The challenge resulting from positive and negative effects of sunlight: how much solar UV exposure is appropriate to balance between risks of vitamin D deficiency and skin cancer?

There is no doubt that solar ultraviolet (UV) exposure is the most important environmental risk factor for the development of non-melanoma skin cancer. Therefore, sun protection is of particular importance to prevent these malignancies, especially in risk groups. However, 90% of all requisite vitamin D has to be formed in the skin through the action of the sun-a serious problem, for a connection between vitamin D deficiency and a broad variety of independent diseases including various types of cancer, bone diseases, autoimmune diseases, hypertension and cardiovascular disease has now been clearly indicated in a large number of epidemiologic and laboratory studies. An important link that improved our understanding of these new findings was the discovery that the biologically active vitamin D metabolite 1,25(OH)(2)D is not exclusively produced in the kidney, but in many other tissues such as prostate, colon, skin and osteoblasts. Extra-renally produced 1,25(OH)(2)D is now considered to be an autocrine or paracrine hormone, regulating various cellular functions including cell growth. We and others have shown that strict sun protection causes vitamin D deficiency in risk groups. In the light of new scientific findings that convincingly demonstrate an association of vitamin D deficiency with a variety of severe diseases including various cancers, the detection and treatment of vitamin D deficiency in sun-deprived risk groups is of high importance. It has to be emphasized that in groups that are at high risk of developing vitamin D deficiency (e.g., nursing home residents or patients under immunosuppressive therapy), vitamin D status has to be monitored. Vitamin D deficiency should be treated, e.g., by giving vitamin D orally. Dermatologists and other clinicians have to recognize that there is convincing evidence that the protective effect of less intense solar UV radiation outweighs its mutagenic effects. Although further work is necessary to define an adequate vitamin D status and adequate guidelines for solar UV exposure, it is at present mandatory that public health campaigns and recommendations of dermatologists on sun protection consider these facts. Well-balanced recommendations on sun protection have to ensure an adequate vitamin D status, thereby protecting people against adverse effects of strict sun protection without significantly increasing the risk of developing UV-induced skin cancer.     

Factors that influence the cutaneous synthesis and dietary sources of vitamin D

The major sources of vitamin D for most humans are casual exposure of the skin to solar ultraviolet B (UVB; 290-315 nm) radiation and from dietary intake. The cutaneous synthesis of vitamin D is a function of skin pigmentation and of the solar zenith angle which depends on latitude, season, and time of day. In order to mimic the natural environment of skin to sunlight exposure, we therefore measured serum 25-hydroxyvitamin D levels in volunteers with different skin types following repeated UV irradiation. Because melanin pigment in human skin competes for and absorbs the UVB photons responsible for the photolysis of 7-dehydrocholesterol to previtamin D3, we also studied the effect of skin pigmentation on previtamin D3 production in a human skin model by exposing type II and type V skin samples to noon sunlight in June when the solar zenith angle is most acute. Vitamin D is rare in food. Among the vitamin D-rich food, oily fish are considered to be one of the best sources. Therefore, we analyzed the vitamin D content in several commonly consumed oily and non-oily fish. The data showed that farmed salmon had a mean content of vitamin D that was approximately 25% of the mean content found in wild caught salmon from Alaska, and that vitamin D2 was found in farmed salmon, but not in wild caught salmon. The results provide useful global guidelines for obtaining sufficient vitamin D3 by cutaneous synthesis and from dietary intake to prevent vitamin D deficiency and its health consequences, ensuing illness, especially, bone fractures in the elderly.     

Ultraviolet exposure and vitamin D synthesis in a sun-dwelling and a shade-dwelling species of Anolis: are there adaptations for lower ultraviolet B and dietary vitamin D3 availability in the shade?

