CIESIN Reproduced, with permission, from: Longstreth, J. D., F. R. de Gruijl, Y. Takizawa, and J. C. van der Leun. 1991. Human health. Chapter 2 in Environmental effects of ozone depletion: 1991 update, 15-24. United Nations Environment Programme (UNEP) panel report. Nairobi, Kenya: United Nations Environment Programme.


CHAPTER 2

HUMAN HEALTH

J.D. Longstreth (USA), F.R. de Gruijl (The Netherlands), Y. Takizawa (Japan), and J.C. van der Leun (The Netherlands)

1991 REPORT SUMMARY

In the past two years, there have been relatively few additions to the scientific literature regarding UV radiation and human health. However, for the most part, the new material confirms the information presented in the 1989 UNEP Report. The possible forms of ocular damage associated with UV radiation have been increased to include age-related near-sightedness, damage to the anterior lens capsule, and nuclear cataract. In the 1989 Report, nuclear cataract was specifically excluded. New data suggest that it should now be included as an effect of UV exposure.

New studies on the immunologic impacts of UV radiation continue to support the theory that UV radiation may exacerbate infectious diseases. Such concerns are not limited to fair-skinned populations but are also observed in deeply pigmented individuals, where pigment may be constitutive or acquired.

Exposure to sunlight has now been associated with another cancer: that of the salivary gland. These findings suggest the possibility of a systemic effect of UV-B in humans, since the salivary gland is rarely, if ever, exposed.

Estimates of increases in skin cancer incidence have been lowered slightly, due to a new action spectrum and associated changes in the biological amplification factor (BAF) and radiation amplification factor (RAF). These new values are probably not significantly different from the original estimates. However, on the basis of this information, it is estimated that a sustained 10% reduction in ozone would result in a 26% increase in non-melanoma skin cancer (NMSC) world-wide. Using very conservative assumptions (detailed in the text), it can be estimated that such an increase would be equivalent to more than 300,000 additional cases of NMSC and 4,500 cases of melanoma. This may be an extremely conservative estimate, possibly off by a factor of two or more.

1989 REPORT SUMMARY

The increases in ultraviolet-B (UV-B) radiation that will result from depletion of stratospheric ozone are likely to result in a variety of impacts on human health. These range from an increased incidence of cataracts and skin cancer to possible increases in the incidence or severity of certain infectious diseases.

Exposure to ultraviolet radiation has been associated with damage to the cornea, lens, and retina of the eye. The principal corneal damage linked to UV exposures is photokeratitis, which appears to be related to acute UV-B exposures. The principal lenticular damage is cataract. The relationship between UV-B exposure and two forms of cataract -- corticular and posterior subcapsular -- appears to be related to cumulative exposure. Both life time cumulative exposure and annual average exposure are directly related to risk. It has been estimated that a 1% decrease in stratospheric ozone will be accompanied by a 0.6% to 0.8% increase in cataract. Retinal damage is rare but can occur particularly in those individuals whose lens have been removed in cataract operations.

Ultraviolet radiation is known to affect the immunological defenses of the skin, the first barrier of the body to foreign agents. In tumor systems and with defined antigens, it is clear that UV radiation compromises the ability of the host to immunologically respond either locally (after low doses) or systemically (after higher doses). Preliminary experiments of infectious diseases using animal models have indicated that UV-B can also adversely affect the ability of animals to respond to or contain various infectious agents. Although there are as yet no epidemiologic data to suggest that such effects occur in human populations, nevertheless, animal data suggest that an increase in the severity of certain infections may occur as UV-B fluxes increase due to ozone depletion. In areas of the world where such infections already pose a significant challenge to the public health care delivery systems, the added insult may be significant.

