Comment on "the effects on human health from stratospheric ozone depletion and its interactions with climate change" by M. Norval, A. P. Cullen, F. R. de Gruijl, J. Longstreth, Y. Takizawa, R. M. Lucas, F. P. Noonan and J. C. van der Leun, Photochem. Photobiol. Sci., 2007, 6, 232.

An increase in solar ultraviolet-B (UVB) radiation reaching the earth's surface is an important consequence of stratospheric ozone depletion. UVB has important effects on human health, both beneficial and harmful. Recent research has found that solar UVB reduces the risk of over 20 types of cancer, respiratory diseases caused by viruses, autoimmune diseases, and, likely, several other diseases, in addition to the well-known effects on bone diseases. On the other hand, solar UVB is an important risk factor for non-melanoma skin cancer and cataracts. Human epidemiological studies have provided evidence that solar UVA may be a more important risk factor for melanoma than UVB. If this result is correct, melanoma risk is not related to ozone depletion. We consider the net effect of solar UVB on human health to be beneficial at or near current levels.     

The effects on human health from stratospheric ozone depletion and its interactions with climate change.

Ozone depletion leads to an increase in the ultraviolet-B (UV-B) component (280-315 nm) of solar ultraviolet radiation (UVR) reaching the surface of the Earth with important consequences for human health. Solar UVR has many harmful and some beneficial effects on individuals and, in this review, information mainly published since the previous report in 2003 (F. R. de Gruijl, J. Longstreth, M. Norval, A. P. Cullen, H. Slaper, M. L. Kripke, Y. Takizawa and J. C. van der Leun, Photochem. Photobiol. Sci., 2003, 2, pp. 16-28) is discussed. The eye is exposed directly to sunlight and this can result in acute or long-term damage. Studying how UV-B interacts with the surface and internal structures of the eye has led to a further understanding of the location and pathogenesis of a number of ocular diseases, including pterygium and cataract. The skin is also exposed directly to solar UVR, and the development of skin cancer is the main adverse health outcome of excessive UVR exposure. Skin cancer is the most common form of malignancy amongst fair-skinned people, and its incidence has increased markedly in recent decades. Projections consistently indicate a further doubling in the next ten years. It is recognised that genetic factors in addition to those controlling pigment variation can modulate the response of an individual to UVR. Several of the genetic factors affecting susceptibility to the development of squamous cell carcinoma, basal cell carcinoma and melanoma have been identified. Exposure to solar UVR down-regulates immune responses, in the skin and systemically, by a combination of mechanisms including the generation of particularly potent subsets of T regulatory cells. Such immunosuppression is known to be a crucial factor in the generation of skin cancers. Apart from a detrimental effect on infections caused by some members of the herpesvirus and papillomavirus families, the impact of UV-induced immunosuppression on other microbial diseases and vaccination efficacy is not clear. One important beneficial effect of solar UV-B is its contribution to the cutaneous synthesis of vitamin D, recognised to be a crucial hormone for bone health and for other aspects of general health. There is accumulating evidence that UVR exposure, either directly or via stimulation of vitamin D production, has protective effects on the development of some autoimmune diseases, including multiple sclerosis and type 1 diabetes. Adequate vitamin D may also be protective for the development of several internal cancers and infections. Difficulties associated with balancing the positive effects of vitamin D with the negative effects of too much exposure to solar UV-B are considered. Various strategies that can be adopted by the individual to protect against excessive exposure of the eye or the skin to sunlight are suggested. Finally, possible interactions between ozone depletion and climate warming are outlined briefly, as well as how these might influence human behaviour with regard to sun exposure.     

