UV Index 3 as a cut-off

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Relative Response (Wn) UV Index - History The UV index was first introduced in Canada in 1992 in response to growing concerns about the potential increase of ultraviolet radiation due to ozone

UV Index 3 as a cut-off Michael Kimlin CRE Sun and Health USC, AUSTRALIA In 1995, the World Health Organization (WHO) with the World Meteorological Organization (WMO), the United Nations Environment

1 Relative Response (Wn) UV Index - History The UV index was first introduced in Canada in 1992 in response to growing concerns about the potential increase of ultraviolet radiation due to ozone depletion(fioletov et al., 2010). UV Index 3 as a cut-off Michael Kimlin CRE Sun and Health USC, AUSTRALIA In 1995, the World Health Organization (WHO) with the World Meteorological Organization (WMO), the United Nations Environment Program (UNEP), the International Agency for Cancer Research (IARC) and the International Commission on Non-Ionizing Radiation Protection (ICNIRP) launched the Global Solar UV Index (UVI) as a vehicle to visualize the amount of UV radiation reaching the Earth s surface (Italia and Rehfuess, 2012, Meves et al., 2003, Azooz and Jallo, 2015). UV Index The UV Index is a simple and informative way of describing the daily danger of solar UV radiation intensity (WHO, 2015). The UV index range is expressed as a numeric value and as bands of color representing the risk level of skin damage due to UV exposure from Low (0-2), Green, to Extreme (11+), Purple. The higher the index value, the greater the potential for damage to the skin and eye, and the less time it takes for harm to occur. Low (0-2): Green Moderate (3-5): Yellow High (6-7): Orange Very High (8-10): Red Various Ultraviolet Exposure categories UV Index Calculation The calculation of UVI involves both effect of different wavelengths, and human susceptibility to them. The calculations are weighted to those UV wavelengths that human skin is most sensitive to according to the McKinlay- Diffey erythema action spectrum curve (WHO, 2002). The UVI is a unitless quantity defined by the formula: 1.00E E E E E Wavelength (nm) Extreme (11+): Purple In reporting the UVI, most emphasis is placed on the maximum UV level on a given day. This occurs around solar noon. Depending on geographical location and whether daylight saving time is applied, solar noon takes place between noon and 2 p.m. 1

The UV energy spectrum (radiation intensity) and the erythemal action spectrum (skin sensitivity) across the range of UV wavelengths is shown below.

Absorption by stratospheric ozone is the main cause for the decrease in UV intensity by several orders of magnitude with decreasing wavelength.

UV induced erythema is primarily caused by UVB, with UVA being 200-300 times less effective than UVB (Halliday and Lyons, 2008).

2 The UV energy spectrum (radiation intensity) and the erythemal action spectrum (skin sensitivity) across the range of UV wavelengths is shown below. The multiplication of these two gives the erythemal UV spectrum, and the surface below this graph (shown in yellow) is the UV index. The value of the UVI from this measurement is 6.3. Absorption by stratospheric ozone is the main cause for the decrease in UV intensity by several orders of magnitude with decreasing wavelength. The erythemal action spectrum highlights that erythemal potential increases with decreasing wavelength. UV induced erythema is primarily caused by UVB, with UVA being times less effective than UVB (Halliday and Lyons, 2008). Ultraviolet radiation measured from space and on the ground at noon during the summer (Fioletov et al., 2010) Figure by Marc Allaart, KNMI, De Bilt (2012) Minimal Erythemal Dose (MED) In order to measure the biological effects of UVR, the concept of minimal erythemal dose (MED) has been developed. The study of the erythemal influence has been frequently based on the minimum dose of UV erythemal radiation that will produce a noticeable reddening of human skin that has not been previously exposed to solar radiation. This dose is known internationally as the MED and is always related to a specific skin type. If the UV irradiance is 1 MED/hour, then it will take an hour for a person exposed to this irradiance to receive the minimum erythemal dosage. 1 MED corresponds to a total dose of 210 J/m². (Greinert et al., 2014). Biological Evidence for low dose UV (less than UVI 3) 2

Low Dose UV and Skin Cancer Squamous Cell Carcinoma Low dose UV has been shown to induce SCC in hairless mice with doses as low as 0.