The relationship between UV-B exposure and two forms of non-melanoma skin cancer, basal cell and squamous cell carcinoma, appears to be one of increased risk with increased total lifetime doses to the target cell. Phenotypic characteristics such as skin color can modify the amount of ambient UV that gets transmitted to the target cell, so that fair-skinned individuals are more susceptible than dark-skinned individuals receiving the same amount of ambient exposure. The relationship between UV-B exposure and melanoma skin cancer is probably more complex; it is certainly less well understood. Some data suggest that intermittent severe exposure, i.e., sunburns, are important. Other studies suggest that early exposures (before the ages of 10-14) are of more concern than those acquired later in life. Using dose-response relationships derived from animal experiments and human epidemiologic studies, it is estimated that a 1% decrease in stratospheric ozone will result in a 3% increase in non-melanoma skin cancer, and a lower but still significant increase in melanoma.

NEW INFORMATION AND RECENT DEVELOPMENTS

The chapter on human health in the 1989 Report is still an adequate review of existing knowledge. However, there are a few new developments that should be mentioned.

OCULAR DAMAGE

Recent literature indicates the possibility of two additional cases where the ocular system was affected by exposure to sunlight (and presumably UV-B), presbyopia, and deformations of the anterior lens capsule. Presbyopia is the loss of the ability of the eye to accommodate changes in focal length. This is thought to result from the aging of the crystalline lens, and it commonly requires the use of reading glasses for viewing near-by objects. In a recent study by Stevens and Bergmanson [1989], an association was found between the early onset of presbyopia and living in areas of high sunlight (and high temperatures). A study of vision problems in a human population in Somalia found that deformations of the anterior lens capsule in the central pupillary area show a strong association with climactic keratopathy, and by inference, reflected UV-B. The deformations found in this case interfere severely with vision [Johnson et al., 1989].

Several recent case-control studies [Collman, et al., 1988; Mohan et al., 1989] have, for the most part, confirmed the relationship, discussed in the 1989 Report, between sunlight exposure and cortical and posterior subcapsular cataract. In contrast to the lack of association between sunlight exposure and nuclear cataract stated in the previous report [Taylor et al., 1988], Mohan et al. [1989] found an association between sunlight and all forms of cataract, including nuclear and mixed.

It was also noted in the 1989 Report that a mechanism for the relationship of cataract to solar exposure was not well understood. In recent literature there are indications that the development of cataract may be related to the loss of the orderly arrangement of densely packed lens crystallin which is required to maintain lens transparency [Andley and Clark, 1989; Taylor, 1989]. Another study indicated that UV irradiation increases fragmentation in the ß-crystallin [Andley and Clark, 1989], which in turn results in an increase of insoluble protein within lens fibers contributing to the formation of opacities [Stevens and Bergmanson, 1989]. In addition, the relationship between ocular melanoma and sunlight exposure has been confirmed by Seddon et al. [1990].

INFLUENCE OF UV-B ON INFECTIOUS DISEASES

As indicated in the 1989 Report, one concern regarding increases in human exposure to UV-B radiation is the possibility of an increase in infectious diseases. With the exception of data showing an exacerbation of herpes infections [Spruance, 1985; Perna et al., 1987], there was little or no information on this issue from human studies. Also, there has been little additional information that could assist in making sound predictions of the consequences of ozone depletion for infectious diseases. Several new reports have appeared which enlarge the list of viruses that may be activated by UV irradiation in vitro. In addition to the herpes simplex virus, these include HIV-1, the human immunodeficiency virus [Zmudzka and Beer, 1990], and a variety of papilloma viruses, the human forms of which have been associated with a variety of hyperplastic, dysplastic, and malignant lesions of the squamous epithelium [Schmitt et al., 1989; Tilbrook et al., 1989; Jensen et al., 1991]. It should be noted that in the case of both herpes infections and HIV, the UV-induced activation has been demonstrated both in vitro and in vivo. However, the in vivo activation of HIV was demonstrated in a transgenic mouse system bearing only a portion of the HIV-1 genome, the long terminal repeat. Nevertheless, it is becoming clear that activation of HIV-1 by UV radiation is a cause for concern. It should also be stressed that the activation of viruses by UV is unlikely to result in an increased rate of infection. It would result in the increased severity of the disease, or a more rapid course of infection.

