REVIEW
SUNSCREENS, UVA, AND CUTANEOUS MALIGNANCY: ADDING EUEL TO THE EIRE JOHN DOBAK, M.D., AND FU-TONG LIU, M . D . , P H . D .
The incidence of cutaneous malignant melanoma (CMM) rose more than 100% in the last decade, making it the second fastest growing cancer rate in the country.' In an attempt to explain this, two epidemiologists, Drs. Frank and Cedric Garland, have made some controversial suggestions that sunscreens may be playing a role.^ Their hypothesis is that the correlation between the growth of CMM incidence and the introduction and increased use of sunscreens may indicate possible CMM induction by sunscreens. The Carlands' work on low serum vitamin D levels and increased cancer risk^''* led them to speculate that inhibition of vitamin D production, combined with intense exposure to ultraviolet A radiation (UVA), both of which are incident to sunscreen use,^'*" places persons at greater risk for CMM. Not surprisingly, the suggestion that sunscreens play a role in the induction of malignancy has come under harsh criticism from many dermatologists and photobiologists.^ Without arguing the validity of the Garlands' views or accepting the belief that sunscreens may play a role in inducing skin cancer, there are some interesting points to consider, in particular, the lack of complete protection from UVA offered by existing sunscreens and the phenomenon of UVA possibly photoaugmentation contributing to sun damage. An examination of the actual protection provided by "broad spectrum" sunscreen formulations on the market suggests that current labeling claims may be giving the consumer a false sense of security.
of ultraviolet light. The first sunscreen agent employed in the United States, in the late 1930s, was homomenthyl salicylate, a UVB absorbing compound.' Most product development since has focused on protection against UVB.^ Until recently, the basic goal of sunscreen formulation was to protect against damaging UVB rays, while transmitting the tanning UVA rays, however, substantial evidence has accumulated that UVA also has deleterious effects, indicating a need to screen against these rays as well.'' In the United States, many sunscreen formulations claim UVA protection, but in fact none of them block all UVA rays.''''^'^ Figure 1 shows the absorbance spectrum of a commercially available sunscreen preparation, containing 7% (0.25 M) octyl dimethyl-PABA, 5% (0.20 M) octyl salicylate, and 3% (0.13 M) oxybenzone, which would give an SPF of 15 or higher depending on the base used."' The curve depicts the percentage of radiation absorbed by a 0.02 mm thick layer of the product, a thickness recommended by the FDA to be applied to the skin for SPF testing and sunscreen use."* Absorption of incident UVA radiation declines to 50% at 360 nm, and falls to near 0% just beyond 370 nm so that nearly half of the UVA range is ineffectively screened. Oxybenzone is often touted to be a UVA blocking sunscreen, but analysis of oxybenzone's absorption spectrum (Fig. 2) indicates that it does not absorb above 360 nm. Thus many products employing oxybenzone as a UVA filter fail to protect against the longer wavelengths of the UVA range.
SUNSCREENS AND UVA
UVA AND CARCINOGENESIS
Ultraviolet A (range 3 2 0 - 4 0 0 nm)^-' was initially thought to contribute little to sun-elicited skin damage.* The more energetic ultraviolet B (UVB) rays (range 2 8 0 320 nm),** which are the primary cause of sunburn erythema,"' were presumed to be the only damaging form
Uultraviolet A is capable of causing various types of structural damage to DNA, which are consistent with transformation induction." Included are dimer formation, DNA-protein crosslinks, strand breaks, and oxidation reactions caused by UVA-induced free radical formation;^""'^' furthermore, UVA is carcinogenic in animals.^^^^'' • Van Weedlan et al. irradiated 24 mice with 22 J/cmVday of UVA. After approximately 350 days of exposure, more than 90% of the mice showed skin tumors; 60% were non-melanoma malignancies.^"* While no melanomas were found, no animal model has yet been developed that allows CMM to be consistently induced solely by ultraviolet radiation.^''
From the Division of Dermatology, Department of Medicine, University of California School of Medicine, San Diego, California. Address for correspondence: Fu-Tong Liu, M.D.,Ph.D., Division of Dermatology, Department of Medicine, University of California at San Diego, San Diego, CA 92093. 544
Sunscreens Dobak and Liu
% Absorbance 100
270 280 290 300 310 320 330 340 350 360 370 380 390 400 410
Wavelength (nm) Figure 1. Theoretical absorbance of 7% octyl dimethyl PABA, 5% octyl salicylate, and 3% oxybenzone through a 0.02 mm thick layer.
SUNSCREENS AND MALIGNANCY
The use of sunscreens and their ability to delay immediate sunburn erythema has allowed sun exposure time to be dramatically increased. Without adequate screening of UVA, this long exposure time has made it possible for a sunbather to absorb a large dose of UVA in a single day (up to 100 J/cm^).''-"-'^ With the minimal dose of UVA necessary to induce erythema being 18 J/cm^ at 385 nm,^'' this dose is clearly significant. It is also important to note that the depth of penetration of UVA through the stratum corneum and epidermis increases steadily as one approaches the long end of the UVA range.^*' Thus, a large percentage of radiation of wavelengths greater than 360 nm is able to pass through the epidermis, and potentially damage dermal structures such as melanocytes, fibroblasts, and collagen. Perhaps even more important than direct carcinogenesis is the effect of UVA photoaugmentation. Exposure to UVA radiation alone, following combined exposure to UVB and UVA, has been shown to potentiate, or augment, skin damage caused by the combined irradiation.^' The sequence of exposure can be reversed, and the enhanced damage still occurs.'" This augmentative effect of UVA has been found to extend to tumor induction. Staberg et al. observed a significant increase (P < 0.05) in malignant squamous cell carcinoma incidence in mice irradiated with artificial sunlight (uvA and B rays) followed by UVA light alone, over mice irradiated with artificial sunlight only.^^'" It is conceivable that reduction of Langerhans' cells by the UVA radiation" results in inefficient immunodestruction of early neoplastic cells, thereby allowing damage incited by the initial combined exposure to be expressed in the form of tumors.
