BIOLOGICAL EFFECTS OF INCIDENT SUNLIGHT

BENEFICIAL EFFECTS OF SUNLIGHT

Moderate exposure to sunshine results, psychologically and physiologically, in a general sense of
fitness, peace of mind, and well-being. It has been documented that the protein beta-endorphin is
expressed following exposure to solar-simulated radiation and that this is responsible for the feeling of
well- being. Sunlight, in particular UvB radiation, plays a vital part in the prevention and treatment
of rickets by producing vitamin D (through the activation of epidermal 7-dehydrocholesterol,
provitamin D3)
Adverse effects of Sunlight
The adverse effects of sunlight have been studied by dividing them into those that are induced by a
single exposure and those multiple exposures. Acute effects(following a single exposure) include
sunburn, immunosuppression, photoallergic reactions, photosensitivity reactions of individuals with
photodermatoses, and photosensitization following drug intake or topical appli- cation. Chronic
effects include photodamage(photoaging), cataracts, solar keratoses, skin cancer(basal cell carcinoma
and squamous cell carcinoma), and some forms of malignant melanoma (lentigo maligna)
Acute erythema
A sunburn may be classified by the intensity of the erythema (redness) response that is induced in the
skin. The threshold response is expressed at 8-10 hours after exposure, and the reaction reduces in
intensity and becomes stable after 24-48 hours. The erythema reaction then subsides, while from three
to five days after exposure, pigment starts to appear. In UVB-induced reactions in the laboratory a
small area of skin is exposed to a series of doses (fluences) of UVB radiation, and the reaction is
graded 24 hours after exposure as
+or- Minimum perceptible erythema(just perceptible redness with patch a ance over the exposed
site)
+1 Minimum erytema with clear borders
+2 Intense erthema without edema
+3 Intense erthema with edema
+4 a violaceouserythema with edema and blistering
These reactions apply to small exposure sites and produce mild sensations on the exposed sites.
For exposure producing responden that include edema, as the erythema subsides,pigmen start to form
and the site Will start to peel within 8-10 days after exposure. In the process of pelling,the stratum
corneum is lost,accompanied by a substansial loss of pigment because the stratum corneum At the
exposed site contains melanin. When an exposure is Made over the whole body, the reactions are quite
different in intensity,especially the inflammatory responden. An exposure At a a dose of +2, whole
body result in a severe erythema with pain,burning sensations and an overall not well felling complaint.
Stringer exposure doses May requirement hospitalization.
Because of the similitary between the erythema action spectrum and the absorptions spectrum
of dna. It is generally accepted that the interactions of uvb radiation with DNA plays an important role
in the erythema responden. It ia believed that the epidermal keratinocytes are the primary locus of
damage induced especially by UVB and short wavelength UVA radiation. Mantap cytokines and
inflammatory mediator are synthesized in the skin and released after exposure to UV radiation,including
eicosanoids,histamine,kinins,interleukins. TNF Alfa substance p,calcitonin generelated peptide and
nitric oxide. The factors play important roles in the rekruitment and activation of monocular cells and
neutrophils in the skin. Resulting in vasodilation and inflammation. Intracellular adhesion molecules
also have been shown to be upregulated in UV radiation exposed B skin, for example,intracellular
adhesion molecules 1 (ICAM-1),vascular Cell adhesion molecules 1 (VCAM-1),or endothelial
adhesion molecules
Acute tanning responden
Melanin pigment is produced by melanocytes that reside on the basement membrane between
the epidermis and the dermis. As stated earlier,melanin is synthesized in vesicles in the golgi apparatus
starting with dopa, which is enzymatically processed to the melanin heteropolymer. Once
polymerization starts,the vesicle ,are converted to melanosomes ( egg shaped membrane enclosed
objects) and are transferred through the dendritic processed of melanocytes to neighboring keratinoctes.
Thus the visually perceived pigment is due to melanin distributed into keratinoctes that reside on the
basement membrane. Cellular migration toward the stratum corneum distributes melanin throughout
the epidermis.
The tannin ability of individuals is genetically determined and is expressed the capacity of the
melanocytes to produced melanin, the amount of melanin. formed within each melanosome, and the
distribution of melanosomes. Light- skinned individuais have melanosomes(0.6-0.7 H long)that are
partially melanized and appear in clusters and therefore only visible pigment. In dark-skinned
individuals are less effective in producin the melanosomes(i u long are more completely melanized and
appear singly dispersed, making them more effective absorbers
The tanning responden of human skin depend on the wavelength of the radiation. When the
skin is exposed to UvB(280-320 nm), the first response is erythema. It is followed by pigment as the
erythema subsides. It is impossible to produce pigment with UVB radiation unless there is a preceding
erythema response. UvA radiation has been divided into two bands for prac- tical reasons, UVA
1(340-400 nm) and UvA2 320-340 nm). UvA2 induces skin reactions like UVB. In light-skinned
individuals there is an erythema response before the appearance of pigment. For melanocompetent
individuals and those with a tolerance for UV radiation(UvB), UVA2 induces a pigment reaction
immediately after exposure, without erythema. When the skin of both lanonomnatent individuals is
exposed to UVAl radiation it induced a pigment reaction immediately after exposure. The color this
pigment is gray,and it disappears within 10-20 minute after the end of the exposure. The treshold for
immediate pigment response is 1-2 j/cm2. If human skin is exposed to larger doses of UVAV radiation
(>10j/cm2), the immediate pigment is more intensely gray decreases intensity over the next two
hours,leaving behind a pigment that persists for week. The pigment that persists after two hours of the
end of exposure is called persistent pigment and is brown. In lighter-skinned individual some
immediately erythema may be evident,which Will disappears with time,leaving behind a lasting
pigment.

