Rev Environ Health 2014; 29(3): 145–155
Nicholas R. Blickenstaff*, Garrett Coman, Collin M. Blattner, Rosa Andersen and Howard I. Maibach
Biology of percutaneous penetration
Abstract
Background: Percutaneous penetration is a passive
process that can occur following skin exposure to chem-
icals used in agriculture, industry, pharmaceuticals,
cosmetics, and in the household. Once a penetrant is
absorbed into the skin it may cause a local reaction or
enter systemic circulation to produce widespread effects.
Improved understanding of the skin barrier and biologi-
cal aspects that impede absorption of topical substances
is essential for advancing the fields of dermatotoxicology
and dermatopharmacology as they pertain to percutane-
ous penetration.
Methods: Pubmed search results for “percutane-
ous ­ penetration”, “absorption”, “stratum corneum”,
“xenobiotics”, “skin factors”, “decontamination”, and
“transdermal” were reviewed from 1965 to 2014. Rel-
evant articles discussing the influence of biological
factors on percutaneous penetration of topical sub-
stances were included.
Results: Absorption of a topical substance across the
skin is most notably influenced by concentration, contact
duration, frequency, and the surface area exposed. The
interplay between these factors, along with skin biology
and the physiochemical properties of the penetrant, can
lead to enhanced percutaneous penetration.
Conclusion: Percutaneous penetration is a highly compli-
cated and dynamic process influenced by numerous skin
and environmental factors. Although research over the
last few decades has provided plenty of new insights to
improve our understanding of percutaneous penetration,
many areas lack clarity due to conflicting data.
*Corresponding author: Nicholas R. Blickenstaff, Department of
Dermatology, University of California San Francisco, 90 Medical
Center Way, San Francisco, CA 94143, USA, Phone: +208-869-7193,
Fax: +415-753-5304, E-mail: BlickenstaffN@derm.ucsf.edu
Nicholas R. Blickenstaff and Garrett Coman: Department of
Dermatology, University of Utah School of Medicine, Salt Lake City,
UT, USA; and Department of Dermatology, University of California
San Francisco, San Francisco, CA, USA
Collin M. Blattner: Department of Dermatology, Des Moines
University, Des Moines, IA, USA
Rosa Andersen and Howard I. Maibach: Department of Dermatology,
University of California San Francisco, San Francisco, CA, USA
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Keywords: aging and dermatopharmacokinetics; biology;
percutaneous penetration; stratum corneum; transdermal.
DOI 10.1515/reveh-2014-0052
Received July 20, 2014; accepted August 21, 2014; previously pub-
lished online September 13, 2014
Introduction
Human skin is fascinatingly complicated. As the largest
organ in the body it serves many vital physiologic and
biochemical functions. While the skin acts as the body’s
first line of defense against infection, temperature change
and other challenges to homeostasis, it also represents a
major pathway for exposure to chemicals and topically
applied substances. Percutaneous penetration occurs via
environmental, occupational, or consumer skin exposure
to chemicals, pharmaceutical products, or cosmetics (1).
Once absorbed into the skin, chemicals may cause local
reactions or enter systemic circulation to produce more
widespread effects. Thus, an accurate understanding of
dermal absorption is necessary to assess the risk to human
health following exposure to topical compounds. This is a
dynamic process, however, and many components inter-
act with a penetrant prior to it gaining systemic access (2).
Although dermatologists and pharmacologists have
been investigating the percutaneous penetration of drugs
and cosmetics since the 1960s, it is a relatively new issue in
environmental health. By applying our knowledge on the
percutaneous penetration of drugs and cosmetics we can
improve our understanding of dermal absorption of toxic
substances in the environment. Previous work by Ngo and
Maibach examined 15 factors that influence percutane-
ous penetration of industrial chemicals (2). This chapter
provides an overview of the key biologic factors that influ-
ence percutaneous penetration in hope of expanding on
this subject.
