FEATURES
SUN PROTECTION
Sunscreens and the Prevention of Ultraviolet Radiation-1nd uced Skin Cancer BETH ANN DROLET, MD MICHAEL J. CONNOR, PhD
S
unscreens were first introduced in the 1920s to protect the skin against the short-term effects of sunlight. Today, much of the interest in sunscreensrelates to their potential ability to prevent the deleterious effects of more long-term sun exposure. Of particular concern is their use in the prevention of skin carcinogenesis.Although many physiciansencourage the use of sunscreens in skin cancer prophylaxis, there is a lack of direct evidence showing that sunscreens do prevent skin tumorigenesis in humans. The purpose of this report is to examine and review the available data on the effectiveness of sunscreens in the prevention of nonmelanoma skin cancers in man. The association of skin cancer and sunlight was first reported by Unnal when he noted an increase in the incidence of cutaneous cancers among persons with sundamaged skin. Many subsequent clinical, epidemiologic, and laboratory studies have documented this relation. The incidence of nonmelanoma skin cancers is increased in susceptible populations living in geographic latitudes with greater sun exposures. Additionally, 90% of skin cancers arise in sun-exposed areas of the body such as the arms and f a ~ e .The ~ , importance ~ of the ultraviolet radiation (UVR) component of sunlight in the induction of skin cancer was demonstrated directly in 1959 when Blum‘ induced cutaneouscancers by irradiating mice with ultraviolet light. Although experimental data of the latter kind are only indirectly applicable to the human situation, experimental rodent models have been of instrumental importance in the study of UVR-induced skin carcinogenesis. Because the relation between malignant melanoma and UVR is much less obvious, we will limit our discussion to nonmelanoma skin cancers, recognizing the need
From the joint Veterans Affairs Wudsworth-UCLA Dermatology Truining Program, Department of Medicine, Uniaersity of California, Los Angeles, School of Medicine, Los Angeles, California. Address reprints requests to: Michael j. Connor, PhD, Division of Dermatology, Department of Medicine, UCLA School of Medicine, Los Angeles,
CA 90024.
0 1992 by Elsevier Science Publishing Co., Inc. 0148-0812/92/$5.00
for further evaluation of the relation of sunscreens and UVR to melanoma.
Sunscreens The function of a sunscreen is to block or filter out the harmful components of incident solar radiation. Sunscreens fall into one of two types: physical or chemical. Physical sunscreens are opaque formulations that act as sun blocks reflecting almost all incident UVR. They are often composed of colloidal metal oxides, particularly zinc. Although extremely efficient, physical sunscreens are of limited value because of their poor cosmetic acceptability. Chemical sunscreens are preparations that contain one or more chromophores that are usually translucent to visible light but selectively absorb UVR. Because chemical sunscreens are more cosmetically acceptable they are used more frequently than physical sunscreens. The most common chromophores used in chemical sunscreens are 1)derivativesof p-aminobenzoic acid (PABA), 2)cinnamates, 3)benzophenones, 4) salicylates, and 5)anthranilates. The Food and Drug Administration has also approved two sunscreens containing 4-tbutyl-4’-methoxydibenzoylmethane (Parsol 1789), an agent that filters out long-wave radiation (ultraviolet A [WA]). These agents are often used in combination to produce products with a broader range of protection.
Solar Spectrum Solar radiation that reaches sea level includes wavelengths of 290 to 1800 nm. Actinic solar wavelengths, that is, those implicated in causing sunburn, photoaging, and photocarcinogenesis,are further divided into the ultraviolet C (WC) (200 to 290 nm), ultraviolet B (UVB) (290to 320 nm),and UVA (320to 400 nm) regions. Solar UVC is aborbed by ozone and other gases in the upper atmosphere and does not reach the earth’s surface; however, UVC is also emitted by artificial sources such as germicidal lamps and mercury arc lamps. Solar UVB, the 571
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erythemic band, is traditionally thought to include the most damaging actinic energy. A high proportion of solar UVB is absorbed by ozone in the upper stratosphere, but the small proportion that does reach the surface of the earth is primarily responsible for the production of sunlight-induced erythema, photoaging, and photocarcinogenesis. The amount of solar UVB reaching a given point on the earth's surface will of course depend on the angle of incidence of the light (the closer the sun is to the horizon, the smaller the angle of incidence and the longer the stratospheric column of air that the light will have to pass through). Both UVB levels and squamous cell carcinoma (SCC) incidence show a strong dependency on latitude.5 Evidence that chemical pollutants are depleting the protective ozone layer has led to the widely held belief that the incidence of skin cancer will increase because of a likely increase in incident UVB. Recently, it has become clear that the UVA wavelengths are also harmful to human skin. Because of the longer wavelength, UVA radiation penetrates deep into the dermis. Solar UVA has been documented to produce erythema,'j immediate pigment darkening and delayed melan~genesis,~ and elastosis and other dermal connective tissue damage.8 Although UVA-induced melanogenesis has been hypothesized to be protective against UVB-induced damage, there is little evidence to support this. In fact, UVA radiation has been shown to augment UVB carcinogenesis9Joand in high doses has been found to be carcinogenic to mice." This potential interaction between UVA and UVB emphasizes the need for sunscreens that will provide protection against both UVA and UVB radiation. Indeed, many of the newer commercial sunscreens are formulated with a combination of UVA- and UVB-absorbing chromophores.
Erythema Erythema is the most obvious component of acute skin phototoxicity, and sunscreens are defined by their efficacy in preventing erythema.12J3The minimal amount of UVR needed to induce erythema, ie, the minimal erythema dose, forms the basis for comparing and evaluating various sunscreens. The minimal erythema dose in caucasions varies from 0.02 to 0.07 J/cm2, which is equivalent to 10 to 35 minutes of noonday sun in New Jersey in June." The potency of a sunscreen is indicated by its sun protection factor, or SPF, which is the ratio of the UVB dose required to induce one minimal erythema dose in the presence of the sunscreen to the minimal erythema dose without the sunscreen. Since the sun protection factor is determined by the minimal erythema dose, predicting the amount of UVB protection a product provides against nonerythemic end
points requires the questionable assumption that the action spectrum of erythema parallels that of other actinic responses. That is, that the wavelengths that cause erythema are the same wavelengths responsible for other actinic effects. Some authors suggest that erythema is a relatively insensitive technique for assessing suns c r e e n ~and , ~ ~phototoxic reactions have been shown to occur at suberythemic UVR doses."jJ7 Pearse and MarkP showed that some of the UVR-induced metabolic changes in the skin are not prevented by the application of a sunscreen despite the ability of the sunscreen to completely prevent the erythematous response. This may imply that wavelengths other than those capable of producing erythema are causing metabolic changes and that these wavelengths are not absorbed by the current sunscreen agents. Whether these metabolic changes are involved in the induction of cutaneous cancers remains unknown. A questionnaire survey done to assess the risk factors for basal cell carcinoma (BCC)found a history of sunburn to be a significant relative risk factor. Additional relative risk factors for skin cancer include red/blonde hair color, prominent freckling in childhood, and light skin ~ 0 l o r . l ~ These same phenotypic characters also correlate with low minimal erythema dose values.20Thus, these epidemiologic data suggest that erythema susceptibility may well be predictive of skin cancer susceptibility and that the sun protection factor may be a coarse but viable indicator of sunscreen ability to prevent UVR-carcinogenesis.
