nonmelanoma skin cancers is inversely related to geographic distance from the
equator and to the melanin content of the skin, with SCC more strongly linked than
6,20 Persons of skin types most sensitive to sunlight, as well as persons
working outdoors, have higher incidences of nonmelanoma skin cancers.
history of SCC and BCC increases the risk at least twofold, depending on the
histology, number of lesions, and degree of invasiveness.
disease characterized by partial or total absence of pigment in the skin, hair, and
eyes, is associated with increased and premature development of skin cancers.
The development of cutaneous malignant melanoma (CMM) also may be linked to
UVR exposure, specifically exposures that induce sunburn. A history of five or more
severe sunburns during adolescence more than doubles the risk of CMM.
nonmelanoma skin cancers, CMM demonstrates an inverse relationship to geographic
distance from the equator and melanin content of the skin.
cancers, however, CMM does not demonstrate a clear relationship to the cumulative
dose of UVR, and it occurs on areas of the body exposed to the sun intermittently
(e.g., on the back in men and the lower legs in women). In addition, it occurs most
commonly in the middle-aged population and in individuals who work indoors, as
well as in those whose sun exposure is limited to weekends and vacations.
history of melanoma is a strong risk factor, as 8% to 12% of melanoma patients
display a familial propensity for the disease.
Mechanisms of carcinogenesis may include damage to DNA and alterations in
immunologic status. Epidermal and dermal DNA can absorb UVR, which can
contribute to abnormal formation of pyrimidine dimers. Under normal circumstances,
these dimers are excised and repaired; however, if left uncorrected, these DNA
lesions, as well as an inactivity of p53 tumor suppressor gene activity, can lead to
interruption of transcription, with possible mutagenesis and malignancy.
Exposure to UV radiation can cause many types of ocular adverse effects including
cataracts, conjunctival degeneration and proliferation, as well as squamous cell
carcinoma of the cornea and conjunctiva.
24 Age-related opacification of the ocular
lens, or senescent cataracts, has been attributed to a lifetime of exposure to sunlight.
The incidence of cataracts increases steadily after age 50, reaching nearly 30% in
25 UVB is absorbed by the cornea and lens, which slowly
results in protein oxidation and precipitation within the lens. UVA penetrates the
ocular lens and can cause cumulative damage to deeper structures of the eye.
Decreased transmittance and increased scattering of light by the opacified lens
eventually result in blurred vision, rings or halos around lights, changes in color
In advanced cases, the only treatment is surgical removal
High exposure of the eye to UVR (which can range from a few seconds of
exposure to arc welding, a few minutes of exposure to a UVC-emitting germicidal
lamp, commercial tanning, or UVR reflection by snow or sand) can cause
conjunctivitis or photokeratitis, a painful inflammation of the cornea. Photokeratitis
usually begins 30 minutes to 24 hours after the exposure, and time to onset depends
on the intensity of the exposure.
26 Conjunctivitis commonly accompanies
photokeratitis and is characterized by the sensation of a foreign body or grit in the
eyes. Varying degrees of photophobia, lacrimation, and blepharospasm also may
26 Because the corneal epithelium has a great regenerative
capacity, photokeratitis tends to be transient, with regression in 24 to 48 hours.
Treatment consists of cool, wet compresses and mild anti-inflammatory analgesics,
such as ibuprofen, aspirin, or naproxen sodium.
PHOTOTOXICITY AND PHOTOALLERGY
The most common type of drug-induced photosensitivity reaction is phototoxicity,
which is an immediate or delayed inflammatory reaction that occurs when a
compound with photosensitizing ability absorbs a sufficient concentration of UVR in
or on the skin, and when the skin is exposed simultaneously to a specific wavelength
27,28 When the offending agent is deposited on the skin surface, it is thought to
act as a chromophore, absorbing UVR. When the chromophore reaches a sufficient
concentration in or on the skin, and when the skin is exposed to the appropriate
wavelength of UVR, energy is emitted and transferred to the surrounding molecules,
which damages the adjacent tissue to cause a phototoxic reaction. The wavelength of
radiation necessary to produce such a reaction depends on the absorption spectrum of
Photoallergy results from a similar mechanism to phototoxicity, except that the
immune system is involved. Most commonly, it
is caused by polycyclic photosensitizers that react with UVA to form antigenic
macromolecules, evoking a delayed hypersensitivity response. In photoallergic
photosensitivity reactions, the suspected medication or chemical agent is altered in
the presence of UVR to become antigenic or to become a hapten (i.e., an incomplete
antigen), which can combine with a tissue antigen. These antigen–antibody or
immune-mediated processes differentiate photoallergic from phototoxic reactions.
