Combined Actions and Interactions of Chemicals in Mixtures

Dermis
The dermis consists of a supportive connective tissue composed mainly of collagen
fibres together with elastic fibres in a matrix of glycosaminoglycan, salt and water.
The dominant structural elements are synthesised by the dermal fibroblasts. The
dermis also contains blood vessels, nerves, hair sacs, sebaceous glands and sweat
glands. The three latter structures may act as an alternative "shunt" in the
percutaneous absorption of chemicals. The dermis is stretching up papillae in
epidermis, providing the viable epidermis with essential nutrients and draining it for
waste products and penetrants. The viable epidermis and the dermis also constitute a
permeability barrier, primarily against lipophilic substances.
7.1.2.2 Percutaneous absorption
Absorption of chemicals through the skin involves several individual transport
processes, including adsorption to the surface of the stratum corneum, passive
diffusion through this barrier, desorption into the viable epidermis, diffusion
through this part of the epidermis and the papillary dermis, and ultimately transfer
into the blood circulation. It has been demonstrated that the rate-limiting event for
dermal absorption of xenobiotics in undamaged skin in most cases is the passive
diffusion through the stratum corneum. The stratum corneum can be considered
morphologically and functionally to represent a two-compartment system
consisting of corneocytes largely composed of fibrous protein networks in an
intercellular matrix, predominantly composed of neutral lipid.
Although not considered totally impermeable to neither water nor lipid soluble
compounds, the intact stratum corneum layer is in practice impermeable for large
molecules (MW>500). Among compounds of lower molecular weight, the best skin
penetrants are soluble in both lipid and water. The major pathway for penetration
appears to be through regions with a high lipid content (the intercellular matrix), and
within series of similar substances the rate of penetration often correlates with their
water/lipid partition coefficients. Hydrophilic substances may penetrate through the
protein-rich, hydrated intracellular regions. Some absorption may occur through
"shunts" (hair follicles and sweat ducts), but the transdermal flux through this pathway
is considered to be minimal. However, for very lipophilic and large molecules
together with electrolytes, the alternative shunt seems to be important for penetration.
Highly lipophilic substances may penetrate the stratum corneum easily, and for such
compounds the viable epidermis and dermis may be the rate-limiting barrier.
7.1.2.3 Test systems
Skin irritancy is most often studied in animal experiments or in studies with human
volunteers. Skin organ cultures with human or animal skin have been used to model
effects of chemical irritants (van de Sandt and Rutten, 1995). Preliminary results
obtained with reconstructed human epidermal tissue cultures hold promise as future
test systems (Coquette et al., 1999; De Burgerolle de Fraisinette, A. et al. 1999).
Compounds or factors that can modulate the barrier function of the stratum corneum
may dramatically affect the effects of dermal irritants. Hydration and delipidization
are known to decrease the barrier function of the stratum corneum. Hydration plays an
extremely important role in the rate of absorption of materials through the skin. In
normal skin, a gradient in water concentration exists through the tissue corresponding
to an average concentration of 0.9 g of water per gram of dry tissue. In vitro studies
have demonstrated that this amount of water increases the rate of absorption of
various materials approximately 5-10 fold compared to dry skin. The stratum corneum
can ultimately absorb three to five times its own weight of water, and this further
hydration may results in an additional 2-3 fold increase in the rate of absorption of
water and other polar molecules (Wester & Maibach 1985). Extraction of lipids from
the skin by delipidization with organic solvents appears to decrease the barrier effect
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