Vitamin D-production and photocarcinogenesis in human skin.
Vitamin D deficiency and skin carcinogenesis are both issues related to solar radiation and are still unresolved in terms of defining proper limits for UV exposure. Both of these problems are of increasing significance worldwide. This project has attempted to find the optimal balance between negative (skin carcinogenesis) and positive (vitamin D production) effects of UV radiation. Known action spectra, an accurate radiative transfer model, epidemiological and other relevant data were applied to define the limits for optimal UV exposure. Skin cancer incidence rates in connection with environmental UV radiation, and vitamin D production from sunlight and from artificial UV sources were investigated by using different mathematical models. The central hypothesis behind this project was that one may arrive at a reliable balance between negative (carcinogenesis) and positive (vitamin D production) effects of ultraviolet (UV) radiation exposure. Attempting to find the balance, this project aimed: •To study vitamin D status and skin cancer incidence rate, and relate them with ambient UV radiation at different latitudes; •To find optimal mathematical models describing the relationship between skin cancer incidence rates and UV exposure, and to estimate the thresholds for carcinogenic UV exposure; •To characterize, in an analytical form, different UV sources with respect to vitamin D production, and to estimate UV exposures which are sufficient for obtaining an optimal vitamin D status; •To search for the most carcinogenic UV region by analyzing epidemiological results; •To find optimal time for sun exposure during the day maximizing the benefits (vitamin D production) and limiting the risks (skin cancer induction) associated with UV exposure. The calculated latitudinal variations of UV doses responsible for biological responses were more pronounced for shorter wavelengths. The north - south gradient of melanoma and non-melanoma skin cancer incidence was influenced differently by UVA and UVB. Squamous cell carcinoma (SCC) was more susceptible to UVB, whereas cutaneous melanoma (CM) was dependent on both UVB and UVA. Thus, the role of UVA is now becoming of higher concern. The ln-ln model showed that SCC depends on the total UV exposures, while basal cell carcinoma (BCC), and even more, CM, depend on exposure patterns. The sigmoidal model indicated that the percentage of CM caused by other factors than UV is 5 to 11%, (i.e. for zero UV exposure). The presumption for this calculation was that incidence rate was 100% for maximum UV exposure.The percentages for BCC and SCC were less than 1% in case of zero UV exposure. Latitudinal gradients were obtained for UVB which is responsible for vitamin D production. However, no latitudinal gradient was found for the serum 25(OH)D concentration, as seen by analyses of published investigations. In addition, theoretically estimated seasonal variation of vitamin D production at different latitudes did not correlated with the reported concentrations of serum 25(OH)D. Around 50% winter to summer increase in serum 25(OH)D was observed in countries further away from the Equator than 23 degrees latitude. A limit was observed for vitamin D production, as it reaches a plateau where UV exposure level is no longer efficient to induce any additional vitamin D in human skin, and only increases skin cancer risk. It was found that after a fast initial increase, the vitamin D production curve rises to a maximum value of around 55 nmol/L. UV exposure is less efficient if the baseline concentrations of 25(OH)D are higher than 50-60 nmol/L. It is still not absolutely clear which UV dose or spectral composition is optimal, but this work uncovered the most reliable solutions from probable ones. It can be concluded that the most beneficial and least dangerous exposures are low (omit low?) suberythemal ones received around midday. This was concluded after determining the variation of the UVA to UVB ratio during the day.
Solar radiation is the main source of ultraviolet (UV) radiation for humans. UV exposure is essential for producing vitamin D. It is a well established fact that vitamin D increases the absorption of calcium which is necessary for the building and maintenance of bones and muscle health. Vitamin D deficiency leads to skeletal disease like osteoporosis and rickets. Furthermore, vitamin D contributes to the prevention of cardiovascular disease, diabetes, certain types of cancer (prostate, colorectal, breast) and contributes to a better outcome of treatment. It is possible to increase the blood level of vitamin D through supplementation. However, commonly recommended daily intakes of vitamin D (400-800 IU) are not sufficient. People can get enough vitamin D by cutaneous synthesis through sunlight exposure only if the radiation contains sufficient UVB. Despite all these benefits, UV has also adverse effects, and, therefore, may be considered to be like a double-edged sword. Excessive UV exposure leads to photoaging and to photoimmunosuppression. UV is a major environmental risk factor responsible for skin cancer, including cutaneous melanoma (CM), the deadliest of the skin cancers, which is increasing in incidence in several white populations. There is strong epidemiological evidence that squamous cell carcinoma (SCC) is linked to a high cumulative dose of UV exposure. This affliction can be prevented by the use of sunscreens as they effectively absorb UVB. The protective role of sunscreens in basal cell carcinoma (BCC) development is not so evident due to the long latency period between the time of UV damage and the manifestation of the disease. BCC and CM incidence reduction through sunscreen use has not yet been proven, and, in fact, it is a controversial matter. Diseases caused by both over- and under-exposure to sunlight are very common and it is necessary to assess further how big the optimal UV exposure is. The conducted work allowed to define a proper UV exposure. We were convincing scientific community and doctors that a controlled sun exposure (as well as phototherapy) may be more advantages than harmful if one considers that vitamin D production in the skin is a saturation process. The initial (pre-exposure) status of calcidiol and the efficiency of solar UV radiation in producing vitamin D at a day time of interest should be considered prior self-tanning. Despite the fact that best time for controlled sun exposure is the midday, a person easily exceeds the optimal exposure time and get a sunburn. Therefore, we pointed out how the pattern of sun exposure of general population must change in order to decrease a total UV dose. The knowledge gained during the present project stimulated the usage of modern communication devices for warning the public about UV danger and efficient solar exposure, as well as personal dosimeters and further education on environmental health for prevention of UV over exposure.