Photoallergic reactions do not occur on first exposure to the medication, but as with
other allergic reactions, they require prior or prolonged exposure (sensitization
period) to the offending agent.
27,28 Once sensitization has occurred, subsequent
exposure to even small amounts of the offending product will produce a photoallergic
Photoprotection encompasses all methods of UVR blocking, including sunscreens,
protective clothing, and sunglasses. Sunscreens are widely used to prevent sunburn
and reduce the incidence of premature aging and carcinogenesis,
clothing and avoiding direct sunlight offer greater protection. Sunburn preventive
agents are those active ingredients that absorb greater than 95% of UVB radiation,
and have the potential to prevent sunburn. Suntanning agents are those with active
ingredients that absorb 85% to 95% of UVB radiation, thereby allowing suntanning
without significant sunburn in the average individual. Chemical sunscreens include
both of the aforementioned designations. Opaque sunblocks, or physical sunscreens,
are those active ingredients that reflect or scatter all UVA, UVB, and visible light,
thereby preventing or minimizing sunburn and suntanning.
were developed to protect against the effects of UVB radiation before adverse effects
of UVA were recognized. Because UVA plays a significant role in many of the
adverse effects associated with UVR exposure, broad-spectrum sunscreen products
with absorption spectra in the UVA range have become commercially available, in
combination with UVB absorbers. These broad-spectrum products provide
additional benefit for patients with photosensitivity reactions caused by wavelengths
not covered by single-ingredient sunscreens. Table 42-2 lists the available sunscreen
chemicals that have been judged to be both safe and effective.
There is a clear association between UV exposure and the development of BCC
34 and limiting UV exposure by starting sunscreen use during childhood is a
key to reduce the lifetime risk of nonmelanoma skin cancers; however, some
investigators have suggested that sunscreen use, through increased UV exposure, may
actually cause melanoma, perhaps because its use allows for a longer exposure to the
35,36 and because historically there was a lack of UVA protection in most
37 Sunscreen use has been thought to be associated with the occurrence of
nevi (pigmented moles), an important risk factor for melanoma development
however, epidemiologic analyses have refuted this proposed association, largely on
the basis of a longer exposure to UVR and less protective clothing in individuals who
Clinical Application of Photosensitivity
you to a recommendation of a sunscreen product.
Meradimate (menthyl anthranilate) 260–380
Oxybenzone (benzophenone-3) 270–350
Sulisobenzone (Eusolex 4360) 260–375
Cinoxate (diethanolamine p-methoxycinnamate) 280–310
Octinoxate (octyl methoxycinnamate, Parsol MCX) 290–320
Avobenzone (butyl methoxydibenzoylmethane, Parsol 1789) 320–400
Aminobenzoic Acid and Ester Derivatives
Para-aminobenzoic acid (PABA) 260–313
Padimate O (octyl dimethyl PABA) 290–315
Octisalate (octylsalicylate) 280–320
Ecamsule (terephthalylidene dicamphor sulfonic acid; Mexoryl) 290–400
Ensulizole (phenylbenzimidazole sulfonic acid) 290–340
One of the most important pieces of information to include in the patient history is
41 Patients can be classified into six sun-reactive skin types
based on their response to initial sun exposure, skin color, tendency to sunburn,
ability to tan, and personal history of sunburn (Table 42-3). This skin typing system
is used by the US Food and Drug Administration (FDA) in its guidelines for
sunscreen agents. J.J.’s fair complexion, propensity to sunburn, and minimal tanning
classify him as skin type II. R.J.’s light brown complexion, minimal sunburn reaction,
and moderate tanning classify her as skin type IV.
Hair and eye colors also provide an indication to skin reactiveness to sunlight.
