Sunscreen photoprotection and vitamin D status.

BACKGROUND: Global concern about vitamin D deficiency has fuelled debates on photoprotection and the importance of solar exposure to meet vitamin D requirements. OBJECTIVES: To review the published evidence to reach a consensus on the influence of photoprotection by sunscreens on vitamin D status, considering other relevant factors. METHODS: An international panel of 13 experts in endocrinology, dermatology, photobiology, epidemiology and biological anthropology reviewed the literature prior to a 1-day meeting in June 2017, during which the evidence was discussed. Methods of assessment and determining factors of vitamin D status, and public health perspectives were examined and consequences of sun exposure and the effects of photoprotection were assessed. RESULTS: A serum level of ≥ 50 nmol L-1 25(OH)D is a target for all individuals. Broad-spectrum sunscreens that prevent erythema are unlikely to compromise vitamin D status in healthy populations. Vitamin D screening should be restricted to those at risk of hypovitaminosis, such as patients with photosensitivity disorders, who require rigorous photoprotection. Screening and supplementation are advised for this group. CONCLUSIONS: Sunscreen use for daily and recreational photoprotection does not compromise vitamin D synthesis, even when applied under optimal conditions. What's already known about this topic? Knowledge of the relationship between solar exposure behaviour, sunscreen use and vitamin D is important for public health but there is confusion about optimal vitamin D status and the safest way to achieve this. Practical recommendations on the potential impact of daily and/or recreational sunscreens on vitamin D status are lacking for healthy people. What does this study add? Judicious use of daily broad-spectrum sunscreens with high ultraviolet (UV) A protection will not compromise vitamin D status in healthy people. However, photoprotection strategies for patients with photosensitivity disorders that include high sun-protection factor sunscreens with high UVA protection, along with protective clothing and shade-seeking behaviour are likely to compromise vitamin D status. Screening for vitamin D status and supplementation are recommended in patients with photosensitivity disorders.

The consequences for human health of stratospheric ozone depletion in association with other environmental factors.

Due to the implementation of the Montreal Protocol, which has limited, and is now probably reversing, the depletion of the stratospheric ozone layer, only modest increases in solar UV-B radiation at the surface of the Earth have occurred. For many fair-skinned populations, changing behaviour with regard to exposure to the sun over the past half century - more time in the sun, less clothing cover (more skin exposed), and preference for a tan - has probably contributed more to greater levels of exposure to UV-B radiation than ozone depletion. Exposure to UV-B radiation has both adverse and beneficial effects on human health. This report focuses on an assessment of the evidence regarding these outcomes that has been published since our previous report in 2010. The skin and eyes are the organs exposed to solar UV radiation. Excessive solar irradiation causes skin cancer, including cutaneous malignant melanoma and the non-melanoma skin cancers, basal cell carcinoma and squamous cell carcinoma, and contributes to the development of other rare skin cancers such as Merkel cell carcinoma. Although the incidence of melanoma continues to increase in many countries, in some locations, primarily those with strong sun protection programmes, incidence has stabilised or decreased over the past 5 years, particularly in younger age-groups. However, the incidence of non-melanoma skin cancers is still increasing in most locations. Exposure of the skin to the sun also induces systemic immune suppression that may have adverse effects on health, such as through the reactivation of latent viral infections, but also beneficial effects through suppression of autoimmune reactivity. Solar UV-B radiation damages the eyes, causing cataracts and pterygium. UV-B irradiation of the skin is the main source of vitamin D in many geographic locations. Vitamin D plays a critical role in the maintenance of calcium homeostasis in the body; severe deficiency causes the bone diseases, rickets in children and osteomalacia in adults. Although many studies have implicated vitamin D deficiency in a wide range of diseases, such as cancer and cardiovascular disease, more recent evidence is less compelling, with meta-analyses of supplementation trials failing to show a beneficial effect on the health outcomes that have been tested. It continues to be difficult to provide public health messages to guide safe exposure to the sun that are accurate, simple, and can be used by people with different skin types, in different locations, and for different times of the year or day. There is increasing interest in relating sun protection messages to the UV Index. Current sun protection strategies are outlined and assessed. Climatic factors affect the amount of UV radiation received by the skin and eyes, separately from the effect of ozone depletion. For example, cloud cover can decrease or increase the intensity of UV radiation at Earth's surface and warmer temperatures and changes in precipitation patterns may alter the amount of time people spend outdoors and their choice of clothing. The combination of changes in climate and UV radiation may affect the number of pathogenic microorganisms in surface waters, and could have an impact on food security through effects on plant and aquatic systems. It remains difficult to quantify these effects and their possible importance for human health.

