ARTICLE
Auteur(s) : C. Piérard-Franchimont, P. Quatresooz, E.
Berardesca, G. Plomteux, G.E. Piérard.
Introduction
The skin plays many roles important for life. One of the most
vital is its barrier function between a constant internal milieu
and the potentially hostile outside environment. Many other major
professional groups, including toxicologists, internists,
environmental scientists, pharmacologists, oncologists and
microbiologists have joined with dermatologists to study this
interplay.
The major impetus to study various environmental effects has been
the dramatic rise in incidence in disorders resulting from
interaction between the environment and the skin. Skin cancers,
various forms of dermatitis and exotic infections are forcing their
attention on physicians. This has generated a general concern
particularly in Europe. Alterations in the earth’s atmosphere and
in the range and nature of chemical substances and microorganisms
that contact human skin appear responsible. Most of these
alterations are man-made and in part due to changed changing social
and economic patterns.
Two major types of threats to the skin can be distinguished.
Physical damage includes trauma and electromagnetic radiation
including ultraviolet light. The other category includes chemical
insults by exogenous compounds called xenobiotics. The uppermost
part of the skin – the stratum corneum – is the main barrier
against xenobiotics. Dermatologists have long studied the barrier
function of the stratum corneum.
Skin barrier structure and function
Forming the interface with a desiccating external environment,
the stratum corneum retards evaporative water loss from the
internal milieu of the body. The stratum corneum also protects
against mechanical insults and the ingress of xenobiotics and
microorganisms. It also provides the first line of defense against
ultraviolet light, screening out most ultraviolet B irradiation.
The stratum corneum is about 10 μm thick and consists of
flattened, dead keratinocytes, called corneocytes, each of them
surrounded by lipid layers. It has been likened to a brick wall,
with its cells as bricks and the lipids as mortar. The stratum
corneum is critical for maintaining the water balance. When it is
completely removed, there is free evaporation, identical to that
from an open water surface, while under normal circumstances the
skin barrier only allows a limited, controlled evaporation. The
rate of evaporation from the skin, commonly termed trans-epidermal
water loss (TEWL), is a sensitive indicator of the skin barrier
function, which can be measured in a non-invasive, objective and
standardized way.
The intercellular lipids, rather than the cells, play the crucial
rule in the water-retaining function of the skin barrier.
Selectively removing only the lipids from the stratum corneum leads
to free evaporation. The composition of the barrier lipids is
unique and quite different from the lipid composition found in
membranes elsewhere in the body. Three main types of fatty
substances (cholesterol, ceramides and free fatty acids) make up
90% of the total amount of barrier lipids. These lipids are
produced in lamellar bodies, small intracellular organelles within
keratinocytes, which discharge their contents into the
intercellular spaces to establish the barrier. Skin barrier
problems are a feature of many common skin disorders and may
actually be the critical stimulus initiating the inflammatory
response. Damage to the skin barrier in itself results in release
of pro-inflammatory cytokines, but as the damage also leads to
increased penetration of allergens and irritants, a deficient skin
barrier also sustains an ongoing inflammatory process.
Consequently, skin barrier problems are a critical factor in many
kinds of dermatitis.
The skin barrier is continuously maintained through homeostatic
processes. Everyday wear-and-tear, such as frequent washing of
hands, and wet work may damage the barrier. The resulting increase
in TEWL stimulates the skin to initiate barrier repair, which
consists of release of the lipid content of preformed lamellar
bodies and acceleration of the lipid synthesis. The result is a
gradual normalization of TEWL, provided there are not problems with
the synthesis of the lipids. If the necessary lipids cannot be
synthesized, TEWL remains continuously elevated, and the result is
chronic dry skin. This can be due either to an inborn defect in the
synthesis of one or more of the crucial lipids, a dietary
disturbance or even a temporary phenomenon, such as the typical dry
skin during winter.
There are two main types of cutaneous reactions to environmental
challenges. Both can appear clinically similar. Irritant contact
dermatitis (ICD) results from direct damage to the skin caused by
exogenous agents. Every person who encounters a toxic substance in
a high enough concentration experiences some damage. Examples from
daily life might include harsh soaps, acid added to swimming pools
or many industrial exposures. In contrast, allergic contact
dermatitis (ACD) only involves a limited number of individuals, is
not concentration-dependent, and requires a period of
sensitization.