3 Low Dose UV and Skin Cancer Squamous Cell Carcinoma Low dose UV has been shown to induce SCC in hairless mice with doses as low as MED per day, although tumors arose more rapidly with increasing UV doses (Rebel et al., 2005). Exposure to 8 mj cm ² UV (about 0.08 of an MED) is sufficient to induce SCC and AK with a latency time of days, with nearly all mice developing multiple skin tumors. Exposure of opossums (Monodelphis domestica) to 25mJcm ² UV from FS40 sunlamps three times per week for 81 weeks has also been shown to induce nonmelanoma skin tumours in about 75% of animals. This dose is about half an MED in the opossums, again showing that subinflammatory doses of UV are able to induce skin cancers in this animal. Weeks from first exposure UV-dose dependency of carcinogenesis in hairless mice , 0.08 and 1 MED correspond to 32, 80 and 1000 J/m² of F40 lamps, respectively. The tumour induction times at 0.08 MED/day originate from (Rebel et al., 2005). Kaplan-meier plots of the prevalence of NMSTs as a function of weeks from first exposure to UVB ( ) OR UVA ( ). Treatment groups were exposed to 250J/m² of UVR ( 150J/m² of UVB) from the FS40 sunlamps or ⁴ J/m² of UVA from the filtered F40BLB lamps three times per week for 81 weeks (Ley, 1997). 3

4 While the UVB component is largely responsible for erythema, there is about 20- fold more UVA than UVB within sunlight. Sub-erythemal UVA ( mj cm ² day ¹) has also been shown to cause SCC in mice (Berking et al., 2002). UVA (2500 mj cm ²) has also been shown to induce a single non-melanoma skin cancer in 30 irradiated opossums. Thus, experiments on UVA photocarcinogenesis indicate that skin cancer may be induced in the absence of UV-induced erythema. Inflammation from another cause may however be required for skin cancer development. In order to get information on the dose of UV that can cause skin cancer in humans, skin obtained from white skinned human donors who underwent cosmetic surgery was grafted onto immunodeficient (SCID or Rag-1) knockout mice, and exposed two to three times per week for up to 10 months with 40 mj cm ² UVB or solar-simulated UV consisting of 30 mj cm ² UVB and mj cm ² UVA. The UVB was filtered to remove wavelengths below 295 nm. UVB induced AK in 10% of grafts, and solar-simulated UV in 18% of grafts (Berking et al., 2002). Histological analysis of human adult skin grafts treated with MBA, UV or a combination of bothᵃ (Berking et al., 2002) Probability of tumor development vs. weeks of irradiation. Sencar mice were exposed to UVB/UVA radiation (triangles), UVA radiation (circles), or no radiation (squares). Skin tumors (ear and dorsum) are indicated by closed symbols, mammary tumors are indicated by open symbols (Berking et al., 2002) The study showed that at least in the absence of an immune system, UV can induce skin cancers in human skin with very low doses, within the order of 10 20% of an average human MED. Also, UVA contributes to the formation of tumors, as there was an increased incidence when UVA was included. Hence this suggests that human skin tumors may be induced with subinflammatory doses of UV. Irradiation of human skin grafted onto Rag-1 mice three times per week for 12 months with 50 mj cm ² UVB ( nm, peak 314 nm) caused the development of solar lentigo in 23%, and melanocytic hyperplasia in 68% of human skin grafts. The changes in melanocytes are associated with early malignancy. The induction of these lesions with such a low dose of UV is consistent with subinflammatory UVB being able to induce melanoma in human skin (Atillasoy et al., 1998). Pigmentation-related changes in human skin xenografts after one exposure of DMBA followed by UVB three times per week over 5 to 9 months. A: Dark pigmentation of skin grafted to SCID mouse after 9 months. B: Irregular pigmentation pattern with epidermal thickening of graft after 8 months. C: Solar lentigo; pigmented macule in center of skin graft after 5 months (Atillasoy et al., 1998). Melanoma UVA (2500 mj cm ²) and UVB (25 mj cm ², about 0.5 MED) have been shown to induce melanocytic hyperplasia in opossums (Ley, 1997). Weeks from first exposure Kaplan-meier plots of the prevalence of MH (B) as a function of weeks from first exposure to UVB ( ) OR UVA ( ). Treatment groups were exposed to 250J/m² of UVR ( 150J/m² of UVB) from the FS40 sunlamps or ⁴ J/m² of UVA from the filtered F40BLB lamps three times per week for 81 weeks (Ley, 1997). 4