Sunburn Cells Epidermis from UVR sites typically contains small numbers of histologically derranged cells referred to as sunbum cells. They are thought to arise when keratinocytes that are in a sensitive stage of the cell cycle, such as the S phase, where the replicating DNA is particularly vulnerable, sustain a lethal dose of UVR. Sunburn cells are induced at levels of UVR that are much less than one minimal erythema dose21; thus, they may be a more sensitive indicator of UVR-induced damage than erythema. The production of sunbum cells has been shown to be significantly reduced by sunscreens." As is the case with erythema, the correlation between the induction of sunburn cells and tumorigenicity of UVR is unknown. Because sunburn cells have sustained a lethal amount of UVR, they lose their ability to replicate and thus their carcinogenic potential; however, they may be a good way to approximate the total amount of UVR injury sustained by the tissue and thus may be used as a measure of the amount of energy a specific sunscreen may absorb effectively. The fact that sunscreens do decrease the number of sunburn cells after UVR exposure further supports their
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shielding effect and, theoretically, their anticarcinogenic capacity.
Unscheduled DNA Synthesis Sunscreens have been demonstrated to be effective in preventing unscheduled DNA synthesis in human epidermal cells irradiated with UVR.22Unscheduled DNA synthesis occurs when pyrimidine and purine precursors are incorporated into DNA outside the normal S phase of the cell cycle and reflects DNA repair processes. Sunscreens with a sun protection factor of 15 have been shown to inhibit UVR induction of pyrimidine dimers between adjacent DNA strands in human skin in V ~ V O Recently, the action spectrum for the induction of pyrimidine dimers has been determined,24and this spectrum closely matches the erythema action spectrum. There is no direct evidence that these photoproducts are responsible for UVR-induced carcinogenesis, but accumulation of DNA injuries has been shown to be both mutagenic and tumorigenic as well as lethal to affected cells.25 Patients afflicted with xeroderma pigmentosum, an autosomal recessive disease in which there is a defect in the DNA excision repair mechanism, are known to be extremely susceptible to UVR-induced tumors. This further supports the theory that photodamage to DNA plays a major role in UVR carcinogenesis. Sunscreens and the avoidance of UVR have been instrumental in protecting patients with xeroderma pigmentosum from cutaneous neoplasms. Assuming that DNA damage is the principal factor in solar-induced carcinogenesis, the ability of the sunscreen to prevent unscheduled DNA synthesis provides persuasive evidence that these agents may prevent carcinogenesis.
Rodent Studies The most convincing evidence that sunscreens do offer protection against skin cancers comes from laboratory studies using mice. In the 1950s Blum demonstrated that cancers could be induced in the skin of albino mice by UVR. Kligman et alZ6found that sunscreens containing 2% octyldimethyl p-aminobenzoic acid (sun protection factor 2) and 7% octyldimethyl p-aminobenzoic acid (sun protection factor 5) could profoundly inhibit the induction of skin tumors by UVR in hairless albino and lightly pigmented mice. Protective effects were even seen with a sun protection factor 2 sunscreen. These findings were later confirmed in a similar study using 5% p-aminobenzoic acid on hairless, lightly pigmented mice.27 Since analogous studies cannot be performed on humans, can we prudently extrapolate these animal data
. ~
to the human situation? In both mouse and human skin, UVR carcinogenesis is a dose-dependent process.28The action spectra for the acute erythematous response in mice skin is similar to that in humansz9 and this same band (290 to 320 nm) has been shown to be tumorigenic in mice.30Likewise, chronic UVR-induced dermal histologic and biochemical changes such as increased elastosis and increases in collagen type I11 are similar in both mice and humans.31 However, there are some major differences between the experimentalrodent model and true human exposure. The life span of the mouse is 2 years, and UVR-induced tumors clearly appear in mice at a greatly accelerated rate. This increased susceptibility is not really surprising, since ~ the mouse is normally a hirsute animal that is largely nocturnal, and murine DNA photodamage repair systems show some differences from those found in humans. Second, in the experimental situation the mice are subjected to multiple treatments with very high daily doses of UVR (often much greater than one minimal erythema dose per day), an event unlikely to occur in humans. Finally, the use of artificial light sources introduces another significant variable. Although these experimental models are extremely suggestive of the preventative capability of sunscreens, one must consider these variables when extrapolating these conclusions to humans.