There is a growing body of literature indicating that the impacts of UV-B on the immune system first demonstrated in mice may also occur in humans. This information is presented in detail below, and contributes to the theory that increases in ambient UV associated with stratospheric ozone depletion could exacerbate the course of infectious diseases.

UV-INDUCED IMMUNOSUPPRESSION IN HUMANS

In the 1989 Report, in addition to the effect of UV-B on herpes infections in humans, the impacts of UV-B on the human immune system were demonstrated by Baadsgaard et al. [1987] and Scheibner et al. [1987] as having an effect on antigen presenting cells. Recent work by Cooper et al. [1991] confirms these impacts and shows that UV-B can suppress sensitization to certain substances in humans. Unlike early studies which showed impacts at very low doses, immunosuppression was observed by Cooper et al. [1991] with UV doses that induced a sunburn. Moreover, these authors found that individuals who received a sunburning dose of UV over most of the body could still have mounted an immunological reaction if they were sensitized in an unirradiated area of skin (the immunosuppressive effect could only be demonstrated locally rather than systemically). The suppression of the sensitization correlated well with skin's local depletion of Langerhans (antigen presenting) cells at the UV irradiated site.

Another study, directed at investigating immunosuppression associated with non-melanoma skin cancer (NMSC), has documented immunosuppression in both cancer patients and healthy individuals following deliberate exposure to UV-B. Yoshikawa et al. [1990] reported a difference in susceptibility to UV-B-induced immunosuppression between a population of healthy volunteers, and a population of NMSC patients. A small area of skin on the buttock of each individual was repeatedly exposed to UV radiation, leading to a pronounced sunburn. After the last exposure, a substance (DNCB) was applied to the sunburned area. Without the UV-B exposure, this procedure would normally sensitize the individual to the substance. A second contact with DNCB, the so-called challenge, at a different area of skin, would lead to a severe, inflammatory reaction at the second site of contact. This reaction is immunologically mediated. The results of this study showed that only 1 out of the 12 skin cancer patients reacted to the challenge, whereas there was a reaction from 22 of the 34 healthy volunteers. Thus, the development of non-melanoma skin cancer is associated with immunosuppression in these individuals. It remains to be seen whether the difference between patients and controls observed by these authors is due to a predisposing flaw in the immune system, or to the development of cancer. A subsequent study by this group [Vermeer et al., 1991] also demonstrated that the proportion of normal individuals in the United States population sensitive to the immunosuppressive effects of UV radiation is independent of skin pigmentation. This confirms the earlier finding of Scheibner et al. [1987] showing the effects on Langerhans cells in individuals of both Celtic and Aboriginal heritage. It clearly indicates that the population at risk for UV-induced immunosuppression is not limited to light-skinned individuals, but includes deeply pigmented individuals as well.

CANCER

In the 1989 Report, the only data presented regarding cancer dealt with tumors of the eye and skin, focusing closely on melanoma and non-melanoma skin cancer (basal cell carcinoma-BCC and squamous cell carcinoma-SCC) in humans. However, two recent reports indicate that other cancers may be associated with exposure to UV-B. Reports by Spitz et al. [1988, 1990] suggest that in addition to lip cancer (normally included in the category of non-melanoma skin cancer), salivary gland cancers may be related to UV radiation exposure. The evidence is somewhat circumstantial and is derived from co-associations between these tumors and melanomas observed in an epidemiologic study designed to examine the relationship between melanoma, lip cancer, and salivary cancer. The study found a significantly increased risk for subsequent lip cancer among men with an initial salivary gland cancer (RR = 8.7), a significantly increased risk for melanoma among women with an initial salivary gland cancer (RR = 7.1), and a significant association between an initial lip cancer and risk of subsequent salivary gland cancer among men (RR = 12.7).

Non-Melanoma Skin Cancer

Although we are able to quantitatively estimate the potential long-term consequences from increased UV-B for skin cancer and cataract, our best estimates are for NMSC, particularly SCC. Because both human and animal studies are in agreement regarding a dose-response relationship, it is possible to develop an action spectrum for carcinogenesis in an animal model.

