ENHANCEMENT OF MUTAGENESIS AND HUMAN SKIN CANCER RATES RESULTING FROM INCREASED FLUENCES OF SOLAR ULTRAVIOLET RADIATION

Abstract— We present a new method for calculating the effects of reduction of atmospheric ozone upon induction of nonmelanoma skin cancer. These estimates are based upon several recent experimental improvements: a model for the atmospheric penetration of UV-B; measurements of the transmission of this radiation by human epidermis; a precise action spectrum for genetic effects (mutation) in Escherichia coli , which was corrected for finite slit width. The calculated radiation amplification factor or percent increase in exposure per one percent decrease in atmospheric ozone is constant at 1.7 for solar zenith angles = 70° and decreases only with larger values of this angle. Thus the estimated increase applies to all heavily populated areas. of the globe. The value is robust: it is almost the same when the albedo is reduced from 0.2 to 0.1 or when the epidermal transmission is assumed to be about fourfold greater.     

SKIN CANCER AND ULTRAVIOLET RADIATION

Abstract. A new model is presented for the calculation of the increased incidence of non-melanoma skin cancer in Caucasians resulting from ozone reduction. The model postulates that the probability of first incidence of such skin cancer is distributed log-normally as a function of total accumulated lifetime dose of harmful ultraviolet radiation. The effect on skin cancer incidence of an increase in harmful ultraviolet radiation due to ozone reduction can then be calculated directly from the extent to which each individual's lifetime accumulated dose is thereby increased. The result of such a perturbation, on average, would be to cause skin cancer to appear at a slightly earlier age. Since skin cancer is predominantly a disease of the elderly, this shift to younger ages has the effect, when integrated over the entire population, of increasing the overall total incidence of skin cancer.     

THE VASCULAR RESPONSE OF HUMAN SKIN TO ULTRAVIOLET RADIATION

The vascular response of human skin to 300 nm (UV-B) and 254 nm (UV-C) ultraviolet radiation was assessed using the reflectance measurement of erythema and the technique of laser Doppler velocimetry. For both wavelengths, the increase in measured Doppler blood flux varied with the increase in erythema in a quadratic manner predicted by a simple model based on the principles of fluid mechanics. This suggests that the mean red blood cell velocity increases significantly in areas of UV-B and UV-C erythema. No qualitative difference in response to these two wavelengths was demonstrated, suggesting that the same blood vessels are involved in the causation of both UV-B and UV-C erythema.     

PROMOTIONAL EFFECTS OF ULTRAVIOLET RADIATION ON HUMAN BASAL AND SQUAMOUS CELL CARCINOMA

Abstract— Recent data on the incidence of basal and squamous cell skin cancer among Caucasians in eight regions of the United States have been analyzed. Principal conclusions are that (1) ultraviolet radiation is an effective promoter of non-melanoma skin tumors; (2) the probability of a skin tumor becoming observable in an individual of some given age is well described by the log-normal distribution: (3) the fluence-response relation for both basal and squamous cell tumors is linear with a positive intercept, although the parameter values are clearly different for the two types; (4) a 1% ozone layer depletion would lead to an eventual 1.7% increase in basal cell carcinoma, and a 2.3% increase in squamous cell carcinoma.     

ULTRAVIOLET RADIATION AND SKIN CANCER: IN MICE AND MEN*

Abstract— In both mice and men the effects of repeated exposures to UVR accumulate. Unresolvable uncertainty pertains in both cases. Incidence of skin cancer in human populations may be influenced by various factors that cannot be separately evaluated. Uncertainty of predictions regarding the effect of increased UVR due to diminution of stratospheric ozone cover is discussed.     

CORRELATION BETWEEN ENDOGENOUS GLUTATHIONE CONTENT AND SENSITIVITY OF CULTURED HUMAN SKIN CELLS TO RADIATION AT DEFINED WAVELENGTHS IN THE SOLAR ULTRAVIOLET RANGE

Abstract— Glutathione depletion of cultured human skin fibroblasts by treatment with buthionine-S,R-sulfoximine (BSO) sensitises them to radiation at a series of defined wavelengths throughout the solar UV range. We now show that there is a close quantitative correlation between cellular glutathione content (as depleted by BSO) and sensitivity to radiation at 365 nm. A weaker correlation is observed when cells are depleted of glutathione using diethylmaleimide. Both fibroblasts and epidermal keratinocytes derived from the same foreskin biopsy are sensitised to radiation at 313 nm by glutathione depletion. However, the keratinocytes are sensitised to a much lesser extent, an observation which agrees quantitatively with the higher residual levels of cellular glutathione remaining after maximum depletion by BSO (approximately 25% for the keratinocytes vs less than 5% for the fibroblasts). At low to intermediate fluence levels, 10 mM cysteamine present during irradiation at 302 nm is able to almost completely reverse the sensitising effects of glutathione depletion suggesting that the endogenous thiol protects against radiation at this wavelength by a free radical scavenging mechanism. At 313 nm, the sensitisation is not reversed by cysteamine suggesting that glutathione plays a more specific role in protection against radiation at longer wavelengths. Xeroderma pigmentosum group A fibroblasts (excision deficient) are also sensitised to radiation at 313 and 365 nm by depletion of glutathione but since the sensitization is less than that observed for the normal strain, we cannot conclude that glutathione protects against a sector of DNA damage susceptible to excision repair. The results provide further evidence that endogenous glutathione is involved in protecting human skin cells against a wide range of solar radiation damage and suggest that while free radical scavenging is involved at the shortest wavelength (302 nm) tested, a more specific role of glutathione is involved in protection against radiation at longer wavelengths.     