Sunscreens and UVR-Induced Immunosuppression There has been an increasing interest in the effects of UVR on the cutaneous immune system and the role that this may play in UVR tumorigenicity. By damaging epidermal DNA, and thus increasing the risk of an unfavorable change in the genotype, UVR can clearly act as a tumor initiator; however, UVR has immunosuppressive effects that could, theoretically, render a person unable to mount a local response to malignant cells. Thus, UVR exposure may promote tumor expression and growth because of its immunosuppressive properties. The observation that transplant patients on long-term immunosuppressive drugs are at a profound increase risk ~ ~ dramatic support for the for developing S C C S offers importance of a competent immune system in minimizing risks for skin cancer. Sunlight has long been known to reactivate herpes simplex virus. S p r u a n ~ edemon~~ strated a definite dose-dependent effect of UVR and the induction of the herpes simplex virus. Additionally, mice irradiated with high doses of UVR are unable to reject highly antigenic transplanted UVR-induced turn or^.^^,^^
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These tumors incite an immune response, leading to rapid rejection in nonirradiated mice. Contact hypersensitivity is also suppressed by UVR in both rodents and humans. Yoshikawa and coworkers36postulated that UVR suppresses contact hypersensitivity only in genetically susceptible patients. Of interest, they found that patients with a history of nonmelanoma skin cancer were more likely to have the contact hypersensitivity reaction abrogated.36Also, contact hypersensitivity is remarkably suppressed by UVR in patients with xerodermal pigmentosum compared with similarly exposed control subjects.37 The precise mechanism of UVR-induced immunosuppression is unknown but may be related to alterations in antigen-presenting cells. UVR can temporarily deplete the epidermis of its Langerhans cell population. This depletion is associated with a marked alteration in the antigen-presenting cell function of the epidermis, which returns to normal within 24 hours. This restoration of function is not simply due to the replenishment of the Langerhans cells but to the appearance of distinct antigen-presenting cells termed T6Dr-k cells. These T6Dr-t cells have the capacity to stimulate autologous T cells, and this stimulation may be responsible for the increase in suppressor T-cell activity seen after UVR.38-40 In contrast to the effects of whole dorsal skin irradiation, localized "micro"-UVR does not lead to immunosuppression in mice, although it still induces S C C S . ~ ~ Since only limited areas of human skin tend to be exposed to chronic sunlight (arms, face, and legs), the implication of potential UVR-induced immunosuppression in the etiology of human skin cancers remains unclear. The literature on the capacity of sunscreens to modulate UVR-immunosuppressionis limited, with most of the studies having been performed on rodents. Gurish et a142 found that the application of benzophenone and p-aminobenzoic acid and its derivatives prevented erythema and histologic changes but were ineffective in preventing the induction of tumor susceptibility in mice irradiated over the dorsal skin with UVR. A combination of padimate 0 and oxybenzone at sun protection factors 6 and 15 were unable to impede UVR-induced suppression of contact hypersensitivity in mice.43The fact that a sunscreen with a sun protection factor of 15 was no more effective than that of a sunscreen with a sun protection factor of 6 may indicate that the erythema action spectrum does not parallel the action spectrum for immunosuppression. In vitro studies of the effects of UVR on the mixed lymphocyte reaction again demonstrated sunscreen failure to negate immunosuppression.44 These preliminary studies, although limited, suggest that available sunscreens fail to prevent the alterations seen in antigen presentation after UVR exposure.
Adverse Effects of Sunscreens Sunscreens are not without adverse effects. Contact hypersensitivity to sunscreen agents has been reported, albeit rarely.45Elderly patients dependent on UVR-driven cutaneous production of vitamin D, to meet their requirements may be at risk for vitamin D depletion with chronic use of sunscreen^.^^ Colon and breast cancer have been associated with low serum levels of vitamin D, and cal~ i u mand , ~ vitamin ~ D derivatives can suppress the proliferation of melanoma cells in tissue c ~ l t u r e ~ ~how,'~; ever, there is no direct evidence that inhibition of the synthesis of cutaneous vitamin D, by sunscreens increases the risks for skin cancer. Sunscreens also reduce the natural UVR-induced skin changes such as tanning and thickening of the stratum comeum, which because they may change the optical properties of the skin may be expected to protect against further damage; however, recent work suggests that the protection afforded by these changes is minimal.50 The daily application of sunscreens can be expensive. Prices range from one to four dollars per ounce, the daily amount recommended for the average adult,51and this may prove a hardship for individuals on low or fixed incomes. Finally, and probably most important, is the effect that sunscreens may have on user behavior. People may extend their time in the sun without concern for the acute erythematous effects, thus increasing their total UVR exposure.
Conclusion Although solar radiation has been a suspected carcinogen for nearly 100 years, skin tumor occurrence is increasing at a striking rate. Solar UVR is a unique carcinogen with a complex mechanism of action, and the prevention of UVR carcinogenesis remains a daunting and challenging task. Until the mechanism of UVR carcinogenesis is more fully understood, it may prove to be very difficult to assess directly the efficacy of sunscreens in this regard. Regardless of their potential unfavorable effects, it cannot be denied that sunscreens, particularly those that block both UVB and UVA, do undoubtedly decrease the amount of UVR absorbed by the human epidermis and that this is of fundamental importance. Their use is recommended to protect against acute erythema, photoaging, and photocarcinogenesis. Encouragement of sunscreen use should be combined with the conventional advice that subjects should reduce (and not increase) their outdoor activities during periods of intense sunlight and avoid unnatural sources of UVR such as tanning booths. Sunscreen use should be combined with wearing protec-
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tive clothing and hats. Parents should counsel their children to reduce exposure. Elderly subjects using sunscreens may need to take supplements or to increase their dietary intake of vitamin D, . As with any other medication, physicians prescribing sunscreens should be aware of the potential hazards of these seemingly benign topical lotions.
References 1. Unna PG. Die Histopathologic der Hautrankheiten. Berlin: A Hirshwald, 1894. 2. Scotto J, Fears TR, Fraumini JFJr. Incidence of Nonmelanomatous Skin Cancer in the United States. Washington, DC. US Dept of Health and Human Services, National Cancer Institute, Publication #83-2433,1983. 3. Pearl DK, Scotto EL. The anatomical distribution of skin cancer. Int J Dermatol 1986;15:502-6. 4. Blum HF. Carcinogenesis by Ultraviolet Light. Princeton, NJ: Princeton Univ Press, 1959. 5. Henriksen, T, Dahlback, A, Larsen, SHH, Moan, J. Ultraviolet-radiation and skin cancer. Effect of an ozone layer depletion. Photochem Photobiol 1990:51:579-82. 6. Pamsh JA, Jaenicke KF. Erythema and melanogenesis action spectra in normal human skin. Photochem Photobiol 1982;36:187-90. 7. Grange RW, Blackett AD, Matzinger BA, et al. Comparative protective efficacy of UVA and UVB-induced tans against erythema and formation of endonuclease sensitive sites in DNA by UVR in human skin. J Invest Dermatol 1985; 851362-4. 8. Kumakiri M, Hashimoto K, Willis I. Biologic changes due to long wave ultraviolet radiation on human skin: ultrastructural study. J Invest Dermatol 1977;69:392-400. 9. Willis I, Mentor JM, Whyte HJ. The rapid induction of cancers in the hairless mouse utilizing the principle of photo-augmentation. J Invest Dermatol 1981;76:404-8. 10. Staberg B, Wulf HC, Klemp P, Paulsen T, Brodthagen H. The carcinogeniceffect of UVA radiation. J Invest Dermatol 1983;81:517-9. Kligman LH, Akin FJ, Kligman AM. The contributions of 11. UVA and UVB to connective tissue damage in hairless mice. J Invest Dermatol 1985;84:272-6. 12. Pathak MA, Fitzpatrick TB, Frenk E. Evaluation of topical agents that prevent sunburn: superiority of PABA and it‘s esters in ethyl alcohol. N Engl J Med 1969;280:1459-63. 13. Synder DS, May M. Ability of PABA to protect mammalian skin from ultraviolet light-induced tumors and actinic damage. J Invest Dermatol 1975;65:543-9. 14. Parrish JA, Anderson RR, Urbach F, Pitts D. Biological effects of ultraviolet radiation with emphasis on the human responses to long wave UVR. New York Plenum Press, 1978.