A sunbather who intermittently uses a UVB sunscreen mimics this laboratory experiment, and perhaps places him/herself at greater risk for sun-induced skin damage and malignancy. Current theory regarding ultraviolet light and the risk of melanoma holds that the number of severe sunburns that a person receives, particularly at a young age, is an important predisposing factor for the later development of melanoma.^^"-''* Additional exposure to UVA associated with use of a sunscreen in the days following a sunburn would again be analogous to Staberg's experimental conditions. Perhaps sunscreens and photoaugmentation are a link between sunburns and melanoma. Persons who combine suntan parlor .exposure with sunbathing also simulate the laboratory exposure. It will be interesting to see what the future incidence of melanoma and other cutaneous malignancies is in the solarium cohort.^'-'^ The photosensitizing properties of some sunscreens may be another link between sunscreens and malignancy. In most sunscreens, the key ingredients absorb the UV light and are converted to excited states. Thus energy from UV radiation is not simply "blocked" by these sunscreens but is converted into other chemically reactive forms. Although most of the excited state molecules, especially those at the outer extracutaneous layers, dissipate their energy uneventfully, some of them may transfer the energy to molecular components in the skin and thereby trigger chemical reactions. For example, if a sunscreen component penetrates into the keratinocytes and subsequently is converted to the excited state by absorbing UV light, it can theoretically transfer the excited state energy to the thymine moieties in DNA 545
International Journal of Dermatology Vol. 31, ND. 8, August 1992
Ab8orbance
260 270 280 290 300 310 320 330 340 350 360 370 380 390 400
Wavelength (nm) Figure 2. Absorbance spectrum of oxybenzone. and result in thymine dimer formation. This type of photosensitized thymine dimer formation has been well established.^^••'^ Although repair mechanisms exist to correct photochemically induced damages in DNA, mutations may eventually result, culminating in neoplastic transformation, especially in individuals with low efficiency in repair processes. The excited states of sunscreen components can also transfer energies or electrons to molecular oxygen to generate singlet oxygen, as well as superoxide radical anion, hydrogen peroxide, and hydroxyl radicals.^'' These highly reactive oxygen species can react with various cell components, resulting in cell damage and, conceivably, mutations. These mechanisms have been considered the bases for cutaneous phototoxic reaction of chemicals^* and presumably can be identified when sunscreens are tested for adverse reactions; however, it is important to point out that various chemical reactions sensitized by sunscreens may not be discernible as acute toxic cutaneous reactions, and carcinogenesis may result only after accumulated insults. A number of factors must be taken into consideration in assessment of the safety of sunscreens with regard to their possible contribution to induction of cutaneous malignancy as a result of their potential photosensitizing activity. These include (1) the penetration of the sunscreen components into inter- or intra-cellular space in epidermis and dermis; (2) the capacity of these compounds to absorb UV radiation (and be converted to the excited states); (3) the energies of the excited states of the sunscreens relative to potential acceptor molecules in the skin and identification of such acceptor molecules; and (4) the presence in the sunscreens or in the skin of chemicals capable of quenching the excited state energy of the sunscreen components or reactive oxygen species.
NEW SUNSCREENS AND EXISTING PROBLEMS
Whether or not sunscreens have played a role in induction of cutaneous malignancy, there is clearly a need to develop products that adequately protect against uvA rays. UVA radiation can incite the clinical signs of many photosensitive diseases and drug-induced photosensitivities.''"'" UVA also contributes to photoaging**^ and erythema.'*^'^^ Many sunscreens in the United States are inadequate protectors against UVA. Dibenzoylmethane derivatives, Eusolex 8020™ and Parsol 1789™, are true UVA screening agents and do provide better UVA protection. Although more extensively used in Europe, Parsol is now available in the United States (Photopjg^rMj. however, Kaidbey et al. have reported that these products absorb only 35% of incident uvA radiation.'' This is most likely due to instability of the compounds. Defiander and Lang report a 36% reduction in absorbance capacity of Parsol 1789 and a 50% reduction in absorbance capacity of Eusolex 8020 within 15 minutes of exposure to ultraviolet light.'*'' There have been problems with contact sensitivity and other allergies to products containing these agents.'*''"'** Adverse reactions to some of the compounds, particularly Eusolex 8020"^, have led to their removal from some European formulas.'*' The recent emphasis in the sunscreen industry in the United States has been the development of ultra high SPF sunscreens (SPF >2O) for which "broad spectrum" UVA protection is claimed; however, such formulations expose the user to numerous chemicals at very high concentrations and are expensive, while only modestly extending coverage into the UVA range.^^ The FDA is now questioning the efficacy of these products and will regulate labeling claims.^' A problem faced by the FDA is development of standardized testing methods for asS46
Sunscreens Dobak and Lm
sessing UVA protection. The 1978 FDA monograph on the efficacy of sunscreen preparations makes no provisions for UVA-absorbing agents, and cites no methods to assess protection against uvA." Methods used to measure uVB protection (SPF determination) are commonly used to assess UVA protection as well, but the skin is often photosensitized to UVA with 8-methoxypsoralen.""'''* SPi-s determined in sensitized skin are significantly higher than those determined in nonsensitized skin.^^ Much of the testing done with Photoplex'''^' involved psoralen skin sensitization, making it difficult to determine its true UVA blocking potential. Furtherore, SPFs can vary with the endpoint selected for testing (erythema, immediate pigment darkening, delayed pigment darkening);"''' for example, the SPF for oxybenzone was found to be lower when immediate pigment darkening (IPD) rather than erythema was used as the endpoint. This discrepancy reflects oxybenzone's inability to protect against long wavelength UVA, the rays primarily responsible for IPD.^'' Thus IPD may be a more valid way to determine protection against UVA, because it measures protection against longer UVA wavelengths. Improvement of UVA protection in sunscreen formulations is of the utmost concern. Existing formulas are well suited to protect the user against the most actively carcinogenic and damaging UVB rays, however, with improved sunscreen use compliance, it is conceivable that the existing formulations may ultimately contribute to actinic damage through intense prolonged UVA exposure and photoaugmentation. Claims of UVA protection or "broad spectrum" coverage need to be substantiated through the adoption of a standard reproducible testing method.
