CIESIN Reproduced, with permission, from: van der Leun, J. C., and F. R. de Gruijl. 1993. Influences of ozone depletion on human and animal health. Chapter 4 in UV-B radiation and ozone depletion: Effects on humans, animals, plants, microorganisms, and materials, ed. M. Tevini, 95-123. Ann Arbor: Lewis Publishers.


Effects on Humans, Animals, Plants, Microorganisms, and Materials

Edited by


Influences of Ozone Depletion on Human and Animal Health

Jan C. van der Leun and Frank R. de Gruijl


The consequences of increased exposure of the human body to UV-B radiation will in the first instance be characterized by the physical properties of this type of radiation. UV-B radiation does not penetrate far into the body; most of it is absorbed in the superficial tissue layers of 0.1 mm depth. This limits the primary effects to the skin and the eyes. There are, however, also systemic effects; these start with a primary reaction in the superficial layers, but have consequences throughout the body.

The sunlight reaching us consists of only approximately 0.5% UV-B radiation, in terms of radiant energy. Yet this small fraction is responsible for most of the effects of sunlight on the body. It is the main cause of sunburn and tanning, as well as the formation of vitamin D3 in the skin, and it has influences on the immune system. UV-B radiation is also the main cause of snowblindness and an important factor in the induction of cataracts. UV-B radiation contributes significantly to the aging of the skin and eyes, and it is the UV-B range that is the most effective in causing skin cancer.

Will all these effects increase with an increase of UV-B irradiance? That is the first impression. Closer study indicates that this is not necessarily so. The effects we observe, such as sunburn or skin cancer, are the end results of complicated chains of events. The chain begins with a primary reaction, a photochemical reaction in the skin. This primary reaction will usually increase with increased UV-B exposure. If the primary reaction leads to damage, repair processes may come into play. For damage to the DNA molecule, several repair systems have been demonstrated to be active in living cells. These may mend the damage, or part of the damage. The repair systems may, however, themselves be damaged by increased UV-B exposure. Even at this early stage in the chain of events it is difficult to predict the outcome. Cells or tissue components which are altered by the radiation may be recognized as foreign by the immune system and removed. Certain functions of the immune system are, however, suppressed by exposure to UV-B radiation. When skin is exposed to more UV-B radiation than it is accustomed to, it has the ability to adapt. The epidermal layers become thicker, and melanin pigment is formed and dispersed throughout the epidermis. These reactions limit the effects of subsequent exposures to UV-B radiation. With such a complicated sequence of events, it is difficult to answer the question of whether or not the final effects on the skin will increase. This is especially so for effects resulting from repeated exposures.

We will see that the outcome is not always an increase of the grossly observable effect. Some effects of UV-B radiation on health will indeed increase, some will not be influenced appreciably and some will even decrease in the case of increased UV-B irradiance.


There appear to be three methods to predict the ultimate health effects of increased UV-B exposure.

Direct Calculation

The most direct way is to investigate a particular health effect of UV-B radiation, with the mechanism, including the entire chain of intermediate steps in quantitative terms. On this basis it should be possible, at least in principle, to make a calculation through the entire system, resulting in a quantitative prediction.

This method is not yet feasible for any effect of increased UV-B radiation on human health. It may be a long time before this goal is achieved. The direct method will always remain vulnerable; every new discovery of an intermediate step in the mechanism may change the prediction.

The Black Box

The other extreme is not to include any mechanistic study, but to consider an entire health effect as a black box. It is known what goes in, the UV-B radiation, and one may observe what comes out, e.g., sunburn. Information on how the effect reacts to increased ambient UV-B irradiance may be acquired by making observations at different geographical locations; do people living closer to the equator have more sunburn? If not, no increase in sunburn is to be expected when the ambient UV-B irradiance increases. Do people living closer to the equator have more skin cancer? If so, more skin cancer is to be expected in case of increased ambient UV-B irradiance.

This method may be used as a first approximation, but it oversimplifies the problem. Going closer to the equator is not a fully realistic simulation of ozone depletion. Places closer to the equator have more light of all wavelengths; ozone depletion increases only the UV-B irradiance. Moreover, places closer to the equator have a different length of the day, higher temperatures and different weather. People living at different latitudes may not be comparable because of different genetic constitutions. Also, if that factor is eliminated by limiting the investigation to people of similar genetic background, they may still have different behavior at different latitudes. Without information on the influence of these complicating factors, this black box method yields very uncertain predictions.

An Intermediate Solution

A third method uses basically the same information as the black box method does--for instance, a latitudinal gradient of the skin cancer incidence. Now the reasoning is guided, however, by as much additional knowledge as possible.

In order to expect any influence of ozone depletion on a particular health effect, the effect in question should be a result of exposure to UV-B radiation. The "action spectrum" shows how a particular effect depends on the wavelength of the radiation; the concept was discussed in earlier chapters. In the first instance this gives a yes-or-no answer: if the action spectrum does not show any influence of UV-B radiation, no change is to be expected in the case of ozone depletion. If UV-B radiation is important in causing the effect, there may be an influence of ozone depletion. The action spectrum may also give quantitative information. Ozone depletion results in an increase of UV-B radiation, but the shorter the wavelength, the stronger the increase, even within the UV-B range. A health effect caused predominantly by the shorter UV-B wavelengths is likely to be influenced more than an effect mainly caused by the longer wavelengths in the UV-B range. This is technically accounted for in the "radiation amplification factor" (RAF, Chapter 2).

Another important piece of information is the dose-effect relationship: it shows how the health effect under consideration depends on the dose of UV radiation received (in technical terms: the radiant exposure). This dose-effect relationship is a dominant factor in determining how much the health effect studied will be influenced by increased UV-B radiation. In the case of a steep dose-effect relationship, the influence may be strong. In the case of a shallow dose-effect relationship or a "saturation", where the effect is the same for different doses, there may be hardly any influence or no influence at all, even if the health effect is caused by short-wavelength UV-B radiation.

Studies on the influence of ozone depletion on human health effects have yielded predictions for effects that increase steeply with increasing UV-B irradiance, for other effects that are not or not appreciably influenced, and even for one set of diseases where increased UV-B irradiance leads to a decreased effect. The reasoning leading to these three different predictions will be explained here, with an example for each of the possibilities mentioned. This will make it easier to explore the influence of increased UV-B irradiance in many other health effects later on.


If human skin is exposed to too much sunlight, it may develop a "sunburn": the skin reddens, becomes tender, and in severe cases blistering may occur. Finally the superficial skin layers slough off and the skin looks normal again. The term sunburn suggests that people first have ascribed the effect to the heat of the sun's rays, but investigations have shown that mainly the UV-B radiation in sunlight is responsible (Figure 1). This is precisely the wavelength range that will increase in the case of ozone depletion. It is not surprising that one of the first expectations was that with ozone depletion there would be more sunburn. The same idea is coming up again and again.

On closer examination, that expectation is not well founded. In the first instance, we may gain some insight by looking at what happens in sunnier areas. People living in northwestern Europe develop sunburns now and then, especially while they are on a vacation in a sunnier region, e.g., in the Mediterranean area. People originating in northwestern Europe who settled in a Mediterranean country, however, do not have more sunburn than those who stayed in northwestern Europe. The skin of the emigrant apparently adapts to the higher UV-B exposures in his new environment. This suggests that the same will happen in northwestern Europe when the UV-B irradiance there gradually increases.