UV and pigmentation: molecular mechanisms and social controversies

Ultraviolet radiation (UVR) is an essential risk factor for the development of premalignant skin lesions as well as of melanoma and non-melanoma skin cancer. UVR exerts many effects on the skin, including tanning, carcinogenesis, immunomodulation, and production of vitamin D. Vitamin D (vit D) is important in the maintenance of healthy bones as well as other purported beneficial effects, amongst which is the potential for reducing risk of malignancy--though oral supplementation is fully capable of maintaining systemic levels. The known medical harm from UV exposure relates primarily to cancer of the skin--the most common organ in man to be affected by cancer. In this review, we summarize the knowledge about the ultraviolet (UV) response in regards to inflammation, immunosuppression, carcinogenesis and the tanning response. We also discuss vit D and UV, as well as public health implications of tanning behavior and commercial interests related to the promotion of UV exposure. As the most ubiquitous human carcinogen, UVR exposure represents both a challenge and enormous opportunity in the realm of skin cancer prevention.     

Melanin content and MC1R function independently affect UVR‐induced DNA damage in cultured human melanocytes

Malignant transformation of melanocytes leads to melanoma, the most fatal form of skin cancer. Ultraviolet radiation (UVR)‐induced DNA photoproducts play an important role in melanomagenesis. Cutaneous melanin content represents a major photoprotective mechanism against UVR‐induced DNA damage, and generally correlates inversely with the risk of skin cancer, including melanoma. Melanoma risk is also determined by susceptibility genes, one of which is the melanocortin 1 receptor (MC1R) gene. Certain MC1R alleles are strongly associated with melanoma. We hereby present experimental evidence for the role of two melanoma risk factors, constitutive pigmentation, as assessed by total melanin, eumelanin and pheomelanin contents, and MC1R genotype and function, in determining the induction and repair of DNA photoproducts in cultured human melanocytes after irradiation with increasing doses of UVR. We found that total melanin and eumelanin contents (MC and EC) correlated inversely with the extent of UVR‐induced growth arrest, apoptosis and induction of cyclobutane pyrimidine dimers (CPD), but not with hydrogen peroxide release in melanocytes expressing functional MC1R. In comparison, melanocytes with loss‐of‐function MC1R, regardless of their MC or EC, sustained more UVR‐induced apoptosis and CPD, and exhibited reduced CPD repair. Therefore, MC, mainly EC, and MC1R function are independent determinants of UVR‐induced DNA damage in melanocytes.     

Vitamin D and melanoma incidence and mortality

The role of vitamin D (25‐OH‐D, or 25‐hydroxyvitamin D) and its potential confounders in relationship to melanoma risk and mortality is discussed. The paradox that ultraviolet radiation (UVR) exposure is the major environmental risk factor for melanoma etiology as well as a major source of vitamin D might be explained by viewing vitamin D levels as the result of a healthy lifestyle rather than a cause of health.     

The challenges of UV-induced immunomodulation for children's health

Exposure to solar ultraviolet radiation (UVR) is recognised to have both beneficial and harmful effects on human health. With regard to immune responses, it can lead to suppression of immunity and to the synthesis of vitamin D, a hormone that can alter both innate and adaptive immunity. The consequences in children of such UV-induced changes are considerable: first there are positive outcomes including protection against some photoallergic (for example polymorphic light eruption) and T cell-mediated autoimmune diseases (for example multiple sclerosis) and asthma, and secondly there are negative outcomes including an increased risk of skin cancer (squamous cell carcinoma, basal cell carcinoma and cutaneous malignant melanoma) and less effective control of several infectious diseases. Many uncertainties remain regarding the amount of sun exposure that would provide children with the most effective responses against the variety of immunological challenges that they are likely to experience.     

MC1R,the cAMP pathway,and the response to solar UV: extending the horizon beyond pigmentation

The melanocortin 1 receptor (MC1R) is a G protein‐coupled receptor crucial for the regulation of melanocyte proliferation and function. Upon binding melanocortins, MC1R activates several signaling cascades, notably the cAMP pathway leading to synthesis of photoprotective eumelanin. Polymorphisms in the MC1R gene are a major source of normal variation of human hair color and skin pigmentation, response to ultraviolet radiation (UVR), and skin cancer susceptibility. The identification of a surprisingly high number of MC1R natural variants strongly associated with pigmentary phenotypes and increased skin cancer risk has prompted research on the functional properties of the wild‐type receptor and frequent mutant alleles. We summarize current knowledge on MC1R structural and functional properties, as well as on its intracellular trafficking and signaling. We also review the current knowledge about the function of MC1R as a skin cancer, particularly melanoma, susceptibility gene and how it modulates the response of melanocytes to UVR.     