Ultraviolet A1 phototherapy: a British Photodermatology Group workshop report.

Whole-body ultraviolet (UV)A1 (340-400 nm) phototherapy was first introduced 30 years ago, but is currently available in the UK in only three dermatology departments. A workshop to discuss UVA1 was held by the British Photodermatology Group in May 2009, the aim of which was to provide an overview of UVA1 phototherapy and its role in practice, and to identify areas in which further studies are required. The conclusions were that UVA1 phototherapy is an effective treatment in several inflammatory skin diseases, including localized scleroderma and atopic eczema (AE); however, deficiencies and limitations exist in the published evidence base. For most diseases, such as AE, other treatments also exist, which are generally more effective than UVA1. However, for some diseases, particularly morphoea, the evidence of efficacy is stronger for UVA1 than for other treatments. Acute adverse effects of UVA1 are minimal. The risk of long-term adverse effects, particularly skin cancer, is unknown. Medium to high doses of UVA1 are needed for efficacy in most situations, but the equipment to deliver such doses is large, expensive and difficult to install. UVA1 is currently underprovided, and the recommendation of the workshop is that more tertiary centres should have access to UVA1 phototherapy in the UK.

Optimization and preliminary characterization of venom isolated from 3 medically important jellyfish: the box (Chironex fleckeri), Irukandji (Carukia barnesi), and blubber (Catostylus mosaicus) jellyfish.

OBJECTIVE: To optimize venom extraction and to undertake preliminary biochemical studies of venom from the box jellyfish (Chironex fleckeri), the Irukandji jellyfish (Carukia barnesi), and the blubber jellyfish (Catostylus mosaicus). METHODS: Lyophilized crude venoms from box jellyfish tentacles and whole Irukandji jellyfish were prepared in water by homogenization, sonication, and rapid freeze thawing. A second technique, consisting of grinding samples with a glass mortar and pestle and using phosphate-buffered saline, was used to prepare crude venom from isolated nematocysts of the box jellyfish, the bells of Irukandji jellyfish, and the oral lobes of blubber jellyfish. Venoms were compared by use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot test. Toxicity of some venoms was determined by intravenous median lethal dose assay in mice. RESULTS: Different venom extraction techniques produced significantly different crude venoms for both box and Irukandji jellyfish. Irukandji and blubber venom SDS-PAGE protein profiles were established for the first time. Analysis of Western blot tests revealed that box jellyfish antivenin reacted specifically with the venom of each jellyfish. Toxicity was found in Irukandji jellyfish venom derived by use of the mortar-and-pestle method, but not in the lyophilized venom. CONCLUSIONS: Glass mortar-and-pestle grinding and use of an appropriate buffer was found to be a simple and suitable method for the preparation of venom from each jellyfish species studied. This study contributes to biochemical investigations of jellyfish venoms, particularly the venom of the Irukandji jellyfish, for which there are, to our knowledge, no published studies. It also highlights the importance of optimizing venom extraction as the first step toward understanding the complex biological effects of jellyfish venoms.

DNA damage in UV-irradiated human skin in vivo: automated direct measurement by image analysis (thymine dimers) compared with indirect measurement (unscheduled DNA synthesis) and protection by 5-methoxypsoralen.