Carcinogenic UV Doses

For a proper assessment of the carcinogenic risk posed by an increased UV load, biologically meaningful UV radiation measurements are needed. It has long been known that UV-B radiation (wavelengths between 280 nm and 315 nm) is the most carcinogenic part of the solar UV spectrum reaching the earth's surface [Roffo, 1934]. This was established in animal experiments, and it is not possible to extract such information for humans from epidemiological data. Therefore, further animal data are needed for a proper definition of a carcinogenic UV dose. A carcinogenic UV dose has been assumed to be approximately equal to effective UV doses for other biologically detrimental effects, such as sunburn or mutations in cells. This was based on a crude similarity in wavelength dependence of the effects, or an assumed mechanism of UV carcinogenesis (mutations leading to malignant cell proliferation). As was pointed out in the 1989 Report, more experimental information has become available on UV carcinogenesis in the Skh:HR1 albino hairless mouse. The available data contain the required spectral information on UV carcinogenesis, albeit in a very implicit way. None of the currently used definitions of a carcinogenic UV dose yield a statistically adequate description of these data [de Gruijl and van der Leun, 1991]. An updated and adequate definition has been produced by using a mathematical technique to derive an action spectrum that can be used as a set of weights to reflect the carcinogenic efficiencies at the UV wavelengths. This newly derived action spectrum, UTR5, is depicted in Figure 2.1. The other curves depict older approximations of the carcinogenic action spectrum.

UTR5 is a genuine carcinogenic action spectrum, as it has been derived from experimental data on UV carcinogenesis. Its applicability to humans may be debatable, but at the moment it probably gives the best estimate of a carcinogenic UV dose.

Increases in Skin Cancer

The new carcinogenic action spectrum slightly alters the risk assessment of ozone depletion. With a new radiation amplification factor (RAF) of 1.4, a 1% decrease in ozone will result in an increase of the annual carcinogenic dose by about 1.4% (for 0deg. to 60deg. latitude). With the earlier action spectra, the RAF was approximately 1.6%.

With the new action spectrum, the new biological amplification factor (BAF) is 1.4 for BCC and 2.5 for SCC. The calculated incidences of BCC and SCC will eventually increase by 1.4 +/- 0.4% and 2.5 +/- 0.7%, respectively, for every 1% increase in the annual carcinogenic dose [de Gruijl and van der Leun, 1991]. The earlier estimates were 1.7% and 2.9%, respectively, for a 1% increase in dosage. These numbers are derived from epidemiologic data of the fair-skinned population in the United States [Scotto et al., 1981].

Taking the new RAF and BAF values, a 1% depletion of ozone will eventually increase the BCC incidence by 2.0 +/- 0.5%, and the SCC incidence by 3.5 +/- 1.0%. This is somewhat lower than the 2.7% and 4.6% presented earlier. These values are in relatively close agreement with the work of Moan [1991] who estimated a 1.6% to 2.3% increase in SCC and BCC in the Norwegian population for a 1% depletion of ozone.

Taking BCC and SCC together in a ratio of 4:1, a 1% ozone depletion will result in a 2.3 +/- 0.4% increase in the incidence of skin cancer, excluding melanomas (these cancers are usually referred to as non-melanoma skin cancers). With 500,000 new cases of a year in the United States, a 2.3% increase amounts to 11,500 additional cases per year.

A precise estimate of the increase in NMSC cases or deaths world-wide would be difficult to develop. A very conservative estimate can be made using the following assumptions: 1) ozone depletion stays constant at 10% for two to four decades; 2) the population sensitive to UV radiation stays constant at 500 million (about 10% of the world population today); and 3) the incidence of NMSC is 232/100,000 (i.e., that observed in the United States in 1977) [Scotto et al., 1981], and melanoma skin cancer (9/100,000) observed in the United States, is equivalent to that of the sensitive population worldwide [Scotto et al., 1991]. On the basis of these assumptions, it is estimated that after three to four decades, a 10% decrease in ozone would be expected to result in 300,000 additional non-melanoma and 4,500 melanoma skin cancers worldwide. It must be emphasized that this is a very conservative estimate, particularly for non-melanoma skin cancer for which there is little current information. There is new information from the northwestern United States indicating an incidence rate of squamous cell carcinoma (SCC) as high as 106/100,000 in 1986. If the 1:4 SCC to basal cell carcinoma (BCC) ratio observed in earlier studies is maintained, the current U.S. incidence rate could be 400/100,000 rather than the 200/100,000 used in the calculation above. It is likely that the other assumptions are equally conservative.