The reasoning is basically correct, but it has weak spots. The UV-B irradiance is not the only difference between northern and more southern regions. Temperatures, for instance, are also different. The cold northern winter requires more clothing, and covered skin will not adapt to UV radiation. It is not impossible to devise a situation where a sunburn becomes more likely under increased UV-B irradiance. In general, however, the avoidance of sunburn depends largely on behavior. In countries with dark winters, such as in northwestern Europe, the irradiance of sunburning UV-B in summer is typically 10 or 20 times higher than in winter. Bridging of that difference requires a lot of adaptation. The adaptation of the skin to UV-B radiation is effected mainly by hyperplasia, a thickening of the most superficial layer of the skin, the epidermis. In a series of repeated exposures, as given in UV-B phototherapy, adaptation typically proceeds by steps of about 20%.[3] This means that with the next exposure the UV dose required for eliciting an observable reddening of the skin, the "minimal erythema dose" (MED), is increased by about 20%. A calculation shows that about 15 of such exposures are necessary to adapt the skin from its winter condition to the increased UV-B irradiance in summer. The avoidance of sunburn depends on going through this process carefully. This becomes not appreciably more difficult at a level of UV-B irradiance increased by, say, 20 or 30%, such as might occur with a gradual ozone depletion. This is a small change for sunburn, approximately equivalent to one of the 15 steps in the adaptation process. If anything, the adaptation will become even a bit easier, as ozone depletion will increase the UV-B irradiance in winter more than in summer. The factor to be bridged by adaptation then becomes slightly smaller.

The conclusion is that in general sunburn, although being a typical UV-B effect, will not become more of a problem under a decreased ozone layer. Some knowledge of the adaptation of the skin to UV radiation was helpful, but basically the conclusion could be reached without detailed knowledge of the mechanisms leading to sunburn.


Photodermatoses are skin diseases where the skin lesions are caused by light. Such lesions may be itching papules, whealing of the skin, fierce reddening and peeling, etc. The more sensitive patients cannot even stand one minute of outdoor daylight. In several of these diseases the UV-B radiation in sunlight is the predominant causative agent. It is understandable that many patients, and their doctors, expect an aggravation of these diseases under a decreasing ozone layer.

There are reasons to question this expectation. In the first place, if we make a comparison with a sunnier area, closer to the equator, we do not observe an increase of these diseases, either in incidence or severity. On the contrary, photodermatoses are more common and more severe in countries with dark winters. Loss of adaptation of the skin to light appears to be a predominant factor in these diseases. Such loss occurs more readily in an area with dark winters than in an always sunny climate. Many patients with photodermatoses may be treated effectively by regular exposures to low-dose UV-B radiation, especially during winter.[2,3] Depletion of the ozone layer will increase the UV-B irradiance, especially in winter. This will, to some extent, improve the patients' condition, in the same way as the exposures given by their doctors.


There are various types of skin cancer. One main class is formed by the cutaneous melanomas, the cancers of the pigment cells. The other main types are basal cell carcinomas and squamous cell carcinomas, cancers of the epithelial cells. These carcinomas of the skin are sometimes, collectively, called "non-melanoma skin cancers". For the present example we will deal with these non-melanoma skin cancers. In white caucasians, the incidence of these cancers ranks high among the various types of cancer; in some populations it is in fact the highest of all. The incidence is lower in more pigmented populations, typically by a factor of 10 or even 100. The mortality rate is low in comparison with that for other types of cancer: approximately 1% in areas with good medical care.

The non-melanoma skin cancers are clearly correlated to sunlight.[4] They occur mostly in light-skinned people, and then predominantly on skin areas most exposed to sunlight, such as the face. In people of comparable genetic background, the incidences are higher in the sunnier geographical areas. Such observations strongly suggest the involvement of sunlight, but do not point to any particular wavelength range in sunlight. Determination of the wavelengths responsible for carcinogenesis requires experimental observations.

Early experiments showed that white rats exposed to sunlight developed skin cancers, but similar rats exposed to sunlight filtered through window glass did not.[5] As the window glass absorbed mainly UV-B radiation, this result indicated that the carcinogenic effect was to a large extent due to the UV-B radiation in sunlight. This was later confirmed in many experiments, mainly with mice. The present state of knowledge on the wavelength dependence is shown in the action spectrum depicted in Figure 2. It gives the carcinogenic effectiveness of UV radiation as a function of wavelength. This action spectrum was determined in experiments where hairless albino mice SKH-HRI were exposed every day to doses of UV radiation in a realistic range for human exposures. In technical terms, carcinogenic effectiveness was defined as the reciprocal value of the daily dose of radiation at a certain wavelength required for the induction of tumors of 1 mm diameter in 50% of a group of mice in 300 days. The tumors in these mice were predominantly squamous cell carcinomas.

The action spectrum confirms that the carcinogenic effectiveness of UV radiation is maximal in the UV-B range, near the 300-nm wavelength. This makes skin cancer another candidate to increase as a result of depletion of the ozone layer.

The dose-effect relationship for carcinogenesis by UV radiation may be investigated in similar experiments. Groups of mice are given daily exposures to UV radiation; the various groups receive different UV doses. In this way the carcinogenic effect may be examined as a function of the daily dose. Experiments with mice receiving daily UV doses which are realistic for human populations lead to tumors in practically all of the animals. Under such conditions, a suitable measure for the carcinogenic effect is tm, the time in which 50% of the mice bear tumors. The dose-effect relationship then gives tm as a function of the daily dose D. Such a relationship is shown in Figure 3. It was determined for tumors of 1 mm diameter in hairless albino mice SKH-HRI.[7] The relationship covers a wide range of daily doses. The highest daily dose was slightly below the dose required for acute reactions in the mouse skin, such as edema or erythema; the lowest was smaller by a factor of 33. This dose range roughly corresponds with the doses received by human populations, with outdoor workers on the high-dose end and people staying indoors and receiving their UV radiation from the lamps used for indoor lighting on the low-dose end.

The relationship depicted in Figure 3 may be expressed mathematically in the form

tm = k1 D[-0.6] (1)


D is the daily dose of ultraviolet radiation

k1 is a proportionality constant

Equation 1 is a power relationship; it is basically in agreement with relationships for similar tumors over a smaller dose range and for larger tumors in the ears of haired mice.[8,9]

In most human populations only a minority of the people develop skin cancers. In such a situation a more suitable measure for the carcinogenic effect is the incidence, the number of new patients with skin carcinomas per 100,000 of the population per year. A directly related quantity in the mouse experiments is the yield, the average number of tumors per mouse. The yield may be related to powers of the daily dose D and the age of the mice, t:

Y = k2 D[c] t[d] (2)


Y is the yield

D is the daily dose uf UV radiation

t is the number of days of exposure (which is approximately equal to the age of the mice)

k2 is a proportionality constant

c and d are numerical exponents

This description of the mouse observations offers the possibility of comparison with human epidemiological data. Human populations are also regularly exposed to ultraviolet radiation, mainly in sunlight. There is, however, more spread in the human data. Human populations have more genetic variability than one strain of hairless albino mice. Moreover, individuals in a human population have different behavior; this includes different exposures to sunlight, even in the same location. Human populations are, however, far greater in size than groups of experimental animals, and this makes it possible to make up meaningful averages. In the Third National Skin Cancer Survey in the United States, the genetic variability was limited by including only the "white" populations in eight cities in the U.S. The incidence was correlated with the UV dose available outdoors.[10]

The relationship between incidence and the ambient UV dose could be described in a way similar to our Equation 2 for mouse data; the values of the exponents c and d were, however, smaller than in the mouse data. Because of the large spread, the human data also allowed different mathematical descriptions.[11] It appears preferable, however, to use an equation which describes experimental as well as epidemiological data.