DROLET AND CONNOR 575 SUNSCREENS AND WR-INDUCED SKIN CANCER 15. Kaidbey K. The photoprotection potential of the new super potent sunscreens. J Am Acad Dermatol 1990;22:449-52. 16. Sutherland BM, Harber LC, Kochever IE. Pyrimidine dimer formation and repair in human skin. Cancer Res 1980; 40~3181-5. 17. Brennar W, Rauschmier W, Honigsmann H. UVB-induced unscheduled DNA synthesis: dose response and time sequence in human skin. J Invest Dermatol 1982;78:335. 18. Pearse AD, Marks R. Response of human skin to ultraviolet radiation: dissociation of the erythema and metabolic changes following sunscreen protection. J Invest Dermatol 1983;80:19 1 - 4. 19. Hogan DJ, To T, Gran L, Wong D, Lane PR. Risk factors for basal cell carcinoma. Int J Dermatol 1989;28:591-4. 20. Andrassi L, Simons S, Fiorini P, Finniani M. Phenotypic characters related to skin type and minimal erythema dose. Photodermatol 1987;4:43- 6. 21. Young AR, Magnus IA. The sunburn cell in hairless mouse epidermis, quantitative studies with UVA radiation and mono- and bifunctional psoralens. J Invest Dermatol 1982;79:218 - 2 1. 22. DeRijicke S, Heenan M. Decrease of ultraviolet-induced DNA injury in human skin by p-aminobenzoic acid esters. Dermatologica 1989;179:196 -9. 23. Freeman SE, Ley RD, Ley KD. Sunscreens protect against UV-induced formation of pyrimidine h e r s in DNA of human skin. Photodermatol 1988;5:243-7. 24. Freeman SE, Hacham H, Gange RW, Maytum DT, Sutherland JC, Sutherland BM. Wavelength dependence of pyrimidine dimer formation in DNA of human skin irradiated in situ with ultraviolet light. Proc Natl Acad Sci USA 1989;86:5606-9. 25. Hart R, Setlow RB, Woodhead A. Evidence that pyrimidine dimers in DNA can give rise to tumors. Proc Natl Acad Sci USA 1977;74:5574-8. 26. Kligman LH, Akin FJ, Kligman AM. Sunscreens prevent photocarcinogenesis. J Am Acad Dermatol 1980;3:30-5. 27. FIindt-Hansen H, Thune P, Larsen T. The inhibiting effects of PABA on photocarcinogenesis. Arch Dermatol Res 1990;282:38-41. 28. DeGruijl FR, Van der Meer JB, Van der Leun JC. Dose time dependent tumor formation by chronic UV exposure. Phtotchem Photobiol 1986;43:275-84. 29. Cole CA, Davies RE, Forbes PD, DAlosio LC. Comparison of the action spectra for the acute vascular responses to ultraviolet radiation in men and albino hairless mice. Photochem Photobiol 1983;37:623-31. 30. Cole CA, Forbes PD, Davies RE. An action spectrum for photocarcinogenesis. Photochem Photobiol 1986;43:27584. 31. Kligman LH, Kligman AM. The nature of photoaging: it’s prevention and repair. Photodermatol 1986;3:215-27. 32. Sheil AG, Mahoney JI, Horvath JS, et al. Cancer following successful cadaveric donor renal transplant. Transplant Today 198 1 ;6:733.
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33. Spruance S. Pathogenesis of herpes simplex labialis: experimental induction of lesions with ultraviolet light. J Clin Microbiol 1985;22:366-8. 34. Kripke ML. Antigenicity of murine skin tumors induced by ultraviolet light. J Natl Cancer Inst 1974;53:1333-6. 35. Daynes RA, Spellman SW, Woodward JG, Steward DA. Studies into transplant biology of ultraviolet light induced tumors. Transplantation 1977;23:343- 8. 36. Yoshikawa T, Rae V, Bruins-Slot W, Vander Berg JW, Taylor R, Streilein JW. Susceptibility to effects of UVB radiation on induction of contact hypersensitivity as a risk factor for skin cancer in humans. J Invest Dermatol 1990; 95:530-6. 37. Morison WL, Bucana C, Hashem N, Kripke ML, Cleaver JE, German JL. Impaired immune function in patients with xeroderma pigmentosum. Cancer Res 1985;45:3929-31, 38. Cooper KD, Fox P, Neisses G, Katz SK. Effects of ultraviolet radiation on human epidermal cell alloantigen presentation: initial depression of Langerhans cell-dependent function is followed by the appearance of T6dr+ cells that enhance epidermal alloantigen presentation. J Immunoll985; 134~129-37. 39. Baadsgaard 0.In vivo ultraviolet irradiation of human skin results in profound perturbation of the immune system. Arch Dermatol 1991;127:99-109. 40. Daynes RA, Spellman C: Evidence for the generation of suppressor cells by ultraviolet radiation. Cell Immunol 1977;31:182- 7. 41. Menzies SW, Greenoak GE, Reeve VE, Gallagher CH. U1traviolet radiation-induced murine tumors produced in the absence of ultraviolet radiation-induced systemic tumor suppression. Cancer Res 1991;51:2773-9.
