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.

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Wavelength Dependence of Skin Cancer Induction by Ultraviolet Irradiation of Albino Hairless Mice

We have compared the therapeutic effectiveness of a new UVB fluorescent sunlamp, the Philips TL-01 lamp, which emits a narrow peak around 311-312 nm, with the currently used Philips TL-12 lamp, in 10 patients with psoriasis. We also compared the tumour inducing capacity of the two lamps in hairless mice. The therapeutic effect of the TL-01 lamp was superior to that of the TL-12 lamp in nine of the 10 patients. In the mice, the median tumour induction time was significantly longer in animals exposed to the TL-01 lamp. Phototherapy with the new type of lamp requires a higher dose than phototherapy with the usual broadband UVB sources. In practice this means that more lamps are needed in the light cabinet. However, the new lamps appear to provide more effective and safer phototherapy for psoriasis.

A new development in UVB phototherapy of psoriasis

Ultraviolet (UV) radiation* of wavelengths longer than 295 nm from sunlight is a ubiquitous part of the natural environment of most organisms. Although beneficial and possibly beneficial aspects of sunlight have long been recognized and studied (Daniels, 1974; Wurtman, 1975), harmful effects, except for sunburn, have received relatively little attention until recently. Photochemical possibilities of natural components of the cell suggest that efficient mechanisms for the partial prevention or repair of resultant damage from exposure to solar radiation must exist for biological entities to survive regular exposure to natural sunlight. Recent work has identified DNA lesions induced by near-UV radiation (Section 2.4). Furthermore, mechanisms of protection and repair of near-UV-induced lesions have been reported (Sections 2.3 and 2.6).

Lethal and Mutagenic Effects of Near-Ultraviolet Radiation

Fluoroquinolone antibacterials are known to be phototoxic, both in vivo and in vitro. The action spectrum for the phototoxicity of the quinolones lies mainly in the UVA region. During studies of systemic drug phototoxicity, Johnson et al. (Dundee) induced dose-dependent phototoxicity in Swiss albino mice, and severe phototoxic reactions were followed by the development of skin tumors. The present study was designed to compare the ability of several quinolones to produce photobiologic effects following chronic, subphototoxic UVA radiation. To compare the activities of different quinolones (lomefloxacin, fleroxacin, ciprofloxacin, ofloxacin and nalidixic acid), doses that result in similar plasma and skin levels of drug were administered by gavage to slightly pigmented Skh-1 hairless mice for up to 78 weeks. 8-Methoxypsoralen (8-MOP) was used as a positive control, and unirradiated, drug-treated and irradiated and unirradiated drug-free controls were also used. No signs of phototoxicity were seen, except for minimal-to-slight erythema and swelling of the skin in animals of the lomefloxacin-UVA group. Skin tumors (1 mm in diameter or larger) were observed in all the irradiated groups and the incidence was increased in all the groups treated with the test articles. The cumulative tumor prevalence was accelerated, the median latent periods were shortened and tumor onset was significantly enhanced by 8-MOP plus UVA, lomefloxacin plus UVA and fleroxacin plus UVA, as compared with vehicle plus UVA-exposed animals. The majority of skin tumors (with the exception of lomefloxacin and 8-MOP) were benign. The majority of squamous cell carcinomas in the lomefloxacin group were of a histologic type different from those previously reported in UVA-exposed animals. Thus, all the fluoroquinolone antibiotics studied have the capability of enhancing UVA-induced phototumorigenesis, but only lomefloxacin caused the development of cystic squamous cell carcinomas in the majority of treated animals.

Fluoroquinolone antibacterials enhance UVA-induced skin tumors

Nonmelanoma skin cancers, like most malignancies, increase in incidence with increasing age. However, in general they are not due to the aging process but are primarily due to solar radiation. Clinically, squamous cell carcinomas and basal cell epitheliomas are the most common cancers that occur in the Caucasian population in the United States. The role of radiation from the sun was suggested by a number of astute clinical observations reported around 1900 and subsequently has been established by epidemiologic and experimental studies. Action spectrum evaluations indicate that the ultraviolet B (UVB) rays are the most carcinogenic. However, recent studies indicate that the UVA rays can augment the cancer-producing effects of UVB rays. Other physical stimuli, including heat and wind, can also accelerate UVB carcinogenesis. Chemicals such as the polycyclic hydrocarbons, the nitrosoureas, and nitrogen mustard have an additive carcinogenic effect with UVB radiation. Also, some chemicals such as croton oil, the phorbol ester—TPA, and all- trans -retinoic (RA) acid can promote UVB-initiated carcinogenesis. RA can also inhibit UVB-induced cancer formation. The role of the immune status has received a great deal of attention. Both in experimental and clinical situations, nonspecific immune suppression results in increased cancer formation. Also, recent studies indicate that a specific T cell suppressor population can be induced in experimental animals with UVB which will inhibit rejection of tumors produced by UVB radiation. Finally, damage to DNA by UVB radiation is well established. Studies with the genetic disease xeroderma pigmentosum support the concept that such damage, if not repaired, will lead to cancer formation. It also has been suggested that unrepaired damage to deoxyribonucleic (DNA) and other macromolecules is at least in part responsible for the aging process in general.