Direct and Indirect Effects of Solar Ultraviolet Radiation on Attached Bacteria and Algae in Lotic Systems

I examined the effects of solar ultraviolet radiation (UVR) on attached bacteria and algal densities in lotic systems in outdoor artificial stream apparatus. Flumes were covered with four types of film for UVR screening treatments, and attached bacterial cell densities and their temporal variations were compared between conditions excluding and including solar UVR. Attached bacterial cell densities were depressed by solar UVR, and both accrual rate and saturated density were significantly lower in the +UVR (full solar radiation) condition than in −UVR and dark conditions. Solar UVR also indirectly affected the rate of algal accrual. Microscopic direct observations of attached bacterial cell density and algae on substrata showed that solar UVR depressed the accrual of attached bacteria and consequently the frequency of sites with high bacterial cell density that can trap suspended algae in the water. The final amount of algal accrual in the +UVR condition was one-fourth of that in the −UVR condition. Therefore, the effects of solar UVR may be more serious in systems where periphyton are frequently removed by floods.     

Tanning Devices – Fast Track to Skin Cancer?

The use of UVB and/or UVA emitting devices for cosmetic tanning is widespread in Western populations including young people and is especially prevalent in females. Several epidemiological studies, although not all, have shown a significant relationship between the use of tanning devices and malignant melanoma after, in some cases, adjustment for confounding factors such as solar ultraviolet radiation (UVR) exposure. A relationship between solar exposure, especially intermittent exposure, and malignant melanoma is well established so it is not surprising that a similar connection has been reported for the use of tanning devices. Several epidemiological studies show that childhood exposure to sunlight is a risk factor for malignant melanoma and this may also be the case for the use of tanning devices, especially if sunburns are obtained. Some studies have evaluated the relationship between the use of tanning devices and non‐melanoma skin cancer and at least one has suggested an association. The use of tanning devices by a substantial minority of young people is a worrying trend in terms of a likely increased incidence of malignant melanoma, and possibly non‐melanoma cancers in the future. Although two recent reviews by epidemiologists conclude that a clear link between tanning devices and malignant melanoma is yet to be proven, there is a strong case for effective legislation to prohibit the use of tanning devices by people under 18 yr of age.     

Climate change and health with an emphasis on interactions with ultraviolet radiation: a review

Climate change is increasingly recognized as a major risk to human health, and health concerns are assuming more importance in international debates on mitigation and adaptation strategies. Health consequences of climate change will occur through direct and indirect routes, and as a result of interactions with other environmental exposures. Heatwaves will become more common and are associated with higher mortality particularly in the elderly and those with pre‐existing cardiovascular and respiratory illnesses. Warmer ambient temperatures will result in more dehydration episodes and increased risks of renal disease and, through effects on pollen seasons, there may be an increase in allergic disease such as asthma and hayfever. Other adverse effects including on air quality, food safety and security and an expanding distribution of some infectious diseases, including vector‐borne diseases, are postulated. A related but separate environmental exposure is that of ultraviolet radiation (UVR). Interactions between climate change and stratospheric ozone (and the causes of ozone depletion) will cause changes to levels of ambient UVR in the future and warmer temperatures are likely to change sun exposure behaviour. Co‐occurring effects on aquatic and terrestrial ecosystems have potential consequences for food safety, quality and supply. Climate change‐related exposures are likely to affect the incidence and distribution of diseases usually considered as caused by UVR exposure; and changes in UVR exposure will modulate the climate change effects on human health. For example, in some regions warmer temperatures due to climate change will encourage more outdoor behaviour, with likely consequences for increasing skin cancer incidence. Although many of the health outcomes of both climate change and the interaction of climate change and UVR exposure are somewhat speculative, there are risks to over‐ or under‐estimations of health risks if synergistic and antagonistic effects of co‐occurring environmental changes are not considered.     