With the help of the data summarized here, it is possible to make a prediction of the influence of ozone depletion on the incidence of skin cancer in human populations. We make the following assumptions:

  1. The action spectrum for carcinogenesis in humans is the same as that in mice.

  2. Population exposure behavior and susceptibility do not vary with latitude or UV exposure.

  3. The exposure habits in human populations will not change after ozone levels decrease.

From assumption 1 we can calculate a radiation amplification factor of 1.4. This means that a 1% decrease of total-column ozone will cause an increase of the carcinogenically effective dose by 1.4%; this is for the yearly dose available outdoors.[12] The RAF does not vary appreciably with latitude between 60deg.S and 60deg.N; for higher latitudes it is smaller.[13] Assumption 3 allows a calculation of the consequences for the incidence of skin cancer. That is the long-term consequence, because skin cancer is a long-term reaction of the skin, typically taking at least several decades. The power relationship in Equation 2 implies that the incidence will not increase in direct proportionality to the doses available. Differentiation of Equation 2 with respect to D gives as a result


which means that the percentage change of the incidence is c times the percentage change of the dose; c is called the "biological amplification factor", abbreviated BAF.[14] This amplification factor originates from the dose-effect relationship. In principle the biological amplification factor is independent of the action spectrum; in the mouse experiments, Equation 2 holds also for practically monochromatic exposures.

Because of a complication, the derivation of the BAF for human populations comes to depend on the action spectrum chosen. For human populations exposed to sunlight, the D in Equation 2 is the carcinogenically effective dose--that is, the dose of sunlight spectrally weighted with the action spectrum for UV carcinogenesis. When the correlation between skin cancer incidence and UV dose was made, the action spectrum for UV carcinogenesis was not yet known.[10] The carcinogenic dose was approximated by "sunburn units" as measured with a Robertson-Berger meter. In this way, the sensitivity curve of this meter was used as an approximation of the action spectrum for photocarcinogenesis. Now that we have an action spectrum for photocarcinogenesis, the correlation of incidence and effective UV dose has to be corrected; this correction depends on the action spectrum. Doing this, the biological amplification factor for squamous cell carcinoma in white populations in the U.S. becomes 2.5, while that for basal cell carcinoma is 1.4.[68]

If the findings about the RAF and BAF are now combined, it can be concluded that a 1% decrease of total-column ozone leads to a 1.4% increase in the carcinogenically effective irradiance. That in turn leads to an increase of the incidence of squamous cell carcinoma by 1.4 x 2.5 = 3.5% and to an increase of the incidence of basal cell carcinoma by 1.4 x 1.4 = 2.0%. These percentage increases of incidence for a 1% decrease in ozone are sometimes referred to as the overall amplification factors (AF). In many cancer registries, squamous cell carcinomas and basal cell carcinomas are lumped together as non-melanoma skin cancers. With a 4:1 ratio of the incidences of basal cell carcinoma and squamous cell carcinoma, the overall amplification factor for non-melanoma skin cancer becomes (4 x 2 + 1 x 3.5)/5 = 2.3. That means a 1% decrease of total ozone will lead to a 2.3% increase of non-melanoma skin cancer.

The expression of these numbers as a consequence of a 1% ozone decrease is given in order to provide the data for calculating the consequences of stronger ozone decreases. It is done in this way because the prediction of ozone depletion has varied markedly with time, reflecting improvements in the atmospheric models. Now that ozone decrease can be measured, the measurements also show variations with place and time. For ozone depletions larger than 1% the fractional increase in the incidence of non-melanoma skin cancer may be calculated with the help of the equation


where p is the percentage of ozone depletion. Some numerical results are shown in Table 1. For the radiation amplification, this equation gives a fair approximation for ozone decreases smaller than 30%.[69] For the biological amplification the equation is the best representation of present knowledge. For depletions p greater than 30% it is better to derive the radiation amplification from the full atmospheric model computations.

This section on non-melanoma skin cancer differs from most other sections in that numbers are calculated. Some comments should, however, be made. The numbers are not as accurate as the decimals given suggest. There are uncertainties which are difficult to quantify. The uncertainties are not primarily of a statistical nature. The main uncertainty results from the fact that the numbers were calculated on the basis of only partially available knowledge. Some indication of what this means for the result may be given by the history of these predictions (see Table 2). The changes are due to improving knowledge. Between McDonald's pioneering work and the value given by the UNEP Coordinating Committee on the Ozone Layer in 1980, the available data and the theory were improved.[15,16] The changes since 1980 were primarily caused by the new finding of a contribution of UV-A radiation (315-400 nm) to carcinogenesis in sunlight. The action spectrum is shown in Figure 2. This contribution to the effect is insensitive to ozone change; that leads to lower predictions.[13] No one could have known this before the carcinogenic contribution of UV-A radiation was observed in experimental work. That means that an uncertainty analysis in 1980 would not have included this uncertainty. In a similar way, the numbers given now may still contain such uncertainties.

An example of a piece of knowledge still lacking is an action spectrum for the induction of basal cell carcinoma. The experimental mice used until now do not react to UV-B radiation by forming basal cell carcinomas. For lack of knowledge it was assumed that basal cell carcinomas would follow the same action spectrum as squamous cell carcinomas. Some support for this assumption came from a limited number of clinical accidents where basal cell carcinomas arose in human skin after exposure to large doses of UV-B radiation.[17]

If new information becomes available, it may be used to improve the predictions given. At the same time, the uncertainty in the predictions will be reduced. There are also pieces of new information that do not change the quantitative predictions. An example is the discovery that UV-B radiation also influences the immune system (see section on infectious diseases). This work was published while the predictions listed in Table 2 were well under way.[18] The influences of UV-B radiation on the immune system were shown to be of quantitative importance in the process of UV carcinogenesis.[19] Yet, because the method of prediction still had the black-box aspect, these unknown influences had already been taken into account implicitly. The observational data used, from mouse experiments as well as human epidemiology, were all obtained in situations where the influences of UV-B radiation on the immune system were already present. That is the reason why the predictions about the influence of ozone depletion on the incidence of non-melanoma skin cancer did not show any discontinuity at the time of this new discovery. There is little doubt that non-melanoma skin cancer will prove to be an example where the incidence will indeed increase with increasing UV-B irradiance.


Cutaneous melanomas are cancers of the pigment cells in the skin. Their incidence is much lower than that of non-melanoma skin cancers, typically by a factor of 10. The mortality rate is, however, much higher; in countries with good medical care the mortality rate has been brought down to 25%, mainly by early diagnosis.

The question of whether or not the incidence of cutaneous melanoma will increase as a result of ozone depletion is complicated. Much of the knowledge relevant in this connection has been reviewed.[20-22] This knowledge is summarized in the present section.

For a long time the clinical impression was that cutaneous melanomas had nothing to do with sunlight. A primary melanoma could occur in a skin region seldom receiving any sunlight. Moreover, statistics in several countries showed indoor workers to have a higher risk of melanoma than outdoor workers, in contrast to the experience with non-melanoma skin cancer.

Newer investigations have not contradicted these observations, but have added data giving the opposite suggestion, that sunlight does play a role. In several countries the incidence is highest in the sunniest areas. The increase in incidence with decreasing latitude is less steep than for non-melanoma skin cancer, but is significant. People who emigrated from northwestern Europe to sunnier countries, such as Israel or Australia, had a higher risk of melanoma than those who stayed in northwestern Europe.[23,24] This was especially true for those who were at childhood age at the time of emigration. Emigrants' children who were born after the move had a risk comparable to that in their new country.

