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UV Radiation and human health

effects
a a
E. C. De Fabo & F. P. Noonan
a
Department of Dermatology , Laboratory of
Photoimmunology and Photobiology The George
Washington University Medical Center , Ross Hall Room
112, 2300 I Street, N.W, Washington, D. C., 20037, USA
Published online: 24 Feb 2007.

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 Intern. J. Environmental Studies, 1996, Vol. 51, pp. 257-268 © 1996 OPA (Overseas Publishers Association)
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UV RADIATION AND HUMAN HEALTH

EFFECTS
E. C. DE FABO and F. P. NOONAN
Downloaded by [University of Teeside] at 01:02 05 October 2014

Department of Dermatology,
Laboratory of Photoimmunology and Photobiology
The George Washington University Medical Center, Ross Hall Room 112,
2300 I Street, N.W, Washington D. C. 20037 (USA)

(Received infinalform 12 May 1996)

In this chapter we describe some of the potential effects of increased UVB radiation, due to
stratospheric ozone depletion, on human health. These effects include immune suppression,
and its role in skin cancer and infectious disease development. We describe also the association
between UVB and cataract development. The concern about increased UVB radiation and its
impact on human health stems from reports of continuous ozone depletion. For example, the
high chlorine levels presently in the stratosphere predict that ozone depletion will last through
most of the next century. Currently, conservative estimates indicate that global ozone in the
Northern hemisphere, from 30-60° N latitude, has been decreasing at a rate of between 0.25%
and 0.3% per year, using 1970 as the baseline. Thus, we are already in a deficit mode of about
4 to 5% within that latitude range. For higher latitudes the losses are greater, in the order of
10% or more. More recent regional intermittent measurements, e.g. from Siberia and Canada,
have indicated even greater ozone losses, with some occasions showing depletions of as much
as 40%. Generally speaking, for each 1% decrease in stratospheric ozone there is an estimated
1 to 2% increase in UVB radiation transmitted to the earth. How much of this UVB radiation
is attenuated by clouds, rain and pollution (e.g. tropospheric ozone is increasing) is a question
of considerable interest and debate as UVB attenuation by such factors can be significant.
However, it is clear that not every day is cloudy, polluted, or rainy, all the time over every
populated area. Thus, the exposure of people, plants, animals and marine organisms to in-
creased UVB radiation is inevitable. Some changes in human health, of the types described,
can therefore be expected to occur over the coming years.

Keywords: Human health, UV radiation, ozone depletion

INTRODUCTION

This chapter considers the ramifications of increased ultraviolet-B (UVB

280-320 nm) radiation on biological systems and how such changes might
257
 258 E. C. D E FABO AND F. P. NOONAN

affect human health. The known effects of UVB radiation include modula-
tion of the immune system with potential effects on infectious diseases,
induction of skin cancer, and formation of some types of cataract.
As has been pointed out elsewhere in this publication the stratospheric
ozone (O3) layer is very thin, and if uniformly layered across the surface of
the earth would be no more than a few (~ 3) millimeters thick. Remarkably,
this gas has the capacity to absorb most of the UVB and all of the UVC
radiation (< 280 nm) emitted from the sun. This is important for biological
evolution since DNA and proteins are very effective UVB/C absorbers.
Damage to DNA is a known cause of malignant mutation and damage to
protein can affect biochemical reactions. Both of these types of damage, if
severe enough, can lead to cellular dysfunction. While mechanisms do exist
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to repair DNA damage, "overloading" the system with excessive UVB ex-
posure may also inactivate the repair mechanisms. If either cellular dysfunc-
tion or damage to repair mechanisms is severe enough then cell death may
ensue.
Clearly, stratospheric ozone is important to living organisms and any
process leading to its loss can have serious consequences. It is now known
that stratospheric ozone depletion is occurring in both hemispheres and
increased levels of UVB have been observed at ground level during ozone
depletion episodes [1,2].