Vitamin D production and photocarcinogenesis in human skin
Two mathematical models describing skin response to ultraviolet (UV) exposure were developed in 2015. These models allow to estimate vitamin D production from different UV sources and to evaluate the importance of UV radiation on incidence of skin cancer.
The definition of proper UV exposure is still under debate mainly because of vitamin D deficiency which is caused by insufficient UV exposure while an overexposure increases the risk of skin cancer. The impact of UV radiation on skin cancer risk was investigated using ln-ln model: ln(RTD)=A(ln(UV)) where relative tumour density (RTD) on different body parts is related to annual UV-effective dose and biological sensitivity to UV radiation (A) which has only slightly changed for basal cell carcinoma (BCC) and cutaneous melanoma (CM) during last decades. However, increased biological amplification factor (A) for squamous cell carcinoma (SCC) indicates a change of the exposure habits in Norwegian population. This model also clearly showed that SCC is dependent on total UV exposure, while BCC, and CM to an even greater extend, are dependent on exposure pattern. The UV dose–response curve for vitamin D generation in humans, as measured by the increments of serum 25(OH)D, is not linear with increasing UV doses and reaches a plateau at about 55 nmol/L after 4–5 weeks. About a half of this increase is equal to the difference between winter and summer 25(OH)D levels, and may be reached after 23 SEDs. The increments decrease with increasing baseline concentration of serum 25(OH)D, and the efficiency of only 0.7 nmol/L per SED is expected on the average when initial concentrations are higher than 50–60 nmol/L. A whole body exposure to 2 SEDs of UVB radiation 3 times per week is expected to rise serum 25(OH)D with an initial rate of 3.9 nmol/L per SED, bringing a winter level of serum 25(OH)D up to a summer level. In addition to mathematical analysis, an open observational experiment was conducted while been involved in another study to clarify if UV exposure has any effect on serum cobalamins (also called vitamin B12), as compared to vitamin D levels, in healthy volunteers. Multiple exposures to UV radiation gave a significant increase in vitamin D levels, but had no effect on cobalamin concentrations. The presented results have been used in the doctoral thesis entitled "Evaluations of skin cancer induction versus vitamin D production from UV exposure". The thesis was submitted to the University of Oslo on 27 February 2015 and successfully defended on 19 January 2016.
UV-indusert D-vitamin og kutan karsinogenese hos mennesker
Ultrafiolett stråling (UV) er en viktig miljøfaktor i utviklingen av alle typer hudkreft. Det er en utfordring at solens UV-spekteret også er hovedkilden til D-vitamin. Prosjektet har utviklet ulike matematiske modeller for å beskrive disse to motstridende biologiske prosesser.
To ulike spektrale komponenter av UV-stråling (UVA og UVB) og total UV-dose mottatt av huden kan gi forskjellige helseeffekter. Induksjon av hudkreft og produksjon av D-vitamin er kompliserte prosesser hvor en ikke-lineær sammenheng mellom dissen effektene og UV-dosen er observert. I våre studier har vi analysert risiko for hudkreft som varierer med breddegrad, tid på døgnet og årstid ved å ta hensyn til eksponering av ulike anatomiske områder og størrelser på hudoverflaten mot solen. Vi har funnet ut at en sigmoidal responskurven beskriver best forekomsten av hudkreft og effektiv årlig UV–dose for erytem. Beregningene viser at forekomsten av hudkreft i omtrent ti prosent av årlige tilfeller av kutan melanom kan være relatert til andre årsaker enn soleksponering, mens plateepitelkreft og basalcellekreft er forårsaket utelukkende av UV-eksponeringen. Imidlertig kunne de anvendte modellene ikke identifisere en sikker UV-dose for lavest mulig risiko for hudkreft. Fravær av en sikker UV-dose skaper utfordringen for anbefalinger av optimal soleksponeringsmønster med hensyn til produskjon av D-vitamin. Mer enn 90% av D-vitamin fremstilles ved uforutsett eksponering mot solen. Siden mange mennesker i verden har D-vitamin mangel, er det åpenbart at folk ikke tilbringer nok tid i solen. I modellene har vi også variert klokkeslett for UV-eksponeringen for å se på effektiviteten til syntese av D-vitamin og induksjon av melanom. Våre beregninger viser at den sikreste tiden for soleksponering (bare 10-15 minutter) kan være mellom et par timer før og rundt middag. Denne konklusjonen er i god korrelasjon med tidligere funn om at UVA har en stor rolle i fremkallingen av kutan melanom.