Skin layers
Human skin is composed of the epidermis, dermis and
fatty subcutaneous layer, creating a formidable barrier
146      Blickenstaff et al.: Biology of percutaneous penetration

that protects underlying tissue from infection, dehydra-
tion, chemicals, and mechanical stress. A main barrier
property of skin is due to the highly hydrophobic stratum
corneum, the outermost epidermal layer (3). This struc-
ture serves as a key rate limiting step for skin absorption
of many chemicals due to its composition of stacked corni-
fied keratinocytes, which are separated by highly ordered
extracellular lipid bilayers (4). These organized lipids/
proteins prevent excessive loss of water from the body,
providing a main resistance to the permeation of most
hydrophilic chemicals.
In order for percutaneous penetration of a chemi-
cal to occur, it must undergo a series of partitioning and
passive diffusion steps. Permeation through the stratum
corneum occurs most commonly through the intercellular
spaces, with the compound partitioning into the lipid-rich
extracellular regions of the stratum corneum (5). Remov-
ing the entire stratum corneum speeds the diffusion of
small water-soluble molecules into systemic circulation
by up to 1000 times (6). In addition to the main intracellu-
lar route, penetrating molecules can follow a transcellular
pathway or bypass the stratum corneum by penetrating
through appendages like sweat pores or sebaceous hair
follicles. Substances that follow the transcellular pathway
go through the corneocytes of the stratum corneum and
in the appendageal route they enter the shunts of hair fol-
licles and sweat glands. Hair follicles serve an important
role in percutaneous penetration with characteristics dif-
ferent from stratum corneum penetration kenetics (7). A
linear correlation between percutaneous permeability
of benzo[a]pyrene and hair density has been observed
in vitro, suggesting that shunt diffusion contributes to
regional variations in dermal absorption (8). Hydrophilic
and/or high molecular weight molecules have also proven
to be particularly prone to the transfollicular shunt
pathway (9–11).
Once a penetrant diffuses through the epidermal
layers it must partition into the dermis, which comprises
several structures and appendages, including blood and
lymph vessels, hair follicles, sweat glands, sebaceous
glands, and nerve endings. An extensive vascular network
is contained within the dermis, enabling most permeating
molecules to be absorbed by superficial dermal capillaries
into the circulatory system. If sufficient concentration of
the penetrating substance is reached, adverse events can
ensue. Thus, understanding the multifactorial nature of
percutaneous penetration is necessary to limit exposure
to toxic substances in the environment, workplace, and
household.
Age-related percutaneous
penetration
Skin aging is a continuous process resulting in a number
of biologic and physiologic changes that may alter percu-
taneous penetration of environmental compounds. Over
time skin thickness changes due to atrophy of the epi-
dermis (12), flattening of the dermoepidermal junction
(13, 14), and thinning of the dermis. Skin factors (Tables 1
and 2) like skin surface pH (15), lipid content (16), stratum

Table 1 Effects of aging on percutaneous penetration.

Skin factor   Age-related   Implication for percutaneous penetration

Cutaneous   Studies are conflicting; overall trends indicate that blood   Enhanced local delivery and diminished
blood perfusion flow may decrease systemic delivery
pH   Studies are conflicting; majority report an increased pH   Fluctuation in amount of unionized (lipophilic)
drug available for percutaneous penetration
Skin thickness   Stratum corneum maintains thickness; epidermal, dermal,   Not always an inverse relationship with the
and whole thickness changes are controversial degree of percutaneous penetration
Hair and pore   Reduction in hair follicles   Decreased percutaneous penetration through
density Sebaceous glands increase in size but produce less sebum the shunt route
Decreased sweat glands
Proteins   Intrinsic: collagen is sparser and less soluble   Increased xerosis, leading to decreased
Extrinsic: collagen is thickened and more soluble, increased percutaneous penetration
synthesis of abnormal elastin
Increased folding and decreased interaction of proteins with
water
Water   Stratum corneum hydration decreases with age   Increased xerosis leading to decreased
percutaneous penetration
Lipids   Studies are conflicting; lipid content appears to decrease   Enhanced percutaneous penetration

Adapted with permission from Konda et al. (15)

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Table 2 Factors affecting percutaneous absorption of chemicals.