EFFECTS OF ULTRAVIOLET RADIATION ON THE IMMUNE SYSTEM IN HUMANS

In experimental animals, exposure to UV-B radiation produces selective alterations of immune function which are mainly in the form of suppression of normal immune responses. This immune suppression is important in the development of nonmelanoma skin cancer, may influence the development and course of infectious disease and possibly protects against autoimmune reactions. The evidence that this form of immune suppression occurs in humans is less compelling and very incomplete. The wavelengths of radiation most affected by a depletion of the stratospheric ozone layer are those known to be most immunosuppressive in animals and it is likely that such depletion will increase any suppressive effect of sunlight on immunity in humans. In addition to establishing whether or not UV-B radiation can cause suppression of immune function in humans, studies are required to determine if melanin can provide protection against such suppression, the role of this suppression in the pathogenesis of skin cancer, the development of infectious disease and vaccine effectiveness, and the capacity for humans to develop adaptive, protective mechanisms which may limit damage from continued exposure to UV-B radiation.     

DNA-PROTEIN CROSSLINKING IN NORMAL HUMAN SKIN FIBROBLASTS EXPOSED TO SOLAR ULTRAVIOLET WAVELENGTHS

Three normal human skin fibroblast cell lines were exposed to the simulated solar UV radiation produced by a fluorescent sunlamp under conditions in which the wavelength components shorter than either 295, 305 or 315 nm were excluded. The level of DNA-protein crosslinks (DPC) was then measured in those cells using the alkaline elution technique either immediately after irradiation or following a 24 h incubation. In each case, cells were exposed to fluences that induce similar levels of DPC. For cells exposed to 10 kJ m(-2) of sunlamp UV > 295 nm, the level of DPC exhibited a 2-5-fold increase following incubation. In contrast, 40-100% of the DPC were removed upon incubation of cells irradiated with either 100 kJ m(-2) of sunlamp UV > 305 nm or 150 kJ m(-2) of sunlamp UV > 315 nm. A major difference between the effects induced by these wavelength regions is that, in addition to DPC, a very high level of pyrimidine dimers is also produced by sunlamp UV > 295 nm, whereas much lower dimer yields result from treatment with either sunlamp UV > 305 nm or sunlamp UV > 315 nm. A potential role for type II DNA topoisomerase in the formation of these DPC resulting from either the change in conformational structure caused by the presence of a high level of dimers or an involvement of this enzyme in dimer excision repair is discussed.     

EFFECTS OF SOLAR RADIATION ON MOTILITY IN: Stentor coeruleus

The effects of solar radiation on the motility of the colored ciliate, Stentor coeruleus, have been assessed as a photodynamic model system for hypericism. The organism has been found to be extremely sensitive to solar radiation–a few minutes of unfiltered radiation suffice to arrest motility and decrease the velocity of movement. Removing UV-B and UV-A radiation prolongs the tolerated exposure times. From the present study, the mechanisms of the photodynamic action in S. coeruleus and in hypericin-sensitized reactions have not been resolved in terms of Type I and II mechanisms.     

ACUTE EFFECTS OF LOW-FLUENCE ULTRAVIOLET LIGHT ON HUMAN T-LYMPHOCYTE SUBSETS

Abstract-The acute effects of low-fluence ultraviolet light, primarily between wavelengths 280 and 320 nm (ultraviolet B) on T-lymphocyte subsets were assessed in virro and in vivo by quantitative cytofluorometric analysis. In virro, 90J/m² of ultraviolet irradiation of human mononuclear cells produced a significant increase in the OKT4 (helper-inducer)/OKT8 (suppressor-cytotoxic) ratio (P>0.008), due primarily to a decrease in the OKT8 subset. In vivo, 24 h after whole-body UV irradiation of human subjects with one half of a minimal erythemal dose of ultraviolet B the OKT4/OKT8 ratios again increased (P > 0.002), again with somewhat greater effects on the OKT8 subset. These results indicate that suberythemal exposure to UV light increases OKT4/OKT8 ratios in normal human subjects because of differential effects on lymphocyte subsets. They suggest that casual exposure to sunlight mediates immunologic changes in normal human subjects.     

THE ULTRAVIOLET DOSE DEPENDENCE OF NON-MELANOMA SKIN CANCER INCIDENCE

Abstract— We correlate annual ultraviolet dose estimates with age specific and age adjusted incidence data for non-melanoma skin cancer in the United States, United Kingdom, Canada and Australia. We first examine (1) a reciprocity or photographic model in which incidence rates (R) are related to exposure (E) which is the product of age (T) and annual dose (D). We also test several models which violate reciprocity including models identified by the labels: (2) Dose potency; (3) Double cause; (4) Age-exposure and (5) separable. Our analyses together with the recent National Cancer Institute study favors the age-exposure model and/or the double cause models. All models lead to biological amplification factors (defined as the ratio of the percent increase in skin cancer incidence due to a 1% increase in dose) greater than unity. For the U.S. we find the biological amplification to be approximately 1.8 for the population center but greater in regions of higher UV annual dose, and less in regions of lower annual UV dose.