8.
Parrish J, Anderson R, Urbach F, Pitts D, eds. UV-A: biological effects of ultraviolet radiation with emphasis on human response to longwave ultraviolet. New York: Plenum Press, 1978.
9.
Creiter F, Bilek P, Doskoczil S. History of sunscreens and the rationale for their use. In: Frost P, Horowitz S, eds. Principles of cosmetics for the dermatologist. St. Louis: Mosby, 1982; 187.
10.
Parrish J, Jaenicke K, Anderson R. Erythema and melanogenesis action spectra of normal human skin. Photochem Photobiol 1982; 6:1 87-191.
11.
Pathek M. Sunscreens and their use in the preventative treatment of sunlight-induced skin damage. J Dermatolog Surg Oncol 1987; 13:739-750.
12.
Diffey B, Farr P. An evaluation of sunscreens in patients with broad-action spectrum photosensitivity. Br J Dermatol 1985; 112:83-86.
13.
Kaidbey K, Cange W, Comparison of methods for assessing photoprotection against ultraviolet A in vivo. J Am Acad Dermatol 1987; 16:346-353.
14.
Knox J, Cuin J, Cockerell F. Benzophenones, ultraviolet light absorbing agents. J Invest Dermatol 1957; 29: 435-444.
15.
Lowe N, Dromgoole S, Sefton J, et al. Indoor and outdoor efficacy of a broad spectrum sunscreen against ultraviolet A radiation in psoralen sensitized subjects. J Am Acad Dermatol 1983; 9:354-360.
16.
Cange W, Soparkar A, Matzinger F, et al.. Ffficacy of a sunscreen containing butyl methoxydibenzoylmethane against ultraviolet A radiation in photosensitized subjects. J Am Acad Dermatol 1986; 15:494-499.
17.
Jarratt M, Hill M, Smiles K. Topical protection against longwave ultraviolet A. ] Am Acad Dermatol 1983; 9: 354-360.
18.
Food and Drug Administration sunscreen drug products for over-the-counter human use. Federal Register 1978; 43:38206-38269.
19.
Peak M, Peak J. Molecular photobiology of UVA. In: Urbach F, Cange R, eds. The biological effects of uvA radiation. New York: Praeger, 1986; 42.
20.
Chew S, Deleo V, Harber L. The effect of UVA radiation on DNA synthesis of guinea pig skin. Photochem Photobioll 988; 47:383-389.
21.
Freeman S, Cange R, Matzinger E, et al. Production of pyrimidine dimers in skin of humans exposed to UVA. Photochem Photobiol 1986; 43 (suppl.):71.
Acknowledgment: Dr. Robert Coltz reviewed this manuscript.
REEERENCES 1.
Lew R, Koh H, Sober A. Fpidemiology of cutaneous melanoma. Dermatol Clin 1985; 3:257-269.
2.
Skolnick A. Sunscreen protection controversy heats up. JAMA 1991; 265:3218-3220.
22.
3.
Carland C, Comstock C, Carland F, et al. Serum 25hydroxyvitamin D and colon cancer: eight year prospective study. Lancet 1989; ii:1176-1178.
Staberg B, Christian W, Poulsen T, et al. Carcinogenic effect of sequential artificial sunlight and UVA irradiation in hairless mice. Arch Dermatol 1983; 119:641-643.
23.
Staberg B, Christian W, Kemp P, et al. The carcinogenic effect of UVA irradiation. J Invest Dermatol 1983; 81: 517-519.
24.
Van Weedlen H, Grujil F, Van der Leun J. Carcinogenesis by UVA with an attempt to assess the carcinogenic risks of tanning with UVA and UVB. In: Urbach F, Cange R, eds. The biological effects of UVA radiation. New York: Praeger, 1986.
25.
Passchier N, Bosnjakovic B, eds. Human exposure to ultraviolet radiation: risks and regulations. Amsterdam: Exerpta Medica International Congress Series, 1987; 744.
26.
Council on Scientific Affairs. Harmful effects of ultraviolet radiation. JAMA 1989; 262:380-384.
4.
5.
Carland F, Carland C, Corham F, Young J. Ceographic variation in breast cancer mortality iti the United States: a hypothesis involving exposure to solar radiation. Prevent Med 1990; 19:614-622. Matsuoka L, Wortsman J, Hanifan N, Holick M. Chronic sunscreen use decreases circulating concentrations of 25-hydroxyvitnmin D. A preliminary study. Arch Dermatol 1988; 124:1802-1804.
6.
Kligman L. Preventing, delaying, and repairing photoaged skin. Cutis 1988; 41:419-420.