5 Summary Animal Models Doses of UVB more than 10-fold lower to produce erythema can induce SCC in animal models. UVA at doses several hundred fold lower to produce erythema can induce skin cancers in animal models and at least contribute to photocarcinogenesis in human skin grafted onto immunodeficient mice. Therefore, it can be suggested that sub-erythemal UVB or UVA may cause melanocytic lesions in a variety of animal models and in human skin grafted onto immunoincompetent mice. This shows that it is possible for sub-erythemal doses of UV to cause skin cancer. Low Dose UV and immunosuppression However, the relative importance of subinflammatory compared to erythemal doses of sunlight in causing skin cancer in humans remains unknown. Low Dose UV and Immunosuppression It is now known that in order for skin cancers to develop, both genetic damage and immunosuppression is required. While it cannot be directly experimentally determined whether or not erythemal doses of UV are required for photocarcinogenesis in humans, photoimmunosuppression and gene mutations can be studied as surrogate markers because these two biologic events are essential for skin cancer induction. Sub-erythemal Doses of UV are Immunosuppressive in Humans Ultraviolet-induced immunosuppression is a key contributor to the development of skin cancer. There are different lab models to describe UV-induced immunosuppression: The local model is when the antigen is applied to UV-irradiated skin of unimmunized individuals. Systemic immunosuppression is when the antigen is applied to an unirradiated skin site of an unimmunized individual who has been exposed to UV at a different skin site. An established or memory immune response can also be suppressed by UV irradiation. 5

UVB and Immunosuppression Daily irradiations with a suberythemal UV dose of 144 mj cm ² UVB can cause increasing levels of immunosuppression (local immunosuppression) with increasing numbers of daily

Increasing doses of single exposures to UVB also cause greater levels of immunosuppression in humans with the suppression being discernible within 48h of irradiation with 300 mj cm ² UVB, which is

6 UVB and Immunosuppression Daily irradiations with a suberythemal UV dose of 144 mj cm ² UVB can cause increasing levels of immunosuppression (local immunosuppression) with increasing numbers of daily irradiations (Halliday and Lyons, 2008). Increasing doses of single exposures to UVB also cause greater levels of immunosuppression in humans with the suppression being discernible within 48h of irradiation with 300 mj cm ² UVB, which is subinflammatory (Poon et al., 2005). UVA and Immunosuppression UVA is immunosuppressive at doses much lower than are required for this waveband to cause erythema (Poon et al., 2005). Irradiation with UVA suppresses reactivation of memory immunity to nickel in humans. UVA also causes systemic suppression of recall immunity in humans (Fourtanier et al., 2005). In mice, UVA suppresses the induction of local immunosuppression and the reactivation of memory immunity. Systemic suppression of the induction of primary CHS can occur with three daily exposures to the relatively low UVA dose of 1680 mj cm ² (Byrne et al., 2002). It has to be noted that unlike UVB, UVA is immunosuppression but not until 48h following exposure. Single-exposure ultraviolet (UV) immunosuppression time course and dose response (Poon et al., 2005) Single-exposure ultraviolet (UV) immunosuppression time course and dose response (Poon et al., 2005) UV and Immunosuppression Humans are not exposed to pure UVB or UVA, but to sunlight, which consists of a mixture of these two wavebands. A single exposure to solar-simulated UV, less than half of what is required to cause erythema has been shown to suppress the reactivation of memory immunity to nickel in humans (Poon et al., 2005) In mice a dose of 1820 mj cm ² solar-simulated UV which is only half that required to cause barely detectable inflammation can cause systemic immunosuppression (Byrne et al., 2002). Summary Sub-erythemal doses of UVB can cause local immunosuppression. Erythemal doses + may be required for systemic immunosuppression in humans UV dose as low as 12.5% of an erythemal dose can cause systemic immunosuppression in mice (Byrne et al., 2002) UVA at doses far too low to be inflammatory can cause local and systemic immunosuppression in humans and mice. UV that mimics the UV portion of the solar spectrum is immunosuppressive in humans and mice at subinflammatory doses. Single-exposure ultraviolet (UV) immunosuppression time course and dose response (Poon et al., 2005) 6