The (immediate) pigment formed immediately after a UVA1 exposure is believed to result from a
phytochemical reaction involving preexisting melanin pigment as well as melanin precursors and
metabolites. It is also believed that some reorganization of microtubules and microfilaments occurs in
immediate pigment. Immediate pigment is reversible for doses smaller than th threshold for persistent
pigment. Persistent pigment is a photochemically initiated enzymatically controlled producuon of
melanin polymer from preexisting monomers and melanin precursors. Within three to five days we
observe melanogenesis, that is, the biological process of producing native pigmentation as a result of
stimulating the melanocytes to produce more pigment. Melanogenis has been documented both for
UVA and for UVB five days after exposure by assessing the distribution and amount of melanin in the
epidermis with AgNO3 staining and DOPA staining(activity of the enzyme tyrosinase). The message
here is that UVAl produces a pigment that may persist depending on the dose of UVA1 radiation, and
the skin response may include an erythema in the early phases of the reaction. In contrast, UVB first
induces an erythema reaction that is then followed by a pigment that may last for weeks or months.
Both reactions to UVA or B result in de novo melanogenesis five days after exposure.
UVB radiation also induced proliferation of epidermal keratinoctes,resulting in a thikening of the
epidermis. This proferative response may be thought of as a repair following the DNA damage in
epidermal keratinocytes. The new keratinocytes are loaded with melanin from adjacent melanocytes
and progress up the epidermis toward the stratum corneum over the next five days. In this way we may
think of UVB pigmentation as due to melanin that is distributed fairly uniformly throughout the
epidermis.in contrast,UVA radiation does not induce a proliferative reapomse. Thus the pigment that is
stimulated by UVA radiation is produced in the melanocytes and is the transferred to the basal
keratinocytes. UVA induced epidermal melanin pigmentation thus resides in the vicinity of the
basement membrane,while UVB induced epidermal pigment is distributed throughout the epidermis.
Epidermal pigment formation also may be stimulated by visible Light. Visible Light does not produce
an erythema (no effect on the blood vessels). The pigment that is produced resembies UVA2 pigment
in that is appears immediately after exposure,and if the dose of Light is sufficient it may last for weeks
or months.
Over the years gilchrest and cowokers have tried to elucidate the mechanism of melanin production and
its dependency on DNA damage,nerve growth factor, and related signaling mechanism. These
investigators have also shown that DNA fragment like those produced by UV radiation (thymine dimers
and 4-6 photoproducts) can stimulated melanogenesis in an animal model. Their interpretation is that
DNA cross links formed by UV exposure undergo excision repair by endnuclease,and the fragment
removed from the DNA chain the signal melanogenesis. It has been shown that POMC (pro-
opiomelanocortin) and the downstream hormones MSH,ACTH,b-endorphin,and lipotropin play
important roles in melanogenesis.
in summary. sunlight is made upof UVB, UVA, and visible radiation therefore it is the balance among
these components that determines the skin responses. The UVA pigment responses include an
immediate pigment (a transient response that lasts minutes to hours) and a persistent pigment that lasts
for weeks to months. Visible light induces a response similar to that of UVA
except that the appearance of the pigment is slightly different. The UVB response starts with an
erythema and develops into a melanin pigment, which may be lost when peeling occurs.
SKIN TYPES~THE GENETIC BASIS OF RESPONSES TO ULTRAVIOLET RADIATION