Ultraviolet radiation: effects on risks of prostate cancer and other internal cancers

Governmental and research agencies worldwide have strongly advocated sun avoidance strategies in an attempt to counter marked increases in skin cancer incidence. Concurrently, there are reports describing widespread Vitamin D3 deficiency. Because 1,25-dihydroxyvitamin D3, through interaction with the Vitamin D receptor, exerts pleiotrophic effects, such deficiency might be expected to have clinical consequences. Indeed, various reports indicate that exposure to ultraviolet radiation (UVR) exerts a protective effect on development of some common diseases including internal cancers and multiple sclerosis. We describe studies indicating that modest exposure reduces risk of prostate cancer. The effect of UVR is mediated by skin type; at lower levels of exposure a relative inability to effect skin pigmentation is protective presumably because it allows more efficient Vitamin D3 synthesis. Polymorphic variants in genes associated with pigmentation including melanocyte stimulating hormone receptor and tyrosinase are also associated with prostate cancer risk. Overall, though preliminary and requiring cautious interpretation, these data indicate that moderate UVR exposure together with characteristics linked with less effective tanning confer reduced prostate cancer risk. Clearly, it is important to define safe levels of UVR that do not result in increased risk of skin cancers such as malignant melanoma.     

UV-A induces persistent genomic instability in human keratinocytes through an oxidative stress mechanism

Ultraviolet-A (UV-A, 320 to 400 nm) radiation comprises 95% of the solar ultraviolet radiation (UVR) reaching the earth's surface. It has been associated experimentally and epidemiologically with malignant melanoma. In this study we investigated whether UV-A radiation can induce a persistent, heritable hypermutability in mammalian cells similar to that observed following ionising radiation (IR). Using the immortalized human skin keratinocyte cell line HaCaT we found that UV-A radiation does lead to a continuing reduction in plating efficiency, an increased "spontaneous" mutant fraction, and an increase in micronucleus formation up to 21 d after initial exposure. Reversal of these effects using catalase may indicate a role for hydrogen peroxide in this phenomenon. These results add to the significance of UV-A radiation as a risk factor in skin carcinogenesis.     

UV light phototransduction depolarizes human melanocytes

Exposure of human skin to low doses of solar UV radiation (UVR) causes increased pigmentation, while chronic exposure is a powerful risk factor for skin cancers. The mechanisms mediating UVR detection in skin, however, remain poorly understood. Our recent studies revealed that UVR activates a retinal-dependent G protein-coupled signaling pathway in melanocytes. This phototransduction pathway leads to the activation of transient receptor potential A1 (TRPA1) ion channels, elevation of intracellular calcium (Ca²⁺) and rapid increase in cellular melanin content. Here we report that physiological doses of solar-like UVR elicit a retinal-dependent membrane depolarization in human epidermal melanocytes. This transient depolarization correlates with delayed inactivation time of the UVR-evoked photocurrent and with sustained Ca²⁺ responses required for early melanin synthesis. Thus, the cellular depolarization induced by UVR phototransduction in melanocytes is likely to be a critical signaling mechanism necessary for the protective response represented by increased melanin content.     