PHOTOIMMUNOLOGY: ULTRAVIOLET RADIATION AND

THE MAMMALIAN IMMUNE SYSTEM

Photoimmunology is the study of the modulation of the mammalian im-

mune system by UV radiation. UV radiation is defined as wavelengths
between 250 and 400 nm which comprise UVC (190-280 nm), UVB,
UVA2 (320-340 nm) and UVA1 (340-400 nm). While most photoim-
munologic effects are modulated by UVB, the role of UVA is currently
under intensive investigation by many laboratories. UVB radiation has a
suppressive or down-regulatory effect on the immune system and it has
been postulated that UVB-induced immunosuppression has evolved to pro-
tect against autoimmune attack on UV-damaged skin [3]. Such an attack
would be harmful to the organism.
UVB immunosuppression or down modulation of cell-mediated immun-
ity (CMI) (one of 2 major arms of the immune response, the other being the
humoral or antibody response) is both dose and wavelength dependent.
UVB-induced immunosuppression has been observed in both experimental
 HUMAN HEALTH 259

animals and in humans. To understand the impacts of UV-induced im-

munosuppression on human health it is important to have some under-
standing of the basic mechanisms involved. Over the past decade or so, the
mechanism of immunosuppression by UVB has been intensively inves-
tigated. While much information has been obtained, the entire story re-
mains to be elucidated. The active waveband has been identified as the
UVB/C range and an action spectrum has been derived within this
waveband, in an experimental mouse model, indicating the existence of a
unique immune-regulating skin photoreceptor modulating immunosup-
pression [3].
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1. Processes Affected by UV-Induced Immune Modulation

The effects of UVB on the immune system appear to be restricted, in
general, to the cell-mediated arm of the immune response. CMI in mam-
malian systems is mediated by T lymphocytes which, in turn, regulate de-
layed type hypersensitivity responses and skin reactions to an applied or
injected foreign substance or antigen. CMI is critical for immune defense
against intracellular pathogens and in immune rejection of tumors and
transplanted organs. Two experimental systems of cell-mediated immunity
have been used to investigate the effects of UVB radiation on the immune
response and these are described below.

2. Immunosuppression of Tumor Destruction

Observations that UV radiation can affect the immune system came from
experiments studying UV induction of skin cancer in mice [4]. In these
experiments it was noted that skin tumors which had been previously in-
duced in mice by UV radiation from UVB-emitting FS40 sunlamps, unlike
most experimentally induced tumors, could not be transplanted into geneti-
cally identical siblings. It was shown that most UV-induced tumors were
highly antigenic and capable of stimulating a very strong immune rejection
response in the host [4, 5]. It was only after the recipients had been treated
with the same UV FS40 sunlamp, prior to transplantation of the tumor,
that the tumor was no longer rejected [5,6]. Thus, UV radiation not only
induced tumor formation but also suppressed the ability of the host to
mount an immune attack on the tumor. It was also shown that this im-
munosuppression of tumor rejection was both dose and wavelength depen-
dent [7, 8]. Radiation mainly in the UVB, was responsible for suppressing
immune attack against UV-induced skin tumors and in a manner indepen-
 260 E. C. DE FABO AND F. P. NOONAN

dent of dose-rate or dose fractionation [8]. The latter observation indicated

a mechanism of action very different from that for the induction of tumors in
photocarcinogenesis experiments [9].
These observations are significant as they point out that the development
of UV-induced skin tumors requires, in addition to malignant transform-
ation of a normal cell [10,11], a suppression of the immune attack against
such highly antigenic tumors. Thus, understanding the mechanism of UVB-
induced immunosuppression should greatly aid in understanding the com-
plete mechanism of skin cancer formation.

3. Immunosuppression of the Contact Hypersensitivity Response

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Another system which is more readily accessible to experimentation and

which has been used in humans as well as in animal models, makes use of
the observation that UVB radiation immunosuppresses the contact hyper-
sensitivity response (CHS) in the skin to a variety of antigens including
topically applied chemicals such as trinitrochlorobenzene (TNCB). The
CHS response has been of great assistance in establishing both the photo-
biologic and photoimmunologic parameters of UVB-induced immunosup-
pression since this response can be quantitated. A classic example of a CHS
response is the well known "poison ivy" rash which is an immune response
against the skin sensitizer urushiol found in some plants of the Genus Rhus.
The redness, swelling and blistering observed in such a CHS response result
from the actions of inflammatory cytokines released both by T lymphocytes
reacting specifically with the applied antigen and by other cell types attrac-
ted to the skin by the products secreted by the activated T lymphocyte.
The CHS response appears to be a good model for investigating UV
immunosuppression since UV suppression of this response shows similar
photobiological and photoimmunological characteristics to the suppression
of tumor rejection [12,13]. This suggests a similar mechanism of initiation
of immunosuppression for both responses.