People who have blonde, red, or light brown hair or blue or green eyes tend to have
greater skin reactivity to sunlight than people with dark-colored hair or eyes. A
history of severe sunburn also can be associated with skin reactivity to sunlight,
although self-reported patient histories of sunburn or tanning may not be consistently
reliable and personal interviews may be a better indicator. J.J.’s propensity to
freckle and his history of severe sunburns as a child may give an indication as to his
skin’s sun reactiveness. Other important information to consider in the patient before
recommending a certain product is medication history, history of sun-reactive
dermatoses, history of allergies (particularly contact hypersensitivities to cosmetics
or other topical agents), and the intended activities during sunscreen use.
adverse effects of UVR. What are the risk factors for these long-term adverse effects of UVR?
The long-term effects of UVR include photocarcinogenesis and premature aging of
the skin (photoaging). The associated risks for the development of these long-term
effects are directly related to the congenital pigmentation of an individual (which
includes skin type and hair and eye color) and intensity, duration, and frequency of
exposure to UVR. With skin type II, J.J. is at high risk for carcinogenesis and
photoaging, whereas R.J., with skin type IV, may be at a lower risk. Excessive sun
exposure, especially during early childhood, increases the risk of nonmelanoma and
melanoma skin cancers. During the first 18 years of life, the average child receives 3
times the dose of UVB of the average adult; consequently, most sun exposure occurs
23,42,43 A history of frequent sunburn or intermittent high-intensity
exposures to UVR may be associated with the occurrence of malignant melanoma,
whereas large cumulative doses of UVR during a lifetime may contribute to the
incidence of nonmelanoma skin cancers. J.J.’s history of several severe sunburns as a
child may more than double his risk of CMM.
42,43 Cumulative doses of UVR received
unintentionally from working outdoors or from participating in outdoor recreational
activities also can contribute significantly to the risk of photocarcinogenesis and
7 A large number of moles, congenital moles more than 1.5 cm wide, and
abnormal moles also appear to be a risk factor for malignant melanoma.
skin cancer is increased among first-degree relatives of patients with skin cancer
because frequent sunburns, suboptimal sunscreen use, and high rates of tanning bed
use are common among children with a personal or family history of skin cancer.
The effectiveness of a sunscreen formulation is based on its SPF and its
46 SPF is a measure of how much solar energy (UV radiation) is
required to produce sunburn on protected skin (i.e., in the presence of sunscreen)
relative to the amount of solar energy required to produce sunburn on unprotected
skin. Because the SPF value increases, sunburn protection increases. It is defined as
the ratio of the minimal dose of UVR required to produce an erythemal response in
sunscreen-protected skin compared with unprotected skin.
tests of volunteers with skin types I through III, using either natural sunlight or a solar
simulator that generates both UVB and UVA.
30,46 Because the SPF can be influenced
by the composition, chemical properties, emollient properties, and pH of the vehicle,
sunscreen formulations must be evaluated on an individual basis.
SPF is commonly misunderstood and is also influenced by a variety of factors
including the amount applied to the skin, the time of initial application before UVR
exposure, the frequency of application, and environmental factors, such as
photodegradation during UVR exposure; therefore, the SPF achieved during actual
use can be significantly less than indicated on the label.
shown to routinely apply only one-fourth to one-half thickness of the layer of
sunscreen used to determine the SPF before marketing.
A popular misconception is that SPF relates to time of solar exposure. For
example, many people believe that if they normally get sunburn in 1 hour, then an SPF
15 sunscreen allows them to stay in the sun for 15 hours (i.e., 15 times longer)
without getting sunburn. This is untrue because SPF is not directly related to time of
solar exposure, but to the amount of solar exposure. Although solar energy amount is
related to solar exposure time, other factors have an impact on the amount of solar
energy. For example, the intensity of the solar energy has an impact on the amount.
Generally, it takes less time to be exposed to the same amount of solar energy at
midday compared with early morning or late evening because the sun is more intense
at midday relative to other times. The following exposures may result in the same
amount of solar energy: one hour at 9 AM versus 15 minutes at 1 PM. Solar intensity is
also related to geographic location, with greater solar intensity occurring at lower
latitudes. Also, because clouds absorb solar energy, solar intensity is generally
greater on clear days than on cloudy days.