Exposure factors
 Contact duration
 Frequency of dosing
 Area of exposed skin
 Concentration of chemicals
Skin factors
 Age
 Skin thickness/anatomic site
 PH
 Skin water content/TEWL
 Skin lipid content
 Cutaneous perfusion
 Skin barrier integrity
 Cutaneous metabolism
Chemical factors
 Molecular weight
 Solubility in water and oils
 Structure
 Irritancy
 Hairiness, pore density, and sweating
corneum (SC) hydration (17), transepidermal water loss
(TEWL) (18), and cutaneous perfusion (15, 19) may also
be altered. These changes can potentiate percutaneous
penetration of certain xenobiotics like water-soluble dies,
whereas lipid-soluble drugs and other chemicals may
have decreased permeability (20).
Previous investigations on skin thickness with aging
have had contradictory findings. The general consensus is
that stratum corneum thickness is retained over time (21),
whereas epidermal and dermal thickness is debatable.
The reported differences in experiments observing skin
layer thickness is likely due to significant variations in
measurements between subjects and between sites within
each individual. Biopsies from three different body sites of
71 human volunteers demonstrated that epidermal thick-
ness varied based on body site, but no decrease occurred
due to age or skin type (22). In contrast, Branchet et al. (23)
performed upper arm skin biopsies and denoted that epi-
dermal thickness decreased with aging at rates of 7.2% and
5.7% of the original value per decade in men and women,
respectively. Meanwhile, dermal thickness decreased 6%
per decade regardless of gender due to gradual changes
in elastic and collagen fiber composition. The dermal-epi-
dermal junction has been analyzed using various imaging
modalities and found to have marked flattening with
aging from progressive loss of dermal valleys, retraction
of the epidermal papillae and loss of basal lamina corru-
gations (24, 25). This flattening increases the fragility of
the epidermal-dermal interface, making it vulnerable to
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Blickenstaff et al.: Biology of percutaneous penetration      147
mechanical forces and penetrants that have bypassed the
stratum corneum.
The stratum corneum in healthy skin is typically
acidic, with pH values ranging from 4.6 and 5.6. Skin
surface pH increases with aging (26–28). Abnormal acidifi-
cation has been linked to decreased epidermal expression
of Na/H+ exchange 1, which leads to altered activity levels
of lipid-producing enzymes β-glucocerebrosidase and
acid sphingomyelinases (29, 30). These enzymes are vital
for ceramide and lipid production, maturation of lamellar
membranes, and maintenance of a healthy microbiome
(31). When ceramides, lipid content, and the natural skin
flora are disturbed, a cycle of increased alkalinity, infec-
tion, dry skin, and a disrupted epidermal barrier ensues.
Increased percutaneous penetration can result. In con-
trast, hyperacidification of the stratum corneum in hair-
less mice using lactobionic acid (LBA) and gluconolactone
(GL) can enhance permeability barrier homeostasis and
stratum corneum desquamation (32). Drugs usually exist
in unionized or ionized forms depending on their pKa
(drug dissociation constant) relative to skin pH. When
skin pH is lower than the pKa value, a weak acid will
predominate in unionized form and a weak base will be
ionized. Given that unionized drugs are more neutral, they
favor lipophilic environments, enabling them to penetrate
through the stratum corneum barrier more effectively.
Lipids form a multilamellar complex that fills most of
the intercellular space of the stratum corneum. They are
critical to the stratum corneum’s mechanical and cohe-
sive properties, enabling it to function as an effective
water barrier. Although it tends to be an accepted assump-
tion that the skin becomes drier, sebaceous gland activ-
ity slows down, and skin surface lipid content decreases
as a person ages, quantitative studies are conflicting (33).
A lipid composition analysis of 28 subjects following
sequential stratum corneum tape strippings of the face,
hands, and legs demonstrated a 30% decrease span-
ning all lipid classes in older subjects (16). Similarly, the
levels of total ceramides, an integral lipid constituent in
the stratum corneum, declined in older healthy subjects
(34). Supportive in vitro and in vivo studies have also dem-
onstrated enhanced percutaneous penetration follow-
ing delipidization with polar and nontoxic solvents (35).
Other studies indicated little or no relationship with aging
(36, 37).
