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OCR for page 75
Chapter 5
DIRECT HUMAN HEALTH HAZARDS
SUMMARY
On the basis of current knowledge, we believe that ozone
depletion and the resultant increase in W would not
result in new health hazards, but would increase existing
ones as described in the following sections. The W
component of sunlight can cause direct damage to the
skin, eyes, and immune system of humans. The W wave-
lengths most affected by ozone concentration are essen-
tially responsible for sunburn, an acute, inflammatory
response of the skin. Although the exact targets and
mechanisms for sunburn are not fully understood, enough
is known about the doses required to predict the
increased risk for any given increase in UV flux. For
small increases in UV, simple sun avoidance measures
would more than offset the increased risk of sunburn.
Much less is known about the long-term effects of
sunlight on skin. Chronic exposure to sunlight leads to
degenerative changes in skin. However, because the
effective wavelengths and the relationships between US
dose and skin response are not known, the magnitude of
the increased risk of degenerative changes that might
accompany ozone depletion cannot be predicted. Epidemio-
logical studies show that sunlight causes more than 90
percent of basal and squamous cell skin cancers and is a
factor in melanoma. Experimental studies and theoretical
considerations suggest that actually the wavelengths most
affected by ozone (i.e., UV-B) cause basal and squamous
cell tumors. Because the dosi~i~etry for humans is
uncertain, only crude estimates can be made for the
increased risk of these cancers as the result of any
given increase in W flux. Techniques to measure
individual UV exposures that either cause or prevent
these cancers are still lacking.
75
OCR for page 76
76
Melanomas are undoubtedly related to sunlight, but
the relationship is more complex and obscure than the
relationship between sunlight and basal and squamous cell
skin cancers. Consequently, the melanoma-sunlight
relationship is more difficult to measure in epidemio-
logical studies and to reproduce in animal experiments.
The relationship of melanoma to W -B is even less clear,
and there is no animal model in which this relationship
can be explored. Current epidemiological data suggest
that individual sensitivity to sun damage, exposure to
sunlight in childhood, the relationship of childhood nevi
to melanoma, and the association between sunlight and
specific histological types of melanoma should be
explored.
In the eye, an acute painful irritation of the
cornea, called photokeratitis, is caused by W-B.
action spectrum for this effect is known, and the
increased hazard for any given increase in UV flux
predictable. The symptoms are easily prevented by
avoiding or reducing exposure to sunlight.
evidence that UV may be involved in the etiology of
certain forms of cataracts, but the wavelengths most
likely involved (W-A) are not those affected by ozone.
Since the last NRC report (NRC 1979a), several new
observations have heightened the awareness and broadened
the understanding of the health hazards of human exposure
to UV. These include a better understanding of the
optical properties of skin and blood; the results of
careful study of various exposure conditions that
influence UV-induced skin cancer in laboratory animals;
demonstration and quantification of two forms of DNA
repair in viva in human skin (see Chapter 3); and
documentation that the immune system of animals and
humans is affected by UV irradiation of skin. UV affects
the immune system in a variety of potentially important
ways. For example, systemic W effects may well be a
contributing factor to the efficacy of UV in inducing
skin cancer.
The
is
There is some
ANATOMICAL AND OPTICAL PROPERTIES OF SKIN AND BLOOD
Humans, like most life forms, live in a complicated,
dependent relationship with the sun. All life derives
its energy from the sun; photosynthesis drives almost all
food chains, and the sun is the major source of heat. UV
photochemistry in the skin is an obligate step in vitamin
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77
D synthesis, and visible light photochemistry within the
retina allows vision. On the other hand, the UV component
of sunlight can injure or kill cells, including intact
living human tissue.
The organ most affected by UV is the skin. The
optical properties of skin determine the amount of
optical radiation reaching various depths in the tissue.
Since the NRC (1976a, 1979a) reports, more accurate
measurement techniques and useful optical models have
made it possible to quantify, predict, and modify the
optical properties of skin (Anderson and Parrish 1981,
Wan et al. 1981). These advances may make it possible to
localize important photobiologic chromophores (molecules
or parts of molecules that absorb light), identify
mechanisms of UV injury, and better quantify risks.
When light enters the skin, a portion is scattered
back to the environment, some is absorbed as it reaches
various layers, and part is transmitted inward to
successive layers of cells, until all the energy of the
incident beam has been dissipated (Figure 5.1). The
epidermis is a 100-micrometer (pm) sheet of cells that
can be viewed as an unpolished optical absorption
filter. A 10-pm layer of dead cells, protein, and
Remittance
Incident Radiation
Stratu m Corneu m-~
(10 ,um)
Epidermis_
(100 ,um)
Dermis
(3 mm)
Regular Reflectance
(=5%)~
Dermal
/ Epidermal Remittance
/ Remittance |
~°~,sorn';~_ /
1~; , ;,/ \_/
Blood Vessels
FIGURE 5.1 Optical interactions of skin layers with W radiation (Parrish et al.