BIOLOGICAL ACTION SPECTROSCOPY

Because of the photoimmunological similarities noted above between UVB-

induced immunosuppression of CHS and tumor rejection, it was hy-
pothesised that a common link between these widely different responses
might exist at the level of the initial absorption of photons [3,12,13]. That
is, immunosuppression by UV radiation may be activated by a common
 HUMAN HEALTH 261

photoreceptor even though very different immune responses result. In order to

test this hypothesis a technique called biological action spectroscopy was
carried out on the suppression of CHS by UVB radiation.
Action spectroscopy can furnish important data about the identity of the
compound which initiates a light-induced biological reaction [14,15]. Brie-
fly, following UVB absorption by a photoreceptor (PR) a signal is initiated.
This signal starts a series of reactions leading to an observable biological
effect. Dose-response relationships are determined at individual wavelengths
responsible for initiating such a light-driven effect. From these determina-
tions it becomes possible to calculate the number of photons needed at each
wavelength to induce some constant level of response (for example, 50%
suppression of the immune response). A plot of the reciprocal of these
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numbers of photons versus wavelength yields the action spectrum. Accord-

ing to action spectrum theory [14,15], the shape of the action spectrum is
exactly congruent to the in vivo absorption spectrum of the unidentified
absorber. In other words, the action spectrum is a reflection of in vivo
absorption by a photoreceptor and can be used to identify the absorber if
no significant screening occurs [14,15].
Such a detailed in vivo action spectrum for UV-induced immunosup-
pression of CHS was determined in our laboratory in an experimental
animal model system. This action spectrum indicates the existence of an
unusual photoreceptor on skin able to initiate systemic immunosuppres-
sion when wavelengths in the UVB range are absorbed [3]. The action
spectrum (wavelength dependence spectrum) indicated that the most effi-
cient wavelengths at immunosuppression were in the UVB/C range with
peak activity at 270-275 nm. Curiously, wavelengths in this region pen-
etrate the least distance into the epidermis and a peak in this region was
unexpected. Nonetheless, repeated experiments continued to confirm this
observation and strongly implied that the photoreceptor, whatever its
identity, was located very close to the surface of the skin. Support for this
model came from the observation that removal of the stratum corneum,
the outermost layer of skin, before UV irradiation abrogated immunosup-
pression by UVB [3].
Following completion of the action spectrum, it was postulated that the
photoreceptor for initiating UV-induced immunosuppression was trans-
urocanic acid (t-UCA) [3]. This was based on: (i) a close fit between the
absorption spectrum of t-UCA and the action spectrum for systemic sup-
pression of CHS, (ii) the location of t-UCA on the surface of skin in the
stratum corneum [16] and, (iii) the ability of UCA to photoisomerize from
the trans to the cis isomer [17]. This hypothesis predicted further that it was
 262 E. C. D E FABO AND F. P. NOONAN

cis UCA which interacted with the immune system and initiated im-
munosuppression [3,12,13].
Since its initial proposal [3], the UCA hypothesis has received substantial
support from other laboratories, reviewed in reference [12] and briefly
summarized as follows: (i) UCA is isomerized in the skin of mice by im-
munosuppressive UV dose [18], (ii) there is greatly decreased UV sup-
pression in animals genetically deficient in skin UCA [19], and enhanced
immunosuppression in mice with enhanced skin UCA levels [20], (iii) de-
layed type hypersensitivity (DTH) and CHS are suppressed [21,22] and
(iv) a splenic antigen presentation defect is initiated by administration of cis-
UCA, but not trans-UCA, in vivo, analogous to the effects caused by UV
irradiation [23], (v) there is an increased UV tumor yield in animals to
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which exogenous UCA was applied [22], consistent with a role for UV
suppression in UV carcinogenesis and (vi) a prolongation of experimental
organ transplants by cis but not trans-UCA [24-26]- Recently, reversal of
UV-induced immunosuppression by a newly developed monoclonal anti-
body against cis UCA, and the observation that cis-UCA suppressed the
CHS response in humans provide additional support for this model
[27,28].
The role of cytokines, protein hormones which mediate and regulate
immune and inflammatory responses, in UV-induced immunosuppression
has been intensively investigated [29, 30]. How cis-UCA may interact with
cytokines, or other immune components, to induce UV immunosuppression
is an area currently under investigation (see Fig. 1).