The incidence of the various types of skin cancer in the general population has been increasing at an annual rate of 2-8% over the past 2 decades. In spite of considerable media coverage on the risk of skin cancer the acquisition of a suntan is still very popular. Thus the UV exposures required for tanning pose a serious carcinogenic risk, particularly to individuals who tan poorly. On the other hand, the presence of natural skin pigment, or the ability to tan easily can protect the skin against some of the harmful effects of subsequent UV exposures (Kollias et al. 1991). We have recently shown (Young et al. 1991) in human volunteers, using an indirect measurement of DNA damage (unscheduled DNA synthesis (UDS) detected by autoradiography), that a tan induced by UV in the presence of a UVB sunscreen (Parsol MCX) preparation containing 5-methoxypsoralen (5-MOP) is more effective at protecting the skin against a subsequent DNA-damaging challenge dose of UV than a tan induced by UV alone, particularly in individuals who tan poorly. No such protection was seen with the same sunscreen lacking 5-MOP. 5-MOP is an ingredient in natural citrus oils and in many other plants. Here we show the same pattern of protective action when measuring, for the first time, DNA damage directly using a monoclonal antibody to thymine dimers (a major category of DNA lesion induced by UV radiation) on fixed human skin sections and automated image analysis. There is a good correlation between UV exposure dose and the levels of thymine dimers in epidermal nuclei. The levels of thymine dimers (measured as absorption by the mean integrated optical density (IOD)) also correlated well with the levels of UDS (grains per nucleus). These findings are of importance in the comparative risk-benefit assessment of sunscreens with and without 5-MOP. The techniques described have applications for measuring other DNA lesions following UV and other exposures.

Photoprotection and 5-MOP photochemoprotection from UVR-induced DNA damage in humans: the role of skin type.

Sites on previously unexposed buttock skin in 18 subjects (skin types I-V) were treated daily for 2 weeks with suberythemogenic doses of solar-simulated radiation (SSR) alone, SSR plus a UVB sunscreen, and SSR plus the same sunscreen with 5-methoxypsoralen at 30 ppm. The three sites of treatment (designated SSR, SSR/S, and SSR/S/5-MOP), and a control site that received no SSR or topical treatment, were challenged with 2MED SSR 1 week after the treatment had ceased. Biopsy samples, taken within 15 min after the challenge dose, were assessed for unscheduled DNA synthesis (UDS, interpreted as a measure of DNA damage), melanin deposition, and stratum corneum thickening. Within a given skin type, when compared with controls, the significant increase in either pigmentation or stratum corneum thickening was similar for SSR and SSR/S/5-MOP. SSR/S inhibited these endpoints. Compared with controls, UDS was significantly reduced in skin types III-V by SSR and in all skin types by SSR/S/5-MOP. SSR/S elicited no effect apart from minimal reductions in skin types IV and V. Thus, the increases in pigmentation and stratum corneum thickening seen in all skin types with SSR and SSR/S/5-MOP were accompanied by reduced UDS in all skin types with SSR/S/5-MOP but only in skin types III-V with SSR. These findings suggest that, although induced pigmentation and stratum corneum thickening may account in part for the reduction of UDS, qualitative differences in induced pigmentation may exist in skin types I-II between SSR and SSR/S/5-MOP treatments. The findings can also be interpreted to indicate that SSR/S/5-MOP treatment can afford protection against DNA damage from subsequent exposure to solar ultraviolet radiation. Risk-benefit considerations on the use of sunscreens with and without 5-MOP are discussed and the conclusion is drawn that the judicious use of 5-MOP sunscreens, particularly in skin types I-II, affords an alternative option to those seeking a suntan.

In vitro photostability and photosensitizing properties of bergamot oil. Effects of a cinnamate sunscreen.

Bergamottin, which accounts for about two-thirds of the absorption of UVA and UVB light by bergamot oil, is shown to be fairly unstable on UV irradiation of solutions of bergamot oil (in ethanol-water, 80:20 (w/w)). Bergamottin photodegradation is partly inhibited by molecular oxygen and also by a cinnamate sunscreen acting as a triplet excited state quencher. On UV irradiation of bergamot oil, type II photodynamic properties, i.e. singlet oxygen production, are observed, which can be mainly attributed to the excitation of bergamottin by light. Therefore bergamottin can be considered as a potential photosensitizer in the photobiological activity of bergamot oil.

Genotoxicity of bergapten and bergamot oil in Saccharomyces cerevisiae.