1978).
OCR for page 78
78
other biomolecules on the outermost surface of the
epidermis is called the stratum corneum. Aromatic amino
acids both free and in protein, urocanic acid, nucleic
acids, and melanin are the major W-absorbing chromo-
phores in the epidermis (Figure 5.2). The dermis is a
l-millimeter (mm) to 4-mm layer of primarily collagenous
connective tissue that provides much of the structural
integrity of the skin. Optical scattering within the
dermis largely determines the average pathlength and
depth of penetration of various wavelengths of radiation.
Dermal scattering is an inverse function of wavelength.
The major pigments in the dermis include hemoglobin and
bilirubin.
In considering the effects of possible changes in the
terrestrial solar spectrum resulting from ozone depletion,
it is important to know the depths to which optical
radiation penetrates human skin (Table 5.l). UV-B is
strongly absorbed by the stratum corneum and by many
2or \1
1L
1.6
cn 1.2
A
LL
J
i:
~ 0.8
o
0.4 _
O
200
I\
\
\
1
\
\
Urocanic Acid
-
\ / DNA \
1 `v, ' \
V ~ ~ ~ 3>~\ Dopa Melanin
~] ~ Tryptophan
\
Tvrmcin.
~ _.
\\\
1 `_ 1 `~
220 240 260 280 300 320 340
WAVELENGTH (nary)
FIGURE 5.2 Optical absorption spectra of the major W-absorbing chromophores in
the epidermis of human skin (concentrations in aqueous solution: urocanic acid 100,u
molar, DNA 100 ,ug/ml, dope melanin 15 ,ug/ml, tryptophan 200,u molar, tyrosine
200 ,u molar) (Anderson and Parrish 1982~.
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79
TABLE 5.1 Approximate Penetration Depths of Optical Radiation in
Fair Caucasian Skin (,um)
Depth to Which Following Percentages
of Incident Energy Penetrate
Wavelength (nary) 507O 37~c 1070 1%
UV-C
250 1.4 2 4.6 9.2
280 1 1.5 3.5 7.0
UV-B
300461428
UV-A
3504060140280
Visible
4006090200400
450100150350690
5001602305301,100
6003805501,3002,500
7005207501,7003,500
Infrared
8008301,2002,8005,500
10001,1001,6003,7007,400
12001,5002,2005,10010,000
SOURCE: Modified from Anderson and Parrish (1971).
molecules within living epidermal cells. About 50 percent
of W -A penetrates fair Caucasian epidermis to be largely
attenuated within the first 50 Am of the papillary
dermis. The longer visible wavelengths penetrate much
further.
Biologically active UV reaches the level of cutaneous
blood vessels. Endothelial cells and connective tissue
elements may be directly affected by the radiation; blood
cells, lymphatics, and humoral substances passing through
the skin may be photochemically altered. The blood flow
to the skin is 30 to 40 times greater than is necessary
to supply nutrients and meet the metabolic needs of skin
cells because it is primarily designed for heat regulation
of the whole body. An equivalent of the entire blood
volume may pass through the skin and be irradiated in a
few minutes. The physiologic, pathologic, and possible
therapeutic implications of this irradiation are just
beginning to be understood.
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80
EFFECTS OTHER THAN CANCER
Acute Responses of Normal Skin to W :
Whole Organ Inflammation
Many photochemical events are triggered by the absorption
of UV and visible light by the variety of molecules
within cells (see Chapter 3). Some of these alterations
may have little consequence, whereas others may change
cell function, cause cell death, or lead to the release
of chemicals that affect adjacent cells or tissues. If
there is sufficient damage to individual cells, the skin
will react as a whole organ. Redness, swelling, heat,
and pain appear after a latent period of several hours,
and last for hours to days. The overall response of skin
to UV is reparative and protective.
The tender redness or erythema (commonly called
sunburn) is the manifestation of UV-induced inflammation
that has received the most attention. The presence and
degree of UV-induced delayed erythema depends on the
exposure and the wavelengths in the irradiating UV. The
reciprocal of the lowest exposure required to induce
erythema plotted against wavelength is the action
spectrum (Figure 2.1). The 250-nm to 290-nm portion of
this curve is the most erythemogenic waveband. Ozone
depletion would have little effect on this waveband.
Erythemal effectiveness falls by a factor of more than
1000 from 290 nm to 320 nm, the UV-B range. Over a wide
range of intensities, both high-intensity radiation for a
short time and low-intensity radiation for a long time
produce the same response (erythema) as long as the same
total dose is given; thus reciprocity holds.
Because the action spectrum, dose-response curve, and
intensity-time reciprocity relationship for sunburn are
known, it is possible to calculate the decrease in time
required to acquire a sunburn for any given ozone deple-
tion. If UV-B increases by 10 percent, the decrease in
time required to acquire a sunburn would be about 10
percent plus a small additional decrease in time because
of the spectral shift to include shorter, more effective
wavelengths.
