SKIN PHOTOPROTECTION BY PIGMENTATION AND SUNSCREENS 221 ratio (intervention sunscreen vs. discretionary use sunscreen) for SCC in trial and total follow-up (1993–2004) of 0.65 (95% CI 0.45–094), representing a cancer protection fac- tor of ~1.5. In this context, it should be remembered that the real SPF of the product was likely to have been much less than 16 because of the way people typically apply sun- screens. Furthermore, given that the mean age of entry into the study was about 50 y, this rural population will have had a high level of baseline UVR-induced DNA mutations in keratinocytes. It is probable that one of the reasons for the benefi ts of long-term sunscreen use in this study was the immunoprotective effects of sunscreens (45). Photoimmunosuppres- sion is thought to play an important role in skin cancer (46). There is considerable mouse evidence that the CPD initiates the antigen-specifi c cutaneous immunosuppression when a given antigen is presented to the skin after UVR exposure (47). Interestingly, organ transplant patients on drug immunotherapy, which is not antigen-specifi c, are very prone to skin cancer, especially SCC (48). It would be reasonable to suppose that earlier sunscreen intervention, especially in areas of high insolation, would have greater long-term benefi ts. VIT AMIN D SYNTHESIS Vit amin D is important for bone development and maintenance, but there is increasing, though controversial, evidence that vitamin D has many other health benefi ts (49). It is well documented that people with pigmented skins have less good vitamin status than those, at comparable latitudes, with lighter skins. This is usually attributed to an inhibi- tory effect of melanin. Laboratory research on the effect of melanin on vitamin D synthe- sis has given confl icting results (50). A recent laboratory study on FST II–VI has shown that melanin has a very modest effect on vitamin D synthesis. Comparisons of FST II versus VI showed that the melanin inhibition factor was 1.5 (51), but this may be suf- fi cient to explain the epidemiological data. It is also likely that cultural and behavioral factors may also explain differences in vitamin D status in different ethnic groups. The most likely reasons for the differences with the DNA protection data is the spatial rela- tionship between melanin and the UVR target. In the basal layer, nuclei are largely under the melanin, whereas the precursor for vitamin D is throughout the epidermis with high concentrations in the upper less melanized epidermal layers. Two recent reviews concluded that sunscreen use has little or no impact on vitamin D synthesis (52,53). A weeklong fi eld study in Tenerife, under a cloudless sky with a maxi- mum UVI of 9, showed a high level of vitamin D synthesis even when optimal applica- tion of an SPF 15 sunscreen ( 2.0 mg/cm2) prevented erythema (54). This intervention group was in contrast to a discretionary sunscreen use group that had a higher level of vitamin D synthesis but presented with sunburn on multiple body sites. Thus, sunscreens may inhibit vitamin D synthesis, but they still allow considerable synthesis with suber- ythemal exposure. It should be noted that we lack data on the effect of a high SPF sun- screen, especially in temperate climates (55). Sunscreens can enable vitamin D synthesis because the threshold UVR dose for this process is much lower than that for erythema. CON CLUSIONS Con stitutive melanin in deeply pigmented skin is very effective at preventing basal layer DNA photodamage, erythema, and skin cancer. Protection against DNA damage and

JOURNAL OF COSMETIC SCIENCE 222 erythema is much lower by facultative tanning in white skin types. A comparison of FST II versus VI shows that melanin has a very modest inhibitory effect on vitamin D photo- synthesis. Melanin protection/inhibition against a given target depends on spatial rela- tionships within the epidermis. Sunscreen protection against erythema depends on its the SPF and application thickness. Used correctly, sunscreens will inhibit erythema in “real- life” situations. There is good experimental evidence that sunscreens will inhibit DNA photodamage and skin cancer. However, to get the equivalent of constitutive protection against skin cancer, it is likely that FST I/II would need an SPF about 60. Sunscreens have a relatively modest effect on vitamin D synthesis. Better sunscreen protection would be achieved with better use. ACK NOWLEDGMENTS I t hank Dr. Paulo Giacomoni for the invitation to contribute to this special edition on sunscreens. It has given me an opportunity to present much of my work on photoprotec- tion over the past few decades. I would also like to thank the many colleagues and stu- dents who made this work possible. REF ERENCES (1 ) M. Bustamante, C. Hernandez-Ferrer, A. Tewari, Y. Sarria, G. I. Harrison, E. Puigdecanet, L. Nonell, W. Kang , M. R. Friedländer, X. Estivill, J. R. González, M. Nieuwenhuijsen, and A. R. Young, Dose and time effects of solar-simulated ultraviolet radiation on the in vivo human skin transcriptome, Br. J. Dermatol., 182, 1458–1468 (2020). (2) M. Bustamante, C. Hernandez-Ferrer, Y. Sarria, G. I. Harrison, L. Nonell, W. Kang, M. R. Friedländer, X. Estivill, J. R. González, M. Nieuwenhuijsen, and A. R. Young, The acute effects of ultraviolet ra- diation on the blood transcriptome are independent of plasma 25OHD3, Environ. Res., 159, 239–248 (2017). (3) M. Bustamante, V. Wucher, and A. R. Y oung, Importance of considering circadian rhythm in the design of in vivo transcriptional studies of acute effects of environmental exposures: commentary to “The acute effects of ultraviolet radiation on the blood transcriptome are independent of plasma 25OHD3”, pub- lished in Environmental Research 2017 Nov:159: 239–248. doi: 10.1016/j.envres.2017.07.045, Envi- ron. Res., 178, 108691 (2019). (4) R. B. Weller, Y. Wang, J. He, F. W. M addux, L. Usvyat, H. Zhang, M. Feelisch, and P. Kotanko, Does incident solar ultraviolet radiation lower blood pressure? J. Am. Heart Assoc., 9(5), e013837 (2020). (5) D. Fajuyigbe and A. R. Young, The im p act of skin colour on human photobiological responses, Pigment Cell Melanoma Res., 29(6), 607–618 (2016). (6) A. R. Young, C. S. Potten, C. A. Cha d wick, G. M. Murphy, J. L. Hawk, and A. J. Cohen, Photoprotec- tion and 5-MOP photochemoprotection from UVR-induced DNA damage in humans: the role of skin type, J. Invest. Dermatol., 97(5), 942–948 (1991). (7) A. R. Young, S. L. Walker, J. S. Kin l ey, S. R. Plastow, D. Averbeck, P. Morliere, and L. Dubertret, Phototumorigenesis studies of 5-methoxypsoralen in bergamot oil: evaluation and modifi cation of risk of human use in an albino mouse skin model, J. Photochem. Photobiol. B, 7(2–4), 231–250 (1990). (8) L. M. Fitzgerald, J. L. Fryer, T. Dw y er, and S. M. Humphrey, Effect of MELANOTAN, [Nle(4), D- Phe(7)]-alpha-MSH, on melanin synthesis in humans with MC1R variant alleles, Peptides, 27(2), 388– 394 (2006). (9) N. G. Jablonski and G. Chaplin, The e volution of human skin coloration, J. Hum. Evol., 39(1), 57–106 (2000). (10) N. G. Jablonski and G. Chaplin, Col l oquium paper: human skin pigmentation as an adaptation to UV radiation, Proc. Natl. Acad. Sci. U.S.A., 107(Suppl. 2), 8962–8968 (2010). (11) R. L. McKenzie and R. M. Lucas, Rea s sessing impacts of extended daily exposure to low level solar UV radiation, Sci. Rep., 8(1), 13805 (2018).