Every day the skin is exposed to hundreds of xenobiotics. These
include both naturally- occurring and synthetic substances in the
environment, workplace and home. Skin exposure to xenobiotics may
be accidental or deliberate, but in most cases, normal everyday
skin exposures do not present a toxicological risk. Some chemicals
are local irritants, while others are more often allergens. Some
substances elicit first an irritant dermatitis and then later an
allergic form.
Irritant contact dermatitis. Two different pathways may be
involved in ICD. Acute ICD is characterized by an inflammatory
reaction that mimics the typical expression of ACD, and is
associated with the release of inflammatory mediators and
cytokines. Chronic ICD is characterized by disturbed barrier
function, associated with increased epidermal turnover leading
clinically to lichenification (thickening of the epidermis).
Irritation normally starts at the level of the stratum corneum and
later involves the dermis, whereas the inflammation of
sensitization starts in the dermis.
The variations in the skin reactions are dependent on the degree
of injury induced, as well as on the effect of an irritant
substance on different cell populations. The physicochemical
characteristics, the concentration, volume and contact time of the
irritant influence the skin response. Furthermore, inter-individual
differences exist based on age, gender, skin typology, previous
skin disease and a range of genetic factors. In a given individual,
reactivity differs according to the skin thickness and body region.
Subjects suffering from atopic dermatitis, seborrheic dermatitis,
or with sensitive skin are reported to be more susceptible to
irritants. Testing for skin irritation can be helpful in monitoring
these conditions and identifying patients at risk for irritant
contact dermatitis and/or with sensitive skin.
Allergic contact dermatitis. ACD is a form of delayed Type
IV T-cell-mediated hypersensitivity. This condition follows skin
contact with small allergens that penetrate into the skin. The skin
response is a two-step reaction. The first or sensitization phase
occurs when the body generates a circulating population of
antigen-specific memory T cells following exposure to a substance.
The second or elicitation phase occurs 48-72 hours after subsequent
re-exposure to the same substance, but only in sensitized
individuals. Elicitation involves cellular infiltration into the
epidermis that results into a cutaneous inflammatory reaction
characterized by erythema, edema and vesiculation.
Occupational contact dermatitis. Both ICD and ACD combine
to account for 90% of occupational dermatoses. Occupational contact
dermatitis is the most prevalent of all occupational diseases in
many countries. In western Europe, occupational contact dermatitis
represents about one-third of all registered occupational
diseases.
Surfactants and the consumer. Surfactants are potentially
irritant agents that each of us encounters daily. Because of their
detergent and foaming properties, surfactants find broad use in
many domestic products (cosmetics and toiletries, cleansing
products, laundry products). Many surfactants are classified,
according to the Dangerous Substance Directive (DSD), as irritant
for the skin and for the eyes [53]. It is not always clear why
ingredients identified as “irritants” are incorporated into
consumer products. Such a classification of surfactants is based on
the hazards linked to the individual substances (intrinsic
irritation properties), and does not take into account the
interaction between the ingredients of the product. The rules about
informing consumers about potential risks of irritation differ with
the product type, with substantial differences between cosmetics as
compared to household cleansers and detergents.
Different solutions exist to develop non-irritating
surfactant-based products. Careful selection of the mildest
surfactants is important. Combination of several adequate
surfactants may also be effective. Nonionic surfactants are
generally considered as the mildest, even if several of them are
classified as skin or eye irritant by the DSD, and are usual
ingredients in body cleansing products for babies, for sensitive
skin or for face-cleansing products. They are also the usual
ingredients in dishwashing liquids for sensitive skin or in
all-purpose cleaners for hard surfaces.
Several anionic surfactants are also well-tolerated by the skin.
They are also regularly used in facial cleansers or products for
baby care. These very mild anionic surfactants are rarely used in
household cleansers, as they clean poorly. Amphoteric surfactants
are never used alone, but rather in combination, and they play no
role in determining the irritation potential of the finished
product. Cationic surfactants are usually used for their
antibacterial properties rather than their surface tension
properties. While some are quite irritating, there are others which
are mild and well-tolerated.
The best way to reduce the irritant effects of surfactants is to
combine several different agents with varying properties. Thus the
consumer should not be dismayed by long lists of surfactants on
package labels. Other additives are possible, but usually less
desirable, because of factors such as increased costs or reduced
consumer acceptance.