Water content of normal stratum corneum ranges
from 10% to 30%. Aberrations in stratum corneum water
content alter permeability and percutaneous penetration.
Hydration of the stratum corneum decreases with age. Skin
hydration of the forehead and forearm in males and females
peaks around 40–50 years of age, with a notable drop off in
148      Blickenstaff et al.: Biology of percutaneous penetration

the seventh decade of life (19). Using an in vivo magnetic of percutaneous absorption of testosterone, estradiol,
resonance technique, an age-associated decrease in mois- hydrocortisone, benzoic acid, acetylsalicylic acid and caf-
ture of the outermost layer of the stratum corneum has been feine in young (18–40 years) and old ( > 65 years) subjects
observed in terms of dynamic shear viscosity under identi- yielded no correlation between diminished cutaneous
cal conditions of season and moisture (38, 39). Percutane- microcirculation efficiency and aged subjects (40).
ous penetration of hydrophilic drugs is diminished due to
decreased hydration in aged stratum corneum leaving less
amount of medium for hydrophilic compounds to traverse
through the epidermis. Roskos et  al. (40) concluded that
Configuration of epidermal lipids
penetration of hydrocortisone, benzoic acid, acetylsalicylic
Keratinocytes are generated in the lowest layer of the
acid, and caffeine is significantly lower in aged individu-
epidermis (i.e., the stratum basale), and differentiate as
als ( > 65 years) compared with young adults (22–40 years);
they move toward the surface. Following terminal differ-
meanwhile, more lipid soluble drugs like testosterone and
entiation in the stratum corneum, these epithelial cells
estradiol do not differ between groups.
produce corneocytes and intercorneocyte lipids essen-
TEWL is a reflection of skin barrier function and
tial in maintaining barrier homeostasis. Corneocytes are
the stratum corneum’s ability to maintain hydration.
rigid structures that maintain skin hydration, whereas
Decreased TEWL values can occur due to improved endog-
intercellular lipids create a hydrophobic interface that
enous barrier function, decreased eccrine sweating, or a
enhances the ionic skin barrier (54). Major lipid species
decrease in the hydration state of the stratum corneum
of the stratum corneum are ceramides (47%), fatty acids
(41). A decrease in TEWL occurs with aging (42–46), and
(11%), cholesterol (24%), and cholesterol esters (18%)
such decrease reflects a less permeable membrane to topi-
(55, 56). Due to this differentiation process, the composi-
cally applied compounds (40, 47, 48). Alikhan et al. (18)
tion of lipids changes throughout the epidermis, influenc-
showed significantly lower TEWL values in nine of 11 ana-
ing penetration of topically applied molecules. Compared
tomic locations in an aged population vs. young adults.
with the stratum corneum, the relatively undifferentiated
They suspect that this is attributed to age-related epider-
basal keratinocytes contain mostly sphingomyelin and
mal atrophy, resulting in smaller water reservoir content.
phosphoglycerides, with a small fraction of cholesterol.
Leveque (49) demonstrated similar findings showing a sig-
The more differentiated granular cells contain additional
nificant biphasic decrease of TEWL on the forearm during
phospholipids and cholesterol, as well as a significant
the second decade and again after the seventh decade of
amount of ceramide and glucosylceramides (57).
life compared with middle aged adults. An explanation
for this reduction in TEWL in the elderly is not obvious,
however, Berardesca (50) hypothesizes that increased cor-
neocyte size and stratum corneum thickness may account
for decreased TEWL after age 60 years.