There are several caveats which must be made with regard to estimates such as those provided above. First, the estimated increases pertain to stationary situations (the new levels of incidence will eventually be reached after the change in ozone, if everything else remains the same). Second, the above estimates are probably most appropriate for SCC. While a similar approach can be used for BCC, these tumors are not normally induced in hairless mice by UV. Third, the slope of the dose-response relationship derived from human epidemiologic data differs for SCC and BCC. Last, a recent study in Maryland watermen found that SCC but not BCC showed a strong relationship to cumulative sun exposure. One possible explanation for this observation is that the dose-response relationship for BCC in humans can become saturated. There is either a portion of the population that is not sensitive, or there is a dose above which additional cases are induced in a non-linear fashion [Strickland et al., 1990; Vitasa et al., 1990]. No similar observation has been made in Australian populations, where one would expect similarly high exposures to occur in a much larger population. Conceivably, the observation of such saturations could be specific to the genetic make-up of the particular population under study. Were the dose-response relationship for BCC to demonstrate such a saturation, the increase in risk due to ozone depletion is likely to be different from those given above. Similar caveats need to be noted also for melanoma as well as the additional caveat that it differs with regard to the human dose measures.

Improved data are leading the way to increase the accuracy of predictions. In this process, the sensitivities of the carcinogenic dose and non-melanoma skin cancer incidence to changes in ozone have become smaller than initially estimated. However, the updated predictions confirm the earlier recognition that an increase in non-melanoma skin cancer will be greater than a comparable decrease of ozone in the atmosphere.

Melanoma Skin Cancer

Although there has been little progress in understanding the etiology of melanomas in humans since the 1989 Report, there are a few points worth mentioning in regard to the involvement of UV radiation.

Animal Experiments

Dr. Kripke and her co-workers at the M.D. Anderson Cancer Center in Houston, Texas, have made, and continue to make, extensive studies of the possible role of UV radiation in the formation of melanomas in mice [Donawho and Kripke, 1991]. Their experiments are based on earlier ones by Berkelhammer et al. [1982], who induced melanomas in mice with chemicals. Romerdahl et al. [1989] found that if UV radiation was substituted for one of the chemicals in the original experiment, the melanomas still occurred, albeit later and in much lower numbers. However, when UV irradiation was added to the chemical exposure, the melanomas occurred sooner. It was demonstrated that the acceleration of the appearance of melanomas by UV irradiation was due to a local effect at the site where the melanoma developed [Romerdahl et al., 1989], possibly being an immunologically mediated effect.

From these experiments, it appears that UV radiation can play various roles in the etiology of melanomas. This could explain the seemingly ambiguous information from the epidemiology on UV radiation as a risk factor for melanomas [de Gruijl, 1989]. It also indicates that UV radiation can be an important co-factor in the genesis of melanomas. The nature of this effect and its possible relevance for melanomas in humans need to be studied further.

Findings in Humans

Scotto et al. [1991] have recently analyzed trends in skin melanoma death rates by cohort for fair skinned males and females in the United States between 1950 and 1984. These authors observed upward trends for older men and women (over 40) and downward trends for the younger cohorts. Assuming that lifestyles remain the same and ultraviolet radiation levels remain constant, these authors project that the 2% to 3% increase in death rates per annum observed since 1950 will discontinue. The curve will eventually bend downward by the second decade of the 21st century. This information is critical in assessing the risks of stratospheric ozone depletion, and would be needed to incorporate the cohort data and age-specific trend analyses into the baseline data. Similar information is also critical to estimate the potential increases in non-melanoma skin cancer. Unfortunately, most countries are not collecting sufficient data on NMSC to be able to conduct such trend and cohort analysis.