Systemic
cis-VCA Target cell factors)
Immune n = G > Skin fibroblast * = $ ^ Antigen-present.ng
regulating cAMP modulation cell alteration
photoproduct ?

UV

ftww-UCA
Photoreceptor Antigen-specific
suppressor T-cell formation

Histidine

FIGURE 1 Suggested mechanism for the activity of UCA in UV-induced immunosuppres-

sion. Adapted from reference 12.
 HUMAN HEALTH 263

Published data strongly implicate a critical role in UV-induced im-

munosuppression for interleukin 10 (IL-10) which is produced both by
keratinocytes in response to UV irradiation [31] and by infiltrating macro-
phages which enter the skin in response to UV irradiation. IL-10 has a well
described role as a down regulator of the function of THj lymphocytes, the
subclass of Tcells which mediates DTH immune responses. Antibodies to
IL-10 inhibit the generation of UV-induced immunosuppression [31] and
IL-10 "knockout" mice have been reported not to show UV-induced sup-
pression of DTH responses [32].

1. UV-induced Immunosuppression and Infectious Diseases

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Since the major role of the immune system is to protect the host against
invading micro-organisms, immunosuppression by ultraviolet radiation
may impair host resistance to disease [33]. Evidence has been produced in
several experimental models of infection with a number of organisms in-
cluding Mycobacteria, Herpes virus, Leishmania, Trichinella indicating that
exposure to UVB suppresses the DTH response to these organisms. There is
very little evidence available on the effect of UVB radiation on infectious
disease in humans, although a recent study demonstrated that the lepromin
response (a cell mediated immune response to Mycobacterium leprae) was
depressed in UV irradiated skin [34].
The effect of UVB-immunosuppression on infectious disease in currently
under study. The topic is a complex one because of the heterogeneity of the
immune response to infectious organisms which usually includes both a
cell-mediated and humoral component. Further, the immune response is a
function not only of the type of infecting organism but also of underlying
genetic differences in the immune response of the host.

2. UV-induced Immunosuppression and Skin Cancer

Cancer of the skin is classified as malignancies of skin basal or squamous
cells (non-melanoma skin cancer) or of the melanocyte (malignant
melanoma). Non-melanoma skin cancers are the most ubiquitous of all
human cancers. Fortunately, they only account for about 1% of all deaths
due to skin cancer [35]. Melanoma, on the other hand, has a much higher
mortality, though it is much less common [35, 36].
Mechanistically, recent studies [10,11,37] have strongly implicated mu-
tations in the p53 tumor suppressor gene in skin cancer induction whereby
cytosine nucleotide in DNA is replaced by thymine (C—>T; or
 264 E. C. DE FABO AND F. P. NOONAN

CC—>TT double base mutations). Such mutations alter the normal

"readout" of the genetic code and can cause disturbances in the regulation of
cell growth. These mutations are seen to occur in human non-melanoma skin
cancer and are considered to be UV "signature lesions". Mutations to other
genes called proto-oncogenes [38] or damage to the enzymes which repair
DNA (see below), may also contribute to the overall development of non-
melanoma and possibly also melanoma skin cancers. Whether mutations to
tumor suppressor genes or proto-oncogenes play a role in immunosuppres-
sive effects by UV remains to be determined. Once malignant transformation
occurs this, in consort with UV immunosuppression and other non-UV fac-
tors, for example, dietary [39] or oxidative factors [40], creates an environ-
ment suitable for the overall development of non-melanoma skin tumors.
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Although most evidence for the role of immunosuppression in skin cancer

development comes from experimental animal studies there are enough simi-
larities with human non-melanoma skin cancer to suggest a comparable
scenario. Further, humans with the rare DNA repair-deficient disease known
as xeroderma pigmentosum have a much greater probability of developing
both melanoma and non-melanoma skin cancer [41].
Though non-melanoma skin cancer has a low mortality, surgical removal
is required making it costly to treat. Surgery also carries with it the risk of
disfiguration to the face and other body parts where the cancer has occured.
In the United States alone, non-melanoma skin cancer will exceed
600,000-1,000,000 new cases each year [35].