7.
Urbach F, Cange R, eds. The biological effects of UVA radiation. New York: Praeger, 1986. 547
International Journal of Dermatoiogy Vol. 31, No. 8, August 1992
27.
Hausser I. Uber spezifische Wirkung des langwelligen Ultraviolett. Strahlentherapie 1939; 69:14-42. 28. Everett M, Yeargers E, Sayre R, Olson R. Penetration of epidermis by ultraviolet rays. Photochem Photobiol 1966; 5:533-542. 29. Kaidbey K, Kligman A. Further studies of photoaugmentation in humans: phototoxic reactions. J Invest Dermatol 1975; 65:472-475. 30. Willis I, Kligman A, Epstein J. Effects of long ultraviolet rays on human skin: photoprotective or photoaugmentative? J Invest Dermatol 1973; 59:416-420. 31. Averer W, Schuler C, StingI B, et al. Ultraviolet light depletes surface markers of Langerhans cells. J Invest Dermatol 1981; 76:202-206. 32. Lew R, Sober A, Cook N, et al. Sun exposure habits in patients with cutaneous melanoma: a case control study. J Dermatol Surg Oncol 1983; 9:981-986. 33. Green A, Siskind V, Bain C, Alexander J. Sunburn and malignant melanoma. BrJ Cancer 1985; 51:393-397. 34. Dubin N, Moseson M, Pasternack BS. Sun exposure and malignant melanoma among susceptible individuals. Environ Hlth Perspect 1989; 81:139-151. 35. Cueron M, Eisinger J, Lamola A. Excited states of nucleic acids. In: Ts'o P, ed. Basic principles in nucleic acid chemistry. Vol I. New York: Academic Press, 1974; 311. 36. Liu F-T, Yang N. Photochemistry of cytosine derivatives. I. Photochemistry of thymidylyl-(3'-->5')-deoxycytidine. Biochemistry 1978; 17:4865. 37. Jori C, Spikes J. Photochemistry of porphyrins. In: Smith K, ed. Topics in photomedicine. New York: Plenum Press, 1984:183. 38. Haber L, Baer R. Photogenic mechanisms of drug-induced photosensitivity. J Invest Dermatol 1972; 58: 327-339. 3i9. Frain-Bell W, Dickson A, Herd J, Sturrock 1. The action spectrum in polymorphic light eruption. Br J Dermatolatol 1973; 89:243-249. 40. Ive H, Lloyd J, Magnus I. Action spectra in idiopathic solar urticaria. Br J Dermatol 1965; 77:229-243. 41. Epstein J. Phototoxicity and photoallergy. In: Fitzpatrick T, Pathak M, Harber L, et al., eds. Sunlight and man. Tokyo: University of Tokyo Press, 1974:459. 42. Kligman L, Akin F, Kligman A. The contributions of
43.
44.
45. 46.
47. 48.
49.
50. 51. 52.
53.
54.
55.
56.
UVA and UVB to connective tissue damage in hairless mice. J Invest Dermatol 1985; 84:272-276. Parrish J, Jaenicke K, Anderson R. Erythema and melanogenesis action spectra of normal human skin. Photochem Photobiol 1982; 6:187-191. Deflandre A, Lang C. Photostability assessment of sunscreens. Benzylidene camphor and dibenzolmethane derivatives. IntJ Cosmet Sci 1988; 10:53-62. Woods B. Dermatitis from Eusolex 8021 sunscreen agent in a cosmetic. Contact Dermatitis 1981; 7:168. Degroot A, Vanderwahl H, Jagtman B, Weyland J. Contact allergy to 4-isopropyldibenzoylmethane and 4(4'-methyl benzylidene) camphor in the sunscreen Eusolex 8021. Contact Dermatitis 1987; 16:245-254. Degroot A, Weyland J. Contact allergy to butylmethoxy dibenzoylmethane. Contact Dermatitis 1987; 16: 278. Schauder S, Ippen H. Photoallergic and allergic contact eczema caused by dibenzoylmethane compounds and other suncreeening agents. Hautarzt 1988; 39:435-440. Schauder S. Changes in sunscreening products in West Germany between 1988 and 1989/90. Zeitschrift fur Hautkrankheiten 1990; 65:1152-1160. Hawk J. Ultraviolet A radiation: staying within the pale. BMJ 1991; 302:1036-1037. Skolnick A. Revised regulations for sunscreen labeling expected soon from FDA. JAMA 1991; 265:3217. Lowe N, Dromgoole S, Sefton J, et al. Indoor and outdoor efficacy of broad spectrum sunscreen against ultraviolet A radiation in psoralen sensitized subjects. J Am Acad Dermatol 1983; 9:354-360. Cange W, Soparkar A, Matzinger E, et al. Efficacy of a sunscreen containing butyl methoxydibenzoylmethane against ultraviolet A radiation in photosensitized subjects. J Am Acad Dermatol 1986; 15:494-499. Jarratt M, Hill M, Smiles K. Topical protection against longwave ultraviolet A. J Am Acad Dermatol 1983; 9: 354-360. Kaidbey K, Gange W. Comparison of methods for assessing photoprotection against ultraviolet A in vivo. J Am Acad Dermatol 1987; 16:346-353. Henschke U, Schulze R. Untersuchungen zum problem der ultraviolett-dosimettrie. III. Ueber pigmentierung durch lanwelliges ultraviolett. Strahlentherapie 1939; 64: 14-42.
