Frederick Urbach

Non‐melanoma skin cancer among caucasians in four areas of the United States

A survey of the incidence of non‐melanoma skin cancer was undertaken in four areas which included about ten million people. Complete reporting of all newly diagnosed cases of skin cancer which occurred during the survey period of September 1, 1971 to February 29, 1972 was obtained by canvassing dermatologists, radiotherapists, pathologists, and other physicians seeing and treating skin cancer. Rates among Caucasians were found two to three times higher than any ever reported before in these area. An estimate of 300,000 new cases of skin cancer per year would amount to about one‐half the total for all other forms of cancer combined in the United States. In all areas, there was an excess liability in males of about 2 to 1. Highest rates were observed in the Dallas‐Ft. Worth area, where increased solar radiation is suspected as a carcinogenic agent.

Fluoroquinolone antibacterials enhance UVA-induced skin tumors

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.

ULTRAVIOLET RADIATION AND SKIN CANCER OF HUMANS

Current scientific evidence indicates that stratospheric ozone has declined worldwide over the past 20 years. The trend estimates are markedly dependent on the geographical location and are highly seasonal. Winter trends are much more negative than those for summer and autumn. Projections based on current assumptions of chlorine release suggest that this decline will continue into the next century. On the basis of the decrease in ozone over the mid-latitudes, an increase in biologically effective ultraviolet radiation (UVR) of 4%-9% is expected, depending on the season and geographical location. However, the UVR penetration to the Earths surface is greatly affected by clouds, aerosols and tropospheric ozone, and current increases, if any, have not been as large as this. Direct evidence for the induction of non-melanoma skin cancer (NMSC) due to UVR has been derived from animal experiments in mice and rats. Numerous epidemiological data confirm that this relationship also holds for human skin. The increase in NMSC incidence in the past two decades is not likely to be due to the decrease in ozone, given the long latency (two to three decades) associated with UVR effects on skin. A knowledge of the action spectrum for NMSC development suggests that a 1% depletion in stratospheric ozone may be expected to increase NMSC, at equilibrium, by about 2.0% The evidence on the role of UVR exposure in the development of malignant melanoma (MM) is less certain. It has been estimated that a 1% reduction in ozone may cause an increase in MM of 0.6%.

Potential effects of altered solar ultraviolet radiation on human skin cancer

–There is highly significant evidence that non‐melanoma skin cancers are primarily due to chronic repeated exposure to solar ultraviolet radiation, and that there is a significant, although somewhat different relationship between solar radiation and the development of cutaneous malignant melanoma.

Enhancement of experimental photocarcinogenesis by topical retinoic acid.

Topical application of retinoic acid (RA) solutions greatly enhanced the response of hairless mouse skin to a moderate dose of simulated sunlight. Tumors appeared much earlier, and in much greater numbers, in animals treated daily with 1 or 10 micrograms of RA in methanol immediately after 2 h exposure to a xenon arc filtered through 2 mm of Schott WG 320 glass (approximately equivalent in human erythema effectiveness to 5 min of mid-summer noon solar exposure in northern mid-latitudes), compared to mice treated with light and methanol only. The higher amount of RA, in combination with light, produced moderate epidermal hyperplasia and some scaling and transient erythema, but no gross ulceration or inflammation of skin. The lower amount of RA, though about equally effective in carcinogenesis, produced minimal epidermal hyperplasia compared to the ultraviolet radiation + methanol control.

UV Doses of Young Adults

Since 1986, people have been informed that they get about 80% of their lifetime ultraviolet (UV) dose by the age of 18. This belief originated from the mathematical conclusion that diligent use of sunscreens (sun protection factor 15 or higher) during the first 18 years of life would reduce the lifetime incidence of nonmelanoma skin cancers by 78%. These data were misconstrued to mean that individuals also got about 80% of their lifetime dose of UV by the age of 18 (linear relationship). However, these calculations were based on the incidence of nonmelanoma skin cancers being related to the square of the UV dose. Careful analysis of UV exposure data shows that Americans actually get less than 25% of their lifetime UV dose by the age of 18. This finding also appears to be true worldwide because Australia, UK and The Netherlands report a similar UV exposure pattern. UV‐initiated damage early in life can be promoted by subsequent exposures to progress into tumors later in life. For example, the nonmelanoma skin cancer, squamous cell carcinoma, is dependent on the cumulative UV dose. Thus, a better educational approach for reducing skin cancers would be to instruct fair‐skinned individuals to protect themselves throughout their lives from being exposed to too much UV radiation.

A CLIMATOLOGY OF SUNBURNING ULTRAVIOLET RADIATION

Abstract— Data are presented from 14 sites where continuous measurements of the suns shortest ultraviolet radiation reaching the earths surface have been made for four or more years. Average daily dose per month and its variability from year to year is shown for each station. Some of the many influences affecting these measurements can be discerned by station intercomparisons. No consistent long term change in solar UV‐B radiation reaching the ground is evident.