Modification of intercellular lipid
Although opinion amongst researchers is not uniform, organization
overall trends indicate that the skin capillary network atro-
phies as one ages, resulting in a gradual decrease in blood Lamellar granules are secretory organelles found in
supply to the viable epidermis (12). Decreased cutaneous keratinocytes responsible for producing ceramides, the
perfusion is thought to play a role in percutaneous pen- predominate lipid in the stratum corneum. Ceramides
etration by enhancing local delivery of topically applied generate stacked lipid structures that surround corneo-
drugs while diminishing systemic delivery. Data from a cytes to provide an impermeable barrier that limits TEWL
wide range of compounds with varying solubility charac- and leaching of natural moisturizing factor from the
teristics demonstrated that penetration rate in an in vitro superficial skin layers. Production of ceramides decreases
chamber increased significantly when the rate of dermal with aging, leading to dry skin and a weakened skin
perfusion increased. Compounds assessed included tes- barrier vulnerable to toxic environmental exposures (58,
tosterone acetate, salicylic acid, benzoic acid, hydrocorti- 59). The degree of ceramide deficiency directly correlates
sone, butter yellow, hexachlorophene, urea, and thiourea with dryness levels in skin (58, 60). Similarly, diseased
(51). Investigations of age-related changes to autonomic skin seen in atopic dermatitis, psoriasis, contact derma-
stimuli demonstrated a significant time delay in blood titis, and some genetic disorders is also characterized by
flow changes in older persons, resulting in decreased decreased levels of ceramide and altered ceramide pro-
blood flow (52, 53). In contrast, in vivo measurements files (61).

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Skin irritants may reduce ceramide production by
solubilizing stratum corneum lipids. Sodium lauryl
sulfate application demonstrated an inverse relationship
between baseline ceramide weight and clinical irrita-
tion, including erythema, scaling, dryness and roughness
when examining ceramide content (62). Other irritants
frequently encountered in the household and in the work-
place also damage lipid bilayers and decrease ceramide
content, including oils, abrasives, alkalis (e.g., detergents,
soda, ammonia, potassium and sodium hydroxides), and
solvents (e.g., benzene, toluene, and acetone) (63).
An increase in percutaneous penetration can occur
in conditions where the proportion of ceramide content
is reduced. This has been shown to correspond with
the degree of skin barrier damage, regardless of the
causative agent. A comparison of topical salicylic acid
­penetration rates in barrier-perturbed skin vs. unmodi-
fied skin, showed a mean 2.2-fold increase in penetra-
tion in acetone-treated skin (p = 0.012), 46-fold in mild
dermatitis, and 157-fold in severe dermatitis, respec-
tively (p < 0.001) (64).
Biotransformation reactions in the
skin
Although the extent of cutaneous metabolism is less com-
pared with hepatic metabolism, it must be considered
when discussing percutaneous penetration of topical sub-
stances. Significant enzymatic activity in the skin gives
it a wide range of biotransforming capacities, including
the transformation of inert substances into toxicologically
active species, conversion of noxious compounds into
harmless metabolites, activation of prodrugs, and modifi-
cation of active drugs into active byproducts (15).
Exogenous chemical compounds often require cuta-
neous metabolism to be degraded into more water-sol-
uble products capable of excretion from the body (65).
The extent of cutaneous metabolism and percutaneous
penetration of endogenous drugs and topically applied
exogenous compounds is influenced by absorption rate
and cutaneous enzyme activity in human skin (66). Com-
pounds that are readily absorbed may rapidly bypass
the stratum corneum and metabolizing enzymes before
cutaneous metabolism takes place. Meanwhile, poorly
absorbable compounds penetrate the stratum corneum
at a slower rate, thus allowing for greater metabolic activ-
ity. Additional consideration must be given to compounds
requiring metabolic enzymes, which are either not present
in viable skin cells or have a low rate of activity. These
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Blickenstaff et al.: Biology of percutaneous penetration      149
substances will undergo minimal cutaneous metabolism
regardless of percutaneous penetration.
The physiochemical characteristics of topical sub-
stances also play a role in cutaneous metabolism. In
highly lipophilic drugs, cutaneous metabolism influences
the percutaneous penetration ratio of metabolite to parent
drug, as well as the total amount of drug that penetrates
the skin. The transformation of lipophilic drugs into more
water-soluble metabolites allows for increased permeabil-
ity through the more aqueous lower layers of the epider-
mis and dermis, compared with the highly hydrophobic
stratum corneum. Increased penetration can, therefore,
be expected when higher metabolic rate constants are
present (67). In vitro permeation studies of benzo[a]
pyrene and testosterone in six mammalian species rein-
forced this point by demonstrating that diffusional and
metabolic processes are intertwined in the percutaneous
penetration of topical compounds (65). Numerous drugs
like propranolol, nitroglycerin, betamethasone 17-valer-
ate, theophylline, and atrazine showed altered penetra-
tion profiles after undergoing cutaneous metabolism (68).