Consumers and cosmetic products. The European Cosmetic
Directive (76/768/EEC) [54] states that the manufacturer or the
person responsible of marketing of a cosmetic product must keep
readily accessible to the competent authorities, for control
purposes, the information concerning the assessment of the safety
for human health of the said finished product. Existing data, if
any, on undesirable effects on human health resulting from use of
the cosmetic products must also be accessible to the authority.
This means that the information regarding the safety of the product
exists but is not directly accessible to the consumer.
Nevertheless, many cosmetic products make label claims of mildness,
skin compatibility or similar virtues; these must be scientifically
proven. With the seventh amendment of the Cosmetic Directive [51],
the situation in Europe will change. After 11 September 2004,
product information will have to be readily accessible to the
public, but it will not have to be present on the label.
Consumers and household cleansers. Whenever a household
cleanser or laundry detergent is a potential skin irritant, the
consumer should be informed on the product label about such a
health hazard. This is done by printing a Saint –Andrew cross, and
a “R-38 skin irritant” symbol on the label or package. The
Dangerous Preparation Directive (DPD, 1999/45/EC) [52] indicates
which products must carry such warnings and defines two basic
procedures for assessing health hazard, and in this case skin
irritation hazard:
1) Conventional calculation method which states that if 20%
or more of ingredients of a finished product are classified as skin
irritants, the product should be classified as “skin
irritant.”;
2) Toxicological determination of the skin irritation
properties of the product by testing.
In addition the DPD requires that if data on humans are available
(e.g. epidemiological surveys, Poison Center data, human
studies), they should be taken into account for the classification,
especially if the data are different from those generated by one of
the two former methods. This requirement is especially important
since toxicological studies on animals are out of favor and do not
always reflect the skin responsiveness in man. In addition, the
calculation method sums all classified ingredients without taking
into account interactions between surfactants which reduces their
irritation potential. The calculation rule often leads to an
over-labeling of finished products as skin irritants.
The absence of the warning label on the product does not exclude
the possibility that some transitory discomfort may occur in
consumers with sensitive skin or after repetitive use. Products
that are not “skin irritants” may also display different levels of
mildness. Well- substantiated skin compatibility claims and
personal experience should allow consumers to choose the most
appropriate products.
Skin and toxic hazards
The percutaneous resorption of xenobiotics results from the
transfer of a chemical from the environment to the blood.
Understanding intoxication following skin contamination calls for
knowledge of the modalities of resorption and diffusion of
xenobiotics through the skin. The ingress of xenobiotics through
the stratum corneum is a passive diffusion process. Two main routes
of penetration can be followed. One way follows the cutaneous
appendages including the hair follicles and the sweat glands. The
other way is transepidermal penetration, either through the
hydrophilic corneocytes or the lipophilic intercellular layers.
Once below the stratum corneum barrier, any toxic compound finds
its way through the living epidermis and in the dermis where it is
resorbed by blood and lymph. The same process occurs with any kind
of topically applied drug.
The percutaneous resorption varies according to a series of
parameters depending upon the size and the physicochemical
properties of the xenobiotic. It also depends on the quality of
skin. Regional differences in absorption are recognized over the
body. The integrity and degree of hydration of the stratum corneum
are also of importance. The coefficient of partition of the
compound between its vehicle, if any, and the stratum corneum, as
well as the time contact of the compound with the skin play
additional roles in the whole complex process.
In many skin disorders, the barrier function is compromised. This
is particularly important to consider in babies who have an
unfavorable ratio between the potential skin area of resorption and
the body volume. Higher body concentrations of toxic xenobiotics
can accumulate in infants. Another example of higher risk is
encountered in some occupational settings where mild abrasions of
the skin are common and occupational dermatoses are prevalent.
Manipulation of toxic compounds is more risky in these conditions
if adequate protection is not maintained.
Conclusion
In many circumstances, environmental xenobiotics pose a threat
to the skin and thus to the individual. While the stratum corneum
barrier function usually offers a high degree of protection, it can
be breached by both physical and chemical damage. The consequences
for workers and consumers can be considerable, so that both
continuing research and a refined regulatory approach are needed to
minimize the social and economic effects of a disturbed interaction
between the skin and the environment.
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