We compared the natural ultraviolet B (UV-B) exposure, dietary vitamin D, and skin-generated vitamin D synthesis for adult males of two species of Jamaican anoles. The more shade-tolerant and thermal-conforming Anolis lineotopus merope, rarely exposed to full sun, experienced less UV-B irradiation in its shady environment than the more heliophilic and thermophilic Anolis sagrei, which frequently basked in full sun during the morning hours (0800-1100 hours). Both species obtained detectable levels of vitamin D(3) in their diet, but the heliophilic A. sagrei obtained more. To compensate for less availability of UV-B and dietary vitamin D, the skin of A. lineotopus merope seems to have acquired a greater sensitivity than that of A. sagrei regarding UV-B-induced vitamin D(3) photobiosynthesis. We assessed this by observing a greater conversion of provitamin D to photoproducts in skin exposed to UV-B from a sunlamp. The reduced skin sensitivity of A. sagrei regarding vitamin D photobiosynthesis may reflect a correlated response associated with less need for vitamin D photobiosynthesis and greater need for UV-B screening capacity as an adaptation to a more damaging UV-B environment. However, the possibility that adaptations for photobiosynthesis of vitamin D and for protection from skin damage could involve independent mechanisms needs investigation. Also, the ability to behaviorally regulate UV-B exposure, as shown for the panther chameleon, would benefit both species of Anolis and should be investigated.     

Formation of fatty acid esterified vitamin D3 in rat skin by exposure to ultraviolet radiation

The formation of fatty acid esters of vitamin D3 was demonstrated in rat skin exposed to artificial ultraviolet rays by using multi-dimensional high-performance liquid chromatography, ultraviolet spectrophotometry, and gas-liquid chromatography-mass spectrometry. This result indicated that the fatty acid esters of 7-dehydrocholesterol in rat skin (at least 80% of 7-dehydrocholesterol in rat skin is esterified) is also isomerized into vitamin D3 ester in vivo. The initial percentage of the esterified form was 84.3% and this did not significantly change up to the time when about half of the skin total vitamin D3 disappeared (2 days). Consequently, it was speculated that the vitamin D3 ester was delivered into the blood circulation from skin without having been hydrolyzed. This was supported by the presence of vitamin D3 ester in rat plasma exposed to ultraviolet radiation. In addition, in connection with the study of the restriction of vitamin D3 synthesis, distribution of total vitamin D3 in rat skin exposed to ultraviolet irradiation in vivo was compared with that in isolated skin exposed to ultraviolet radiation. The dermal layer of the isolated skin contained about 4 times more total vitamin D3 than that of in vivo skin. This finding suggests not only that ultraviolet rays could not penetrate deeply into the in vivo skin, but that the restriction of cutaneous synthesis of vitamin D3 observed in vivo may arise from this reduced penetration of ultraviolet rays.     

Vitamin D and multiple sclerosis

Vitamin D is a principal regulator of calcium homeostasis. However, recent evidence has indicated that vitamin D can have numerous other physiological functions including inhibition of proliferation of a number of malignant cells including breast and prostate cancer cells and protection against certain immune mediated disorders including multiple sclerosis (MS). The geographic incidence of MS indicates an increase in MS with a decrease in sunlight exposure. Since vitamin D is produced in the skin by solar or UV irradiation and high serum levels of 25-hydroxyvitamin D (25(OH)D) have been reported to correlate with a reduced risk of MS, a protective role of vitamin D is suggested. Mechanisms whereby the active form of vitamin D, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) may act to mediate this protective effect are reviewed. Due to its immunosuppressive actions, it has been suggested that 1,25(OH)(2)D(3) may prevent the induction of MS.     

Calvarial cells synthesize 1 alpha,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3

A metabolite of vitamin D has been isolated in pure form from incubation of 25-hydroxyvitamin D3 with embryonic chick calvarial cells that had been grown on Cytodex 1 microcarrier beads. The isolation involved dichloromethane extraction of the cells and incubation medium, followed by Sephadex LH-20 column chromatography and high-performance liquid chromatography of the extract. The metabolite was identified as 1 alpha,25-dihydroxyvitamin D3 by means of ultraviolet absorption spectroscopy, mass spectrometry, and sensitivity to oxidation by periodate. This metabolite was not produced by cell-free medium or by cells from embryonic chick liver, skin, or heart. In conclusion, (1) kidney cells are not unique in having 25-hydroxyvitamin D3:1 alpha-hydroxylase activity as previously believed and (2) vitamin D target tissues such as the skeleton may play a direct role in mediating the metabolism of 25-hydroxyvitamin D3 to 1 alpha,25-dihydroxyvitamin D3, a vitamin D metabolite active at those sites.     