Photocarcinogenesis, skin cancer, and aging

The hairless mouse has been used as an experimental model for photocarcinogenesis for about 20 years. Although the carcinogenesis action spectra for mice and man are not known, acute responses to ultraviolet radiation (UVR) in the biologically active UVB and UVC region (wavelengths below 320 nm) can be compared. Vascular response (predominantly edema) action spectra for monochromatic radiation in the Skh:HR-l (albino hairless) male mouse were determined. These action spectra were found to be very similar to the human erythema action spectrum that had been developed using the same monochromator. The accuracy of this experimentally derived action spectrum was tested with a series of polychromatic source spectra. The mice were exposed to radiation from a long arc Xe lamp filtered by varying thicknesses of Schott WG320 filters, which yielded a wide range of biologically effective spectra. Spectral irradiance measurements, when weighted with the mouse edema and human erythema action spectra and multiplied by the irradiation time required to elicit a threshold response (edema), yielded a constant weighted dose regardless of irradiation spectral quality. The integrated effective dose was approximately 200 J/m2 of 297 nm equivalent energy, agreeing with requirements for the monochromatic 297 nm dose in the mice as well as for minimal human erythema. These data suggest a commonality in the UVR chromophores of mice and men as they relate to the acute responses described, and a direct additivity of effectiveness from the UVR components in a polychromatic beam, at least over the portion of the UVR spectrum tested (λ > 295 nm).

Comparison of action spectra for acute cutaneous responses to ultraviolet radiation: man and albino hairless mouse.

— Albino hairless (Skh:HR) mice were exposed to a series of daily (5 days/wk) doses of ultraviolet radiation (UVR) from a bank of fluorescent sun lamps (type FS40T12); the 24 animals in each group were examined weekly and skin changes, including tumor locations and sizes, were recorded. Primary endpoints were time to reach a specified proportion of mice bearing one or more tumors, (incidence) and time to reach a specified number of tumors per survivor (tumor yield). By these criteria, the effectiveness of the treatment increased over the range in which the skin could tolerate exposures without exhibiting overt damage (e.g. ulceration). For the 6 tolerated daily dose levels, corresponding tumor median latent periods (time to 50% incidence) described a linear relationship with log dose. A second study tested the effect of dose-delivery (time-dose reciprocity). Three groups of animals were treated with a weekly dose, delivered entirely either on 1 day, or one-third on each of 3 days, or one-fifth on each of 5 days, chosen so that the 1-day exposure did not produce overt damage. This weekly dose coincided with the 4th of the 6 dose levels in the first experiment. Effectiveness of treatment increased directly with the number of fractions per week. The basis for this dose reciprocity failure is not known, but we expect to investigate the ratio of sublethal to lethal damage in epidermal cells, and to evaluate tumor growth promotion by single vs fractionated exposures.

Photocarcinogenesis in hairless mice: dose-response and the influence of dose-delivery.

— Skin tumors were induced in hairless mutant mice following a single exposure to ultraviolet radiation (UV). Tumors were first noted as early as 7 weeks following irradiation. The UV, emitted by FS20/40T12 fluorescent lamps, was principally in the 280–320 nm spectral region with a peak at 313 nm. Single (skin surface) doses of 3 times 104 J/m2 to 24 times 104 J/m2 were delivered in 3 h or less. The higher doses resulted in more severe acute damage as well as greater tumor yield.



Most of the tumors were benign hyperplastic epithelial papillomas; 4 out of 96 tumors examined histologically proved to be squamous cell carcinomas. This appears to be the first report of experimental carcinogenesis due to a single UV exposure, not requiring exogenous chemical promotion.

Induction of skin tumors in hairless mice by a single exposure to UV radiation.

Summary

Two types of fluorescent blacklight lamps with distinctly different emission spectra bear the same code designations One type, which we refer to as BL-O, has most of its UV radiation emission centered over 350 nm The other (BL-N) type concentrates more energy around 365 nm The spectral differences are correlated with the manufacturer's shift in the type of phosphor used in the lamps Whether this change is detrimental to photobiological experiments depends in part on the user's ability to independently verify emission spectra

P. D. Forbes

Papers

Comparison of action spectra for acute cutaneous responses to ultraviolet radiation: man and albino hairless mouse.

Photocarcinogenesis in hairless mice: dose-response and the influence of dose-delivery.

Induction of skin tumors in hairless mice by a single exposure to UV radiation.

Emission spectrum differences in fluorescent blacklight lamps.