Scab diameters on pig skin resulting from hot particle exposures under varying conditions.

The National Council on Radiation Protection and Measurements (NCRP) in NCRP Report Number 106 recommended a limit of 10(10) beta particles emitted from radioactive particles with sizes less than 1 mm (hot particles) to prevent acute deep ulceration. This recommendation was determined, in part, by regressing the diameter of the scabs induced by fissioned 235UC2 hot particles as a function of the logarithm of the number of beta particles emitted from the sources for one study. To validate this recommendation and the approach used by the NCRP, external irradiations of pig skin using radioactive sources of less than 600 microm in the largest dimension were carried out. The hot particles used included fissioned 235UC2 and activated 170Tm, 175Yb, and 46Sc. Results indicated a strong correlation between scab diameter and dose for scabs induced using fissioned 235UC2, activated 170Tm, and 46Sc, but not for 175Yb. The correlation value decreased with decreasing beta particle energy, with the exception of 46Sc, which had scabs with diameters greater than twice the maximum beta particle range. The larger scabs from 46Sc are thought to be due to dose contributions from the gamma rays. The results also give an ulceration threshold less than that given by NCRP to prevent acute deep ulceration. It was concluded that regression analysis of scab diameter as a function of either number of beta particles emitted from the hot particles or dose did not yield either precise or accurate thresholds but was useful in determining probable ranges of doses which lead to scab induction.

Consensus workshop on the toxic effects of long-term PUVA therapy.

The possibility that there is an increased risk of melanoma in patients with psoriasis treated with psoralen-UV-A (PUVA) therapy has raised concern on the part of physicians and patients about the long-term safety of this treatment. In response to this concern, the National Psoriasis Foundation sponsored a workshop at which invited participants with expertise in PUVA therapy, psoriasis treatment, melanoma and nonmelanoma skin cancer, and epidemiological and clinical trials were asked to develop a consensus on the following 3 issues: the risk of long-term adverse effects of PUVA therapy with emphasis on nonmelanoma and melanoma skin cancer; the guidelines for physicians and patients for selection and use of PUVA therapy with consideration of the risk-benefit ratio of this treatment compared with the risk-benefit ratios of alternative treatments; and the directions for further evaluation of the long-term effects Of PUVA therapy.

Photocarcinogenesis: an overview.

Photocarcinogenesis represents the sum of a complex of simultaneous and sequential biochemical events that ultimately lead to the occurrence of skin cancer. These events, initiated by UV radiation of appropriate wavelength, include the formation of DNA photoproducts: DNA repair; mutation of proto-oncogenes and tumor suppressor genes; UV-production of radical species with subsequent effects on mutation and extra-nuclear function; and other epigenetic events that influence the course of carcinogenesis. The epigenetic influences may include immunological responses, antioxidant defenses, and dietary factors. This review represents an effort to provide current research results in the aforementioned areas and an attempt to meld these events into a comprehensive overview of photocarcinogenesis. If effective prevention and intervention strategies for skin cancer are to developed, a more thorough understanding of the disease process is imperative.

Quinolone antibacterials: a new class of photochemical carcinogens.

Hairless mice were exposed orally to antibiotics of the fluoroquinolone group alone and in combination with irradiation with UVA over an extended period of time to determine the possible skin carcinogenicity in comparison with that with 8-methoxypsoralen, i.e. a known photochemical skin carcinogen. Animals exposed to UVA and fleroxacin, ciprofloxacin, nalidixic acid and ofloxacin exhibited an increase in the number of benign skin tumors when compared with animals exposed to UVA alone. Animals exposed to lomefloxacin and UVA exhibited a specific type of neoplastic progression. In addition to benign papillomas and solar keratoses, a number of cystic squamous cell carcinomas were observed. In the positive control group, which was given 8-methoxypsoralen and UVA, a number of papillomas and superficial squamous cell carcinomas were found. In animals exposed to UVA alone, only a few benign tumors were seen; in unexposed animals, no cutaneous neoplasms were observed. It is concluded that fluoroquinolones warrant further study, because they have potential photocarcinogenic properties.

UV-induced skin cancer in a hairless mouse model.

Ultraviolet (UV) radiation is a very common carcinogen in our environment, but epidemiological data on the relationship between skin cancers and ambient solar UV radiation are very restricted. In hairless mice the process of UV carcinogenesis can be studied in depth. Experiments with this animal model have yielded quantitative data on how tumor development depends on dose, time and wavelength of the UV radiation. In combination with epidemiological data, these experimental results can be transposed to humans. Comparative studies on molecular, cellular and physiological changes in mouse and man can further our fundamental understanding of UV carcinogenesis in man. This is likely to improve risk assessments such as those related to stratospheric ozone depletion, and to yield well-targeted intervention schemes, e.g. prescribing a specific drug or diet, for high-risk individuals.