42. Gurish MF, Roberts LK, Kruger GL, Daynes RA. The effects of various sunscreening agents on skin damage and the induction of tumor susceptibility in mice subjected to ultraviolet radiation. J Invest Dermatol 1981;76:246-51. 43. Fisher MS, Mentor JM, Willis I. Ultraviolet radiation-induced suppression of contact hypersensitivity in relation to Padimate 0 and Oxybenzone. J Invest Dermatol 1989; 92:337 -41. 44. Mommaas AM, van Pragg MCG, Bavinck JN, Out-Luiting C, Vermeer BJ, Claas FH. Analysis of the protective effect of topical sunscreens on the UVB-radiation-induced suppression of the mixed-lymphocyte reaction. J Invest Dermatol 1990;95:313- 6. 45. Dromgoole SH, Maibach HI. Sunscreening agent intolerance: contact and photocontact sensitization and contact urticaria. J Am Acad Dermatol 1990;22:1068-78. 46. Matsuoka LY, Wortsman J, Hanifan N. Chronic sunscreen use decreases circulatory concentrations of 25-hydroxyvitamin D. Arch Dermatol 1988;124:1802-04. 47. Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight year prospective study. Lancet 1989; ii: 1176 - 8. 48. Frampton RJ, Omond SA, Eisman JA. Inhibition of human cancer cell growth by 1-25-dihydroxyvitamin D3. Cancer Res 1983;43:4443- 7. 49. Deluca HF, Ostrem V. The relationship between vitamin D and cancer. Adv Exp Med Biol 1987;206:413-29. 50. Young AR, Potten CS, Chadwick CA, Murphy GM, Cohen AJ. Inhibition of UV radiation-induced DNA damage by a 5-methoxypsoralen induced tan. Pigment Cell Res 1988;1:350-54. 51. Sunscreens. Consumer Reports 1991;56:400-6.
SUN PROTECTION
Sunscreens and the Prevention of Ultraviolet Radiation-1nd uced Skin Cancer BETH ANN DROLET, MD MICHAEL J. CONNOR, PhD
S
unscreens were first introduced in the 1920s to protect the skin against the short-term effects of sunlight. Today, much of the interest in sunscreensrelates to their potential ability to prevent the deleterious effects of more long-term sun exposure. Of particular concern is their use in the prevention of skin carcinogenesis.Although many physiciansencourage the use of sunscreens in skin cancer prophylaxis, there is a lack of direct evidence showing that sunscreens do prevent skin tumorigenesis in humans. The purpose of this report is to examine and review the available data on the effectiveness of sunscreens in the prevention of nonmelanoma skin cancers in man. The association of skin cancer and sunlight was first reported by Unnal when he noted an increase in the incidence of cutaneous cancers among persons with sundamaged skin. Many subsequent clinical, epidemiologic, and laboratory studies have documented this relation. The incidence of nonmelanoma skin cancers is increased in susceptible populations living in geographic latitudes with greater sun exposures. Additionally, 90% of skin cancers arise in sun-exposed areas of the body such as the arms and f a ~ e .The ~ , importance ~ of the ultraviolet radiation (UVR) component of sunlight in the induction of skin cancer was demonstrated directly in 1959 when Blum‘ induced cutaneouscancers by irradiating mice with ultraviolet light. Although experimental data of the latter kind are only indirectly applicable to the human situation, experimental rodent models have been of instrumental importance in the study of UVR-induced skin carcinogenesis. Because the relation between malignant melanoma and UVR is much less obvious, we will limit our discussion to nonmelanoma skin cancers, recognizing the need
From the joint Veterans Affairs Wudsworth-UCLA Dermatology Truining Program, Department of Medicine, Uniaersity of California, Los Angeles, School of Medicine, Los Angeles, California. Address reprints requests to: Michael j. Connor, PhD, Division of Dermatology, Department of Medicine, UCLA School of Medicine, Los Angeles,
CA 90024.
0 1992 by Elsevier Science Publishing Co., Inc. 0148-0812/92/$5.00
for further evaluation of the relation of sunscreens and UVR to melanoma.
Sunscreens The function of a sunscreen is to block or filter out the harmful components of incident solar radiation. Sunscreens fall into one of two types: physical or chemical. Physical sunscreens are opaque formulations that act as sun blocks reflecting almost all incident UVR. They are often composed of colloidal metal oxides, particularly zinc. Although extremely efficient, physical sunscreens are of limited value because of their poor cosmetic acceptability. Chemical sunscreens are preparations that contain one or more chromophores that are usually translucent to visible light but selectively absorb UVR. Because chemical sunscreens are more cosmetically acceptable they are used more frequently than physical sunscreens. The most common chromophores used in chemical sunscreens are 1)derivativesof p-aminobenzoic acid (PABA), 2)cinnamates, 3)benzophenones, 4) salicylates, and 5)anthranilates. The Food and Drug Administration has also approved two sunscreens containing 4-tbutyl-4’-methoxydibenzoylmethane (Parsol 1789), an agent that filters out long-wave radiation (ultraviolet A [WA]). These agents are often used in combination to produce products with a broader range of protection.
Solar Spectrum Solar radiation that reaches sea level includes wavelengths of 290 to 1800 nm. Actinic solar wavelengths, that is, those implicated in causing sunburn, photoaging, and photocarcinogenesis,are further divided into the ultraviolet C (WC) (200 to 290 nm), ultraviolet B (UVB) (290to 320 nm),and UVA (320to 400 nm) regions. Solar UVC is aborbed by ozone and other gases in the upper atmosphere and does not reach the earth’s surface; however, UVC is also emitted by artificial sources such as germicidal lamps and mercury arc lamps. Solar UVB, the 571
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erythemic band, is traditionally thought to include the most damaging actinic energy. A high proportion of solar UVB is absorbed by ozone in the upper stratosphere, but the small proportion that does reach the surface of the earth is primarily responsible for the production of sunlight-induced erythema, photoaging, and photocarcinogenesis. The amount of solar UVB reaching a given point on the earth's surface will of course depend on the angle of incidence of the light (the closer the sun is to the horizon, the smaller the angle of incidence and the longer the stratospheric column of air that the light will have to pass through). Both UVB levels and squamous cell carcinoma (SCC) incidence show a strong dependency on latitude.5 Evidence that chemical pollutants are depleting the protective ozone layer has led to the widely held belief that the incidence of skin cancer will increase because of a likely increase in incident UVB. Recently, it has become clear that the UVA wavelengths are also harmful to human skin. Because of the longer wavelength, UVA radiation penetrates deep into the dermis. Solar UVA has been documented to produce erythema,'j immediate pigment darkening and delayed melan~genesis,~ and elastosis and other dermal connective tissue damage.8 Although UVA-induced melanogenesis has been hypothesized to be protective against UVB-induced damage, there is little evidence to support this. In fact, UVA radiation has been shown to augment UVB carcinogenesis9Joand in high doses has been found to be carcinogenic to mice." This potential interaction between UVA and UVB emphasizes the need for sunscreens that will provide protection against both UVA and UVB radiation. Indeed, many of the newer commercial sunscreens are formulated with a combination of UVA- and UVB-absorbing chromophores.