The responses of the skin to UV radiation are to a great extent genetically determined. The first-hour
exposure to midday sun following the winter months of no exposure has been used to characterize skin
types for white-skinned persons.

Skin Type I : always burns. never tans

Skin Type II : usually bums. rarely tans
Skin Type III : rarely burns. usually tans
Skin Type IV : never burns, always tans

“Skin typing" of individuals in practical situations usually means a visual classification of individuals
based on their pigment level; persons planning studies should keep in mind that skin color and skin UV
reactivity, although probably related, are not the same. While this classification scheme is useful to
identify individuals at risk from UV radiation-induced skin cancer, it remains controversial when its
use is extended to predicting the threshold dose of UVB or UVA to produce an erythema or pigment.
These skin types have also been called “sun-reactive” skin types because this scheme the response to
UV rather than the skin color. There have been modifications of the scheme for none/bite individuals.
Epidermal melanin pigmentation has been classified as constitutive and facultative pigmentation.
Constitutive pigmentation refers to the pigment found in skin areas that have never been exposed to UV
radiation or any chronic insult. facultative pigmentation is pigment produced in response to UV
radiation exposure or other pigment-inducing insult. Persons with the genetic ability to pigment
following a UV exposure are called melanocompetent and those individuals who produce essentially
no pigment are called melanocompromised

IMMUNE RESPONSES TO ULTRAVIOLET RADIATION

It is accepted that UVB causes immunosumpression and that this effect has important implications for
photocarcinogenesis and exacerbation of infectious diseases. Assays for immunosuppression have
included local and systemic suppression of contact hypersensitivity to DNFB (dinitrofluorobenzene)
and systemic suppression of delaye type hypersensitivity to Candida albicans or alloantigen. Studies
have been conducted in both animal models and human subjects. While UVB induced
immunosumpression has been well documented, the effects of UVA on the immune System are still
under study. Initial results indicate that it also plays a role. UV-induced immunosuppression in humans
was recently reviewed in depth [23].
Exposure of skin to UV light impairs sensitization to haptens applied directly to the irradiated
area of the skin. Hapten-specific tolerance may develop due to the generation of specific T suppressor
cells, and it has been proposed that apoptosis plays an important role in immune reactions. In particular,
data indicate that T suppressor cells may induce the death of antigen-presenting cells in the presence of
the specific hapten and that the Fas/FasL system is involved in the process. (Fas. also called CD95 or
APO-l, is a surface molecule that indu ces apoptotic cell death.) Studies to assess the effectiveness of
sun protection products (sunscreens) have shown that UVC (wavelengths shorter than 290 nm) is also
very effective in inducing inununosuppression. A controversy ha: developed relating to the protective
ability of sunscreen products against immunosuppression. which may be associated with improper
definition of the output of the light source used in the studies.