Erythema, however, is only one component of a complex
tissue response. Recent studies (Parrish et al. 1981)
have revealed other important components in this response
involving a variety of kinds of skin cells, blood vessels,
and circulating factors, each having its own thresholds,
dose-response curves, and action spectra. Cell injury
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81
and alterations of skin can occur without erythema. It
has been shown that abnormal differentiation of keratino-
cytes, DNA injury, and pigment production can occur at
suberythemogenic UV doses. The chromophore, molecular
mechanisms, and complex cascade of mediators and events
are poorly understood and may vary with wavelength.
Long-term Effects of UV
on Skin: Solar Degeneration
Chronic exposure to the sun causes a complex of changes
in skin called actinic or solar degeneration. The skin
appears thick and furrowed but may also have zones of
thinned epidermis. Hyperpigmentation and hypopigmenta-
tion, dilated blood vessels, and a leathery appearance
are the other symptoms of the condition sometimes referred
to as "sailor's skin'' or "farmer's skin" because excessive
occupational exposure often causes these changes, espe-
cially on the back of the neck.
been called "premature aging," but there is no convincing
evidence that the cellular mechanisms and connective
tissue alterations are the same as those that occur in
natural aging. The action spectrum for solar degenera-
tion is not known, and therefore the potential effects of
ozone depletion are not known.
This condition has also
Effects of UV on the Immune System
diverse collection of
The immune system is a complex and
circulating and noncirculating cells in the body that
provide protection against certain diseases and infec-
tions. The system recognizes foreign molecules or cells
and initiates complex reactions to dilute, reject, or
counteract them. Recently, it has been discovered that
W can alter the immune systems of animals and humans.
For example, a mild sunburn results in the decreased
viability and function of lymphocytes (circulating white
blood cells) in humans for up to 24 hours (Morison et al.
1979), and in animals certain allergic reactions (Morison
et al. 1981c), skin graft rejection (Morison et al. 1980),
and other immune functions can be altered by giving other-
wise tolerable doses of W to intact skin. Most of what
is now known about this topic, which is termed photo-
immunology, has been learned since the NRC (1979a) report.
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82
The immune system is well represented in the skin by
Langerhans cells in the epidermis, mast cells and lympho-
cytes in the dermis, and other cellular elements perco-
lating through the lymphatics and capillaries of the
dermis. All these components of the immune system are
therefore exposed to environmental light, and may be
altered as a result of such exposure. The most detailed
studies have been performed on experimental animals.
Skin cancers induced in mice by UV-B radiation are
highly antigenic, and many are rejected by an immunologic
reaction even when transplanted into genetically similar
mice, i.e., mice from the same highly inbred strain.
These tumors, however, grow in immunosuppressed mice.
The tumors that survive in the primary host do so because
the UV irradiation has induced systemic, immunologic
alterations that suppress specific immune responses. The
mechanism, in part, involves the generation of regulatory,
thymus-derived (T) suppressor cells in the lymphoid
tissue of W-irradiated mice (Fisher and Kripke 1978,
Spellman and Daynes 1978). Repeated exposure of mice to
UV radiation induces a population of regulatory cells
that prevent immunologic rejection of W-induced tumors.
This effect has been demonstrated by cell transfer and
reconstitution experiments (Fisher and Kripke 1978). The
suppression is specific for W -induced tumors.
W -irradiated mice also fail to respond to contact
sensitizing antigens involved in allergic contact
dermatitis and contact hypersensitivity. (The action
spectrum for the inhibition of contact hypersensitivity
is discussed in Chapter 3.) This represents a second
systemic alteration in W-irradiated mice. It is also
associated with antigen-specific T suppressor cells and
is thought to be caused by a UV-induced alteration in the
cells (Langerhans cells or macrophages) that present
antigen to lymphocytes in the initiation of an immune
response (Greene et al. 1979; Kripke 1980, 1981; Noonan
et al. 1981b).
Some evidence indicates that W can alter antigen
presentation in a way that activates the suppressor cell
pathway (Saucer et al. 1980, Towes et al. 1980), and thus
affect the immune response. It does this by direct inter-
action with antigen-processing cells. Suberythmogenic
amounts of radiation are required for altering the
function of Langerhans cells, and even the systemic
alteration is produced by erythmogenic W exposures.
Some of the effects of UV on immunologic pathways could
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83
determine whether skin cancer develops or not (Fisher and
Kripke 1981). Current efforts are directed toward
understanding how UV alters antigen-presenting cells,
defining the alteration in these cells that triggers
suppressor cell production, and determining which immune
responses are affected by the alteration.