Erythema Erythema is the most obvious component of acute skin phototoxicity, and sunscreens are defined by their efficacy in preventing erythema.12J3The minimal amount of UVR needed to induce erythema, ie, the minimal erythema dose, forms the basis for comparing and evaluating various sunscreens. The minimal erythema dose in caucasions varies from 0.02 to 0.07 J/cm2, which is equivalent to 10 to 35 minutes of noonday sun in New Jersey in June." The potency of a sunscreen is indicated by its sun protection factor, or SPF, which is the ratio of the UVB dose required to induce one minimal erythema dose in the presence of the sunscreen to the minimal erythema dose without the sunscreen. Since the sun protection factor is determined by the minimal erythema dose, predicting the amount of UVB protection a product provides against nonerythemic end
points requires the questionable assumption that the action spectrum of erythema parallels that of other actinic responses. That is, that the wavelengths that cause erythema are the same wavelengths responsible for other actinic effects. Some authors suggest that erythema is a relatively insensitive technique for assessing suns c r e e n ~and , ~ ~phototoxic reactions have been shown to occur at suberythemic UVR doses."jJ7 Pearse and MarkP showed that some of the UVR-induced metabolic changes in the skin are not prevented by the application of a sunscreen despite the ability of the sunscreen to completely prevent the erythematous response. This may imply that wavelengths other than those capable of producing erythema are causing metabolic changes and that these wavelengths are not absorbed by the current sunscreen agents. Whether these metabolic changes are involved in the induction of cutaneous cancers remains unknown. A questionnaire survey done to assess the risk factors for basal cell carcinoma (BCC)found a history of sunburn to be a significant relative risk factor. Additional relative risk factors for skin cancer include red/blonde hair color, prominent freckling in childhood, and light skin ~ 0 l o r . l ~ These same phenotypic characters also correlate with low minimal erythema dose values.20Thus, these epidemiologic data suggest that erythema susceptibility may well be predictive of skin cancer susceptibility and that the sun protection factor may be a coarse but viable indicator of sunscreen ability to prevent UVR-carcinogenesis.
Sunburn Cells Epidermis from UVR sites typically contains small numbers of histologically derranged cells referred to as sunbum cells. They are thought to arise when keratinocytes that are in a sensitive stage of the cell cycle, such as the S phase, where the replicating DNA is particularly vulnerable, sustain a lethal dose of UVR. Sunburn cells are induced at levels of UVR that are much less than one minimal erythema dose21; thus, they may be a more sensitive indicator of UVR-induced damage than erythema. The production of sunbum cells has been shown to be significantly reduced by sunscreens." As is the case with erythema, the correlation between the induction of sunburn cells and tumorigenicity of UVR is unknown. Because sunburn cells have sustained a lethal amount of UVR, they lose their ability to replicate and thus their carcinogenic potential; however, they may be a good way to approximate the total amount of UVR injury sustained by the tissue and thus may be used as a measure of the amount of energy a specific sunscreen may absorb effectively. The fact that sunscreens do decrease the number of sunburn cells after UVR exposure further supports their
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shielding effect and, theoretically, their anticarcinogenic capacity.
Unscheduled DNA Synthesis Sunscreens have been demonstrated to be effective in preventing unscheduled DNA synthesis in human epidermal cells irradiated with UVR.22Unscheduled DNA synthesis occurs when pyrimidine and purine precursors are incorporated into DNA outside the normal S phase of the cell cycle and reflects DNA repair processes. Sunscreens with a sun protection factor of 15 have been shown to inhibit UVR induction of pyrimidine dimers between adjacent DNA strands in human skin in V ~ V O Recently, the action spectrum for the induction of pyrimidine dimers has been determined,24and this spectrum closely matches the erythema action spectrum. There is no direct evidence that these photoproducts are responsible for UVR-induced carcinogenesis, but accumulation of DNA injuries has been shown to be both mutagenic and tumorigenic as well as lethal to affected cells.25 Patients afflicted with xeroderma pigmentosum, an autosomal recessive disease in which there is a defect in the DNA excision repair mechanism, are known to be extremely susceptible to UVR-induced tumors. This further supports the theory that photodamage to DNA plays a major role in UVR carcinogenesis. Sunscreens and the avoidance of UVR have been instrumental in protecting patients with xeroderma pigmentosum from cutaneous neoplasms. Assuming that DNA damage is the principal factor in solar-induced carcinogenesis, the ability of the sunscreen to prevent unscheduled DNA synthesis provides persuasive evidence that these agents may prevent carcinogenesis.
Rodent Studies The most convincing evidence that sunscreens do offer protection against skin cancers comes from laboratory studies using mice. In the 1950s Blum demonstrated that cancers could be induced in the skin of albino mice by UVR. Kligman et alZ6found that sunscreens containing 2% octyldimethyl p-aminobenzoic acid (sun protection factor 2) and 7% octyldimethyl p-aminobenzoic acid (sun protection factor 5) could profoundly inhibit the induction of skin tumors by UVR in hairless albino and lightly pigmented mice. Protective effects were even seen with a sun protection factor 2 sunscreen. These findings were later confirmed in a similar study using 5% p-aminobenzoic acid on hairless, lightly pigmented mice.27 Since analogous studies cannot be performed on humans, can we prudently extrapolate these animal data
. ~
to the human situation? In both mouse and human skin, UVR carcinogenesis is a dose-dependent process.28The action spectra for the acute erythematous response in mice skin is similar to that in humansz9 and this same band (290 to 320 nm) has been shown to be tumorigenic in mice.30Likewise, chronic UVR-induced dermal histologic and biochemical changes such as increased elastosis and increases in collagen type I11 are similar in both mice and humans.31 However, there are some major differences between the experimentalrodent model and true human exposure. The life span of the mouse is 2 years, and UVR-induced tumors clearly appear in mice at a greatly accelerated rate. This increased susceptibility is not really surprising, since ~ the mouse is normally a hirsute animal that is largely nocturnal, and murine DNA photodamage repair systems show some differences from those found in humans. Second, in the experimental situation the mice are subjected to multiple treatments with very high daily doses of UVR (often much greater than one minimal erythema dose per day), an event unlikely to occur in humans. Finally, the use of artificial light sources introduces another significant variable. Although these experimental models are extremely suggestive of the preventative capability of sunscreens, one must consider these variables when extrapolating these conclusions to humans.