ULTRAVIOLET RADIATION INDUCED SKIN CANCER

Photocarcinogenesis is not a cosmetic concern except for the generally held Opinion that the UV light-
absorbing agents used in cosmetic (over-the counter) suncreens help to lower the incidence of dermal
malignancies.
Skin cancer has been classilied as nonmelanoma skin cancer and as cutaneous malignant melanoma.
Nonmelanoma skin cancer (NMSC) includes basal cell carcinoma and squamous cell carcinoma. These
malignant lesions are formed in the epidermis and may invade the dermis. NMSC has the highest
incidence of any cancer. approximately one million new cases a year in the United States. Mortality
from NMSC is low, but morbidity is considerable with respect to disfigurement. Sun exposure is-linked
to the skin cancer epidemic as the incidence of NMSC increases in proportion to the cumulative sunlight
exposure and is highest in people in skin types I and II. In the case of melanoma, the effects of UV are
not clear except in lentigo maligna melanoma (a subclass of cutaneous melanoma), where sun exposure
has been shown to increase the incidence.

UV radiation causes cancer in the skin by damaging the ability of the skin cells to control proliferation.
The cells have three ways to combat UV damage and minimize cancer risk, including DNA repair,
apoptosis, and immunosurveillanoe. UV radiation can damage skin cells by forming dimers in DNA
between adjacent pyrimidine residues, potentially leading to UV “signature“ mutations that can
accumulate over time. The cell can reSpond to the damage by repairing the DNA to avoid the effects of
the mutations or if the damage ts too great by inducing cell death through apoptosis to remove potential
cancer cells from the population

UV radiation is a complete carcinogen: it can act alone as an inititor and a promoter in formation of
cancer. UV can also act as a promoter with initiating events inside the cell, such as DNA mutations
arising from DNA polymerase incorpcration errors, depuzination. deamination cf 5-methylcytosine, or
oxidative damage from free radicals. UVA, while a complete carcinogen, is much less effective than
UVB. However, it may act as a cocarcinogen in combination with UVB, as in solar radiation.

There is an additional premalignant, benign lesion-actinic keratosis-in which the epidermis proliferates,
producing a hyperkeratotic lesion [19]. These lesions are characteristic of photodamaged skin of
individuals with skin type I or II, and they may spontaneously disappear. However, actinic keratoses
have p53 mutations as NMSC.
CHRONIC EFFECTS OF ULTRAVIOLET RADIATION

The chronic effects of UV radiation or sunlphotoaging,wrinkles, freckles, leathery appearance, red

neck) have been recognized for a long time Clinically the syndrome ts characterized by coarseness,
wrinkling,mottled pigmentation,solar lentigos (age spots or liver spots),laxity,telangiectasias,and
atrophy. increased numbers of benign and malignant neoplasm develop with age. the importance of
these changed impacts the cosmetic industry. Unlike intrinsic or aging, photoaging is related to
cumulative damage to the cellular constituents of the skin. At least in part At the DNA level by UV
and infrared radiation [19]. Photoaging accounts for more than 90% of the skin's age-associated
cosmetic problems and is almost synonymous with “true chronologic aging” in the public's mind. It has
been pointed out lately that photoaging changes start in skin at a very young age The increase of freckles
(solar lentigenes) ts noticeable by the age of three to five years. The perception that sun exposure and
tanning are signs of well being together with the proliferation of tanning salons, has increased the
occurrence of skin photoaging in the general population. Chronologic aging of the skin without sunlight
exposure leads to remarkably few visible changes. In contrast, photoaging leads to marked changes in
the skin such as wrinkles, roughness, sallowness. motled hyperpigmentation. telangiectasias. laxity, and
a variety of benign and malignant neoplasms. Evidence of photoaging is found primarily in the dermal
connective tissue, although sun-damaged skin typically has a thicker stratum comeum. The extracellular
matrix of the dermis consists mainly of type lcollagen, some type III collagen, elastin. proteoglycans,
and iibronectin. Chronically sun exposed sites show a loss of mature type I collagen and a relative
increase in type III collagen. The most familiar feature of photoaging is a massive accumulation of
elastotic material in the upper and middle dermis. This phenomenon, known as solar elastosis. involves
a marked increase in the elastin content of the dermis, an increase in the size of the elastin tibers, and
the displacement of structural material from the dermis. The “elastotic material" that lills the dermis is
so called because it stains well with elastin specific histologic stains .