Mycosis fungoides, nitrogen mustard and skin cancer

The prevalence of epithelial cancer was determined in 202 patients with mycosis fungoides and the Sézary syndrome and was found to be 10.5%. In an attempt to establish a possible association with topically applied nitrogen mustard, it was noted that 4.0% of these patients had lesions prior to nitrogen mustard therapy (although over half subsequently developed further lesions) and 6.5% of the patients developed them de novo after therapy. In two patients in this latter group, malignancies developed in areas not usually associated with solar‐induced cancer. These findings indicate that epidermal neoplasia is not uncommon in these patients and that nitrogen mustard may function as a carcinogen or a co‐carcinogen.

Ultraviolet radiation and skin cancer in man

Abstract Skin cancers are the most common malignant tumors of white-skinned people. It is well established that nonmelanoma skin cancer is almost entirely caused by chronic exposure to solar ultraviolet radiation (uvr), and malignant melanoma is strongly related to ultraviolet radiation exposure. In the U.S.A., 300,000–400,000 new skin cancers develop per year, almost all of which are preventable. About 5,000 deaths per year are due to nonmelanoma skin cancer, and a similar number are due to malignant melanoma. Reducing outdoor exposure during the 2 hr between 11 am and 1 pm will prevent 50% of the daily carcinogenic uvr dose from reaching the skin. Most of the skin cancers occur in a small proportion of the population (particularly Irish, Scottish, and Welsh) who are genetically predisposed to sunburning and who suntan little. Anthropogenic disturbance of the stratospheric ozone layer by aircraft exhaust and chlorofluorocarbons may result in a significant increase in solar uvr reaching earth and may cause an increase of 60% or more in skin cancer incidence early in the next century.

The biological effects of increased ultraviolet radiation: an update.

In the spring of 1971 the possible effect of a future fleet of supersonic transport aircraft on stratospheric ozone content was suggested. Initially, it was postulated that water and the oxides of nitrogen emitted as combustion products of aircraft engines operating in the stratosphere could have such an effect (MacDonald, 1971; Johnston, 1971). In 1974 Molina and Rowland published a paper suggesting that manmade chlorofluorocarbons might also affect stratospheric ozone. Partial destruction of this protective ozone layer would allow an increased amount of potentially harmful ultraviolet radiation to reach the surface of the earth. Because of this concern, the Environmental Studies Board of the National Academy of Sciences assembled a committee of photobiologists, under the chairmanship of Kendric Smith, to study and report on the biological consequences of an increase in terrestrial ultraviolet radiation (NAS, 1973). To realize the progressive increase in concern (and information), it is interesting to compare this initial 46 page report with the 368 pages addressing the same matters in 1986 (EPA, 1986) and 463 pages in 1987 (Hoffman, 1987). The significant volume of research carried out up to that time provided many valuable insights into UV-B effects, but in a number of cases involved isolated experiments with large UV-B doses from which few conclusions could be drawn about quantitative dose-response relationships and the existence of a threshold. The most recent report (Hoffman, 1987) on potential effects in increased ultraviolet radiation on biologic systems was published in December 1987, and brought the available information up to date through 1986. In the following two years several important scientific advances have been made, which were not available to the E P A reviewers. NASA published a report documenting stratospheric ozone changes from 1969 to 1986 (Watson et al., 1988); Frederick and Lubin (1988) described the latest radiative transfer model which includes all orders of Rayleigh scattering and absorption by ozone, as well as absorption by any additional gases or particulates specified for a given set of calculations, and a new skin erythema action spectrum was accepted (McKinlay and Diffey. 1987). Since these observations and calculations significantly affect predictions of possible bioiogic effects by increasing U V R , it was considered appropriate to bring up to date the EPA (Hoffman, 1987) report with new data. In so doing, an effort was also made to address some of the unresolved questions. Reviewers were asked to consider whether quantitative relationships can be established between UVB changes and biological effects over the range from zero change up to that covered by experimental results, whether there is evidence for or againht the existence of a dose-response threshold, and whether there is any evidence indicating an effect of the rate of UV-B change (relating to the ability of organisms to adapt). In cases where information was not available, the reviewers were invited to suggest the most important research studies needed to answer these questions. This collection of papers is designed to update our knowledge to February 1089, The major findings of this update are: 0 Taken alone, the decrease in ozone over the northern hemisphere (Watson et al., 1988) implies an increase in biologically effective UVR of 4% in summer. However, even small increases in tropospheric absorption by polluting gases or particulates could more than offset predicted enhancement o f UVR, particularly near densely populated areas. This is much lower than previous estimates. and may explain the observation of Scotto et ill. (1988). 0 The increase in biologically effective UVR over and near the Antarctic continent in the Austral spring is very much greater than in previous decades, and can exceed UVR values for summer at 34.5” North. 0 Current attempts to generate a unified action spectrum for plant effects are not likely to be successful. U V response of plants is complicated by shielding, pigments, environmental stresses and photorepair. Overor underestimates of UVR biological effectiveness occur depending on the action