ORAHGE FLOWER WATER
From the collection of "La Pharmacie Frangaise," New Orleans, Louisiana, Mr. Ben Bavly, Curator. 548
SUNSCREENS, UVA, AND CUTANEOUS MALIGNANCY: ADDING EUEL TO THE EIRE JOHN DOBAK, M.D., AND FU-TONG LIU, M . D . , P H . D .
The incidence of cutaneous malignant melanoma (CMM) rose more than 100% in the last decade, making it the second fastest growing cancer rate in the country.' In an attempt to explain this, two epidemiologists, Drs. Frank and Cedric Garland, have made some controversial suggestions that sunscreens may be playing a role.^ Their hypothesis is that the correlation between the growth of CMM incidence and the introduction and increased use of sunscreens may indicate possible CMM induction by sunscreens. The Carlands' work on low serum vitamin D levels and increased cancer risk^''* led them to speculate that inhibition of vitamin D production, combined with intense exposure to ultraviolet A radiation (UVA), both of which are incident to sunscreen use,^'*" places persons at greater risk for CMM. Not surprisingly, the suggestion that sunscreens play a role in the induction of malignancy has come under harsh criticism from many dermatologists and photobiologists.^ Without arguing the validity of the Garlands' views or accepting the belief that sunscreens may play a role in inducing skin cancer, there are some interesting points to consider, in particular, the lack of complete protection from UVA offered by existing sunscreens and the phenomenon of UVA possibly photoaugmentation contributing to sun damage. An examination of the actual protection provided by "broad spectrum" sunscreen formulations on the market suggests that current labeling claims may be giving the consumer a false sense of security.
of ultraviolet light. The first sunscreen agent employed in the United States, in the late 1930s, was homomenthyl salicylate, a UVB absorbing compound.' Most product development since has focused on protection against UVB.^ Until recently, the basic goal of sunscreen formulation was to protect against damaging UVB rays, while transmitting the tanning UVA rays, however, substantial evidence has accumulated that UVA also has deleterious effects, indicating a need to screen against these rays as well.'' In the United States, many sunscreen formulations claim UVA protection, but in fact none of them block all UVA rays.''''^'^ Figure 1 shows the absorbance spectrum of a commercially available sunscreen preparation, containing 7% (0.25 M) octyl dimethyl-PABA, 5% (0.20 M) octyl salicylate, and 3% (0.13 M) oxybenzone, which would give an SPF of 15 or higher depending on the base used."' The curve depicts the percentage of radiation absorbed by a 0.02 mm thick layer of the product, a thickness recommended by the FDA to be applied to the skin for SPF testing and sunscreen use."* Absorption of incident UVA radiation declines to 50% at 360 nm, and falls to near 0% just beyond 370 nm so that nearly half of the UVA range is ineffectively screened. Oxybenzone is often touted to be a UVA blocking sunscreen, but analysis of oxybenzone's absorption spectrum (Fig. 2) indicates that it does not absorb above 360 nm. Thus many products employing oxybenzone as a UVA filter fail to protect against the longer wavelengths of the UVA range.
SUNSCREENS AND UVA
UVA AND CARCINOGENESIS
Ultraviolet A (range 3 2 0 - 4 0 0 nm)^-' was initially thought to contribute little to sun-elicited skin damage.* The more energetic ultraviolet B (UVB) rays (range 2 8 0 320 nm),** which are the primary cause of sunburn erythema,"' were presumed to be the only damaging form
Uultraviolet A is capable of causing various types of structural damage to DNA, which are consistent with transformation induction." Included are dimer formation, DNA-protein crosslinks, strand breaks, and oxidation reactions caused by UVA-induced free radical formation;^""'^' furthermore, UVA is carcinogenic in animals.^^^^'' • Van Weedlan et al. irradiated 24 mice with 22 J/cmVday of UVA. After approximately 350 days of exposure, more than 90% of the mice showed skin tumors; 60% were non-melanoma malignancies.^"* While no melanomas were found, no animal model has yet been developed that allows CMM to be consistently induced solely by ultraviolet radiation.^''
From the Division of Dermatology, Department of Medicine, University of California School of Medicine, San Diego, California. Address for correspondence: Fu-Tong Liu, M.D.,Ph.D., Division of Dermatology, Department of Medicine, University of California at San Diego, San Diego, CA 92093. 544
Sunscreens Dobak and Liu
% Absorbance 100
270 280 290 300 310 320 330 340 350 360 370 380 390 400 410
Wavelength (nm) Figure 1. Theoretical absorbance of 7% octyl dimethyl PABA, 5% octyl salicylate, and 3% oxybenzone through a 0.02 mm thick layer.
SUNSCREENS AND MALIGNANCY
The use of sunscreens and their ability to delay immediate sunburn erythema has allowed sun exposure time to be dramatically increased. Without adequate screening of UVA, this long exposure time has made it possible for a sunbather to absorb a large dose of UVA in a single day (up to 100 J/cm^).''-"-'^ With the minimal dose of UVA necessary to induce erythema being 18 J/cm^ at 385 nm,^'' this dose is clearly significant. It is also important to note that the depth of penetration of UVA through the stratum corneum and epidermis increases steadily as one approaches the long end of the UVA range.^*' Thus, a large percentage of radiation of wavelengths greater than 360 nm is able to pass through the epidermis, and potentially damage dermal structures such as melanocytes, fibroblasts, and collagen. Perhaps even more important than direct carcinogenesis is the effect of UVA photoaugmentation. Exposure to UVA radiation alone, following combined exposure to UVB and UVA, has been shown to potentiate, or augment, skin damage caused by the combined irradiation.^' The sequence of exposure can be reversed, and the enhanced damage still occurs.'" This augmentative effect of UVA has been found to extend to tumor induction. Staberg et al. observed a significant increase (P < 0.05) in malignant squamous cell carcinoma incidence in mice irradiated with artificial sunlight (uvA and B rays) followed by UVA light alone, over mice irradiated with artificial sunlight only.^^'" It is conceivable that reduction of Langerhans' cells by the UVA radiation" results in inefficient immunodestruction of early neoplastic cells, thereby allowing damage incited by the initial combined exposure to be expressed in the form of tumors.