Confronted with these seemingly conflicting indications, most researchers tend to accept the mounting evidence that sunlight appears to play some role. It is difficult, however, to come to a coherent conception. Interpretation of the observations is usually attempted along the following lines. The fact that outdoor workers have a lower risk than indoor workers is ascribed to adaptation due to the regular exposures. Indoor workers are exposed very little during their work. When they go on a weekend or holiday trip they may suddenly receive a high dose of UV radiation to which the skin is not adapted. The emigration studies suggest that the exposures in childhood are decisive. The combination would suggest sudden exposure to high doses during childhood to be the important factor. Some epidemiological case-control studies have indeed found that melanoma patients reported more sunburn experiences than control persons; such studies draw heavily on the memories of the people questioned and on the absence of bias. An unsatisfactory element in these explanations is that office workers are not at childhood age. The interpretation is not made any easier by the trend analyses. Cutaneous melanoma has for decades shown one of the fastest-rising incidences among all types of cancer. The increase was steepest in the cohorts born between 1875 and 1925.[25] Recent trend analyses show a reversal of this tendency. Younger age groups in the U.S.A. have a markedly lower risk of dying from cutaneous melanoma than their parents' age groups had. The reversal occurred in males for those born after 1950 and in females born after 1930.[26] The overall mortality in populations is still rising, but if the reversal persists, the overall mortality will peak in about 20 years and then go down. As long as only the increases were known, the usual explanation was in terms of increased exposure to sunlight. People had more leisure time than earlier generations and more means to go on vacation to sunny areas; moreover, they covered less of the skin with clothing. This explanation may have had some plausibility, but the reversal is difficult to interpret in these terms. Most of the factors increasing the exposure, particularly the travel to sunnier areas, occurred after 1930-1950. Whatever the explanation, the data obtained in trend analysis make it clear that any prediction of an influence of ozone depletion on cutaneous melanoma will be one made against a baseline that is changing, so far for unknown reasons.

As long as it is not really known that UV-B radiation is involved, a prediction of an influence of ozone depletion on the incidence of cutaneous melanomas cannot even begin to be made. Most of the epidemiological observations suggesting a causative role for sunlight in cutaneous melanoma do not point to any particular wavelength range in sunlight. One possible exception is the role of episodes of severe sunburn; sunburn is mainly an effect of UV-B radiation. But the role of sunburn episodes rests on a shaky base, the memories of people. A role of UV-B radiation in melanoma can also be hypothesized on the assumption of analogy with non-melanoma skin cancer.

Knowledge of the wavelengths involved in the production of cutaneous melanoma has been lacking for so long because it has proved difficult to find an animal model for doing the necessary experiments. Whereas non-melanoma skin cancers have been related to sunlight in cattle, goats, sheep, cats and dogs, no such observations are available for cutaneous melanoma. Experimental induction of non-melanoma skin cancer by UV-B radiation has succeeded in mice, rats, hamsters and guinea pigs, starting from 1928.[27] It was only recently, however, that researchers found two animal models for the induction of melanomas by ultraviolet radiation alone: a marsupial, the South American opossum Monodelphis domestica, and a fish, the platyfish-swordtail hybrid.[28,29] Both of these animals were shown to develop melanomas after exposure to UV-B radiation. From the viewpoint of the problem of melanoma in humans, these are more far-removed models than those available for non-melanoma skin cancer. Yet the new models give support to the idea that solar UV-B radiation may play a role in the formation of cutaneous melanoma.

Because the animal models for UV-induced cutaneous melanoma were found only recently, data such as an action spectrum or a dose-effect relationship are not yet available. As was explained in the section on non-melanoma skin cancer, these data are essential for a good quantitative prediction.

In the present situation the only possible way to make any prediction about the influence of ozone depletion on the incidence of cutaneous melanoma is the black-box method. One such prediction was made by the U.S. Environmental Protection Agency on the basis of the correlation of the incidence with geographic latitude in the U.S.A.[30] The latitudinal gradient was significant, but not as steep as for non-melanoma skin cancer. The conclusion was that a 1% decrease of total-column ozone would, other things being equal, lead to a 2% increase of the incidence of cutaneous melanoma. Such a prediction implies the assumption that (a) the latitudinal gradient of the incidence was due to the latitudinal gradient of UV-B radiation and (b) a change in UV-B load by ozone decrease would have a similar effect. Because of the many unknowns involved, the validity of these assumptions appears questionable. Real improvement will have to wait for an action spectrum and, even more important, for a dose-effect relationship.


The eye is also directly accessible to solar UV radiation. It is protected to some extent by its shaded position in the eye socket and under the eyebrow. The shielding is especially effective with a high sun, when there is a great amount of UV-B radiation in sunlight.

One of the adverse effects caused by UV radiation in the eyes is "snowblindness". It occurs typically when the eyes are exposed to UV radiation coming from unusual directions, such as in snow-covered mountains. Snowblindness is very painful, sometimes described as the feeling of having sandpaper in the eyes. It usually starts several hours after exposure and gives the victim a very uncomfortable night; the pain may even last several days, depending on the severity. The eyes usually heal spontaneously.

The medical name for the condition is photokeratitis. It is an acute inflammation of the superficial layers of the eye, the cornea and conjunctiva. The effect is dose related. In severe cases there may be lasting damage. The eye has no adaptation against this effect; the eye even tends to become more sensitive to the next exposure. The action spectrum was determined experimentally in rabbits.[31] Within the solar spectrum, the most effective wavelengths are in the UV-B range. The radiation amplification factor was calculated to have a value of 1.1 or 1.2.[32]

The eyes may be protected by UV-absorbing sunglasses. In spite of this possibility, snowblindness is a frequently occurring problem. There is little doubt that increased solar UV-B irradiance, with unchanged behavior, will lead to increased incidence and severity of snowblindness.


Cataracts are opacities in the lens of the eye which impair vision. Cataracts occur mainly in elderly people and may ultimately lead to blindness. In countries with good medical facilities, surgery can prevent most cataracts from causing blindness. Even so, the cataract is one of the main causes of blindness in a country such as the U.S. In developing countries, cataracts result in a much higher incidence of blindness. It was estimated in 1985 that cataracts were responsible for 17 million cases of blindness, accounting for more than 50% of the blindness in the world.[33] The problem is increasing with increasing life expectancy, especially in the developing countries.

It is becoming increasingly clear that sunlight, among other factors, plays a role in the formation of cataracts. Ophthalmologists distinguish three main types of cataract: nuclear cataract, which occurs in the nucleus of the lens; cortical cataract, which occurs in the surrounding cortex; and posterior subcapsular cataract, which occurs beneath the posterior capsule of the lens.[34] An association with sunlight was reported for cortical cataracts by Taylor et al.,[34] for posterior subcapsular cataract by Bochow et al.[35] and for nuclear cataract by Mohan et al.[36]

In some of the epidemiological studies, the UV radiation in sunlight is stated to be responsible.[35] It is questionable whether the methods followed in epidemiological studies have the resolving power to reach such a conclusion. Taylor et al., in a study on Maryland "watermen", even singled out UV-B radiation as the causative agent, in distinction from UV-A radiation.[34] All exposures of the watermen were to full sunlight, and the individual exposures had to be reconstructed years afterward. Moreover, the exposures to solar UV-B radiation and UV-A radiation were highly correlated. This again raises the question about resolving power. A predominant role of UV-B radiation is, however, supported by data from animal experiments. Pitts et al. determined an action spectrum for the induction of cataracts in rabbits; the action spectrum peaked in the UV-B range.[31] For this action spectrum, the radiation amplification factor was calculated:[32]

RAFcataract = 0.7 (5)

With this experimental result, the interpretation of epidemiological findings in terms of UV-B exposures appears to be supported.