Wavelength dependence of skin cancer induction by ultraviolet irradiation of albino hairless mice.

Information on the variation in carcinogenicity with wavelength is crucial in risk assessments for skin cancers induced by UV radiation. Until recently the wavelength (lambda) dependencies of other detrimental UV effects, such as sunburn, have been used as substitutes. Direct information on the lambda dependency can only be obtained from animal experiments. To this end we accumulated a large data set on skin tumors induced by chronic UV exposure of albino SKH:HR1 mice (14 different broadband UV sources and about 1100 mice); the data come from the Photobiology Unit of the former Skin and Cancer Hospital in Philadelphia and from the Department of Dermatology of the University of Utrecht. The lambda dependency was extracted from this data set (a statistically satisfactory description with chi 2 = 13.4, df = 7) and represented by the Skin Cancer Utrecht-Philadelphia action spectrum, i.e., a set of factors to weight the exposures at different wavelengths according to their respective effectiveness (inversely proportional to the daily exposure required for a median tumor induction time of 300 days). The fits obtained with other already available action spectra proved to be poor (chi 2 > 60, df = 11). The maximum effectiveness was found at 293 nm, and above 340 nm the effectiveness showed a shoulder at about 10(-4) of the maximum. A sensitivity analysis of the final solution for the lambda dependency showed a large margin of uncertainty above 340 nm and an information gap below 280 nm. The large variation in tumor responses in the present data set can be transformed to a coherent, common dose-response relationship by proper spectral weighting with this single action spectrum.

Tumors of the skin in the HRA/Skh mouse after treatment with 8-methoxypsoralen and UVA radiation.

8-Methoxypsoralen (8-MOP) with and without UVA radiation was administered to HRA/Skh mice (36 animals per treatment group) three times a week in the feed for a total dose of 9-80 mg/kg/week for 52 weeks. Most of the animals at the top dose of 8-MOP with UVA radiation had developed skin toxicity and/or skin tumors by 52 weeks. The skin lesions seen after treatment with 8-MOP and UVA radiation were characterized as squamous cell hyperplasia, squamous cell papilloma, and squamous cell carcinoma and are similar to what has been reported in humans after exposure to 8-MOP and UVA. Squamous cell hyperplasia and acute inflammation of the cornea were also seen in some of the treated female mice. Oral administration of 8-MOP and UVA did not result in a carcinogenic response to other organ systems. There were no increases in skin neoplasms after 8-MOP or UVA radiation alone. 8-MOP given in combination with UVA was carcinogenic to the skin of mice at dose levels similar to those used to treat psoriasis in humans.

Sunscreen testing using the mouse ear model.

During the developmental stages of sunscreen formulation it is desirable to have a simple, accurate and inexpensive biological model to test product effectiveness. Another desirable attribute is a quantitative, unbiased response endpoint for evaluation. We have developed such a test system based upon the ear swelling response of hairless albino mice. With this system, irradiation times are greatly reduced; furthermore, the response parameter is metric and can be determined noninvasively with an inexpensive micrometer. Protection factors determined with the mouse ear model show high correlation with the sun protection factors as determined on human subjects (r = 0.92) and were linearly related over a wide range of values. This new method affords a simple, accurate and inexpensive system for evaluation of efficacy and safety of new products.

Toxicity of 8-methoxypsoralen, 5-methoxypsoralen, 3-carbethoxypsoralen, or 5-methylisopsoralen with ultraviolet radiation in the hairless (HRA/Skh) mouse.

An experimental design to simulate PUVA therapy (oral 8-methoxypsoralen followed by uv radiation) has been tested in a 13-week subchronic study to determine the relative toxicities of 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP), 5-methylisopsoralen (5-MIP), and 3-carbethoxypsoralen (3-CEP) in inbred hairless mice (HRA/Skh). Drug was administered by 1-hr pulse feedings three times a week after mice were fasted overnight; individually housed animals were then exposed to uv radiation (320-400 nm; less than 2% output less than 320 nm). 8-MOP or 5-MOP administered orally (at doses of approximately 240 or 480 mg/m2 body surface area per week) followed one-half hour later with uv radiation of 2 J/cm2 for 13 weeks were found to cause skin toxicity including inflammation, hyperplasia, ulceration, and cellular atypia. Dose-related toxicity was not seen in other organ systems. Corresponding levels of 5-MIP or 3-CEP with uv radiation did not produce skin toxicity. These studies show that the psoralens with two potential DNA-binding sites (8-MOP and 5-MOP) were more toxic than psoralens with only one photoreactive site (5-MIP and 3-CEP).

Ocular effects of treatment with various psoralen derivatives and ultraviolet-A (UVA) radiation in HRA/Skh hairless mice.