Low Dose (sub erythemal) of UV are Mutagenic Melanomas have been shown to contain significantly elevated numbers of UVR signature mutations compared with internal cancers; Low Dose UV and genetic

7 Low Dose (sub erythemal) of UV are Mutagenic Melanomas have been shown to contain significantly elevated numbers of UVR signature mutations compared with internal cancers; Low Dose UV and genetic mutations Mutations that give cells a growth advantage inhibit cell death by apoptosis or other mechanisms, establish genomic instability or overcome senescence can all contribute to the development of cancer. Such mutations are an essential step in the formation of skin cancer; UV can cause gene mutations in normal keratinocytes that result in the formation of benign skin lesions, while inflammatory responses, developing for unknown reasons as a post-uv exposure event, drive progression beyond an initial lesion; UV induced mutations can cause epidermal cells to make pro-inflammatory factors or to induce them in the surrounding stroma, creating an oxidizing environment in which additional oncogenic mutations are likely to take place, even in the absence of UV. The high level of mutations in melanomas that have the signature of UVR-induced damage indicates that the normal mechanisms that detect and repair this damage must be defective in this system. UVR causes DNA damage in the form of cyclobutane pyrimidine dimers (CPD) and 6-4 photoproducts (6-4PP), which are repaired by nucleotide excision repair (NER) and if it not repaired, can lead to mutation. The 6 4PP are less abundant and efficiently repaired, whereas the more abundant CPDs repair is slower and misrepair of these lesions produce the UVR signature C>T and CC>TT mutations. Defects in checkpoint mechanisms have been identified in melanomas and are likely to be responsible for increased mutation load in melanoma. UVR causes both G1 and G2 phase checkpoint arrest in vitro cultured cells: The G1 arrest appears to be through a p53-dependent mechanism The G2 arrest is independent of p53, and involves a block in the cdc25- dependent activation of the mitotic cyclin dependent kinase (CDK) complexes (p16/cdkn2a) (A) Different forms of DNA damage are repaired by specific repair mechanisms. (B) The extent of damage and success of repair determine the outcome, either cell cycle checkpoint arrest to allow for repair and return to proliferation or where damage is too extensive for successful repair, senescence, or death (Pavey et al., 2013). Cell cycle checkpoints: Cell cycle checkpoints are triggered in response to specific stresses and utilize different signaling mechanisms to arrest the cells at specific points in the cell cycle until the stress has been resolved. (Pavey et al., 2013) 7

8 UVB and Mutation Sub-erythemal UV doses are able to induce mutations (Mouret et al., 2006). Chronic irradiation with 0.5 MED UV for 59 or 75 days has been shown to cause the formation of p53 patches in hairless mice. The majority of these patches contained mutant p53 (Rebel et al., 2005). Checkpoint Defects (G2 p16) The melanoma susceptibility gene CDKN2A which encodes the cell cycle inhibitor p16ink4a (p16) is commonly defective in melanoma. Mutations of p16/cdkn2a have also been identified in non-melanoma skin cancers (Pavey and Gabrielli, 2002). Average numbers of mutant p53 patches in Xpc-deficient mice (open diamonds) and wild-type littermates (closed diamonds) (n=4) at 1.0 of a wild-type MED/day. Wild-type SKH1 data at 1.0 MED (closed circles and regression line) are derived from (Rebel et al., 2005). P16/CDKN2A, which is functionally inactivated in a high proportion of melanoma cell lines and in 10-30% of tumors, is a direct effectors of cell cycle progression (Pavey et al., 2001). Melanoma associated mutations of p16 disrupt its ability to promote senescence arrest. In addition to this role, increased p16 expression has been correlated with the G2 phase checkpoint arrest in response to suberythemal UVR (Pavey et al., 2013). G2 phase checkpoint and repair response to UV lesions detected in S phase (Pavey et al., 2013) The studies show that in response to suberythemal dose of UVB, basal and suprabasal layer cells (keratinocytes and melanocytes h after exposure ) in human skin arrest in G2 phase, and this is associated with increased levels of p16 (Pavey et al., 2001). Summary Several studies identified p53 mutations in a majority of human non-melanoma skin cancers (NMSC) and the commonest preneoplastic lesion, actinic keratosis, from sun-exposed body sites (Roshan and Jones, 2012). Clusters of p53-positive epidermal keratinocytes (p53 patches) are clonal outgrowths of keratinocytes that contain mutations in p53 and are related to the formation of carcinomas (Nicolien et al., 2005). Loss of p16 function may not only provide a growth advantage by disabling the senescence mechanism, thus extending the proliferative capacity of the cells, but may also result in cells undergoing mitosis with an increased burden of UVinduced DNA mutations, the result of an inability to delay in G2 phase to permit complete repair of the UV-induced lesions(pavey and Gabrielli, 2002) It is therefore suggests that low dose UV is able to induce signature UV mutations. p16 expression is a delayed response, peaking at 24h after UV exposure. The proportion of cells expressing p16 dramatically increased at 16h post-irradiation with 250 Jm ² UVB, peaked at 24h, and substantially diminished by 72h postirradiation. Similar data were obtained with 150 and 875 Jm ² UVB. Photocarcinogenesis in humans could only occur in response to UV doses too low to cause erythema if these low doses are able to suppress immunity and mutate genes in humans 8