UV-Induced Cutaneous Photobiology

Abstract

Ultraviolet radiation (UVR) present in sunlight is a major environmental factor capable of affecting human health and well being. The organ primarily affected by UVR is the skin, which is composed of a variety of different cell types. Here, UVR is needed for production of active vitamin D as well as producing undesirable effects such as sunburn, premature cutaneous photoaging, and promoting skin cancer development. Depending on the radiation dose, UVR influences virtually every cutaneous cell type investigated differently. Since the end of the nineteenth century, sun exposure has been known to induce skin cancer, which is now the human malignancy with the most rapidly increasing incidence. In several experimental models, mid-range UVR has been demonstrated to be the major cause of UV-induced cutaneous tumors. The stratospheric ozone layer protecting the terrestrial surface from higher quantum energy solar radiation is being damaged by industrial activities resulting in the possibility of increased UVR exposure in the future. Investigations in the field of experimental dermatology have shown that within the skin an immunosurveillance system exists that may be able to detect incipient neoplasms and to elicit a host responses against it. This article reviews the literature on studies designed to investigate the effects of UVR on cutaneous cellular components, with special focus on the immune system within the skin and the development of UV-induced cancer.     

Melanin content and MC1R function independently affect UVR-induced DNA damage in cultured human melanocytes

Malignant transformation of melanocytes leads to melanoma, the most fatal form of skin cancer. Ultraviolet radiation (UVR)-induced DNA photoproducts play an important role in melanomagenesis. Cutaneous melanin content represents a major photoprotective mechanism against UVR-induced DNA damage, and generally correlates inversely with the risk of skin cancer, including melanoma. Melanoma risk is also determined by susceptibility genes, one of which is the melanocortin 1 receptor (MC1R) gene. Certain MC1R alleles are strongly associated with melanoma. We hereby present experimental evidence for the role of two melanoma risk factors, constitutive pigmentation, as assessed by total melanin, eumelanin and pheomelanin contents, and MC1R genotype and function, in determining the induction and repair of DNA photoproducts in cultured human melanocytes after irradiation with increasing doses of UVR. We found that total melanin and eumelanin contents (MC and EC) correlated inversely with the extent of UVR-induced growth arrest, apoptosis and induction of cyclobutane pyrimidine dimers (CPD), but not with hydrogen peroxide release in melanocytes expressing functional MC1R. In comparison, melanocytes with loss-of-function MC1R, regardless of their MC or EC, sustained more UVR-induced apoptosis and CPD, and exhibited reduced CPD repair. Therefore, MC, mainly EC, and MC1R function are independent determinants of UVR-induced DNA damage in melanocytes.     

The impact of skin colour on human photobiological responses

Terrestrial solar ultraviolet radiation (UVR) exerts both beneficial and adverse effects on human skin. Epidemiological studies show a lower incidence of skin cancer in people with pigmented skins compared to fair skins. This is attributed to photoprotection by epidermal melanin, as is the poorer vitamin D status of those with darker skins. We summarize a wide range of photobiological responses across different skin colours including DNA damage and immunosuppression. Some studies show the generally modest photoprotective properties of melanin, but others show little or no effect. DNA photodamage initiates non‐melanoma skin cancer and is reduced by a factor of about 3 in pigmented skin compared with white skin. This suggests that if such a modest reduction in DNA damage can result in the significantly lower skin cancer incidence in black skin, the use of sunscreen protection might be extremely beneficial for susceptible population. Many contradictory results may be explained by protocol differences, including differences in UVR spectra and exposure protocols. We recommend that skin type comparisons be done with solar‐simulated radiation and standard erythema doses or physical doses (J/m²) rather than those based solely on clinical endpoints such as minimal erythema dose (MED).     