Several lines of evidence suggest that at least some
of the above observations may apply to species other than
mice. UV-B exposure can suppress immune responses in
guinea pigs and rabbits, and both local and systemic
suppression have been reported (Haniszko and Suskind
1963; Morison et al. 1980, 1981c). UV irradiation of
guinea pigs, for example, results in a suppression of
delayed hypersensitivity responses to contact allergens
and injected hap/en-protein conjugates (Jessup et al.
1978. Morison et al. 1981c, Noonan et al. 1981b). In
rabbits, the rejection of full-thickness skin grafts is
delayed by treatment with oral methoxsalen and W-A
radiation (a photochemotherapy for psoriasis) (Morison et
al. 1980). The role of T suppressors in these phenomena
is being investigated. There are a few reports of local
suppression of contact hypersensitivity in human subjects
following W exposure (Horowitz et al. 1974, O'Dell et
al. 1980). There are increased UV-associated skin cancers
in renal transplant patients (Marshall 1974). Although
these cannot be ascribed to the immunosuppressive therapy
with certainty, the observation is consistent with what
would be expected if there were an immunological involve-
ment in human photocarcinogenesis. The effects of UV-B
radiation on Langerhans cells in human skin appear to be
similar to those reported in rodents (Aberer et al. 1981).
Human studies in this new area of research are less
advanced from the viewpoint of pathophysiologic mechanisms
than animal studies, but it has been firmly established
that exposure to UV radiation does affect the immune
function in humans. In normal human volunteers, single
exposures to sunburn-causing doses of UV-B radiation
(Morison et al. 1979) or oral methoxsalen and W -A
radiation (Morison et al. 1981a) produce an alteration in
the distribution and function of subpopulations of
circulating lymphocytes. These effects are reversible
within 48 to 72 hours. However, repeated exposure to
such radiation may cause more long-lasting changes in
lymphocyte viability and function (Morison et al. 1981b).
The quantitative implications of the above observa-
tions are not clear. It is possible that UV-induced
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84
alterations of immune function are important in mediating
the beneficial effects of W radiation in the treatment
of skin disease and the harmful effects of such exposure,
such as the development of skin cancer.
Effects of W on the Eye
Because solar W radiation is present during most of th
daylight hours, the eye is exposed daily to some amount
of solar W radiation throughout life. W-B is mostly
absorbed within the cornea and conjunctive. The acute
effects of excessive exposure to these wavelengths are
primarily conjunctivitis and a corneal inflammation
reaction known as photokeratitis. After W exposure,
there is a period of latency varying more or less
inversely with the amount of exposure. The latent period
may be as short as 30 minutes or as long as 24 hours, but
it is typically 6 to 16 hours. Photoconjunctivokeratitis
causes the sensation of a foreign body or sand in the
eye, varying degrees of excessive tearing, blinking, and
intolerance of light. Corneal pain can be very severe,
and the individual may be incapacitated for a period of
time. These acute symptoms usually last from 6 to 24
hours, and almost all discomfort usually disappears
within 48 hours. Rarely does exposure result in
permanent damage. Unlike the skin, the ocular system
does not develop tolerance or significant defenses
against future W exposures. Anatomic conformations
protect human eyes from acute overexposure to the W
component of sunlight as do physiologic bright-light-
avoidance responses when there is sufficient visible
light to incite this protective response. There is
epidemiological evidence that chronic exposure to
sunlight may cause certain types of cataracts in humans
and experimental evidence that W-induced photochemical
changes (with and without the addition of exogenous
photosensitizers) in the lens can cause cataracts. The
action spectrum for these changes, however, appears to be
in the W-A range and therefore would not be affected by
ozone depletion.
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85
CANCER EFFECTS
Basal and Squamous Cell Skin Cancers
What Was Known by 1979
Basal and squamous cell skin cancers constitute the most
common malignancies in humans. These cancers are usually
easily treatable but have a definite morbidity, cost,
inconvenience, cosmetic liability, and mortality. The
NRC Climatic Impact Committee (NRC 1975) and the Committee
on Impacts of Stratospheric Change (NRC 1979a) were asked
to predict whether increased exposure to W-B would be
likely to increase basal and squamous cell skin cancer
incidence rates. To do so, they had to make judgments on
the basis of limited evidence from epidemiological
studies, backed up by clinical and pathological observa-
tions and the results of animal experiments, because
human experimentation was out of the question. The same
approach had to be used in 1964 to assess the relationship
between cigarette smoking and lung cancer. The Surgeon
General's report on smoking and health stated that deter-
mination of whether the confirmed association between an
event and a disease is causal is a matter of judgment
that goes far beyond any statement of statistical proba-
bility. It listed a number of criteria that must be used
in assessing circumstantial evidence. These criteria
included the consistency, strength, specificity, temporal
relationship, and coherence of the association (Surgeon
General 1964).