Sunscreens and UVR-Induced Immunosuppression There has been an increasing interest in the effects of UVR on the cutaneous immune system and the role that this may play in UVR tumorigenicity. By damaging epidermal DNA, and thus increasing the risk of an unfavorable change in the genotype, UVR can clearly act as a tumor initiator; however, UVR has immunosuppressive effects that could, theoretically, render a person unable to mount a local response to malignant cells. Thus, UVR exposure may promote tumor expression and growth because of its immunosuppressive properties. The observation that transplant patients on long-term immunosuppressive drugs are at a profound increase risk ~ ~ dramatic support for the for developing S C C S offers importance of a competent immune system in minimizing risks for skin cancer. Sunlight has long been known to reactivate herpes simplex virus. S p r u a n ~ edemon~~ strated a definite dose-dependent effect of UVR and the induction of the herpes simplex virus. Additionally, mice irradiated with high doses of UVR are unable to reject highly antigenic transplanted UVR-induced turn or^.^^,^^
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These tumors incite an immune response, leading to rapid rejection in nonirradiated mice. Contact hypersensitivity is also suppressed by UVR in both rodents and humans. Yoshikawa and coworkers36postulated that UVR suppresses contact hypersensitivity only in genetically susceptible patients. Of interest, they found that patients with a history of nonmelanoma skin cancer were more likely to have the contact hypersensitivity reaction abrogated.36Also, contact hypersensitivity is remarkably suppressed by UVR in patients with xerodermal pigmentosum compared with similarly exposed control subjects.37 The precise mechanism of UVR-induced immunosuppression is unknown but may be related to alterations in antigen-presenting cells. UVR can temporarily deplete the epidermis of its Langerhans cell population. This depletion is associated with a marked alteration in the antigen-presenting cell function of the epidermis, which returns to normal within 24 hours. This restoration of function is not simply due to the replenishment of the Langerhans cells but to the appearance of distinct antigen-presenting cells termed T6Dr-k cells. These T6Dr-t cells have the capacity to stimulate autologous T cells, and this stimulation may be responsible for the increase in suppressor T-cell activity seen after UVR.38-40 In contrast to the effects of whole dorsal skin irradiation, localized "micro"-UVR does not lead to immunosuppression in mice, although it still induces S C C S . ~ ~ Since only limited areas of human skin tend to be exposed to chronic sunlight (arms, face, and legs), the implication of potential UVR-induced immunosuppression in the etiology of human skin cancers remains unclear. The literature on the capacity of sunscreens to modulate UVR-immunosuppressionis limited, with most of the studies having been performed on rodents. Gurish et a142 found that the application of benzophenone and p-aminobenzoic acid and its derivatives prevented erythema and histologic changes but were ineffective in preventing the induction of tumor susceptibility in mice irradiated over the dorsal skin with UVR. A combination of padimate 0 and oxybenzone at sun protection factors 6 and 15 were unable to impede UVR-induced suppression of contact hypersensitivity in mice.43The fact that a sunscreen with a sun protection factor of 15 was no more effective than that of a sunscreen with a sun protection factor of 6 may indicate that the erythema action spectrum does not parallel the action spectrum for immunosuppression. In vitro studies of the effects of UVR on the mixed lymphocyte reaction again demonstrated sunscreen failure to negate immunosuppression.44 These preliminary studies, although limited, suggest that available sunscreens fail to prevent the alterations seen in antigen presentation after UVR exposure.
Adverse Effects of Sunscreens Sunscreens are not without adverse effects. Contact hypersensitivity to sunscreen agents has been reported, albeit rarely.45Elderly patients dependent on UVR-driven cutaneous production of vitamin D, to meet their requirements may be at risk for vitamin D depletion with chronic use of sunscreen^.^^ Colon and breast cancer have been associated with low serum levels of vitamin D, and cal~ i u mand , ~ vitamin ~ D derivatives can suppress the proliferation of melanoma cells in tissue c ~ l t u r e ~ ~how,'~; ever, there is no direct evidence that inhibition of the synthesis of cutaneous vitamin D, by sunscreens increases the risks for skin cancer. Sunscreens also reduce the natural UVR-induced skin changes such as tanning and thickening of the stratum comeum, which because they may change the optical properties of the skin may be expected to protect against further damage; however, recent work suggests that the protection afforded by these changes is minimal.50 The daily application of sunscreens can be expensive. Prices range from one to four dollars per ounce, the daily amount recommended for the average adult,51and this may prove a hardship for individuals on low or fixed incomes. Finally, and probably most important, is the effect that sunscreens may have on user behavior. People may extend their time in the sun without concern for the acute erythematous effects, thus increasing their total UVR exposure.
Conclusion Although solar radiation has been a suspected carcinogen for nearly 100 years, skin tumor occurrence is increasing at a striking rate. Solar UVR is a unique carcinogen with a complex mechanism of action, and the prevention of UVR carcinogenesis remains a daunting and challenging task. Until the mechanism of UVR carcinogenesis is more fully understood, it may prove to be very difficult to assess directly the efficacy of sunscreens in this regard. Regardless of their potential unfavorable effects, it cannot be denied that sunscreens, particularly those that block both UVB and UVA, do undoubtedly decrease the amount of UVR absorbed by the human epidermis and that this is of fundamental importance. Their use is recommended to protect against acute erythema, photoaging, and photocarcinogenesis. Encouragement of sunscreen use should be combined with the conventional advice that subjects should reduce (and not increase) their outdoor activities during periods of intense sunlight and avoid unnatural sources of UVR such as tanning booths. Sunscreen use should be combined with wearing protec-
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tive clothing and hats. Parents should counsel their children to reduce exposure. Elderly subjects using sunscreens may need to take supplements or to increase their dietary intake of vitamin D, . As with any other medication, physicians prescribing sunscreens should be aware of the potential hazards of these seemingly benign topical lotions.