Reviews on sun exposure and artificial light and melanoma

Melanoma is the most common form of cancer among young adults aged 25-29 years and the second most common cancer in those aged 15-29 years. We reviewed all the evidence regarding risk factors for melanoma, looking in particular at childhood exposure to ultraviolet radiation (UV). UV radiation is clearly the predominant environmental and thus potentially modifiable risk factor for melanoma. All activities related to tan-seeking behaviour and history of sunburns were shown to be significantly associated to melanoma. Host factors, such as pigmentary characteristics, and genetic predisposition plays also an important role. UV exposure is not only due to the sun but also to indoor tanning devices that have been shown to lead to an elevated risk of melanoma. The strongest evidence for a link between artificial UV and melanoma is found among individuals who had their first exposure to indoor tanning before the age of 30: they have a 75% increase risk of developing melanoma than individuals who had no exposure to indoor tanning. Prevention is very important, especially for children and young adults, as childhood and adolescence are critical periods in the development of later melanoma. Indoor tanning is a widespread practice in most developed countries, particularly in Northern Europe and the USA. In the recent decades more and more people, especially teenagers and women, are exposed to substantially high radiant exposures of UV through artificial sources and these trends raised a considerable concern. In fact the International Agency for Research on Cancer concluded that the association between skin cancer and exposure to solar radiation and the use of UV-emitting tanning devices are causal. Interesting analyses carried out in Iceland showed that when interventions to discourage sunbed use were introduced the incidence of melanoma among women decreased. All this evidence encouraged many countries to introduce regulations on sunbed use to avoid exposure before the age of 18.     

Molecular mechanisms of ultraviolet radiation-induced immunosuppression

Solar ultraviolet radiation (UVR) is well known for its immunosuppressive properties. UVR can suppress immune reactions both in a local and a systemic fashion. One of the major molecular mediators of photoimmunosuppression is UVR-induced DNA damage. In contrast to immunosuppressive drugs, UVR does not act in a general but antigen-specific fashion. This is due to the induction of regulatory T cells. Epidermal Langerhans cells harboring UVR-induced DNA damage appear to be essentially involved in the induction of these cells. Cytokines including interleukin (IL)-12, -18 and -23 exert the capacity to reduce UVR-induced DNA damage via induction of DNA repair. Accordingly, these cytokines prevent UVR-mediated immunosuppression. In contrast to IL-18, IL-12 and IL-23 can also inhibit the suppressive activity of regulatory T cells by a mechanism which still needs to be determined. Clarification of the molecular mechanisms underlying UVR-induced immunosuppression will help to develop new immunosuppressive therapeutic strategies by utilizing UVR-induced regulatory T cells for the treatment of immune-mediated diseases. In addition, these insights will contribute to a better understanding of photocarcinogenesis since suppression of the immune system by UVR essentially contributes to the induction of skin cancer.     

Occupational skin diseases caused by solar radiation

UV radiation is present in sunlight and can be emitted from numerous artificial sources. Outdoor workers are exposed to sunlight in a wide variety of occupations like sailors, fishers, construction workers, farmers, and other. Presented are the skin diseases caused by sunlight exposure. They may be of little medical importance such as stigmata or create problems like photoaging, skin carcinoma, melanoma, phototoxic and photoallergic reactions. Shown are briefly data on skin cancer in the Rijeka region in outdoor occupations, the legislation and necessity for prevention. Psoriatic patients need particular caution because they are exposed to UVR, tars, and immunosuppressive drugs during the treatment.     

Photo-induced events in the human melanocytic system: photoaggression and photoprotection

The human skin is submitted to solar, essentially ultraviolet radiation (UVR), aggressions, and develops, for sufficient doses, erythema and pigmentation. The individual sun-sensitivity depends on the nature and the quantity of melanins present in the epidermis. These parameters are inherited as genetic traits which account for the large variations of the constitutive and adaptive pigmentation encountered in the caucasian populations. From red-haired skin-sensitive individuals, to dark-haired sun-resistant individuals, phaeomelanins (red) and eumelanins (black) are mixed in variable proportions. Pure melanins extracted from red hairs and black hairs behave differently when submitted to ultraviolet radiations: phaeomelanins develop aggressive species of molecules responsible for DNA damages, mutations, and cell death. On the contrary, eumelanins are less toxic for the major cellular metabolisms. The sun-sensitive populations suffer from more skin cancer of all types than the dark ones. In particular, they are exposed significantly to higher risk of melanoma and to the risk of bearing more nevi following large solar exposures early in the life.