9 Skin Cancer may be induced with Sub-erythemal Doses of UV With low dose UV (less than an MED): Studies have indicated that sub-erythemal doses of UV may cause benign skin tumors. UV induced immunosuppression and gene mutations may be sufficient to cause skin carcinogenesis. Summary Other considerations: Most studies in this area (low dose UV) have been conducted in animal models large area of research; Limited human studies and epidemiological data Dose rate of UV UVI based on erythema as an end point Other possible factors to consider eye, Vitamin D (Prof Lucas this afternoon will discuss balance) Skin cancer may occur in response to lower doses of UV than are required to cause erythema. Skin cancer, immunosuppression and gene mutations can all occur in response to lower doses of UV radiation than are required to cause erythema (Halliday and Lyons, 2008). Thank you MED 9

10 References ATILLASOY, E. S., SEYKORA, J. T., SOBALLE, P. W., ELENITSAS, R., NESBIT, M., ELDER, D. E., MONTONE, K. T., SAUTER, E. & HERLYN, M UVB induces atypical melanocytic lesions and melanoma in human skin. The American journal of pathology, 152, AZOOZ, A. & JALLO, N Estimation of UV Index from Integrated Detector Type Measurements. American Institute of science 1, 5. BERKING, C., TAKEMOTO, R., BINDER, R. L., HARTMAN, S. M., RUITER, D. J., GALLAGHER, P. M., LESSIN, S. R. & HERLYN, M Photocarcinogenesis in human adult skin grafts. Carcinogenesis, 23, 181. BYRNE, S. N., SPINKS, N. & HALLIDAY, G. M Ultraviolet A Irradiation of C57BL/6 Mice Suppresses Systemic Contact Hypersensitivity or Enhances Secondary Immunity Depending on Dose. Journal of Investigative Dermatology, 119, FIOLETOV, V., KERR, J. B. & FERGUSSON, A The UV Index: Definition, Distribution and Factors Affecting It. Canadian Journal of Public Health / Revue Canadienne de Sante'e Publique, 101, I5-I9. FOURTANIER, A., MOYAL, D., MACCARIO, J., COMPAN, D., WOLF, P., QUEHENBERGER, F., COOPER, K., BARON, E., HALLIDAY, G., POON, T., SEED, P., WALKER, S. L. & YOUNG, A. R Measurement of Sunscreen Immune Protection Factors in Humans: A Consensus Paper. Journal of Investigative Dermatology, 125, GREINERT, R., DE VRIES, E., ERDMANN, F., ESPINA, C., AUVINEN, A., KESMINIENE, A. & SCHÜZ, J European Code against Cancer 4th Edition: Ultraviolet radiation and cancer. Cancer Epidemiology. HALLIDAY, G. M. & LYONS, J. G Inflammatory Doses of UV May Not Be Necessary for Skin Carcinogenesis. Photochemistry & Photobiology, 84, ITALIA, N. & REHFUESS, E. A Is the Global Solar UV Index an Effective Instrument for Promoting Sun Protection? A Systematic Review. Health Education Research, 27, KAPPES, U. P., LUO, D., POTTER, M., SCHULMEISTER, K. & RÜNGER, T. M Short- and Long-Wave UV Light (UVB and UVA) Induce Similar Mutations in Human Skin Cells. Journal of Investigative Dermatology, 126, KELLY, D. A., YOUNG, A. R., MCGREGOR, J. M., SEED, P. T., POTTEN, C. S. & WALKER, S. L Sensitivity to sunburn is associated with susceptibility to ultraviolet radiation-induced suppression of cutaneous cell-mediated immunity. The Journal of Experimental Medicine, 191, 561. KIM, S.-I., PFEIFER, G. P. & BESARATINIA, A Mutagenicity of ultraviolet A radiation in the laci transgene in Big Blue mouse embryonic fibroblasts. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 617, 71. LEY, R. D Ultraviolet radiation A-induced precursors of cutaneous melanoma in Monodelphis domestica. Cancer research, 57, MEVES, A., REPACHOLI, M. H. & REHFUESS, E. A Commentary Global Solar UV Index: a physician's tool for fighting the skin cancer epidemic.international Journal of Dermatology. References MOURET, S., BAUDOUIN, C., CHARVERON, M., FAVIER, A., CADET, J. & DOUKI, T Cyclobutane Pyrimidine Dimers Are Predominant DNA Lesions in Whole Human Skin Exposed to UVA Radiation. National Academy of Sciences. NICOLIEN, K., ANJA, W., SANDER, B., HENK, J. V. K. & FRANK, R. D. G Relationship between UV-induced mutant p53 patches and skin tumours, analysed by mutation spectra and by induction kinetics in various DNA-repair-deficient mice. Carcinogenesis, 26, PAVEY, S., CONROY, S., RUSSELL, T. & GABRIELLI, B Ultraviolet radiation induces p16cdkn2a expression in human skin. Cancer research, 59, PAVEY, S. & GABRIELLI, B α-melanocyte stimulating hormone potentiates p16/cdkn2a expression in human skin after ultraviolet irradiation. Cancer research, 62, PAVEY, S., RUSSELL, T. & GABRIELLI, B G 2 phase cell cycle arrest in human skin following UV irradiation. Oncogene, 20, PAVEY, S., SPOERRI, L., HAASS, N. K. & GABRIELLI, B DNA repair and cell cycle checkpoint defects as drivers and therapeutic targets in melanoma. Pigment cell & melanoma research, 26, PERSSON, A. E., EDSTROM, D. W., BACKVALL, H., LUNDEBERG, J., PONTEN, F., ROS, A. M. & WILLIAMS, C The mutagenic effect of ultraviolet-a1 on human skin demonstrated by sequencing the p53 gene in single keratinocytes. Photodermatology, Photoimmunology & Photomedicine, 18, 287. POON, T. S. C., BARNETSON, R. S. C. & HALLIDAY, G. M Sunlight-Induced Immunosuppression in Humans Is Initially Because of UVB, Then UVA, Followed by Interactive Effects. Journal of Investigative Dermatology, 125, REBEL, H., KRAM, N., WESTERMAN, A., BANUS, S., VAN KRANEN, H. J. & DE GRUIJL, F. R Relationship between UVinduced mutant p53 patches and skin tumours, analysed by mutation spectra and by induction kinetics in various DNArepair-deficient mice. Carcinogenesis, 26, RECIO, J. A., NOONAN, F. P., TAKAYAMA, H., ANVER, M. R., DURAY, P., RUSH, W. L., LINDNER, G., DE FABO, E. C., DEPINHO, R. A. & MERLINO, G Ink4a/arf deficiency promotes ultraviolet radiation-induced melanomagenesis. Cancer research, 62, ROSHAN, A. & JONES, P. H Chronic low dose UV exposure and p53 mutation: Tilting the odds in early epidermal preneoplasia? International Journal of Radiation Biology, 88, WIGAN, M., PINDER, A., GILES, N., PAVEY, S., BURGESS, A., WONG, S., STURM, R. A. & GABRIELLI, B A UVR-induced G2-phase checkpoint response to ssdna gaps produced by replication fork bypass of unrepaired lesions is defective in melanoma. Journal of Investigative Dermatology, 132, TEMIS UV radiation monitoring: UV index and UV dose, 10

The Global Solar UV Index and Health Effects of UV Exposure

German Meteorological Service, Human Biometeorology, Stefan-Meier-Str. 4, D-79104 Freiburg, Germany The Global Solar UV Index and Health Effects of UV Exposure Introduction Everyone is exposed to Ultraviolet