Over the years, collective evidence has confirmed the
existence of an association between basal and squamous
cell skin cancers and sunlight. Epidemiological surveys
have consistently identified an overwhelming predominance
of these cancers in Caucasians, increasing mortality and
incidence rates with decreasing latitude, higher rates of
disease in outdoor than in indoor workers, and rates of
disease increasing more rapidly at older ages. These
associations have always been relatively strong and have
been accepted as biologically rational: the skin is indeed
exposed to the sun, and increased incidence rates with
advancing age favor a sequence in which disease does not
precede but follows exposure.
The supporting clinical data have also been consistent
in showing concentrations of these skin cancers among
fair-complexioned individuals, particularly those with
blue eyes who sunburn easily and have Celtic ancestors.
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105
The argument was built on the facts that sunburn and
melanoma are often found in the same tissue, melanomalike
lesions can be induced by irradiation of chemically
induced benign pigmented lesions in experimental animals,
and individuals with xerodema pigmentosum have an extra-
ordinarily high prevalence of melanoma (Kraemer 1980,
Takebe et al. 1977). An additional argument was that one
could read a pathogenetic relevance in the similarity of
the erythema and DNA-damaging action spectra. As
discussed in the next section, since 1976, the case for
an association between W-B and melanoma has been
weakened rather than strengthened by the results of
additional clinical, pathological, and epidemiological
studies. Furthermore (with the exception of a single
animal), it has not been possible to use W -B alone to
induce melanomas in experimental animals.
The only statistical association that has been
repeatedly found nationwide and worldwide is the one
between melanoma incidence or mortality rates and
latitude. Although widespread, the association is not
totally consistent. There is still no clear evidence,
although cohort analysis shows an increased incidence
with age, that the latitude association is a dose-related
relationship. There seems to be no doubt that Western
countries have been living through a rapid increase in
melanoma incidence (Houghton et al. 1980, Lee et al.
1979). Each successive cohort studied has had higher
incidence rates. The epidemic has been affecting popula
tions at many different latitudes with varying background
incidence levels. ~ ~ ~ ~
~_ ~_
The epidemiological picture ot higher
Incidence rates In each successive birth cohort is
reminiscent of the earlier lung cancer epidemic in those
same countries, which resulted from the Progressive
. .
adoption of the habit ot cigarette smoking by more ana
more members of each younger generation.
In spite of grave reservations about the nature of
the observed statistical association, NRC (1975, 1976a,
1979a) used the existing statistical association between
either latitude or R-B meter readings and melanoma
incidence or mortality to make predictions about the
. . .
likely increase in melanoma incidence, given future
increases in UV-B exposure.
It was clearly recognized
that this decision was made without knowledge of the
percentage of skin melanomas in the United States likely
to be caused either wholly or in part by UV-B exposure
and without good evidence pinpointing other factors that
would be more powerful determinants of the future
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106
incidence rates. It was argued that the predictions
would be useful even if the association between latitude
and melanoma incidence turned out to be indirect or an
extremely remote index of the true causative factor.
Lacking any epidemiological clues to major etiological
factors other than sunlight, NRC (1976a, 1979a) tried to
provide a behavioral explanation (changes in exposure
patterns) for epidemiological inconsistencies on the
basis of variability in personal susceptibility recognized
in series of clinical observations. Following through on
this line of reasoning the earlier studies had emphasized
the need for new and more extensive data that would
permit, for individuals with varying levels of innate
susceptibility, analysis of measurements of exposure to
sunlight.
Advances in Knowledge
Much new information about melanoma has been collected
and published since 1979. Some of this information
confirms the association between melanoma and latitude
and levels of UV intensity. Much of it underscores and
extends the inconsistent and sometimes paradoxical
findings from past epidemiological studies, and some of
it provides interesting new avenues for exploration.
When the 1973-1976 incidence data from the NCI SEER
program are plotted against the 1977-1978 NCI R-B meter
measurements of accumulated dose in eight geographic
locations, the results are consistent with those of
earlier analyses and show a definite relationship between
melanoma and measurements of annual solar W flux (Scotto
et al. 1982) (Figure 5.7). The slope resulting from this
statistical analysis is similar to that obtained for
basal -elf cancers (Figure 5.5) and is virtually the same
as the slopes previously developed from other bodies of
data (Scott and Straf 1977, Scotto et al. 1982). Other
newly published studies of incidence data again con-
sistently report higher rates of melanoma at lower
latitudes (Crombie 1979, Jensen and Bolander 1980, Malec
and Eklund 1978). Several reported studies of trends in
incidence have confirmed the continuation of the worldwide
increase.