Suggested SPF for Various Skin Types
Complexion Skin Type Skin Characteristics
Very fair I Always burns easily; never tans 20–30
Fair II Always burns easily; tans minimally 15–20
Light III Burns moderately; tans gradually 10–15
Medium IV Burns minimally; always tans well 8–10
Dark V Rarely burns; tans profusely 8
Very dark VI Never burns; deeply pigmented 8
In 1978, the FDA Over-the-Counter (OTC) Review Panel on sunscreens
reclassified sunscreens from cosmetics to drugs intended to protect the structure and
function of the human integument against actinic damage. In 1999, the FDA finalized
its original regulations for OTC sunscreens (available at:
regulations listed the active ingredients that can be used in sunscreens as well as
labeling and testing requirements. They also provide for uniform, streamlined
labeling for all OTC products intended for use as sunscreens to assist consumers in
making decisions on sun protection.
Additionally, cosmetic regulations required tanning preparations that do not
contain a sunscreen ingredient to display the following warning: “Warning—this
product does not contain a sunscreen and does not protect against sunburn. Repeated
exposure of unprotected skin while tanning may increase the risk of skin aging, skin
cancer, and other harmful effects to the skin even if you do not burn.”
In 2006, the FDA introduced further regulations on sunscreen labeling. The term
sunscreen was redefined: “A product with active ingredients to affect the structure or
function of the body by absorbing, reflecting, or scattering the harmful, burning rays
of the sun, thereby altering the normal physiological response to solar radiation.”
These ingredients also help to prevent diseases such as sunburn and may reduce the
chance of premature skin aging, skin cancer, and other harmful effects attributable to
the sun when used in conjunction with limiting sun exposure and wearing protective
clothing. Sunscreen ingredients may also be used in some products for
nontherapeutic, nonphysiologic uses (e.g., as a color additive or to protect the color
In 2007, the FDA proposed a new amendment to its original regulations, which
sets standards for formulating, testing, and labeling sunscreen products.
rule, which did not take effect until June of 2012, limited the maximum SPF value on
sunscreen labeling to “SPF 50+,” as well as establishing that claims of water
resistance must tell how much time a user can expect to receive the stated level of
SPF protection while sweating or swimming, based on standard testing.
products being “waterproof” or “sweatproof” are no longer allowed, nor can
products be identified as “sunblocks.” Qualifications for products to be labeled as
“broad spectrum” were standardized and must provide protection against both UVA
and UVB radiation. Additional warnings about skin cancer and skin aging were
added to products that were not broad spectrum or have low SPF ratings <15. The
SPF maximum of 50+ resulted due to the lack of data that SPF levels higher than 50
provide any additional benefit.
57 Despite this new regulation, products listed with
SPF >50 are still available for purchase.
In November 2014, the Sunscreen Innovation Act (SIA) was enacted, which
provided a new process for the FDA review of the efficacy and safety of
nonprescription sunscreen active ingredients.
58 The act amended the Food, Drug, and
Cosmetic Act to provide specific timelines and deadlines requiring FDA review of
time and extent applications (TEAs) for sunscreen ingredients. This helps to ensure
that timely decisions are made on ingredients that had been pending review.
response to the SIA in early 2015, the FDA made tentative determinations on eight
ingredients that had been pending review, including bemotrizinol, bisoctrizole,
drometrizole trisiloxane, octyl triazone, amiloxate, diethylhexylbutamido triazone,
ecamsule, and enzacamene. These ingredients were found to have insufficient
evidence of safety and effectiveness at the concentrations in question and are in need
of more data to determine whether they are generally recognized as safe and effective
(GRASE) for use in over-the-counter sunscreen products.
Substantivity is a measure of the sunscreen formulation’s effectiveness. The
substantivity of a sunscreen formulation is its ability to be absorbed by, or adhere to,
the skin while swimming or perspiring. The substantivity of a product largely
depends on the vehicle, as well as the active ingredient.
61 The affinity of a sunscreen
to the keratinaceous layer of the stratum corneum is directly related to the keratin or
vehicle partition coefficient. The saturation of the active agent in keratin depends on
the drug’s lipophilicity, whereas its substantivity is independent of its lipophilicity.
Sunscreen compounds with a high solubility in the product’s vehicle penetrate the
skin most easily. Classically, vehicles such as water-in-oil emulsions or ointments
tend to have a higher degree of substantivity. Some of the newer products have
improved substantivity with the addition of a polymer, such as polyacrylamide, to the
Molar Absorptivity, Absorption Spectrum, and Photostability
The molar absorptivity and absorption spectrum determine the effectiveness of an
individual sunscreen agent, mostly by its chemical structure. Molar absorptivity is a
measure of the amount of UVR absorbed by a particular sunscreen, and it depends on
the concentration of the sunscreen in the product and the amount applied to the skin.