Anatomic site variability in
absorption
Many parameters vary by anatomic site, including skin
thickness, epidermis to dermis ratio, and hair follicle dis-
tribution; hence, skin permeability fluctuates depending
on the anatomic site of exposure. Steroid application to
multiple body regions found the scrotum to be most absor-
bent, followed by the forehead, scalp, hand, and forearm
(69). A wide variety of chemicals have been subsequently
tested and noted to follow this pattern of regional variabil-
ity in permeability (70).
To expand upon our understanding of the influence of
anatomic site on percutaneous penetration, Rougier et al.
(71) applied benzoic acid (BA) to humans followed by tape
stripping 30 min afterwards. They found that total BA pen-
etration was three times greater at the forehead than at the
back. Marrakchi and Maibach (26) showed variations in the
face in relation to percutaneous penetration by measuring
biophysical parameters in young (24–34 years) and old
(66–83 years) volunteers. They measured skin blood flow,
TEWL, stratum corneum hydration (capacitance), temper-
ature, pH, and sebum content of the skin surface. For both
groups, they found that skin blood flow was highest in the
nose, perioral and nasolabial areas showed the highest
TEWL values, the neck had the highest capacitance value,
and the chin was the most alkaline area. Sebum content
150      Blickenstaff et al.: Biology of percutaneous penetration
was most pronounced in the nasolabial area in the young
group and the chin in the old group.
Biologic changes following skin
occlusion
Occlusion refers to the direct or indirect covering of the
skin using tape, gloves, impermeable dressing, transder-
mal devices, or certain topical vehicles (e.g., petrolatum)
(72). Skin occlusion influences percutaneous penetration
by significantly increasing stratum corneum hydration.
Increased water presence on the skin surface alters par-
titioning between the penetrant and the skin by causing
corneocyte swelling, increased skin surface temperature
and blood flow, and changes to epidermal lipid compo-
sition and DNA synthesis (73, 74). Additionally, occlusion
may increase the pH and alter the skin microbiome (75).
Although exceptions have been reported (74, 76, 77),
percutaneous penetration of model compounds tends
to be significantly enhanced under occlusive conditions
(77–80). Feldmann and Maibach (78) showed a 10-fold
increase in cumulative absorption of topical 14C hydrocor-
tisone with occlusion compared with non-occluded skin.
Likewise, Bucks et al. (77) demonstrated that absorption
of estradiol, progesterone, and testosterone increased
by 8-, 2.4- and 2.5-fold, respectively, under occlusion vs.
non-occlusion in human subjects. Similar penetration
profiles have been documented with 14C-radiolabled pes-
ticides, Azodrin and Malathion, which increased 3- and
10-fold, respectively, under occlusive conditions (81).
Occlusion also enhances permeation of volatile chemicals
in vivo as determined by Bronaugh et al. (82). Fragrance
materials, safrole and cinnamyl anthranilate, cinnamic
alcohol, and cinnamic acid were compared in occluded
and non-occluded application sites. The authors found
that occlusion of skin resulted in greater permeation of
all the compounds. By preventing evaporation, 84% of
applied cinnamic acid and 75% of cinnamic alcohol were
absorbed compared with 39% and 25%, respectively.
Skin health and integrity
There is substantial research demonstrating that a com-
promised skin barrier plays a role in atopic dermatitis
and other skin diseases like psoriasis, eczema, and ich-
thyosis. Tsai et al. (83) assessed barrier disruption on the
permeability of compounds with various lipophilicities.
Using acetone-disrupted hairless mouse skin as a model
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membrane, the authors showed that both hydrophilic
and amphipathic compounds, including sucrose, caffeine
and hydrocortisone, had increased permeability in vitro.
These findings coincide with the conventional under-
standing that hydrophilic molecules have the greatest
enhancement of penetration under conditions of physical
or chemical insult (84).