Although the overall increase in the incidence of
melanoma is virtually universal, the incidence on specific
body sites has increased at various rates (Scotto et al.,
1982). A report that melanoma of the eye has not
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107
Skin Melanoma
Wh its f emales
ite Males
7
6
to 1 0
if:
CC
CC
A:
of
en
en
9
8
U]
A:
LL
an
j O
° ~ 5 _,
_ ~
~ O
To 4 _
~ °
·L CC _
3 ~ `,,
L
100
o
o
o
Detroit
1 1 1 1
120 1 40
.
o
a
~c
<0
_ at
~.
c
c
In 0 6 z
1
a
x
in
1 1 1 1 1
160 180
SOLAR UV RADIATION INDEX
FIGURE 5.7 Annual age-adjusted incidence rates for skin melanoma (SEER data,
1973-1976) among white females (open symbols) and males (closed symbols), accord-
ing to one year's W measurements at selected areas of the United States. The W
radiation index is the total Robertson-Berger meter counts over a one-year period
multiplied by 10-4. The meters read W-B between 290 rim and 320 nrn, as well as
some W-A. (J. Scotto, National Cancer Institute, personal communication, 1981.)
200
importance, because this
increased in incidence has some
tumor occurs in the back of the eye, where UV does not
penetrate, and is therefore unlikely to be associated
with exposure to UV (Strickland and Lee 1981). A new
series of reports on the occupational incidence of
melanoma has provided very consistent information (Lee
1981), as has a second series of studies of the incidence
of melanoma in immigrant and indigenous residents of
Israel (Movshovitz and Modan 1973). Each series,
however, provides information that has to be reconciled
with that of the other.
In the occupational series, four
studies from different parts of the world and from very
different latitudes failed to demonstrate any excess
incidence of or mortality from melanoma among outdoor as
compared with indoor workers of similar status. All four
studies confirmed earlier reports of the correlation of
increasing incidence with higher socioeconomic status.
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108
In the second series, individuals born in high-incidence
areas had higher incidence rates than did all immigrants.
Immigrants from areas of lower incidence who had moved
into areas of higher incidence assumed higher incidence
rates, and their risk of developing melanoma increased
with the number of years they had lived in their new and
more dangerous locations. This is true for Israel
(Anaise et al. 1978), Australia (Holman et al. 1980), and
California (T. Mack, University of Southern California,
personal communication, 1981). In the California study,
California-born residents have the highest rates of
melanoma incidence and immigrant Midwesterners who have
moved to California have the lowest rates. The incidence
rates for California residents born halfway between
California and the Midwest fall somewhere in between.
This ranking of incidence rates by place of birth among
California residents does not hold for melanoma of the
eye or for melanoma in parts of the body other than the
skin.
A report of a high incidence of melanoma among workers
at the Lawrence Livermore National Laboratory may provide
a unique opportunity to identify contributory, if not
causative, etiological factors (Austin et al. 1981).
Most other recent information concerns individual
susceptibility and the etiology of specific histological
types of melanoma, and precancerous conditions.
Individual Susceptibility. Although Scandinavian
populations have unusually high incidence rates of skin
melanoma for their latitude of residence, it is now known
that they also have high incidence rates of melanoma of
the eye, which cannot readily be related to either
sunlight or UV-B exposure (Strickland and Lee 1981).
This combination suggests an underlying susceptibility to
melanomas in general.
There are a number of reports of higher incidence
rates of melanomas in women during the later years of
reproductive life in populations with different base
rates of melanoma incidence and among different ethnic
groups (Jensen and Bolander 1980, Lee and Storer 1980)
The possibility of a specific hormonal component in the
etiology of a certain proportion of these tumors is now
being considered. Some early analysis of data collected
at the University of Sydney suggests that in the women
with higher incidence rates the ratio of superficial
spreading melanoma to nodular and other histological
types (Table 5.7) is higher than average. This increased
.
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ratio has also been found in other groups, for example,
among men in the highest socioeconomic classes. It is
also found on body sites with the highest rates of
increasing incidence, namely, women's lower legs and
men's trunks (backs) (McCarthy et al. 1980).
These early findings could explain a number of other
recent reports that note that the proportion of small and
thin newly diagnosed melanomas is steadily increasing in
populations with both very high and moderate incidence
rates. One interpretation would be that the superficial
spreading melanoma is the major cause of the increased
rate in the groups identified above; another is that
lesions are being detected at an earlier stage in those
groups and are being treated while they are small and
thin. Clinicians have always associated the lentigo
melanoma with excessive exposure to W. Some clinicians
believe that melanomas of this type are undercounted,
particularly in the lower latitudes, where they are more
common. It is the view of these clinicians that these
cancers usually progress so slowly that they rarely reach
a serious point during life, and thus remain undiagnosed.
Without good diagnosis and reliable reporting, there can
be no valid assessment of the distribution of these
cancers over the body. Clinical observation would lead
us to be believe that they virtually always appear on
exposed areas of the body. If they are relatively rarely
diagnosed and are not lethal, the published incidence
rates of 6 percent to 10 percent among all melanomas must
be taken as uncertain. If, for example, superficial
spreading and nodular melanomas were not associated with
exposure to UV and all incidence cases could be accurately
counted, the proportion of lentigo melanomas among all
melanomas would be higher in high-incidence areas, such
as Texas or Australia, than in low-incidence areas.