Reintroduction of a classic vitamin D ultraviolet source

As early as 1930 sunlamps claiming to provide ultraviolet (UV) exposure to make vitamin D were sold to the public in the US and Canada for home use. Today even with dietary supplementation of vitamin D many people do not get enough solar UV exposure to maintain sufficient vitamin D levels. There is growing interest in the availability of sunlamps for this purpose. The original Sperti Sunlamp, with label claiming vitamin D benefit was approved by the American Medical Association in 1940 as a sunlamp. This intermediate pressure mercury lamps ultraviolet B emission lines, at 297, 302, and 313 nm are able to convert 7-dehydrocholesterol in the skin to vitamin pre-D3 initiating the natural process of vitamin D formation. Today's KBD Vitamin D lamp, an updated model of the earlier type source. In order to comply with modern safety guidance, the source is filtered to remove unnecessary UVC radiation and is equipped with a timer to control the dose administered. The 5 min timer provides an exposure, at 20 in. from the user's skin, of one standard erythemal dose (SED). The SED represents a suberythemal dose for even the most sensitive skin type I individual.     

The preventive effect of vitamin D3 on radiation-induced hair toxicity in a rat model

Our aim is to investigate the protective effect of vitamin D3 especially from radiation-induced hair toxicity. A model of skin radiation injury was developed and a single fraction of 20 Gy Gamma irradiation was applied to the right dorsal skin of fourteen rats. All animals were randomly divided into 2 groups: Group I: irradiation alone (n = 7) and Group II: irradiation and 0.2 microg vitamin D3 given IM (n = 7). Fifty days after post-irradiation rats were sacrificed. The outcomes were evaluated on the basis of histopathological findings and immunohistochemical staining for Vitamin D receptor (VDR) in skin and hair follicles. The number of hair follicles in the radiation field for the group of animals irradiated without pretreatment was significantly lower than outside of the irradiated area (p = 0.016) as it is expected. Contrarily the number of hair follicles did not show significant difference in the pretreated group between the irradiated field and outside of the fields (p = 0,14). Skin of the vitamin D3 pretreated group demonstrated stronger immunoreactivity for VDR compared to irradiation alone group. These results indicate that administration of vitamin D3 may protect hair follicles from radiation toxicity. Further clinical trials should be conducted to prove the preventive effect of vitamin D3 as well as dosing and timing of the agent on radiation-induced alopecia.     

Human skin pigmentation, migration and disease susceptibility

Human skin pigmentation evolved as a compromise between the conflicting physiological demands of protection against the deleterious effects of ultraviolet radiation (UVR) and photosynthesis of UVB-dependent vitamin D(3). Living under high UVR near the equator, ancestral Homo sapiens had skin rich in protective eumelanin. Dispersals outside of the tropics were associated with positive selection for depigmentation to maximize cutaneous biosynthesis of pre-vitamin D(3) under low and highly seasonal UVB conditions. In recent centuries, migrations and high-speed transportation have brought many people into UVR regimes different from those experienced by their ancestors and, accordingly, exposed them to new disease risks. These have been increased by urbanization and changes in diet and lifestyle. Three examples-nutritional rickets, multiple sclerosis (MS) and cutaneous malignant melanoma (CMM)-are chosen to illustrate the serious health effects of mismatches between skin pigmentation and UVR. The aetiology of MS in particular provides insight into complex and contingent interactions of genetic and environmental factors necessary to trigger lethal disease states. Low UVB levels and vitamin D deficiencies produced by changes in location and lifestyle pose some of the most serious disease risks of the twenty-first century.     

Availability of vitamin D photoconversion weighted UV radiation in southern South America