That renders it possible to make a prediction on the influence of ozone depletion on the incidence of cataracts.[33,39] Taylor et al. concluded from their observations in watermen that a doubling of the cumulative UV-B exposure corresponded to a 1.6-fold increase in the incidence of cortical cataracts.[34] If this is interpreted, by analogy with non-melanoma skin cancer, as a dose-effect relationship according to a power law, that would read

I = k3 D[0.7] (6)


I is the incidence

D is the UV-B exposure

k3 a proportionality constant

Differentiation of this equation with respect to D shows that


which implies that the biological amplification factor becomes

BAF = 0.7 (8)

If it is assumed that the RAF and BAF found (Equations 5 and 8) apply to all forms of cataract, a 10% loss of total-column ozone would lead to a 7% increase in the cataract-effective UV-B doses, and that in turn would lead to a 0.7 x 7 = 5% increase in the incidence of cataracts. It would take several decades for this increase to come to full effect, because the formation of a cataract is a slow process, typically taking at least several decades.

This prediction may be made more explicit by taking into account the estimate that there are 17 million blind people in the world as a consequence of cataracts.[33] The calculation given shows that if during the past decades there would have been a sustained worldwide reduction of total-column ozone by 10%, the number of blind people would be higher by 0.05 x 17,000,000 = 850,000. Taking into account that cataract-induced blindness mostly occurs in the latter decades of life, the number of additional blind people per year would have been roughly 850,000/25 = 34,000. Recognizing the large uncertainties in this reasoning, it appears that it is better to give the estimate as a round number, 30,000 additional blind people per year.

A similar conclusion applies with respect to reductions of stratospheric ozone in the future. Such a conclusion will have to be qualified, however, by the additional condition that all other influences would remain equal. Under that condition, a sustained 10% loss of ozone worldwide would, in the long term, lead to 30,000 additional blind people per year. Important "other influences" include the size of the world population, the life expectancy and the availability of medical care. There are good reasons to expect that these factors will not remain equal, but by themselves will produce a tendency of increasing incidence of cataracts and cataract-related blindness. The increase calculated for ozone depletion will be superimposed on any increase caused by the other factors.


There is concern that one consequence of increased UV-B irradiance might be an increase of certain infectious diseases.[39,40] The concern arose from an increasing number of observations showing influences of UV-B radiation on the immune system. This has led to an entire new discipline called photoimmunology, a merger of photobiology and immunology.

Many influences of UV-B radiation on the immune system are suppressive. UV-B exposures can, for instance, suppress the resistance of the mouse immune system against UV-B-induced tumors.[41,42] Furthermore, the induction of hypersensitivity to contact allergens may be suppressed by prior exposure of the skin to UV-B radiation, both in mice and in humans; this may even lead to tolerance of the host to the allergen.[43,45] After sensitization to a contact allergen, the reaction of the skin to a challenge with the allergen may be suppressed by prior UV-B irradiation.[46] These observations raise the question of such suppressions also weakening the body's defense against infections. Might increased UV-B irradiance lead to an increase in the incidence or severity of infectious diseases? The answer is by no means obvious. The suppressions summarized are not signs of a general immunosuppression. They are quite specific. Many immune responses are not affected by UV irradiation. The same UV-B exposures that suppress the resistance of the mouse immune system against UV-B-induced tumors do not change the reaction of the animal to chemically induced tumors.[47] The changes caused by UV-B radiation are mediated through the skin. Infections that have a phase in the skin are, therefore, the most likely ones to be influenced. Malaria is such a candidate, as the mosquito brings the infection into the skin. The possibility that other infections, not contracted through the skin, are influenced cannot be ruled out, however, because the immune changes also lead to systemic effects.

It will be very difficult to make predictions on what effects are to be expected of ozone depletion in this context. In this case, that is not primarily due to the lack of photobiological data. The UV-B doses needed for the various influences on the immune system are fairly well known. One action spectrum is already available, for systemic suppression of contact sensitization in mice.[45] As far as the wavelengths available in sunlight are concerned, this suppression is clearly an effect of UV-B radiation. The radiation amplification factor was calculated to be about 0.9.[32] From these viewpoints, this influence on the immune system could well be increased in the case of increased UV-B irradiance. The real difficulty is in lack of knowledge on how to proceed with the prediction on infectious diseases.

The immune system itself is very complex, with several subsystems helping or suppressing each other. What UV-B irradiation does to some of the subsystems is known for certain experimental conditions, but this knowledge is far from sufficient to predict the overall outcome for the entire system. Moreover, the infectious agents themselves may be influenced by the UV-B radiation. It has long been known that bacteria and viruses may be inactivated by UV-B radiation; it has to be added now that the same type of radiation may activate viruses in the living cell.[49] The question of whether or not infectious diseases will be influenced by increased UV-B irradiation will be very difficult to answer along general lines.

Special investigations have been made in experiments with a few infections. Leishmaniasis is a tropical infectious disease. The parasite is brought into the skin by the sandfly. In experiments, the infection was brought into the skin of UV-B exposed and unexposed animals. In the UV-B exposed animals, the skin showed less initial reaction to the infection, but later the disease spread more fiercely through the body.[50]

In experiments with herpes simplex infections, the UV-B exposed animals were also affected more than the unexposed controls.[51] This appears to correlate with human experience; a latent herpes infection may exacerbate on exposure to sunlight.[52] Activation of the herpes virus may play a role here, besides the influence of UV-B irradiation on the immune system.

Activation of viruses by UV-B radiation was demonstrated in experiments with papilloma viruses and with HIV-1, the human immunodeficiency virus.[53,54] Such observations give, of course, reason for concern.

Activation of viruses by increased UV-B radiation would not lead to an increased rate of infection, but it might result in a more rapid course of the infection or an increased severity of the disease. Any prediction on the practical consequences would, however, carry a large uncertainty, in view of the differences between the conditions in the experiments and in real life.

For the time being it may be best to look for direct indications of any influences of UV-B radiation on infectious diseases in humans. One method to do this is, again, to look at what happens with respect to infectious diseases at the various geographical latitudes. It is obvious that infectious diseases are a much greater problem in tropical and subtropical areas than at higher latitudes. This roughly correlates with the UV-B irradiances at these latitudes. There are, however, many more differences--for instance, temperature, humidity, environmental conditions for vectors such as insects, living conditions for humans, including hygienic conditions, preventive medicine and medical care. It would not be justified to single out UV-B irradiance from such a list of possible causes, especially not if we also take into consideration areas like Australia and the southern U.S. In those areas infectious diseases are no great problem, in spite of a comparatively high UV-B irradiance. Infectious diseases form a problem field which is apparently too complex to be handled by a simple black box method.

Clinical evidence may also be considered. Dermatology has a longstanding interest in the influence of UV-B radiation on skin diseases. Apart from the photodermatoses, where the skin lesions are caused by sunlight, there are diseases that are aggravated by sun exposure, e.g., lupus erythematosus, an autoimmune disease.[55] There are, however, also skin diseases where sunlight improves the condition of the skin. Psoriasis, for example, is a widespread noninfectious skin disease; exposures to UV-B radiation form an effective medical treatment.[56]

The fact that UV radiation may act in both ways, aggravating or improving the condition of the skin, also applies to infectious skin diseases. Almost 100 years ago, Finsen dealt with the influence of light on two skin infections.[57] He found that patients having smallpox reacted unfavorably to sunlight. Exposure to sunlight aggravated the disease. The lesions became more virulent and left deeper scars; the patients had higher fever and a greater probability of dying. The practical solution was that patients with smallpox were kept out of the light; even the indoor daylight was excluded. This observation was later extended to vaccinia lesions; van't Riet and van der Leun found that scarring by cowpox vaccination could be prevented by keeping the lesions covered with a black cloth during the active stage.[58] A seemingly opposite observation was made by Finsen for another serious infectious disease, lupus vulgaris (skin tuberculosis).[57] He found that the lesions could be healed by repeated local exposures to UV radiation. It was the first effective treatment for this disfiguring disease, and Finsen was awarded the Nobel prize (1903). Later, heliotherapy was given to many patients with tuberculosis, not only of the skin, but also of the lungs. In several cases, the exposures to sunlight severely aggravated the condition of the lungs.[59]

Many of these early observations were made with regard to full sunlight, and it cannot be established afterwards what wavelength range was responsible. At least in the case of skin tuberculosis it was clearly UV radiation that was effective. The observations show that infectious diseases of the skin may react to light in opposite ways, and that even with the same infectious agent the skin and the lungs could show opposite reactions.