A sunbather who intermittently uses a UVB sunscreen mimics this laboratory experiment, and perhaps places him/herself at greater risk for sun-induced skin damage and malignancy. Current theory regarding ultraviolet light and the risk of melanoma holds that the number of severe sunburns that a person receives, particularly at a young age, is an important predisposing factor for the later development of melanoma.^^"-''* Additional exposure to UVA associated with use of a sunscreen in the days following a sunburn would again be analogous to Staberg's experimental conditions. Perhaps sunscreens and photoaugmentation are a link between sunburns and melanoma. Persons who combine suntan parlor .exposure with sunbathing also simulate the laboratory exposure. It will be interesting to see what the future incidence of melanoma and other cutaneous malignancies is in the solarium cohort.^'-'^ The photosensitizing properties of some sunscreens may be another link between sunscreens and malignancy. In most sunscreens, the key ingredients absorb the UV light and are converted to excited states. Thus energy from UV radiation is not simply "blocked" by these sunscreens but is converted into other chemically reactive forms. Although most of the excited state molecules, especially those at the outer extracutaneous layers, dissipate their energy uneventfully, some of them may transfer the energy to molecular components in the skin and thereby trigger chemical reactions. For example, if a sunscreen component penetrates into the keratinocytes and subsequently is converted to the excited state by absorbing UV light, it can theoretically transfer the excited state energy to the thymine moieties in DNA 545
International Journal of Dermatology Vol. 31, ND. 8, August 1992
Ab8orbance
260 270 280 290 300 310 320 330 340 350 360 370 380 390 400
Wavelength (nm) Figure 2. Absorbance spectrum of oxybenzone. and result in thymine dimer formation. This type of photosensitized thymine dimer formation has been well established.^^••'^ Although repair mechanisms exist to correct photochemically induced damages in DNA, mutations may eventually result, culminating in neoplastic transformation, especially in individuals with low efficiency in repair processes. The excited states of sunscreen components can also transfer energies or electrons to molecular oxygen to generate singlet oxygen, as well as superoxide radical anion, hydrogen peroxide, and hydroxyl radicals.^'' These highly reactive oxygen species can react with various cell components, resulting in cell damage and, conceivably, mutations. These mechanisms have been considered the bases for cutaneous phototoxic reaction of chemicals^* and presumably can be identified when sunscreens are tested for adverse reactions; however, it is important to point out that various chemical reactions sensitized by sunscreens may not be discernible as acute toxic cutaneous reactions, and carcinogenesis may result only after accumulated insults. A number of factors must be taken into consideration in assessment of the safety of sunscreens with regard to their possible contribution to induction of cutaneous malignancy as a result of their potential photosensitizing activity. These include (1) the penetration of the sunscreen components into inter- or intra-cellular space in epidermis and dermis; (2) the capacity of these compounds to absorb UV radiation (and be converted to the excited states); (3) the energies of the excited states of the sunscreens relative to potential acceptor molecules in the skin and identification of such acceptor molecules; and (4) the presence in the sunscreens or in the skin of chemicals capable of quenching the excited state energy of the sunscreen components or reactive oxygen species.
NEW SUNSCREENS AND EXISTING PROBLEMS
Whether or not sunscreens have played a role in induction of cutaneous malignancy, there is clearly a need to develop products that adequately protect against uvA rays. UVA radiation can incite the clinical signs of many photosensitive diseases and drug-induced photosensitivities.''"'" UVA also contributes to photoaging**^ and erythema.'*^'^^ Many sunscreens in the United States are inadequate protectors against UVA. Dibenzoylmethane derivatives, Eusolex 8020™ and Parsol 1789™, are true UVA screening agents and do provide better UVA protection. Although more extensively used in Europe, Parsol is now available in the United States (Photopjg^rMj. however, Kaidbey et al. have reported that these products absorb only 35% of incident uvA radiation.'' This is most likely due to instability of the compounds. Defiander and Lang report a 36% reduction in absorbance capacity of Parsol 1789 and a 50% reduction in absorbance capacity of Eusolex 8020 within 15 minutes of exposure to ultraviolet light.'*'' There have been problems with contact sensitivity and other allergies to products containing these agents.'*''"'** Adverse reactions to some of the compounds, particularly Eusolex 8020"^, have led to their removal from some European formulas.'*' The recent emphasis in the sunscreen industry in the United States has been the development of ultra high SPF sunscreens (SPF >2O) for which "broad spectrum" UVA protection is claimed; however, such formulations expose the user to numerous chemicals at very high concentrations and are expensive, while only modestly extending coverage into the UVA range.^^ The FDA is now questioning the efficacy of these products and will regulate labeling claims.^' A problem faced by the FDA is development of standardized testing methods for asS46
Sunscreens Dobak and Lm
sessing UVA protection. The 1978 FDA monograph on the efficacy of sunscreen preparations makes no provisions for UVA-absorbing agents, and cites no methods to assess protection against uvA." Methods used to measure uVB protection (SPF determination) are commonly used to assess UVA protection as well, but the skin is often photosensitized to UVA with 8-methoxypsoralen.""'''* SPi-s determined in sensitized skin are significantly higher than those determined in nonsensitized skin.^^ Much of the testing done with Photoplex'''^' involved psoralen skin sensitization, making it difficult to determine its true UVA blocking potential. Furtherore, SPFs can vary with the endpoint selected for testing (erythema, immediate pigment darkening, delayed pigment darkening);"''' for example, the SPF for oxybenzone was found to be lower when immediate pigment darkening (IPD) rather than erythema was used as the endpoint. This discrepancy reflects oxybenzone's inability to protect against long wavelength UVA, the rays primarily responsible for IPD.^'' Thus IPD may be a more valid way to determine protection against UVA, because it measures protection against longer UVA wavelengths. Improvement of UVA protection in sunscreen formulations is of the utmost concern. Existing formulas are well suited to protect the user against the most actively carcinogenic and damaging UVB rays, however, with improved sunscreen use compliance, it is conceivable that the existing formulations may ultimately contribute to actinic damage through intense prolonged UVA exposure and photoaugmentation. Claims of UVA protection or "broad spectrum" coverage need to be substantiated through the adoption of a standard reproducible testing method.