Ultraviolet radiation (UVR) plays a key role in several biological functions, including human health. Skin exposure to UVR is the main factor in vitamin D photoconversion. There is also evidence relating low levels of vitamin D with certain internal cancers, mainly colon, breast and prostate, as well as other diseases. Several epidemiological studies have shown an inverse relationship between the above-mentioned diseases and latitude, in accordance with the ultraviolet radiation latitudinal gradient. The aim of this study is to determine whether UV irradiance levels in the southern South America are sufficient to produce suitable levels of vitamin D year around. For this purpose, vitamin D photoconversion weighted-irradiance was analyzed between S.S. de Jujuy (24.17°S, 65.02°W) and Ushuaia (54° 50'S, 68° 18'W). In addition to irradiance, skin type and area of body exposed to sunlight are critical factors in vitamin D epidemiology. Due to a broad ethnic variability, it was assumed that the skin type in this region varies between II and V (from the most to the less sensitive). All sites except South Patagonia indicate that skin II under any condition of body area exposure and skin V when exposing head, hands, arms and legs, would produce suitable levels of vitamin D year round (except for some days in winter at North Patagonian sites). At South Patagonian sites, minimum healthy levels of vitamin D year round can be reached only by the more sensitive skin II type, if exposing head, hands, arms and legs, which is not a realistic scenario during winter. At these southern latitudes, healthy vitamin D levels would not be obtained between mid May and beginning of August if exposing only the head. Skin V with head exposure is the most critical situation; with the exception of the tropics, sun exposure would not produce suitable levels of vitamin D around winter, during a time period that varies with latitude. Analyzing the best exposure time during the day in order to obtain a suitable level of vitamin D without risk of sunburn, it was concluded that noon is best during winter, as determined previously. For skin type II when exposing head, exposure period in winter varies between 30 and 130 min, according to latitude, except for South Patagonian sites. During summer, noon seems to be a good time of day for short periods of exposure, while during leisure times, longer periods of exposure without risk of sunburn are possible at mid-morning and mid-afternoon. At 3 h from noon, solar zenith angles are almost the same for sites between the tropics and North Patagonia, and at 4 h from noon, for all sites. Then, in these cases, the necessary exposure periods varied slightly between sites, only due to meteorological differences.     

24-Dehydrovitamin D is potent inhibitor of rat liver microsomal vitamin D-25-hydroxylase

A pathway has been described in the skin for the synthesis of 24-dehydrovitamin D3 (delta 24D3) from 24-dehydroprovitamin D3. The physiologic function of delta 24D3 is unknown, but has been proposed as a potential inhibitor of hepatic vitamin D-25-hydroxylase. We validated an assay for vitamin D-25-hydroxylase in rat hepatic microsomes, using nanomolar amounts of [3H]D3 as substrate, and found that delta 24D3 competitively inhibits vitamin D-25-hydroxylase activity. The apparent Ki was approximately 17 nM, indistinguishable from the Km of approximately 15 nM, suggesting that both delta 24D3 and cholecalciferol have similar affinity for the enzyme. We found no [3H]delta 24D3 in serum or liver extracts after repletion of vitamin D-depleted rats with [3H]vitamin D3 for 4 h or 6 days. A dose of 1 microgram delta 24D3 to vitamin D- and calcium-depleted rats was unable to promote any elevation in the 45Ca transport by everted duodenal sacs or to increase levels of plasma calcium: thus no evidence for biological conversion of delta 24D3 to vitamin D3 was observed. Further studies are needed to determine whether delta 24D3 is released from the skin to the circulation and is taken up by the liver, before physiological relevance can be attributed to this inhibitor.     

A novel pathway for hormonally active calcitriol

Calcitriol [1alpha,25(OH)2D3], the hormonally active form of vitamin D3 (D3) is produced in both renal and extrarenal tissues. Our findings demonstrate that physiological doses of UVB radiation at 300 nm induce the conversion of 7-dehydrocholesterol (7-DHC) via preD3 and D3 into calcitriol in the pmol range in epidermal keratinocytes. The hydroxylation of photosynthesized D3 to calcitriol is strongly suppressed by ketoconazole, a known inhibitor of cytochrome P450 mixed function oxidases. The UVB-induced formation of calcitriol in human skin is demonstrable in vivo by the microdialysis technique. These results suggest that human skin is an autonomous source of hormonally active calcitriol.     

Vitamin D and overall mortality

Vitamin D is a steroid molecule, mainly produced in the skin that regulates the expression of a large number of genes. Several meta‐analyses of epidemiological studies support the evidence that low vitamin D serum level, which is highly prevalent worldwide, could be a ‘new’ risk factor for many chronic diseases including cancer, and for all‐cause mortality. A meta‐analysis in healthy subjects suggested that current doses of vitamin D supplements could be associated with decrease in total mortality rates. However, these associations are insufficient to establish causality between vitamin D and all‐cause mortality. Furthermore, long‐term health effects of high doses of vitamin D, that is, prolonged supplementation and association with different baseline vitamin D levels, remain to be investigated. Several trials are ongoing but population‐based, placebo‐controlled randomized trials with total mortality as the main endpoint should be planned to confirm a real beneficial effect of vitamin D for non‐skeletal diseases and to prove causality.     