The question of what depletion of the ozone layer will do to infectious diseases is still open. The pieces of knowledge available give good reasons for concern, but more investigations are clearly needed. One part of the answer is likely to be that the consequences will be different for different infectious diseases.


Increased UV-B irradiance might also have consequences for the effectiveness of vaccination programs. Even less can be stated here with certainty than was concluded with regard to the direct influences on infectious diseases. There are, however, observations showing that immunization through UV-treated skin may render the individual more susceptible to the administered antigen, rather than less susceptible.[50] The concern is that increased UV-B irradiance might interfere with the effectiveness of vaccinations, which especially in poor countries are the main way of controlling infectious disease. More research in this area is urgently needed.


UV-B irradiation leads to the formation of vitamin D3 in the skin. This vitamin is necessary for the formation and maintenance of our bone system and for several other health effects. The vitamin may also be supplied via the diet, but the formation in the skin by solar UV-B radiation usually forms an important part of the supply.

The metabolism of vitamin D and its medical consequences were investigated extensively in recent years.[60] Two results of these studies are of direct relevance with respect to the consequences of depletion of the ozone layer:

  1. The formation of vitamin D3 in the skin by UV-B radiation is self-limiting. This implies that exposure of the skin to too much UV-B radiation does not lead to the formation of too much vitamin D3.

  2. Deficiencies of vitamin D3 occur in several groups of the population, such as dark-skinned children living in northern cities and elderly people who stay indoors practically all of the time.

These results make it relatively easy to predict the consequences of ozone depletion. Because the formation of vitamin D3 in the skin by UV-B radiation is self-limiting, it is not to be expected that increased UV-B irradiance will lead to intoxication by vitamin D3. Some of the deficiencies may be relieved by increased UV-B irradiance. The formation of vitamin D3 in the skin of darkly pigmented children in northern cities may be expected to increase. Such an improvement is not to be expected for people whose shortage of vitamin D3 is due to being indoors all the time. Solar UV-B radiation hardly comes indoors, due to the strong absorption of this type of radiation by window glass. This situation will not change appreciably in case of ozone depletion.

In short, depletion of the ozone layer is not expected to lead to intoxication by too much vitamin D3, and some of the deficiencies may be relieved.


Much of what was set out in this chapter on the consequences of ozone depletion for human health applies in principle also to the health of animals. In fact, several conclusions on human health effects were partly based on observations in experimental animals, e.g., the action spectra for UV-induced skin cancer and cataract. Many animals have skins and eyes just as vulnerable to ultraviolet radiation as the human equivalents. This is not limited to mammals; even trout can develop sunburn.

There are, of course, also differences. Many animals have their skins protected by dense fur. Nocturnal animals will not be bothered too much by what happens to the sunlight at daytime. The immune systems of humans and animals are not identical.

The problem of possible consequences of ozone depletion for animal health is much broader than that for human health because of the numerous different species. Yet, there are even fewer data available for animals. Very little appears to be known about UV effects in wild animals. Most information relates to experimental animals; it is good to keep in mind that these animals are highly selected, usually for investigating problems of human health. Some more independent information is available on domestic animals from veterinary medicine.

A first general impression from comparison of animal and human data is that the effects are rather similar; this holds at least for the effects that are recognized. Animals of several species develop skin cancer in sparsely haired, light-colored parts of the skin. This applies to cows, goats, sheep, cats and dogs.[61-63] The cancers found were mainly squamous cell carcinomas. The observations strongly suggest sunlight as the cause; as these animals received full-spectrum sunlight, the wavelengths responsible cannot be specified. Similar tumors can, however, be induced experimentally in mice, rats and hamsters; in such experiments, the most effective wavelengths are in the UV-B range.[64]

Cancers of the eye also occur in many animal species, including horses, sheep, swine, cats and dogs, and are particularly frequent in cattle.[65] In several experiments designed to investigate the induction of skin cancer by ultraviolet radiation, a fraction of the animals also developed eye cancers. This occurred in mice, rats and hamsters and in the (nocturnal) South American opossum Monodelphis domestica.[28,66,67] In all of these experiments the irradiation had a strong UV-B component. Photokeratitis (snow blindness) and cataract were induced experimentally in rabbits; the action spectra showed a high effectiveness of UV-B radiation.[31]

In the species where these effects occur, an increased UV-B irradiance may be expected to lead to increased incidence of skin cancer, cancer of the eye, photokeratitis and cataract. It is hard to imagine that such effects would not also occur in some wild animals. The problems may, of course, be strongly modified by circumstances. A mole, living mainly underground, will have little problems with increased solar UV-B irradiance. A short lifespan, as may be usual for many animals in the wild, may also markedly influence the consequences of increased UV-B irradiance; it may limit the possibilities for chronic damage to develop. A short life is very likely to prevent a cataract from proceeding to blindness. But that does not necessarily mean that the consequence is less serious. A gazelle grazing in the steppe is exposed to sunlight practically all day. All that time it has to be on the watch for approaching predators. When solar UV-B radiation begins to impair its vision, its chances to escape will decrease. For this animal, the slight UV-B damage may be the very reason why its life is so short. If so, increasing UV-B radiation may make it even shorter.


In the present chapter an attempt was made to estimate the health effects of ozone depletion in quantitative terms as much as possible. In the area of animal health that was not possible at all, and with respect to human health it was possible only for two effects, skin cancer and cataract. For some potentially important effects, such as a possible influence on infectious diseases, even the direction is not clear. In our assessment, the state of knowledge on effects in areas other than health is certainly not better.

Fragmentary as the knowledge available may be, it has been sufficient in a first decisive phase: it has convinced the major nations that action is necessary to protect the ozone layer. The present knowledge is unlikely to be sufficient in the next phase. Even with the most drastic protective action, the ozone layer will be damaged for the century to come. Policymakers will have to know the effects to be expected and the possibilities for developing response strategies. Questions likely to come up are: What are the most important effects, and where should the response effort go? That takes more than expressions of concern. It requires quantitative knowledge, if possible for all potentially important effects. The same type of knowledge will be needed when the cost of further protective actions will have to be weighed against the damage to be prevented.

This means that many scientific investigations have to be developed well beyond the present orienting stage. Key elements needed for quantitative estimations are the action spectra and dose-effect relationships for all effects of concern. This is a great challenge to photobiologists.


The authors wish to thank Sharon A. Miller for many improvements in the manuscript. Much of our work reflected in this chapter was supported by the Dutch Ministry of Housing, Physical Planning and the Environment, and by the Royal Dutch Academy of Sciences.


1. Parrish, J. A., K. R. Jaenicke, and R. R. Anderson. "Erythema and Melanogenesis Action Spectra of Normal Human Skin," Photochem. Photobiol. 36:187-191 (1982).

2. Van Weelden, H. and J. C. van der Leun. "Lichtinduzierte Lichttoleranz bei Photodermatosen; ein Fortschrittsbericht," Z. Hautkr. 58:57-59 (1983).

3. Van der Leun, J. C., and H. van Weelden. "UVB Phototherapy: Principles, Radiation Sources, Regimens," Curr. Probl. Dermatol. 15:39-51 (1986).