Exposure factors that alter
­percutaneous penetration
Many variables affect the percutaneous penetration of
exogenous substances contacting the skin. Increases
in concentration of applied dose, surface area, multiple
dose-applications, and duration of contact can all esca-
late the body burden of a chemical.
Yeung et  al. (85) performed both in vivo (rhesus
monkeys) and in vitro (excised human skin) studies and
found that percutaneous absorption of topically applied
BA increased in accordance with increasing drug con-
centration. These results are in accordance with those of
other studies, which demonstrated a direct relationship
between topical dosage and percutaneous absorption
(86,  87). For some compounds, however, the absorptive
capacity of skin can become saturated at relatively high
dosages (88). Repeated application of a topical compound
to saturated skin then results in resistance to further pen-
etration from ensuing doses. Wester et al. (89) studied the
effect of application frequency on percutaneous absorp-
tion of hydrocortisone in rhesus monkeys. They found
increased absorption using a single, highly concentrated
dose compared with the equivalent amount of drug
divided into separate smaller doses.
Time exposure is also an important factor when
assessing the percutaneous penetration potential of a
substance. Short-term in vitro skin exposure can result in
significant absorption. Application of malathion, followed
by immediate washing with soap and water resulted in the
persistence of 10% of the total applied dose, which was
later absorbed into the body (90). Washing 25 min post-
application of benzo[a]pyrene and dichlorodiphenyl-
trichloroethane (DDT) showed similar results, with some
benzo[a]pyrene and all of the DDT eventually absorbed
into the skin. These findings reinforce the notion that
although early washing is helpful, it may not provide com-
plete decontamination (91).
Sved et al. (92), meanwhile, shed light on the role of
surface area in percutaneous penetration. They noted
that as the surface area of an applied dose of nitroglycerin

increased, the total amount of material absorbed and the
systemic availability of nitroglycerin also increased. Per-
cutaneous absorption studies by Wester and Noonan later
confirmed these findings by showing that surface area of
applied dose relative to body weight determines systemic
availability of a topical compound (88).
Physiochemic properties of the
penetrant
Absorption of chemicals across the skin is dramatically
influenced by the physiochemic properties of the pen-
etrant. Quantitative structure-permeability relationship
models (QSPR) developed in recent years compare passive
percutaneous penetration of exogenous compounds in
vitro with their physiochemical characteristics (93–95). In
general, molecular weight, hydrophobicity (as measured
by the octanol-water partition coefficient, Ko/w), dissoci-
ation constant (pKa), solubility in polar and nonpolar sol-
vents, melting point, and hydrogen bonding are the most
influential variables (96–98).
Studies have shown more pronounced dermal pen-
etration in lipophilic molecules of low molecular weight
( < 500 Dalton) due to the stratum corneum’s composition
of intercellular lipids surrounded by keratin-filled corneo-
cytes (99). The partition coefficient is useful in estimating
the potential distribution of a chemical in skin because it
describes the ratio of concentrations of an un-ionized com-
pound between a mixture of two immiscible solvents (100).
Increasing hydrophobicity of chemicals leads to a linear
increase in octanol/water partition coefficients, which
in turn, favor absorption through the lipid-rich stratum
corneum. Studies by Feldmann and Maibach and Bucks
et al. demonstrated that this holds true until a cutoff point
is reached. By investigating the percutaneous penetra-
tion of multiple steroids with differing lipophilicities, they
observed a reduction in absorption of compounds with
lipophilicities extending beyond log Po/w > 3 (77, 101). In
contrast, polar molecules have increased interactions that
hinder complete penetration through the skin (102).
Vehicle effects
The way in which a chemical is introduced to the skin sub-
stantially impacts the rate of dermal penetration. Vehicles
(formulations) that alter the structure of the lipophilic
domains in the stratum corneum can enhance flux of a
chemical or drug molecule through the skin (103). Biologic
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Blickenstaff et al.: Biology of percutaneous penetration      151
factors like chemical solubility and concentration as well
as skin pH all influence the percutaneous penetration of
a chemical and its ability to partition between the vehicle
and stratum corneum (104).