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DROLET AND CONNOR 575 SUNSCREENS AND WR-INDUCED SKIN CANCER 15. Kaidbey K. The photoprotection potential of the new super potent sunscreens. J Am Acad Dermatol 1990;22:449-52. 16. Sutherland BM, Harber LC, Kochever IE. Pyrimidine dimer formation and repair in human skin. Cancer Res 1980; 40~3181-5. 17. Brennar W, Rauschmier W, Honigsmann H. UVB-induced unscheduled DNA synthesis: dose response and time sequence in human skin. J Invest Dermatol 1982;78:335. 18. Pearse AD, Marks R. Response of human skin to ultraviolet radiation: dissociation of the erythema and metabolic changes following sunscreen protection. J Invest Dermatol 1983;80:19 1 - 4. 19. Hogan DJ, To T, Gran L, Wong D, Lane PR. Risk factors for basal cell carcinoma. Int J Dermatol 1989;28:591-4. 20. Andrassi L, Simons S, Fiorini P, Finniani M. Phenotypic characters related to skin type and minimal erythema dose. Photodermatol 1987;4:43- 6. 21. Young AR, Magnus IA. The sunburn cell in hairless mouse epidermis, quantitative studies with UVA radiation and mono- and bifunctional psoralens. J Invest Dermatol 1982;79:218 - 2 1. 22. DeRijicke S, Heenan M. Decrease of ultraviolet-induced DNA injury in human skin by p-aminobenzoic acid esters. Dermatologica 1989;179:196 -9. 23. Freeman SE, Ley RD, Ley KD. Sunscreens protect against UV-induced formation of pyrimidine h e r s in DNA of human skin. Photodermatol 1988;5:243-7. 24. Freeman SE, Hacham H, Gange RW, Maytum DT, Sutherland JC, Sutherland BM. Wavelength dependence of pyrimidine dimer formation in DNA of human skin irradiated in situ with ultraviolet light. Proc Natl Acad Sci USA 1989;86:5606-9. 25. Hart R, Setlow RB, Woodhead A. Evidence that pyrimidine dimers in DNA can give rise to tumors. Proc Natl Acad Sci USA 1977;74:5574-8. 26. Kligman LH, Akin FJ, Kligman AM. Sunscreens prevent photocarcinogenesis. J Am Acad Dermatol 1980;3:30-5. 27. FIindt-Hansen H, Thune P, Larsen T. The inhibiting effects of PABA on photocarcinogenesis. Arch Dermatol Res 1990;282:38-41. 28. DeGruijl FR, Van der Meer JB, Van der Leun JC. Dose time dependent tumor formation by chronic UV exposure. Phtotchem Photobiol 1986;43:275-84. 29. Cole CA, Davies RE, Forbes PD, DAlosio LC. Comparison of the action spectra for the acute vascular responses to ultraviolet radiation in men and albino hairless mice. Photochem Photobiol 1983;37:623-31. 30. Cole CA, Forbes PD, Davies RE. An action spectrum for photocarcinogenesis. Photochem Photobiol 1986;43:27584. 31. Kligman LH, Kligman AM. The nature of photoaging: it’s prevention and repair. Photodermatol 1986;3:215-27. 32. Sheil AG, Mahoney JI, Horvath JS, et al. Cancer following successful cadaveric donor renal transplant. Transplant Today 198 1 ;6:733.
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33. Spruance S. Pathogenesis of herpes simplex labialis: experimental induction of lesions with ultraviolet light. J Clin Microbiol 1985;22:366-8. 34. Kripke ML. Antigenicity of murine skin tumors induced by ultraviolet light. J Natl Cancer Inst 1974;53:1333-6. 35. Daynes RA, Spellman SW, Woodward JG, Steward DA. Studies into transplant biology of ultraviolet light induced tumors. Transplantation 1977;23:343- 8. 36. Yoshikawa T, Rae V, Bruins-Slot W, Vander Berg JW, Taylor R, Streilein JW. Susceptibility to effects of UVB radiation on induction of contact hypersensitivity as a risk factor for skin cancer in humans. J Invest Dermatol 1990; 95:530-6. 37. Morison WL, Bucana C, Hashem N, Kripke ML, Cleaver JE, German JL. Impaired immune function in patients with xeroderma pigmentosum. Cancer Res 1985;45:3929-31, 38. Cooper KD, Fox P, Neisses G, Katz SK. Effects of ultraviolet radiation on human epidermal cell alloantigen presentation: initial depression of Langerhans cell-dependent function is followed by the appearance of T6dr+ cells that enhance epidermal alloantigen presentation. J Immunoll985; 134~129-37. 39. Baadsgaard 0.In vivo ultraviolet irradiation of human skin results in profound perturbation of the immune system. Arch Dermatol 1991;127:99-109. 40. Daynes RA, Spellman C: Evidence for the generation of suppressor cells by ultraviolet radiation. Cell Immunol 1977;31:182- 7. 41. Menzies SW, Greenoak GE, Reeve VE, Gallagher CH. U1traviolet radiation-induced murine tumors produced in the absence of ultraviolet radiation-induced systemic tumor suppression. Cancer Res 1991;51:2773-9.
42. Gurish MF, Roberts LK, Kruger GL, Daynes RA. The effects of various sunscreening agents on skin damage and the induction of tumor susceptibility in mice subjected to ultraviolet radiation. J Invest Dermatol 1981;76:246-51. 43. Fisher MS, Mentor JM, Willis I. Ultraviolet radiation-induced suppression of contact hypersensitivity in relation to Padimate 0 and Oxybenzone. J Invest Dermatol 1989; 92:337 -41. 44. Mommaas AM, van Pragg MCG, Bavinck JN, Out-Luiting C, Vermeer BJ, Claas FH. Analysis of the protective effect of topical sunscreens on the UVB-radiation-induced suppression of the mixed-lymphocyte reaction. J Invest Dermatol 1990;95:313- 6. 45. Dromgoole SH, Maibach HI. Sunscreening agent intolerance: contact and photocontact sensitization and contact urticaria. J Am Acad Dermatol 1990;22:1068-78. 46. Matsuoka LY, Wortsman J, Hanifan N. Chronic sunscreen use decreases circulatory concentrations of 25-hydroxyvitamin D. Arch Dermatol 1988;124:1802-04. 47. Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight year prospective study. Lancet 1989; ii: 1176 - 8. 48. Frampton RJ, Omond SA, Eisman JA. Inhibition of human cancer cell growth by 1-25-dihydroxyvitamin D3. Cancer Res 1983;43:4443- 7. 49. Deluca HF, Ostrem V. The relationship between vitamin D and cancer. Adv Exp Med Biol 1987;206:413-29. 50. Young AR, Potten CS, Chadwick CA, Murphy GM, Cohen AJ. Inhibition of UV radiation-induced DNA damage by a 5-methoxypsoralen induced tan. Pigment Cell Res 1988;1:350-54. 51. Sunscreens. Consumer Reports 1991;56:400-6.