Vitamin D-production and photocarcinogenesis in human skin
We have in 2013 worked mostly with ultraviolet radiation (UV) from the carcinogenic point of view. Epidemiological data and implicit-explicit analysis of ambient UV doses have helped us to reach several conclusions about skin response to large and small doses of UVA and UVB radiations.
Solar radiation is a risk factor for all three major forms of skin cancer. For squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) there is a clear relationship with the UV exposure where UVB is the most important etiological factor. Nevertheless, studies on latitudinal gradients of UVA, UVB and cutaneous melanoma (CM) incidence rates indicate a significant role of UVA. Furthermore, the relative roles of accumulated versus intermittent exposure should be considered as two groups with a different causative impacts of UVA and UVB radiations. Further investigations on the functional UV dependency of the rates of skin cancer indicated that the differences between relative tumour density on heavily sun exposed skin and less exposed skin are large for SCC, smaller for BCC and nonexistent for CM. Uncertainties regarding the CM dose-response relationship promoted us to put this most problematic case under the question of adverse effect of sunbed emitting high fluence rates of UVA. We found that sunbed use has not been a major factor for CM induction for the time period studied and for younger age group (15 - 54 years old). However, for men and women older than 55 years, the incidence rates are still increasing. Taking into account all considerations relevant for melanomagenesis, UVA has a systemic cumulative action promoting UVB-induced premelanoma damage. This conclusion includes also negative stimulus of aberrant UVA to UVB ratio and inadequate cutaneous level of 25-hydroxyvitamin D.
Vitamin D-production and photocarcinogenesis in human skin
Investigations of UV penetration into human skin and its effects are the foci of this project. We are analysing the feasibility of our optical transfer model connecting the response of biological tissue with exact UV spectral regions which are responsible for vitamin D synthesis and skin cancer generation.
The main reasons for health problems related to sun exposure levels and, at the same time, the strategies of skin protection depend on UV penetration into human skin and must be investigated in more details. Nevertheless, the first scientific attempts to adapt biological action spectra for the optimization of the beneficial and harmful UV effects cannot be made solely from the known physiological properties of the skin. Our recent publications indicate that the theoretically estimated vitamin D level in blood and the risk of skin cancer do not follow the measured ones in a standard manner.
Analysis of the latitudinal relation between solar radiation and photocarcinogenesis showed that environmental risk for cutaneous malignant melanoma can only partly be explained by ambient UV doses. However, most investigators tend to conclude that UV is a major melanomagenic agent. We have found a possible solution taking into account the known action spectra for solar carcinogenesis, as well as effects arising in the UVA region.
In addition to UVA-related etiology, we paid attention to the seasonal cutaneous synthesis of vitamin D where photochemical production is driven only by UVB radiation. It was concluded that the photosynthetic capacity of UV to give vitamin D, strongly implicates changing physical properties of the skin. Finally, on theoretical platform we discovered an additional meaning of biological UVA and UVB sensitivity. When differently pigmented skin is used for simulations, these two UV regions are divided at 325 nm by crossing point of so-called reflectance spectra (manuscript in preparation).
On the basis of recent findings (still susceptible to alternative explanations), we have started to use our bio-optical model. A coupled air-tissue model with the radiative transfer equation generates well a possible cutaneous response function in the UV-VIS region. The first results were presented in the 36th Meeting of the American Society for Photobiology (Montreal, Canada, 2012) and, with mathematical support, are being prepared for publication. At this stage of our project we are evaluating optical transfer diagnosis for a further spectroscopic study on human skin in vivo.
Vitamin D-dannelse og UV karsinogenese
Solstråling er hovedkilden til D-vitamin hos mennesker, men samtidig en viktig årsak til alle hudkreftformer. Balansen mellom disse to effektene (den positive og den negative), vil bli studert ved beregninger, spektroskopi og epidemiologi.