MELANOMA SKIN CANCER

The relationship between sunlight and melanoma is not as clear-cut as that

for non-melanoma skin cancer. There is limited experimental animal data
directly implicating UV radiation and melanoma. Despite this, however,
there is compelling evidence associating sunlight with melanoma in humans
[42-44]. The mechanism for melanoma development is also complicated,
involving multiple factors such as the inability to tan efficiently, genetic
susceptibility (familial tendency), occupation and outdoor exposure
[43,45,46]. The role of immunosuppression in melanoma is not straight-
forward either. For example, though most non-melanoma skin cancers are
found in sun-exposed body areas, malignant melanoma can be found in
parts of the body not usually exposed to sunlight [47]. This can be ex-
plained, partially, by invoking systemic immunosuppression by sunlight,
but many other factors are also likely to be involvedr [40].
 HUMAN HEALTH 265

The limited experimental animal data on UV and melanoma is itself not

unequivocal. For example, an opossum model [41], implicates UVB and
melanoma development while another study implicates UVA in the devel-
opment of melanoma in a fish model [49]. The best evidence, albeit correla-
tive and not causal, for a link between sunlight and melanoma is
epidemiological data. Some of this data implicates childhood exposure to
sunlight with melanoma development later in life. Other melanoma inci-
dence data implicates migration from less sunny climates such as in Eng-
land and Scotland, to areas of high solar flux such as Queensland, Australia
at a young age [47, 50].
Other risk factors for melanoma development include number of dysplas-
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tic nevi (moles) [46,47] and occupation. Paradoxically, office workers ex-
hibit more sensitivity to melanoma development than individuals who work
outdoors suggesting intermittent UV exposure is important [47, 51, 52].

CATARACT

UVB appears to play a role in some, but not all, forms of cataract. The
action spectrum for cataract development in humans is not known but a
number of animal experiments have been carried out and have implicated
UVB to varying extents. Epidemiologic studies of cataract development
have implicated exposure to UVB, in particular the Chesapeake Bay water-
man study [53]. Other studies suggest that UVB radiation is a risk factor
for Posterior Subcapsular cataract, a type of cataract which accounts for
about 40% of those cataracts removed by surgery in the USA [54]. Some
risk analyses have been completed estimating the number of new cases of
cataract which will occur as a result of each per cent decline in stratospheric
ozone, but the data available are very limited and much more remains to be
determined [35].

CONCLUSIONS

Solar UVB radiation (280-320 nm) causes a variety of effects, e.g. mutation
and denaturation, in important biomolecules such as DNA and protein.
Skin cancer development requires malignant transformation in the DNA of
skin cells and UVB-induced changes in the immune system. These changes
involve the production of regulatory immune cells which "suppress" the
attack response against initiated tumor cells allowing their outgrowth. UVB
 266 E. C. DE FABO AND F. P. NOONAN

induces the suppression of a variety of other T-cell mediated immune

responses, including contact hypersensitivity, delayed hypersensitivity to
herpes virus, and the formation of skin lesions in Leishmaniasis. The mech-
anism, as well as the short or long-term effects, of such immunological
perturbations is largely unknown but appears to involve the activation of a
skin photoreceptor identified as urocanic acid. UVB radiation has also been
linked to the development of some types of cataracts in humans and ani-
mals. In this chapter we review briefly some of the known impacts of
increased UVB radiation on human health including immune suppression,
skin cancer and cataract formation. We also describe mechanism(s) thought
to be involved in certain of these processes.
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Acknowledgements
The authors would like to thank Dr. Lindsay J. Webber, for her excellent
comments and suggestions and review of this manuscript.

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