In order to determine the genotoxic potential of bergapten (5-methoxypsoralen (5-MOP] and bergamot oil (BO), the genetic effects of 5-MOP and BO (containing equivalent amounts of 5-MOP) were studied in haploid and diploid yeast (Saccharomyces cerevisiae) using solar simulated radiation (SSR). At equal doses of SSR, equal concentrations of 5-MOP alone or 5-MOP in BO have a similar influence on survival and on the induction of cytoplasmic "petite" mutations, reverse and forward mutations, mitotic gene conversion and genetically aberrant colonies including mitotic crossing over. No reciprocity is found between SSR dose and 5-MOP concentration for cytotoxic, mutagenic and recombinogenic effects. In the presence of chemical filters (Parsol 1789, a UVA filter, and Parsol MCX, a cinnamate derivative acting as a UVB filter) considerable protection is observed against the induction of genetic effects by 5-MOP and BO containing 5-MOP in haploid and diploid cells. As indicated by the lower induction kinetics, the protection is higher than expected from the light-absorbing properties, suggesting photochemical interaction. The protection is slightly higher for BO than for 5-MOP. The induction of genetic effects by 5-MOP alone or BO containing 5-MOP is independent of oxygen. Experiments on suction blister fluids taken from patients after topical treatment with BO containing 5-MOP indicate that in comparison with water the bioavailability and thus the genotoxic effects of the compounds are decreased. Moreover, in addition to the filtering effect against the photoinduced genotoxic effects of BO, the presence of chemical filters apparently reduces the penetration of BO containing 5-MOP and provides a reduction in biological effectiveness.

Phototumorigenesis studies of 5-methoxypsoralen in bergamot oil: evaluation and modification of risk of human use in an albino mouse skin model.

The skin of the female hairless albino mouse (Skh 1) was used to study the enhancement of solar simulated radiation (SSR) tumorigenesis by 5-methoxypsoralen (5-MOP) in model perfumes that contain bergamot oil. This work was done in association with yeast mutagenicity studies and human skin phototoxicity studies. Analyses of time-to-onset of tumour observation with 5-MOP at 0, 5, 15 and 50 ppm show a highly significant 5-MOP dose effect and the data indicate that 5-MOP has phototumorigenic potential even at 5 ppm. The addition of 0.5% UVB and 0.5% UVA sunscreens significantly reduces the tumorigenicity associated with the vehicle (i.e. 5-MOP at 0 ppm) and 5-MOP at all concentrations. Pairwise comparisons of 5-MOP (at 5 or 15 ppm) plus sunscreens with vehicle plus sunscreens show that the sunscreens afford total protection at the lower 5-MOP concentrations. Additional studies show that a 5-6 h delay between 5-MOP application and SSR exposure defers the time-to-onset of tumours as does intermittent 5-MOP and SSR treatment. A comparison of 5-MOP at 50 ppm in bergamot oil with 5-MOP at 50 ppm prepared from pure 5-MOP crystals shows identical results, indicating that the active phototumorigenic agent in bergamot oil is 5-MOP and not other related compounds, which may be present at greater concentrations. Analyses of tumour histology at death show, in general, similar patterns of malignancy for all groups. Thus although it is possible to delay tumorigenesis by various strategies, the tumours that eventually develop are just as likely to be malignant, if not more so, when compared with non-delayed groups.

Phototoxic properties of perfumes containing bergamot oil on human skin: photoprotective effect of UVA and UVB sunscreens.

As part of an international cooperative study of the photophysical, photomutagenic and photocarcinogenic properties of bergamot oil and the effect of UVA and UVB sunscreens, the phototoxic properties of model perfumes containing 5, 15 and 50 ppm 5-methoxypsoralen (5-MOP) in bergamot oil with and without a sunscreen have been investigated on human skin. It has been confirmed that the photosensitivity of human skin is maximal 2 h after perfume application. Interestingly the addition of a UVA sunscreen is more efficient for decreasing the phototoxic properties of bergamot oil than is a UVB sunscreen. The addition of sunscreens in a model perfume containing 50 ppm 5-MOP in bergamot oil can reduce the phototoxic properties of this perfume to a toxicity equivalent to that produced by the application of a model perfume containing 15 ppm 5-MOP without sunscreens. However, despite their promising protective effect in vitro, UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes cannot suppress the phototoxicity of bergamot oil on human skin.

Cumulative effects of ultraviolet radiation on the skin: cancer and photoaging.