4. Urbach, F. "Geographic Pathology of Skin Cancer," in The Biologic Effects of Ultraviolet Radiation, with Emphasis on the Skin, F. Urbach, Ed. (Oxford: Pergamon Press, 1969), pp. 635-650.

5. Roffo, A. H. "Ueber die physikalisch-chemische Aetiologie der Krebskrankheit," Strahlentherapie 66:328-350 (1939).

6. De Gruijl, F. R., and J. C. van der Leun. "Action Spectra for Carcinogenesis," in The Biologic Effects of UVA Radiation, F. Urbach, Ed. (Overland Park, Kansas, Valdenmar Publ., 1992), pp. 91-97.

7. De Gruijl, F. R., J. B. van der Meer, and J. C. van der Leun. "Dose-Time Dependency of Tumor Formation by Chronic UV Exposure," Photochem. Photobiol. 37:53-62 (1983).

8. Forbes, P. D., H. F. Blum, and R. E. Davies. "Photocarcinogenesis in Hairless Mice: Dose-Response and the Influence of Dose Delivery," Photochem. Photobiol. 34:361-365 (1981).

9. Blum, H. F. Carcinogenesis by Ultraviolet Light (Princeton, N. J.: Princeton University Press, 1959).

10. Scotto, J., T. R. Fears, and F. Fraumeni. "Incidence of Nonmelanoma Skin Cancer in the United States," Publ. no. NIH 82-2433, U.S. Department of Health and Human Services (1981).

11. Fears, T. R. and J. Scotto. "Estimating Increases in Skin Cancer Morbidity due to Increases in Ultraviolet Radiation Exposure," Cancer Invest. 1:119-126 (1983).

12. Longstreth, J. D., F. R. de Gruijl, Y. Takizawa, and J. C. van der Leun. "Human Health," in Environmental Effects of Ozone Depletion: 1991 Update, J. C. van der Leun and M. Tevini, Eds. (Nairobi: United Nations Environment Programme, 1991), pp. 15-24.

13. Kelfkens, G., F. R. de Gruijl, and J. C. van der Leun. "Ozone Depletion and Increase in Annual Carcinogenic Ultraviolet Dose," Photochem. Photobiol. 52:819-823 (1990).

14. Van der Leun, J. C. and F. Daniels, Jr. "Biologic Effects of Stratospheric Ozone Decrease: A Critical Review of Assessments," in Impacts of Climatic Change on the Biosphere, CIAP Monograph 5, Part 1--Ultraviolet Radiation Effects, D. S. Nachtwey, Ed. (U.S. Dept. of Transportation, Climatic Impact Assessment Program, Washington, D.C., 1975), pp. 7-107 to 7-124.

15. McDonald, J. E. "Relationship of Skin Cancer Incidence to Thickness of Ozone Layer," statement submitted to hearings before the House Subcommittee on Transportation Appropriations, March 2, 1971. Congr. Rec. 117(39):3493 (1971).

16. United Nations Environment Programme, Co-ordinating Committee on the Ozone Layer, Report of the Fourth Session, Bilthoven (1980).

17. Schuppenhausen, E. and H. Ippen. "Lichtschaden durch Lichtabusus," in Photodermatosen und Porphyrien, H. Ippen and G. Goerz, Eds. (Düsseldorf: Publ. H. Ippen, 1974), pp. 8-9.

18. Kripke, M. L. and M. S. Fisher. "Immunologic Parameters of Ultraviolet Caranogenesis," J. Natl. Cancer Inst. 57:211-215 (1976).

19. De Gruijl, F. R. and J. C. van der Leun. "Systemic Influence of Preirradiation of a Limited Skin Area on UV-Tumorigenesis," Photochem. Photobiol. 35:379-383 (1982).

20. Lee, J. A. H. "Melanoma and Exposure to Sunlight," Epidemiol. Rev. 4:110-136 (1982).

21. Elwood, J. M., R. P. Gallagher, G. B. Hill, and J. C. G. Pearson. "Cutaneous Melanoma in Relation to Intermittent and Constant Sun Exposure--The Western Canada Melanoma Study," Int. J. Cancer 35:427-433 (1985).

22. De Gruijl, F. R. "Ozone Change and Melanoma," in Atmospheric Ozone Research and its Policy Implications, T. Schneider et al., Eds. (Amsterdam: Elsevier Science Publishers, 1989), pp. 813-821.

23. Katz, L., S. Ben-Tuvia, and R. Steinitz. "Malignant Melanoma of the Skin in Israel: Effect of Migration," in Trends in Cancer Incidence: Causes and Practical Implications, K. Magnus, Ed. (New York: Hemisphere Publishers, 1982), pp. 419-426.

24. Holman, C. D. J. and B. K. Armstrong. "Cutaneous Malignant Melanoma and Indicators of Total Accumulated Exposure to the Sun: An Analysis Separating Histogenic Types," J. Natl. Cancer Inst. 73:75-82 (1984).

25. Stevens, R. G. and S. H. Moolgavkar. "Malignant Melanoma: Dependence of Site-Specific Risk on Age," Am. J. Epidemiol. 119:890-895 (1984).

26. Scotto, J., H. Pitcher, and J. A. H. Lee. "Indications of Future Decreasing Trends in Skin-Melanoma Mortality Among Whites in the United States," Int. J. Cancer 49:490-497 (1991).

27. Findlay, G. M. "Ultraviolet Light and Skin Cancer," Lancet 2:1070-1073 (1928).

28. Ley, R. D., L. A. Applegate, R. S. Padilla, and T. D. Stuart. "Ultraviolet Radiation-Induced Malignant Melanoma," Photochem. Photobiol. 50:1-5 (1989).

29. Setlow, R. B., A. D. Woodhead, and E. Grist. "Animal Model for Ultraviolet Radiation-Induced Melanoma: Platyfish-Swordtail Hybrid," Proc. Natl. Acad. Sci. U.S.A. 86:8922-8926 (1989).

30. Longstreth, J. D., Ed. Ultraviolet Radiation and Melanoma--With a Special Focus on Assessing the Risks of Ozone Depletion, Vol. IV (Washington, D.C.: U.S. Environmental Protection Agency, 1987).

31. Pitts, D. G., A. P. Cullen, and P. D. Hacker. "Ocular Effects of Ultraviolet Radiation from 295 to 365 nm," Invest. Ophthalmol. Vis. Sci. 16:932-939 (1977).

32. Madronich, S., L. O. Björn, M. Ilyas, and M. M. Caldwell. "Changes in Biologically Effective Ultraviolet Radiation Reaching the Earth's Surface," in Environmental Effects of Ozone Depletion: 1991 Update, J. C. van der Leun and M. Tevini, Eds. (Nairobi: United Nations Environment Programme, 1991), pp. 1-13.

33. Maitchouk, I. F. "Trachoma and Cataract: Two WHO Targets," Int. Nurs. Rev. 32:23-25 (1985).

34. Taylor, H. R., S. K. West, F. S. Rosenthal, B. Munoz, H. S. Newland, H. Abbey, and E. A. Emmett. "Effect of Ultraviolet Radiation on Cataract Formation," New England J. Med. 319:1429-1433 (1988).

35. Bochow, T. W., S. K. West, A. Azar, B. Munoz, A. Sommes, and H. R. Taylor. "Ultraviolet Light Exposure and the Risk of Posterior Subcapsular Cataract," Arch. Ophthalmol. 107:369-372 (1989).

36. Mohan, M., R D. Sperduto, S. K. Angra, R. C. Milton, R. L. Mathur, B. A. Underwood, N. Jaffery, C. B. Pandya, V. K. Chhabra, R. B. Vajpayee, V. K. Kalra, and Y. R. Sharma, The India-U.S. case-control study group. "India-U.S. Case-Control Study of Age Related Cataracts," Arch. Ophthalmol. 107:670-676 (1991).

