 5- fluorouracil) and physical methods of superficial skin destruction (e.g., cryosurgery). Various therapies to improve the features of chronic photodamage (scaliness, coarse and fine wrinkling, telangiectasis, and irregular pigmentation) including chemical peels, the topical use of 5-fluorouracil, alpha-hydroxy acids, and all- transretinoic acid have been tried. Although the beneficial cosmetic effects of some of these treatments have received wide publicity, there are insufficient data demonstrating sustained improvement, reversibility of tissue pathology, or the preservation of normal skin function by those agents. There is no information regarding long-term positive, negative, or toxic effects of these agents. Conflicting data exist demonstrating both prevention and potentiation effects of topical retinoids in the development of UVR-induced skin tumors in animals. There are indications that systemic use of beta-carotene and certain retinoids may be beneficial in prevention of sun damage in people with certain disorders. Long-term, large-scale studies of normal individuals in the general population are in progress.

WHAT ARE THE DIRECTIONS FOR FUTURE RESEARCH?

The following recommendations for future research are not listed according to any particular priority.

CONCLUSIONS AND RECOMMENDATIONS

CONSENSUS DEVELOPMENT PANEL

David R. Bickers, M.D.
Professor and Chairman Department of Dermatology Director Skin
Diseases Research Center Case Western Reserve University and University Hospitals C

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