8.
Parrish J, Anderson R, Urbach F, Pitts D, eds. UV-A: biological effects of ultraviolet radiation with emphasis on human response to longwave ultraviolet. New York: Plenum Press, 1978.
9.
Creiter F, Bilek P, Doskoczil S. History of sunscreens and the rationale for their use. In: Frost P, Horowitz S, eds. Principles of cosmetics for the dermatologist. St. Louis: Mosby, 1982; 187.
10.
Parrish J, Jaenicke K, Anderson R. Erythema and melanogenesis action spectra of normal human skin. Photochem Photobiol 1982; 6:1 87-191.
11.
Pathek M. Sunscreens and their use in the preventative treatment of sunlight-induced skin damage. J Dermatolog Surg Oncol 1987; 13:739-750.
12.
Diffey B, Farr P. An evaluation of sunscreens in patients with broad-action spectrum photosensitivity. Br J Dermatol 1985; 112:83-86.
13.
Kaidbey K, Cange W, Comparison of methods for assessing photoprotection against ultraviolet A in vivo. J Am Acad Dermatol 1987; 16:346-353.
14.
Knox J, Cuin J, Cockerell F. Benzophenones, ultraviolet light absorbing agents. J Invest Dermatol 1957; 29: 435-444.
15.
Lowe N, Dromgoole S, Sefton J, et al. Indoor and outdoor efficacy of a broad spectrum sunscreen against ultraviolet A radiation in psoralen sensitized subjects. J Am Acad Dermatol 1983; 9:354-360.
16.
Cange W, Soparkar A, Matzinger F, et al.. Ffficacy of a sunscreen containing butyl methoxydibenzoylmethane against ultraviolet A radiation in photosensitized subjects. J Am Acad Dermatol 1986; 15:494-499.
17.
Jarratt M, Hill M, Smiles K. Topical protection against longwave ultraviolet A. ] Am Acad Dermatol 1983; 9: 354-360.
18.
Food and Drug Administration sunscreen drug products for over-the-counter human use. Federal Register 1978; 43:38206-38269.
19.
Peak M, Peak J. Molecular photobiology of UVA. In: Urbach F, Cange R, eds. The biological effects of uvA radiation. New York: Praeger, 1986; 42.
20.
Chew S, Deleo V, Harber L. The effect of UVA radiation on DNA synthesis of guinea pig skin. Photochem Photobioll 988; 47:383-389.
21.
Freeman S, Cange R, Matzinger E, et al. Production of pyrimidine dimers in skin of humans exposed to UVA. Photochem Photobiol 1986; 43 (suppl.):71.
Acknowledgment: Dr. Robert Coltz reviewed this manuscript.
REEERENCES 1.
Lew R, Koh H, Sober A. Fpidemiology of cutaneous melanoma. Dermatol Clin 1985; 3:257-269.
2.
Skolnick A. Sunscreen protection controversy heats up. JAMA 1991; 265:3218-3220.
22.
3.
Carland C, Comstock C, Carland F, et al. Serum 25hydroxyvitamin D and colon cancer: eight year prospective study. Lancet 1989; ii:1176-1178.
Staberg B, Christian W, Poulsen T, et al. Carcinogenic effect of sequential artificial sunlight and UVA irradiation in hairless mice. Arch Dermatol 1983; 119:641-643.
23.
Staberg B, Christian W, Kemp P, et al. The carcinogenic effect of UVA irradiation. J Invest Dermatol 1983; 81: 517-519.
24.
Van Weedlen H, Grujil F, Van der Leun J. Carcinogenesis by UVA with an attempt to assess the carcinogenic risks of tanning with UVA and UVB. In: Urbach F, Cange R, eds. The biological effects of UVA radiation. New York: Praeger, 1986.
25.
Passchier N, Bosnjakovic B, eds. Human exposure to ultraviolet radiation: risks and regulations. Amsterdam: Exerpta Medica International Congress Series, 1987; 744.
26.
Council on Scientific Affairs. Harmful effects of ultraviolet radiation. JAMA 1989; 262:380-384.
4.
5.
Carland F, Carland C, Corham F, Young J. Ceographic variation in breast cancer mortality iti the United States: a hypothesis involving exposure to solar radiation. Prevent Med 1990; 19:614-622. Matsuoka L, Wortsman J, Hanifan N, Holick M. Chronic sunscreen use decreases circulating concentrations of 25-hydroxyvitnmin D. A preliminary study. Arch Dermatol 1988; 124:1802-1804.
6.
Kligman L. Preventing, delaying, and repairing photoaged skin. Cutis 1988; 41:419-420.