The cumulative effects of solar exposure are skin cancer and photoaging. This relationship has been established by epidemiological, clinical, and pathological investigation. Understanding of the mechanisms of skin cancer and photoaging requires the study of model systems. For example, the study of cancerprone xeroderma pigmentosum patients has indicated that effective DNA repair is a major defence mechanism against skin cancer. However, there are few human models. The hairless albino mouse has been shown to be a good model for both photocarcinogenesis by ultraviolet radiation (UVR) alone and UVR in association with 8-methoxypsoralen and photoaging and may provide much information on mechanistic aspects. The use of sunscreens is often advocated as a means of preventing the cumulative effects of solar exposure. Animal data support this approach but such data must be interpreted with caution.

Effects of butylated hydroxytoluene upon PUVA-tumorigenesis and induction of ornithine decarboxylase activity in the mouse.

Psoralen photochemotherapy (PUVA) is widely used in the treatment of psoriasis. Some therapy regimen have been associated with increased risk of skin cancer. Free radical species are thought to play a role in psoralen phototoxicity and photocarcinogenesis. It has been reported that the antioxidant butylated hydroxytoluene (BHT) inhibits acute phototoxicity by PUVA but does not reduce therapeutic efficacy. It has also been shown that BHT inhibits UVB-induced erythema, tumorigenesis and induction of ornithine decarboxylase (ODC) activity--ODC activity is thought by some to be associated with tumor promotion. Therefore, we have investigated the effect of BHT on psoralen tumorigenesis and PUVA-induced epidermal ODC activity. SKH-Hr-1 hairless albino mice were treated with topically applied 8-MOP and exposed to UVA (3X weekly) for 31 weeks with and without BHT administered either in the diet or topically. Induction of ODC activity was determined in similar experimental groups 24 h after a single exposure to UVA. Neither route of BHT administration had any effect on 8-MOP phototumorigenesis. However, BHT when administered in the diet reduced induction of ODC activity by 40% (p less than 0.05). These data indicate different mechanisms for UVB- and PUVA-induced carcinogenesis and again bring into question the relationship between induction of ODC activity and photocarcinogenesis.

Photophysical, photochemical and photobiological properties of pyrrolocoumarins; a new class of photoactive compounds.

With the aim of finding new photoactive compounds that may reduce the side effects of 8-methoxypsoralen photochemotherapy we report on some photophysical, photochemical and photobiological properties of recently synthesized pyrrolocoumarins, in particular 4-methyl-N-ethyl-pyrrolo[3,2-g]coumarin (PCNEt) which has an absorption maximum in the UV-A (320-400 nm). Laser (347 nm) flash photolysis studies showed triplet transients that were quenched by O2 and by ground state PCNEt. Singlet minus triplet spectra were broad (350-550 nm) and, at 700 nm, indicated solvated electron and radical production. PCNEt complexes with DNA in the dark and photobinds to thymine but does not form DNA cross-links. PCNEt was phototoxic in yeast with an action spectrum similar to its absorption spectrum. PCNEt showed photohaemolytic activity but was not phototoxic on guinea pig skin. These data suggest that PCNEt may photosensitize via several mechanisms: direct DNA photobinding, photodynamic action, or photoproduction of radicals.

Aspects of psoralen phototumorigenesis with emphasis on the possible role of tumour promotion.

8-Methoxypsoralen in combination with UVA radiation (PUVA) is carcinogenic in mice and probably so in man. PUVA is genotoxic and so has tumour initiation potential. Some evidence suggests that PUVA has other biological effects which may be equated with tumour promotion. Thus, the use of a two-stage model, similar to that of chemical carcinogenesis, may be a useful experimental approach for the further understanding of PUVA carcinogenesis.

A strain of hairless mouse susceptible to tumorigenesis by TPA alone: studies with 8-methoxypsoralen and solar simulated radiation.

Hairless albino mice were painted with 8-methoxypsoralen (8-MOP) and exposed to solar simulated radiation (SSR) for 0, 3 or 6 weeks and subsequently treated with the promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). TPA was highly tumourigenic in non-pretreated mice. Pretreatment with 8-MOP + SSR did not increase this level of tumorigenesis. It is proposed that 8-MOP + SSR tumour induction was the result of promotion of innate initiated cells and that this mouse strain might be useful as a promoter testing model.