D-vitaminmangel og hudkreft representerer store helseproblemer og kostnader både i Norge og globalt. Balansen mellom dem avgjøres av soldosen og eksponeringsmønsteret (bråsoling vs jevn eksponering). Dessverre fokuseres det i dag i Norge langt mer på hudkreft enn på D-vitaminets positive virkning på en rekke helsetilstander. Vår gruppe følger aktivt med i den internasjonale D-vitaminforskningen. Vi har allerede vist at en bedret D-vitaminstatus vil redde langt flere liv enn de ca 250 årlige dødsfallene av hudkreft i landet. Mye av grunnkunnskapen om D-vitamindannelse i hud er ennå ukjent. Her vil beregninger av UV penetrasjon i hud, målinger av reflektans av solstråling fra hud gi uunværlige bidrag. Den reflekterte strålingen speiler den absorberte strålingen, og vi har utstyr til å måle reflektansen spektralt fra forskjellige hudtyper, normal så vel som syk hud, noninvasivt. På den måten vil vi kunne bestemme D-vitamindannelsen i forskjellige hudlag.Diffusjonsberegninger vil så gi oss D-vitaminmengdene som når fram til blodsirkulasjonen i løpet av sin levetid. På liknende vis vil vi kunne beregne de karsinogene UV-dosene som når ned til forskjellige hudlag. Forskjellige hudkrefttyper oppstår i forskjellig dybde.
Beregningene vil foregå i samarbeid med fysikkgrupper ved de fysiske instituttene ved universitetene i Bergen og i Oslo. (Prof. Arne Dahlback og prof. Jakob Stamnes).
Vi vil også fortsette våre epidemiologiske studier av hudkreft og samholde insidensratene på forskjellige steder i Norge og i verden for øvrig med be beregnede UV-dosene, de årlige så vel som de sesongvise. Disse beregningene vil bli evaluert ved å sammenligne dem med målte doser ved enkelte målestasjoner i Norge og i utlandet.
Daily, seasonal, and latitudinal variations in solar ultraviolet A and B radiation in relation to vitamin D production and risk for skin cancer.
Int J Dermatol 2016 Jan;55(1):e23-8. Epub 2015 nov 6
PMID: 26547141 - Inngår i doktorgradsavhandlingen
Layer Thickness of SPF 30 Sunscreen and Formation of Pre-vitamin D.
Anticancer Res 2016 Mar;36(3):1409-15.
Phototherapy and vitamin D.
Clin Dermatol 2016 Sep-Oct;34(5):548-55. Epub 2016 mai 20
The relationship between UV exposure and incidence of skin cancer.
Photodermatol Photoimmunol Photomed 2015 Jan;31(1):26-35. Epub 2014 okt 13
PMID: 25213656 - Inngår i doktorgradsavhandlingen
Influence of multiple UV exposures on serum cobalamin and vitamin D levels in healthy females.
Scand J Public Health 2015 May;43(3):324-30. Epub 2015 mar 4
Vitamin D and ultraviolet phototherapy in Caucasians.
J Photochem Photobiol B 2015 Jun;147():69-74. Epub 2015 mar 23
PMID: 25846579 - Inngår i doktorgradsavhandlingen
Minimal and maximal incidence rates of skin cancer in Caucasians estimated by use of sigmoidal UV dose-incidence curves.
Int J Hyg Environ Health 2014 Nov;217(8):839-44. Epub 2014 jun 17
PMID: 25023193 - Inngår i doktorgradsavhandlingen
Ultraviolet-radiation and health: optimal time for sun exposure.
Adv Exp Med Biol 2014;810():423-8.
PMID: 25207380 - Inngår i doktorgradsavhandlingen
Sunbed use and cutaneous melanoma in Norway.
Scand J Public Health 2013 Dec;41(8):812-7. Epub 2013 aug 1
Cutaneous malignant melanoma incidence rates in Norway.
Scand J Public Health 2013 Jun;41(4):336-9. Epub 2013 feb 25
Biologically efficient solar radiation: Vitamin D production and induction of cutaneous malignant melanoma
Dermatoendocrinol 2012; 4:1-9
UV-Radiation and Health: Optimal Time for Sun Exposure
In: Reichrath J, ed. Sunlight, Vitamin D and Skin Cancer, Second Edition. In Press 2012
North-South gradients of melanomas and non-melanomas. A role of vitamin D?
Dermatoendocrinol. Accepted 2012
Sol, solarier, D-vitamin og hudkreft: Mye nytt under solen
Bestpractice Onkologi 2012; 6:28-32
Penetration of optical radiation into tissue
Abstract book 36th Meeting of the American Society for Photobiology, 2012: p. 78, Montreal, Canada
Malignant melanomas on head/neck and foot: differences in time and latitudinal trends in Norway
J. Eur. Acad. Dermatol. Venereol. 2011, in press
Solar radiation and human health
Rep. Prog. Phys. 2011, 74, 066701-(56pp)