There are no available data with which to test this
hypothesis (Lee and Strickland 1981). This is one
example of the growing interest in specific histological
types of melanoma. Much more detailed histological
descriptions at the time of diagnosis are needed to
provide the basis for pursuing this potentially fruitful
research.
Other preliminary data suggest that individuals with
melanomas sunbathe less and use more sunscreens than do
control subjects. Furthermore, they may have less
residential, occupational, and recreational exposure to
the sun. These findings seem to apply to both susceptible
and less susceptible individuals (S. Graham, State
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111
University of New York at Buffalo, personal communication,
1981). There is considerable evidence of familial
concentration of melanoma (S. Graham, State University of
New York at Buffalo, personal communication, 1981). In a
recent study of 214 patients with melanomas, an appropri-
ate group of controls, and family members of both groups,
it was found that family members of patients with
melanomas have high relative risks that are of the order
of eightfold for all first-degree relatives (parents,
offspring, and siblings) and twelvefold for parent-
offspring pairs (Duggleby et al. 1981). These very high
risks in family members could be consistent with other
studies reported below. It is perhaps important to
mention that this high relative risk found in relatives
of the individuals first identified as having melanoma
(which may be of great importance in clarifying the
etiology of melanoma) occurs in relatively few instances
and can account for only a few among all cases of
melanoma.
Precursor Lesions. There have been a number of recent
reports of precursor dysplastic nevi (Clark et al. 1978;
Elder et al. 1980, 1981; Reimer et al. 1978; Wiskemann
1977). Dysplastic nevi are usually large irregular moles
on the skin that exhibit evidence of abnormal histological
development (dysplasia). It was first believed that these
lesions were always part of a familial condition called
B-K Mole Syndrome (Clark et al. 1978; Green et al. 1978,
1980). However, it is now believed that there are both
familial and sporadic dysplastic nevus syndromes and that
the progression from a typical (i.e., histologically
normal) nevus to a melanoma is analogous to the
progression in the cervix from normal endothelial cells
to squamous cell carcinoma in situ. It is also believed
that on the skin, as on the cervix or in the bronchi,
dysplasia is likely to occur in multiple sites. A body
of histopathological, clinical, and biochemical evidence
is being accumulated to explore this hypothesis, and some
tentative results from laboratory experiments suggest
that the fibroblast cells of patients with dysplastic
nevi and hereditary cutaneous melanoma are peculiarly
sensitive to W radiation (Smith et al., in press).
During the past 5 years, there has been an increased
number of laboratory and case control studies of
individual human beings and population-based incidence
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112
studies. Preliminary results are available from very
few. Other investigators expect that their results are
likely to strengthen evidence favoring individual types
of susceptibility and to emphasize the need to analyze
melanoma incidence rates by histological type (Sober et
al. 1979). There does not seem to be any reason to
expect strengthening of evidence in support of a hypo-
thesis that lengthy accumulation of exposures to W
radiation per se is the overriding or even one of the
most important causes of melanoma other than lentigo
maligna melanoma. There is an increasing number of
individually inconclusive reports that all suggest that a
history of acute exposures such as sunburn or marked skin
sensitivity to sun exposure may be particularly important
(Beitner et al. 1981, Jung et al. 1981, Paffenbarger et
al. 1978, Sober et al. 1979). In light of the inconsis-
tent and inconclusive state of knowledge about a possible
dose-response relationship between melanoma and W. we
are unwilling to make quantitative estimates of the
effects of reduced concentrations of atmospheric ozone on
the incidence of melanoma.
~,£ ., ~ ~ _.-~
PROTECTION AGAINST DAMAGE FROM SUNLIGHT
Most of the direct human health hazards predicted to
result from a depletion of stratospheric ozone concentra-
tion, and a consequent increase in solar W. stem from
exposure of the skin--increased incidence of sunburn,
solar degeneration, skin cancer, and immune system
effects. All skin is not equally susceptible to UV
damage, however. There are two principal intrinsic
barriers to UV. One is the stratum corneum on the
outermost surface of the skin, which absorbs the most
biologically active wavelengths of UV. This layer is
approximately the same in all individuals and can be
thickened as a reparative response to W injury of skin.
The other physiologic, chemical, and optical protector
against UV is a pigment called melanin, which is produced
by cells in the epidermis called melanocytes. This pig
The production of
ants pigment is increased after sun exposure (tanning).
The base line amount of melanin and the cape-city to
increase melanin production are genetically determined.
White persons have much less melanin than blacks.
Caucasians have different levels of melanin in their skin
In general, those with the least base line pigment have
.
ment gives skin its brownish color.
.
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113
the least capacity for tanning. These individuals are
the most susceptible to sun damage of all kinds. The
base line pigmentation of very dark skinned races
protects against UV-B radiation 30 times better, and
of moderately dark-skinned races 3 to 5 times better,
than that of fair Caucasians.