7.
Urbach F, Cange R, eds. The biological effects of UVA radiation. New York: Praeger, 1986. 547
International Journal of Dermatoiogy Vol. 31, No. 8, August 1992
27.
Hausser I. Uber spezifische Wirkung des langwelligen Ultraviolett. Strahlentherapie 1939; 69:14-42. 28. Everett M, Yeargers E, Sayre R, Olson R. Penetration of epidermis by ultraviolet rays. Photochem Photobiol 1966; 5:533-542. 29. Kaidbey K, Kligman A. Further studies of photoaugmentation in humans: phototoxic reactions. J Invest Dermatol 1975; 65:472-475. 30. Willis I, Kligman A, Epstein J. Effects of long ultraviolet rays on human skin: photoprotective or photoaugmentative? J Invest Dermatol 1973; 59:416-420. 31. Averer W, Schuler C, StingI B, et al. Ultraviolet light depletes surface markers of Langerhans cells. J Invest Dermatol 1981; 76:202-206. 32. Lew R, Sober A, Cook N, et al. Sun exposure habits in patients with cutaneous melanoma: a case control study. J Dermatol Surg Oncol 1983; 9:981-986. 33. Green A, Siskind V, Bain C, Alexander J. Sunburn and malignant melanoma. BrJ Cancer 1985; 51:393-397. 34. Dubin N, Moseson M, Pasternack BS. Sun exposure and malignant melanoma among susceptible individuals. Environ Hlth Perspect 1989; 81:139-151. 35. Cueron M, Eisinger J, Lamola A. Excited states of nucleic acids. In: Ts'o P, ed. Basic principles in nucleic acid chemistry. Vol I. New York: Academic Press, 1974; 311. 36. Liu F-T, Yang N. Photochemistry of cytosine derivatives. I. Photochemistry of thymidylyl-(3'-->5')-deoxycytidine. Biochemistry 1978; 17:4865. 37. Jori C, Spikes J. Photochemistry of porphyrins. In: Smith K, ed. Topics in photomedicine. New York: Plenum Press, 1984:183. 38. Haber L, Baer R. Photogenic mechanisms of drug-induced photosensitivity. J Invest Dermatol 1972; 58: 327-339. 3i9. Frain-Bell W, Dickson A, Herd J, Sturrock 1. The action spectrum in polymorphic light eruption. Br J Dermatolatol 1973; 89:243-249. 40. Ive H, Lloyd J, Magnus I. Action spectra in idiopathic solar urticaria. Br J Dermatol 1965; 77:229-243. 41. Epstein J. Phototoxicity and photoallergy. In: Fitzpatrick T, Pathak M, Harber L, et al., eds. Sunlight and man. Tokyo: University of Tokyo Press, 1974:459. 42. Kligman L, Akin F, Kligman A. The contributions of
43.
44.
45. 46.
47. 48.
49.
50. 51. 52.
53.
54.
55.
56.
UVA and UVB to connective tissue damage in hairless mice. J Invest Dermatol 1985; 84:272-276. Parrish J, Jaenicke K, Anderson R. Erythema and melanogenesis action spectra of normal human skin. Photochem Photobiol 1982; 6:187-191. Deflandre A, Lang C. Photostability assessment of sunscreens. Benzylidene camphor and dibenzolmethane derivatives. IntJ Cosmet Sci 1988; 10:53-62. Woods B. Dermatitis from Eusolex 8021 sunscreen agent in a cosmetic. Contact Dermatitis 1981; 7:168. Degroot A, Vanderwahl H, Jagtman B, Weyland J. Contact allergy to 4-isopropyldibenzoylmethane and 4(4'-methyl benzylidene) camphor in the sunscreen Eusolex 8021. Contact Dermatitis 1987; 16:245-254. Degroot A, Weyland J. Contact allergy to butylmethoxy dibenzoylmethane. Contact Dermatitis 1987; 16: 278. Schauder S, Ippen H. Photoallergic and allergic contact eczema caused by dibenzoylmethane compounds and other suncreeening agents. Hautarzt 1988; 39:435-440. Schauder S. Changes in sunscreening products in West Germany between 1988 and 1989/90. Zeitschrift fur Hautkrankheiten 1990; 65:1152-1160. Hawk J. Ultraviolet A radiation: staying within the pale. BMJ 1991; 302:1036-1037. Skolnick A. Revised regulations for sunscreen labeling expected soon from FDA. JAMA 1991; 265:3217. Lowe N, Dromgoole S, Sefton J, et al. Indoor and outdoor efficacy of broad spectrum sunscreen against ultraviolet A radiation in psoralen sensitized subjects. J Am Acad Dermatol 1983; 9:354-360. Cange W, Soparkar A, Matzinger E, et al. Efficacy of a sunscreen containing butyl methoxydibenzoylmethane against ultraviolet A radiation in photosensitized subjects. J Am Acad Dermatol 1986; 15:494-499. Jarratt M, Hill M, Smiles K. Topical protection against longwave ultraviolet A. J Am Acad Dermatol 1983; 9: 354-360. Kaidbey K, Gange W. Comparison of methods for assessing photoprotection against ultraviolet A in vivo. J Am Acad Dermatol 1987; 16:346-353. Henschke U, Schulze R. Untersuchungen zum problem der ultraviolett-dosimettrie. III. Ueber pigmentierung durch lanwelliges ultraviolett. Strahlentherapie 1939; 64: 14-42.
ORAHGE FLOWER WATER
From the collection of "La Pharmacie Frangaise," New Orleans, Louisiana, Mr. Ben Bavly, Curator. 548