Sunscreens with an absorption spectrum in the UVB range, with a maximal
absorption between 310 and 320 nm, are the most effective in preventing a sunburn.
Sunscreens with absorption spectra in the UVB range are para-aminobenzoic acid
(PABA) and its esters, cinnamates, and the salicylates. Sunscreens with absorption
spectra that extend into the UVA range are the anthranilates (e.g., meradimate),
dibenzoylmethanes (e.g., azobenzene), and benzophenones (e.g., oxybenzone).
Photostability means the ability to stabilize under sunlight. The process of
photostability is a key factor in sunscreen protection efficacy. High photostability
means the sunscreen will maintain a higher UVA protective barrier longer and not
degrade as quickly as other UVA filters when exposed to the sun.
Table 42-2 shows the 17 ingredients that act as sunscreens currently approved in
the United States, along with their FDA-allowable maximal concentration and
Chemical organic sunscreens are compounds capable of absorbing UVR, thereby
protecting the skin structures from the adverse effects of the selective wavelengths
30 After application to the skin, these aromatic compounds convert the high
UVR energy into harmless longer-wave radiation, which may or may not be
30 Chemical organic sunscreens usually are nonopaque because
they do not absorb the wavelengths of visible light.
Commonly used in the past and the first widely used UV filter, PABA absorbs UVR
in the UVB range from 260 to 313 nm, with maximal absorption around 290 nm; its
molar absorptivity is considered to be high.
46 PABA readily penetrates and binds to
the stratum corneum and, after several days of application, may remain in the skin and
provide protection even after swimming, perspiration, and bathing, making it an ideal
candidate for water-resistant sunscreens.
It is commonly formulated as an alcoholic
mixture, which can cause stinging, dryness, or tightness, particularly when applied to
the face. Its major disadvantage is the potential to cause contact or photocontact
dermatitis, which has been reported to happen in approximately 4% of the
62 Responsible for more sensitivity reactions than any other sunscreen,
PABA can also cause cross-sensitivity reactions with benzocaine, thiazides,
sulfonamides, paraphenylenediamine (a common ingredient in hair dyes), and other
PABA derivatives. It can cause discoloration of clothes as well. The use of PABA in
commercial sunscreens has decreased to the point where many of the newer
sunscreens are promoted as being PABA-free.
The PABA esters include octyldimethyl PABA (Padimate O) and glyceryl PABA.
These esters are incorporated easily into formulations, demonstrate good
substantivity, and do not discolor clothing. Their absorption spectra are similar to
those of PABA ( Table 42-2). With a maximal absorption of 311 nm, Padimate O has
the lowest likelihood of any PABA ester to cause cross-sensitivity reactions or
contact and photocontact dermatitis.
Octinoxate (octyl methoxycinnamate), which has high molar absorptivity and a
maximal absorption of 305 nm, is the most commonly used cinnamate and most potent
64 Cinnamates are related chemically to balsam of Peru, balsam of Tolu,
coca leaves, cinnamic acid, cinnamic aldehyde, and cinnamic oil, ingredients that are
used in perfumes, topical medications, cosmetics, and flavorings.
not bind well to the stratum corneum, leading to poor substantivity. Cinnamate-based
sunscreens tend to be comedogenic because the vehicle may contain other occlusive
ingredients that are added to improve the substantivity. Cinnamates are often used in
combination with benzophenones, appear to be nonstaining, and rarely cause contact
Salicylates are weak UVB absorbers often found in PABA-free products. Topical
salicylates are considered among the safest sunscreens, even though they must be
used in high concentrations to meet the SPF requirement.
molar absorptivities, are incorporated easily into formulations, and are used to boost
the SPF of combination products, particularly oxybenzone and avobenzone.
Octisalate and homosalate are water insoluble, which leads to high substantivity.
Sensitization to the salicylates is rare
; however, it has been reported with the use of
Octocrylene has a absorption profile similar to the salicylates and cinnamates, with a
peak absorption at 307 nm. It has low irritation potential and low substantivity;
however, it has become increasingly popular because of its ability to photostabilize
Benzophenones, such as oxybenzone and dioxybenzone, are UVB-absorbing
sunscreens that have absorption spectra extending into the UVA range.
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