37. Hollows, F. and D. Moran. "Cataract-The Ultraviolet Risk Factor," Lancet 2:1249-1250 (1981).

38. U.S. EPA, Assessing the Risks of Trace Gases that Can Modify the Stratosphere, Vol. III (Washington, D.C.: U.S. Environmental Protection Agency, 1987).

39. Van der Leun, J. C. and M. Tevini, Eds. Environmental Effects Panel Report: Pursuant to Article 6 of the Montreal Protocol on Substances that Deplete the Ozone Layer (Nairobi: United Nations Environment Programme, 1989).

40. Van der Leun, J. C. and M. Tevini, Eds. Environmental Effects of Ozone Depletion: 1991 Update. Panel Report Pursuant to Article 6 of the Montreal Protocol on Substances that Deplete the Ozone Layer (Nairobi: United Nations Environment Programme, 1991).

41. Fisher, M. S. and M. L. Kripke. "Systemic Alteration Induced in Mice by Ultraviolet Light Irradiation and its Relationship to Ultraviolet Carcinogenesis," Proc. Natl. Acad. Sci. U.S.A. 74:1688-1692 (1977).

42. Daynes, R. A., C. W. Spellman, J. G. Woodward, and D. A. Stewart. "Studies into the Transplantation Biology of Ultraviolet-Induced Tumors," Transplantation 23:343-348 (1977).

43. Kripke, M. L. "Immunological Unresponsiveness Induced by Ultraviolet Radiation," Immunol. Rev. 80:87-102 (1984).

44. Yoshikawa, T., V. Rae, W. Bruins-Slot, J. W. van den Berg, J. R. Taylor, and J. W. Streilein. "Susceptibility to Effects of UV-B Radiation on Induction of Contact Hypersensitivity as a Risk Factor for Skin Cancer in Humans," J. Invest. Dermatol. 95:530-536 (1990).

45. Toews, G. B., P. R. Bergstresser, and J. W. Streilein. "Epidermal Langerhans Cell Density Determines Whether Contact Hypersensitivity or Unresponsiveness Follows Skin Painting with DNFB," J. Immunol. 124:445-453 (1980).

46. Noonan, F. P., E. C. DeFabo, and M. L. Kripke. "Suppression of Contact Hypersensitivity by UV Radiation and its Relationship to UV-Induced Suppression of Tumor Immunity," Photochem. Photobiol. 34:683-689 (1981).

47. Kripke, M. L., R. M. Thorn, P. H. Lill, C. I. Civin, M. S. Fisher, and N. H. Pazmino. "Further Characterization of Immunologic Unresponsiveness Induced in Mice by UV Radiation: Growth and Induction of Non-UV Induced Tumors in UV-Irradiated Mice," Transplantation 28:212-217 (1979).

48. DeFabo, E. C. and F. P. Noonan. "Mechanism of Immune Suppression by Ultraviolet Irradiation In Vivo. I. Evidence for the Existence of a Unique Photoreceptor in Skin and Its Role in Photoimmunology," J. Exp. Med. 157:84-98 (1983).

49. Zmudzka, B. Z. and J. Z. Beer. "Yearly Review: Activation of Human Immunodeficiency Virus by Ultraviolet Radiation," Photochem. Photobiol. 52:1153-1162 (1990).

50. Giannini, M. S. H. and E. C. DeFabo. "Abrogation of Skin Lesions in Cutaneous Leishmaniasis," in Leishmaniasis: The First Centenary (1885-1985)--New Strategies for Control, D. T. Hart, Ed. (London: Plenum Press, 1987).

51. Spruance, S. L. "Pathogenesis of Herpes Simplex Labialis: Experimental Induction of Lesions with UV Light," J. Clin. Microbiol. 22:366-368 (1985).

52. Perna, J. J., J. E. Mannix, J. E. Rooney, A. L. Notkins, and S. E. Straus. "Reactivation of Latent Herpes Simplex Virus Infection by Ultraviolet Radiation: A Human Model," J. Am. Acad. Dermatol. 17:197-212 (1987).

53. Schmitt, J., J. R. Schlehofer, K. Mergener, L. Gissmann, and H. zur Hausen. "Amplification of Bovine Papillomarvirus DNA by N-Methyl-N'-nitro-N-nitrosoguanidine, Ultraviolet Irradiation, or Infection with Herpes Simplex Virus," Virology, 172:73-81 (1989).

54. Valerie, K., A. Delers, C. Bruck, C. Thiriart, H. Rosenberg, C. Debouck, and M. Rosenberg. "Activation of Human Immunodeficiency Virus Type 1 by DNA Damage in Human Cells, Nature 333:78-81 (1988).

55. Cripps, D. J. and J. Rankin. "Action Spectra of Lupus Erythematosus and Experimental Immunofluorescence," Arch. Dermatol. 107:563-567 (1973).

56. Van Weelden, H., H. Baart de la Faille, E. Young, and J. C. van der Leun. "A New Development in UVB Phototherapy of Psoriasis," Brit. J. Dermatol. 119:11-19 (1988).

57. Finsen, N. R. Ueber die Bedeutung der chemischen Strahlen des Lichtes für Medicin und Biologie (Leipzig: Vogel, 1899).

58. van der Leun, J. C. "Ultraviolet Erythema: a Study on Diffusion Processes in Human Skin," Ph.D. Thesis, University of Utrecht, Utrecht, The Netherlands, (1966), statement 5.

59. Sorgo, J. "Die Lichtbehandlung der Lungentuberkulose," in Handbuch der Lichttherapie, W. Hausmann and R. Volk, Eds. (Wien: Julius Springer, 1927), pp. 284-301.

60. Holick, M. F. "Photosynthesis of Vitamin D in the Skin: Effect of Environment and Lifestyle Variables," Fed. Proc. 46:1876-1882 (1987).

61. Emmett, E. A. "Ultraviolet Radiation as a Cause of Skin Tumors," Crit. Rev. Toxicol. 2:211-255 (1973).

62. Dorn, C. R., D. O. N. Taylor, and R. Schneider. "Sunlight Exposure and Risk of Developing Cutaneous and Oral Squamous Cell Caranomas in White Cats," J. Natl. Cancer Inst. 46:1073-1078 (1971).

63. Nikula, K. J., S. A. Benjamin, G. M. Angleton, W. J. Saunders, and A. C. Lee. "Ultraviolet Radiation, Solar Dermatosis, and Cutaneous Neoplasia in Beagle Dogs," Radiat. Res. 129:11-18 (1992).

64. Stenbäck, F. "Species-Specific Neoplastic Progression by Ultraviolet Light," Oncology 31:209-225 (1975).

65. Russell, W. O., E. S. Wynne, G. S. Loquvam, and D. A. Mehl. "Studies on Bovine Ocular Squamous Carcinoma ("Cancer Eye"). I. Pathological Anatomy and Historical Review," Cancer 9:1-52 (1956).

66. Lippincott, S. W. and H. F. Blum. "Neoplasms and Other Lesions of the Eye Induced by Ultraviolet Radiation in Strain A Mice," J. Natl. Cancer Inst. 3:545-554 (1943).

67. Freeman, R. G. and J. M. Knox. "Ultraviolet-Induced Corneal Tumors in Different Species and Strains of Animals," J. Invest. Dermatol. 43:431-436 (1964).

68. De Gruijl, F. R. and J. C. van der Leun. "Influence of Ozone Depletion on the Incidence of Skin Cancer: Quantitative Prediction," in Environmental UV Photobiology, L. O. Bjorn, J. Moan, and A. R. Young, Eds. (Overland Park, Kansas, Valdenmar Publ., 1993), in press.

69. Madronich, S. Personal communication.