Chemical-vehicle-skin interactions create a concen-
tration gradient, which influences the solubility of a com-
pound in its vehicle, as well as the chemical’s ability to
partition into and diffuse through the skin barrier. The
lipophilic stratum corneum favors partitioning of lipo-
philic substances over water; therefore, when the vehicle
is in water, the partition coefficient increases with increas-
ing solute lipophilicity (105). In contrast, stratum corneum
proteins are more polar than octanol, favoring percutane-
ous absorption of hydrophilic chemicals (106). Hilton et al.
examined vehicle effects on in vitro percutaneous absorp-
tion through human and rat skin. They demonstrated that
the lower the solubility of a compound in its vehicle, the
greater the potential for the compound to partition out of
the vehicle and into the skin, leading to faster absorption
of the compound (103). The distribution of chemical in
the skin layers increases as partitioning increases until all
chemical binding sites are saturated. Once this threshold
is reached, concentration of unbound chemical increases
while the partition coefficient decreases. Stratum corneum
pH further influences the binding rate of chemicals by dic-
tating the ionization of a compound. Less ionization of a
chemical occurs in vehicles with lower pH values. In turn,
this increases the binding rate of chemicals with a positive
lop P, thus allowing lipid membrane permeation to occur
more readily. The opposite is true for high pH values, as
chemicals with a negative log P are favored (107).
Additionally, many topical pharmaceutic formula-
tions utilize chemicals like surfactants and solvents to
stabilize the product and enhance skin penetration of
other compounds present in the formulation. These pen-
etration enhancers are usually small, pharmacologically
inert molecules with the ability to increase the range of
compounds that can be effectively delivered through the
skin by increasing fluidity of the lipid bilayer. Altering
the highly ordered lipid bilayers with enhancers lessens
the diffusional resistance of the stratum corneum to most
solutes, thereby improving dermal absorption (108). High
throughput methodologies have been developed to iden-
tify and quantify the effects of chemical mixtures on per-
cutaneous absorption (109–111).
Wash effect
Skin decontamination is a major focal point in der-
matotoxicology. When chemical exposure occurs,
152      Blickenstaff et al.: Biology of percutaneous penetration
decontamination methods reduce penetration and mini-
mize skin damage, especially following contact with cor-
rosive and systemically toxic chemicals. Washing with
soap and water is the most commonly employed decon-
tamination method, and has been shown to decrease the
percentage of absorbed contaminant dose by more than
50% in human and rats (112). However, this is not the
most effective decontaminant solution for all chemicals
(113), as hydrophobic chemicals are thought to be more
easily removed by lipid solvents like methanol. Efficacy of
decontaminant solutions in removing chemicals from the
skin is quite variable (114) due to the physiochemical dif-
ferences that alter chemical affinity for stratum corneum
binding sites.
Another challenge to effective decontamination sur-
rounds the unintended consequence of “wash-in” effect,
where instead of washing chemical contaminants off the
skin, chemical is washed into the skin. This enables chem-
icals to remain in the skin and become bioavailable via
the cutaneous blood supply, increasing both local cutane-
ous and general systemic toxicity (115). Surfactants have
been attributed to this “wash-in” effect, which have been
associated with delipidation, membrane irritation, skin
irritation, and increased water permeability in human
skin. When taken collectively, much work remains to be
done before the perfect decontamination practices can be
recommended.
Conclusion
Percutaneous penetration involves the transport of a
chemical through the outer stratum corneum and remain-
ing epidermal layers, into the vascularized dermis where
it can be absorbed into systemic circulation. This is an
extremely interesting and challenging process, influenced
by multiple skin, chemical, and environmental factors.
Improving our knowledge of percutaneous penetration
is essential for advancing the fields of dermatotoxicol-
ogy and dermatopharmacology. Although research over
the last few decades has provided an abundance of new
insights to improve our understanding of percutaneous
penetration, many areas lack clarity due to conflicting
data.
Future studies on barrier function and dermatop-
harmacokinetics as a function of skin aging, the meta-
bolic processes of chemicals within skin, and the ways
by which we can optimize decontamination methods are
needed to expand our comprehension of the biological
factors guiding percutaneous penetration.
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