While the acute responses of skin to UV radiation have been studied extensively, photoaging studies
have been less prominent. Evidence 15 now forth coming that phctoaging changes may be produced in
the laboratory with a relatively small number of exposures.

REVERSAL OF PHOTOAGING
There have been a number of pharmacologic developments to reverse the visual signs of
rhotoaging. These include retinoic acid and its derivatives, alphahydroxy acids, antioxidants, and many
natural products. These materials have been tuned and have performed with variable effectiveness.
Solar photoaging is a profound change at the skin architecture that evolves over a long time to the final
state with elastotie material in the dermis. However it has been shown that solar elastosis can be found
histologically in young people-therefon prevention is a better approach than repair [23-25].
PHOTOSENSITIZATION
A number of materials including pharmaceutical and cosmetic ingredients are potential
photosensitizing agens. A photosensitizer absorbs light and induces a photochemical action that may
result in the production of free radicals in the skin. Organic free radicals and reactive oxygen substances
(which include superoxide anion, singlet oxygen. hydroxyl radical, and hydrogen peroxide) are very
reactive-short-lived-chemical species that can cause inflammatory reactions by producing damage to
subcellular organelles, which may lead to tissue damage. They may also damage cell membranes or
induce cell death by apoptosis. The release of photoproducts may lead to photoallergy. Another
expression of photosensitization is hyperpigmentation induced by the combination of a drug and UV
light. as in Berloque dermatitis (bergamot oil). Photosensitizing compounds can be used therapeutically.
The psoralens. for example. are potent photomitizing agents that produce cross-links in the DNA and
thus act a antiproliferative agents. This is useful for conditions such as psoriasis. Psoralens are also used
to treat vitiligo (a disease of hypopigmentation) because of their high pigment-producing potential.
There is another group of skin diseases that are induced by UV light, the photodermatoses. like
actinic prurigo. porphyrias. polymorphous light erruption, actinic reticuloid. and others. It is not clear
whether an endogenous photosensitizer plays a role in all cases such as in porphyrias. Photosensitization
is a common phenomenon, especially in counuies with severe winters when peOple receive little sun
exposure. It is reported that as many as 10% of the population has some form of photosensitization
disorder. It is therefore important to maintain a high degree of vigilance in conducting tests for the
photosensitizing potential of cosmetic materials.

PROTECTIVE MECHANISM OF THE SKIN

The skin develops tolerance to UV radiation following multiple exposures. Two factors, skin
thickening and tanning, have been identified as playing significant roles in protecting the skin from the
adverse effects of solar UV radiation. Skin thickening results from exposure to UVB only. The other
mechanism of adaptive ‘photoprotection is pigmentation. Tanning occurs following eitposure to both
UVB and UVA. Because of the simultaneous induction of proliferation along with new pigment
formation, the UVB pigment is distributed throughout the epidermis. The stratum comeurn of UVB-
exposed skin is well stained with melanin granules following a UVB exposure. Therefore ,the UVB tan
is protective, although the protection factor is low. The controversy of whether melanin effective
photoprotectant has raged for years. The absorbance of melanin in the critical UVB range is modest
The unanswered question is: Is the end product of melanogenesis,melanin a photoproteciant
against subsequent irradiation, or does the very process of melanogenesis free radical quenching by
DOPA per se act as a photoprotectant at the time of irradiation? The presence of urocanic acid has been
shown to provide some protection on the surface of l he stratum corneum. Urocanic acid is produced in
the epidermis as an enzymatic breakdown of filaggrin,a protein in the keratinocytes. It is a weak UVB
filter providing a protection factor of approximately 2. Urocanic acid also undergoes a cis-trans
isomerization reaction when exposed to UV radiation, Which has been shown to play a role in the
induction of immunosuppression.
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