Hairless (HRA/Skh) mice were administered one of four dietary concentrations (50, 100, 625 or 1250 ppm) of 8-methoxypsoralen (8-MOP) or 5-methoxypsoralen (5-MOP), or molar equivalent concentrations of 5-methylisopsoralen (5-MIP) or 3-carbethoxypsoralen (3-CPS) by 'pulse feeding' technique, 3 days per week for 13 weeks. For the final 11 weeks psoralen derivative administration was followed by exposure to 0.2 or 48 J/cm2 of unfiltered ultraviolet-A (UVA) radiant energy from FR74T12PUVA lamps. At 0 and 13 weeks eyes were dilated with 0.2% atropine solution and were examined using a binocular indirect ophthalmoscope with a +20.0 D condensing lens. The lids, cornea, anterior chamber and the lens were evaluated for pathological changes. Ocular damage consisting of dense central corneal opacification was seen at significant levels in animals given 8-MOP or 5-MOP and exposed to UVA. In addition, opacities in the area of the posterior lens were seen in all experimental groups and appeared to be related to drug treatment, independent of light exposure, and therefore appeared not to be related to drug-light interaction. Some corneal and lenticular opacification was seen at non-significant levels in all experimental and control groups.

Effect of indoor lighting on normal skin.

A small but measurable component of some indoor lighting is ultraviolet radiation (UVR); whether it is sufficient to modify the indoor worker's risk for chronic skin changes is not directly answerable with available technology. A first approach to this question involves a) estimating a range of annual background solar exposure for indoor workers currently at risk; b) determining whether, and at what levels, UVR exposure is a part of specified indoor lighting; and c) calculating the increment in risk implied by a and b. This algorithm predicts that some lighting conditions that meet NIOSH recommended standards would still result in significant increases in the risk of cumulative UVR damage, including skin cancer. More information concerning actual exposure conditions, the relation of spectral effectiveness for luminosity and UVR production, and dose-time reciprocity are required to improve our predictions of long-term cutaneous effects of indoor lighting.

Skin-tumour promoting activity of methyl ethyl ketone peroxide--a potent lipid-peroxidizing agent.

The tumour-promoting activity of methyl ethyl ketone peroxide (MEKP) was tested on the skin of hairless mice using a two-stage initiation-promotion protocol. When ultraviolet radiation in the UVB region (280-320 nm) was used as tumour initiator, MEKP showed weak promoting activity. The promotional activity of MEKP was potentiated by diethyl maleate, which is known to deplete intracellular glutathione, suggesting that lipid peroxidation may be important in the tumour promotion.

Different biologic effectiveness of blacklight fluorescent lamps available for therapy with psoralens plus ultraviolet A.

In 1976 we reported a change in spectral distribution of "blacklight" fluorescent lamps. It was not possible to determine the spectral composition of these lamps by any codes or packaging materials. Phototherapy booths utilizing standard BL-HO lamps will accept lamps of at least two spectral distributions; both types are commercially available. This study was conducted to determine the biologic efficacy of these two lamp types that we refer to as BL-O and BL-N. The BL-O spectrum had a peak emission at approximately 350 nm with 98% of the energy between 320 and 400 nm. The BL-N spectrum had its peak emission at 365 nm with a range from 340 to 400 nm. The BL-O spectrum was at least 2.5 to 4 times as effective as BL-N in causing minimally perceptible phototoxicity in albino hairless mice given oral doses of 8 mg/kg of 8-methoxypsoralen. Food and Drug Administration (FDA)-approved specifications imply that the BL-O spectrum is to be used for psoralens and ultraviolet A (PUVA) phototherapy. If lamps with the BL-N spectrum are replaced by lamps with the BL-O spectrum, the metered dose must be reduced to no more than one-fourth of the previous dose or the patient may suffer serious phototoxic reactions.

An animal model to determine sunscreen protectiveness against both vascular injury and epidermal cell damage.

Sunscreen preparations can reduce the erythemogenic ( sunburning ) effects of solar ultraviolet radiation (UVR). Less is known about the ability of sunscreens to protect against other forms of UVR-induced damage. This study was designed to yield data on epidermal cell damage at UVR doses sufficient to provoke vascular changes (edema and erythema) in hairless mice, and to determine the comparative effectiveness of a commercial sunscreen in protecting against these two criteria of injury. The sunscreen (Piz Buin 12 Sun Protection Cream) was used at full concentration and at three serial dilutions. The dorsa of 144 hairless mice were treated with one of six sunscreen or vehicle preparations and subsequently irradiated with one of six exposures to an appropriately filtered xenon arc solar simulator. Vascular responses were determined by observing the animals for alterations in the gross appearance of the treated and irradiated sites (edema and erythema). Epidermal cell damage was assessed by determining the sunburn cell ( SBC ) indices in the epidermis removed 24 hours after irradiation. Both the vascular responses and SBC indices indicated that the sunscreen provided concentration-dependent protection against radiation damage. Furthermore, SBC indices provided a relatively continuous variable for quantification of sunscreen effectiveness.