The range of base line pigmentation, and the capacity
for tanning (i.e., for increasing melanin production), in
fair Caucasians has been arbitrarily divided into four
categories (see NRC 1979a, Appendix H), depending on the
person's assessment of his or her own propensity to
sunburn (relative absence of base line melanin) and
ability to tan. Information is obtained by asking a
standardized question about response to sun exposure.
This method, called "skin typing," has proved to be a
useful shorthand for categorizing persons in terms of
responses to phototherapy, sunscreen testing, and
clinical surveys. It is, however, not quantitative and
is subject to cohort and interviewer bias. It simply
predicts photobiologic response on the basis of the
subject's memory of past photobiologic response.
Two additional excellent barriers against UV are
.
~ ~ ~_ ~l~=n~--mh~mi~ I S
available. Were are now ex~ll=~ ~ =~ A.. ~
that when applied to the skin absorb W before it reaches
viable cells. They provide a wide range of added protec-
tion that can reach a factor of more than 10. This means
that if it normally requires 25 minutes of sun exposure
at noon in June to cause minimal sunburn in a fair person,
a sunscreen with a protection factor of 10 would change
the requirement to 250 minutes. This large amount of
protection is more than enough to cover the UV increases
likely to result from possible ozone depletion. Screening
provided by protein, melanin, and topically applied sun-
screens is most likely additive (Hawk and Parrish 1982).
The other means of protection is the most effective.
Avoidance of sunlight between 11:00 a.m. and 2:00 p.m.
greatly reduces the exposure of skin to UV-B. Even modest
changes in human behavior can decrease solar W exposure
by factors that are much greater than the least conserva-
tive factors estimated for ozone-related increases in W.
Finally, the possible anticarcinogenic effects of
$-carotene and synthetic retinols are being explored,
but the roles of these compounds are complicated and
controversial at this time.
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114
RESEARCH RECOMMENDATIONS
The following list of research recommendations is not
exhaustive but has been limited to those issues that
should receive attention first. Two of the several
direct human health hazards that might be expected to
result from an increase in the intensity of solar UV
radiation should be emphasized in future research:
immune system effects and skin cancer. The list is not
organized according to priority.
1. Photoimmunology is a new and important area of
research. It appears that erythmogenic (sunburn-causing)
UV exposures can cause systemic alterations in the immune
systems of animals and humans. The implications of these
findings for understanding the pathogenesis of skin cancer
and certain other diseases must be investigated. The
identification of common mechanisms would be an important
contribution. As an initial step, studies to determine
the magnitude of UV-B effects on the human immune system,
the dose-response relationships, and the effective wave-
lengths should be vigorously pursued.
2. The use of animal models to study W-induced skin
cancer (experimental photocarcinogenesis) has proved
valuable in understanding the role of UV in the develop-
ment of human skin cancer other than melanoma. Further
animal studies are needed to understand interactions among
parameters such as intermittent exposures, different wave-
lengths, dose rates, and agents that modify cellular
responses to W irradiation.
3. An animal model for light-induced melanoma must
be discovered before it will be possible to determine if
a reduction in stratospheric ozone concentration will
cause an increased incidence of melanoma in humans.
Dose-response relationships and effective wavelengths
should be determined.
4. Prospective studies of patients undergoing various
forms of phototherapy and photochemotherapy could be
helpful in obtaining quantitative information about the
relationship of certain UV wavebands to human skin cancer.
5. Epidemiological studies of skin cancer incidence
and mortality rates have supplied valuable evidence
confirming the existence of an association between basal
and squamous cell skin cancers and sunlight. As basal
and squamous cell skin cancers are not routinely reported
to cancer registries, it will be necessary to maintain
routine surveillance by periodic surveys during the next
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115
50 years. These incidence surveys should be at intervals
no longer than 10 years and should collect data that can
be subjected to cohort as well as cross-sectional
analysis.
6. In addition to (5) above, epidemiological
research on skin cancer other than melanoma should
concentrate on retrospective and prospective studies of
individual human beings. The latter will need some
simple measures of effective individual exposure to W -B
to correlate with incidence and/or documentation of
complete protection from UV exposure to correlate with
prevention of skin cancer.
7. Information obtained since 1979 makes it clear
that the etiology of malignant melanoma is even more
complex than previously believed. A number of risk
factors are involved, and, in addition, there are various
subtypes of melanoma. In order to determine the associa-
tion between UV and melanoma, it is essential to determine
the incidence of and latitude dependence of the various
melanoma subtypes. To do this, careful epidemiological
studies based on reliable clinical and much more detailed
histological descriptions at the time of diagnosis are
needed.
8. Epidemiological studies of individual human
beings and their effective exposures are essential in
learning more about the etiology of melanoma. These
studies should include some that focus on the experience
of children, some that explore associations between the
development of nevi and the sensitivity to sunlight
exposure, and some that explore the protective aspects of
exposure to wavelengths other than W -B.
Representative terms from entire chapter:
squamous cell