Other information contributes to a better understanding of the possible mechanism involved in the induction of melanoma by UV radiation. A study of possible mutations in ras-oncogenies in human melanomas showed that melanomas occurring in sun-exposed skin areas exhibit a high frequency (7 out of 10) of point mutations in the N-ras gene [Van't Veer et al., 1989]. These mutations occurred at a location where two neighboring thymines are situated on a complementary strand of the DNA. Neighboring thymine are potential sites of UV damage (the thymine can be "welded" together to form a dimer). Thus, UV radiation is implicated in this particular mutation of the N-ras oncogene, and may be implicated in the etiology of melanomas (of the non-lentigo malignant types) in areas of skin regularly exposed to sunlight.

LINKAGES

Animal Health

The consequences of increased UV-B irradiation on the health of animals was only briefly touched upon in the 1989 Report. Data obtained from experimental animals were used to give an insight into the impacts of UV radiation on human health. Most of the exposures used in experimental animal studies differ greatly from what would occur in the natural environment (the use of hairless or shaved animals, and very high doses of UV-B). Both wild and domestic animals have dense fur coats protecting their skins against UV radiation. Yet, there are indications that sunlight causes cancers in domestic animals that are similar to those observed in humans. These are limited to eye tissue or sparsely haired, light-colored skinned animals. Skin tumors have been almost exclusively SCC and have been observed in cows, goats, sheep [Emmett, 1973], cats [Dorn et al., 1971] and dogs [Madewell et al., 1981]. Eye tumors are also SCC, and they have been observed in horses, dogs, cats, sheep, swine, and particularly in cattle [Hargis, 1981]. The 1989 Report discussed in some detail skin tumors induced in experimental animals with UV radiation. However, eye tumors have also been induced in guinea pigs and hamsters [Freeman and Knox, 1964], and rats and mice [Roffo, 1934, 1939]. While pigmentation appears to protect cattle (white-faced Herefords were more susceptible than black Angus) [Anderson, 1963], in experiments with hamsters and rats, the eyes in pigmented animals were more susceptible than the eyes of albinos [Freeman and Knox, 1964].

Toxicity of CFC Substitutes

The Montreal Protocol requires the phase out of fully halogenated chlorofluorocarbons. Most of these will be replaced with new chemicals, which have not yet been released into the environment. A secondary effect of the human response to stratospheric ozone depletion will be the exposure of human and environmental populations to a new class of chemicals and their degradation products. Clearly, the toxicity of these chemicals to the ozone layer, and the human and environmental populations, needs to be characterized. The U.S. Environmental Protection Agency has recently reviewed the toxicity information available for two classes of these replacement chemicals: aqueous and terpene cleaning chemicals, and hydrofluorcarbon (HFC) and hydrochlorofluorocarbons (HCFC) [U.S. EPA, 1990a, 1990b]. Table 2.1 lists the aqueous and terpene cleaners which were reviewed.

The preliminary information presented in the report on cleaners [U.S. EPA, 1990a] indicated that in general "...the aqueous and terpene cleaners can be used in a manner that is safe to workers, the general population and the environment given appropriate technological changes and exposure control practices." Table 2.2 lists the hydrofluorocarbons and hydrochlorofluorocarbons for which the review was performed.

The report on HFCs and HCFCs also concluded that these chemicals could be used in a manner consistent with safety for humans and environmental populations [U.S. EPA 1990b]. However, both reports cautioned that these were interim assessments based on limited data and a variety of assumptions. As more data are accumulated, it is conceivable that these conclusions may change. For instance, preliminary information on HCFC-123 suggests that it has induced an increase in non-malignant tumors. This has resulted in manufacturers lowering their allowable exposure limits from 100 ppm to 10 ppm while maintaining that the compound can be used safely, given the above constraints [Weise, 1991].


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