Cellular and molecular effects of vitamin D on carcinogenesis

Epidemiologic data suggest that the incidence and severity of many types of cancer inversely correlates with indices of vitamin D status. The vitamin D receptor (VDR) is highly expressed in epithelial cells at risk for carcinogenesis including those resident in skin, breast, prostate and colon, providing a direct molecular link by which vitamin D status impacts on carcinogenesis. Consistent with this concept, activation of VDR by its ligand 1,25-dihydroxyvitamin D (1,25D) triggers comprehensive genomic changes in epithelial cells that contribute to maintenance of the differentiated phenotype, resistance to cellular stresses and protection of the genome. Many epithelial cells also express the vitamin D metabolizing enzyme CYP27B1 which enables autocrine generation of 1,25D from the circulating vitamin D metabolite 25-hydroxyvitamin D (25D), critically linking overall vitamin D status with cellular anti-tumor actions. Furthermore, pre-clinical studies in animal models has demonstrated that dietary supplementation with vitamin D or chronic treatment with VDR agonists decreases tumor development in skin, colon, prostate and breast. Conversely, deletion of the VDR gene in mice alters the balance between proliferation and apoptosis, increases oxidative DNA damage, and enhances susceptibility to carcinogenesis in these tissues. Because VDR expression is retained in many human tumors, vitamin D status may be an important modulator of cancer progression in persons living with cancer. Collectively, these observations have reinforced the need to further define the molecular actions of the VDR and the human requirement for vitamin D in relation to cancer development and progression.     

1,25-Dihydroxyvitamin D3 stimulated increase of 7,8-didehydrocholesterol levels in rat skin

A convenient, accurate assay was developed for determining skin cholesta-5,7-dien-3 beta-ol (7,8-didehydrocholesterol) concentrations. Ultraviolet spectrophotometry provided quantitation of the sterol from rat skins following saponification and chromatography on Lipidex and high-performance liquid chromatography. Correction for recoveries was accomplished by using 7,8-didehydro[3 alpha-3H]cholesterol as an internal standard. Chronic dosing of vitamin D-deficient rats with 1,25-dihydroxyvitamin D3 caused a 4-fold increase in skin 7-dehydrocholesterol content. This rise was not the result of changes in food consumption, body weight, or plasma calcium. Cholesterol concentrations were not significantly elevated although some of the other nonsaponifiable lipid components found in the high-performance liquid chromatogram appeared to be increased by the treatment. These results suggest that the vitamin D hormone 1,25-(OH)2D3 may exert a positive feedback regulation on the production of vitamin D3 in skin.     

Vitamin D analogues in the treatment of psoriasis.

Psoriasis is a chronic hyperproliferative skin disease in which inflammatory and immunologic processes may play important pathophysiologic roles. Recently the skin has been identified as a target tissue for vitamin D. Because 1,25-dihydroxy vitamin D3 inhibits epidermal proliferation and promotes epidermal differentiation, it has been introduced for the treatment of psoriasis vulgaris. In addition to 1,25-(OH)2-D3, synthetic vitamin D3 analogues have undergone clinical evaluation. Calcipotriol (INN) (calcipotriene [USAN]) has been studied most extensively. Compared with 1,25-(OH)2-D3, calcipotriol is about 200 times less potent in its effects on calcium metabolism, although similar in receptor affinity. Topical calcipotriol 50 micrograms/g applied twice daily is efficacious and safe for the treatment of psoriasis. Because topical calcipotriol is slightly more efficacious than betamethasone 17-valerate and dithranol, calcipotriol should be considered a first line drug in the management of psoriasis. These results illustrate that it is possible to separate the vitamin D effects on the cellular level from those on calcium metabolism not only in vitro, but also in a clinical setting.     

The evolutionary significance of vitamin D, skin pigment, and ultraviolet light.

Vitamin D is essential for normal growth, calcuim absorption, and skeletal development. Vitamin D deficiency can cause death, immobilization, or pelvic deformities which prevent normal childbirth. In the past these problems were extremely common in North America and Europe, and were only elminated by adding vitamin D to food. Prior to that, variations in available vitamin D affected health, survival and reproductive efficiency sufficiently to have evolutionary significance. Vitamin D is naturally present in few foods; most comes from the photo-conversion of 7-dehydrocholesterol in skin. The limiting factor in this conversion is the availability of ultraviolet light less than310 nm. Seasonal and geographic variations in natural ultraviolet radiation cause parallel variations in blood vitamin D levels, intestinal calcuim absorption, and clinical vitamin D deficiency. These physiological variations can be abolished by exposure to comparable artificial ultraviolet radiation, or by dietary vitamin D supplements. Ultraviolet radiation less than310 nm is absorbed by skin pigment, but is also increases skin pigmentation. This has led to the hypothesis that skin pigment regulates skin vitamin D production. Little direct evidence exists to test this reasonable hypothesis, but necessary and sufficient conditions for establishing it can be outlined. Until this hypothesis is experimentally tested, it is impossible to evaluate the corollary hypothesis: that racial variations in the efficiency of cutaneous vitamin D production restricted the evolution of dark-skinned peoples to tropical latitudes and thereby caused the geographic distribution of the races.     

Skin is an autonomous organ in synthesis, two-step activation and degradation of vitamin D(3): CYP27 in epidermis completes the set of essential vitamin D(3)-hydroxylases

The current understanding of the vitamin D(3) system shows skin as the unique site of vitamin D(3) production and liver is thought to be the main site of conversion to 25(OH)D(3). Skin is capable of activating 25(OH)D(3) via 1alpha-hydroxylation and the resulting 1alpha,25(OH)(2)D(3) plays a role in epidermal homeostasis in normal and diseased skin. It also rapidly up-regulates the major vitamin D(3) metabolizing enzyme 24-hydroxylase at the mRNA level, which is an established indicator for 1alpha,25(OH)(2)D(3)-presence. We investigated the capability of primary human keratinocytes to produce 25(OH)D(3) and subsequent metabolites from vitamin D(3). Thus, by orchestrating the entire system of production, activation and inactivation, skin could be independent of other organs in supply of hormonally active vitamin D(3). First, we demonstrated substantial conversion of (3)H-D(3) to (3)H-25(OH)D(3) in primary human keratinocytes. 25-Hydroxylation was slow, followed first order rate kinetics and was not saturable under our experimental conditions. Then we showed expression of 25-hydroxylase mRNA and compared it to levels of 1alpha-hydroxylase and 24-hydroxylase. Pre-incubation with vitamin D(3) resulted in dose and time dependent up-regulation of 24-hydroxylase mRNA, whereas neither 1alpha-hydroxylase nor 25-hydroxylase expression was affected. Since both, D(3) and 25(OH)D(3) are lacking intrinsic 24-hydroxylase-inducing capacity, up-regulation had to be the consequence of a two-step activation process via 25-hydroxylation and subsequent 1alpha-hydroxylation. 24-Hydroxylase-activities closely followed the corresponding mRNA levels. When 1alpha,25(OH)(2)D(3) itself or its precursor 25(OH)D(3) were used as inducing agents, 24-hydroxylase mRNA and enzyme activity followed a transient time course. In contrast, induction observed with physiological doses of D(3) remained high, even after a 20 h-time period. These differing characteristics may be explained by the slow but constant formation of 1alpha,25(OH)(2)D(3) from a large reservoir of D(3) in the target cell, providing constant supplies for induction.     

Sunlight,skin cancer and vitamin D: What are the conclusions of recent findings that protection against solar ultraviolet (UV) radiation causes 25-hydroxyvitamin D deficiency in solid organ-transplant recipients,xeroderma pigmentosum,and other risk groups?

A connection between vitamin D deficiency and severe health problems including various types of cancer has been demonstrated. We have shown that patients that have to protect themselves against solar UV radiation for medical reasons, including patients with xeroderma pigmentosum (XP), basal cell nevus syndrome (BCNS), lupus erythematodes (LE) or transplant recipients, are at risk to develop vitamin D deficiency. We conclude that 25-hydroxyvitamin D serum levels as a measure of vitamin D status have to be analyzed in patients that have to protect themselves against solar UV radiation for medical reasons. Suboptimal vitamin D status has to be substituted (e.g. via oral treatment) to protect against serious vitamin D deficiency-related health problems without increasing the risk to develop solar UV-induced skin cancer. Our finding that protection against solar UV radiation causes vitamin D deficiency underlines the need for re-defining dermatological recommendations for solar UV protection in skin cancer prevention programs.