FIGURE 3.1 Schematic of epidermis. The basal cell layer is the deepest layer of the epidermis differentiating to spinous cells then to granular cells and eventually terminally differentiating to stratum corneum.
The SC is the outer layer of the epidermis and serves as the main functional barrier. A theoretical model is a brick-and-mortar-like structure where bricks represent terminally differentiated nonviable keratinocytes, also known as corneocytes, embedded in intercellular lipid membranes (3). As corneodesmosomes (protein bridges between corneocytes) degrade, lacunar spaces are created within the SC referred to as an aqueous pore pathway. These spaces can extend and form continuous networks, creating a pathway for penetration across the SC (4).
The major components of the SC lipid membranes are free fatty acids, ceramides, and esterols (5). Melanocytes are neural crest-derived, pigment-synthesizing dendritic cells that reside primarily in the basal layer. Merkel cells are mechanosensory receptors also present in the basal layer. Langerhans cells are dendritic antigen-processing and antigen-presenting cells in the epidermis (6). They form 2–8% of the total epidermal cell population, mostly found in a suprabasal position. The dermal–epidermal junction (DEJ) is a basement membrane zone that forms the interface between the epidermis and the dermis. The major functions of the DEJ are to attach the epidermis and dermis to each other and to provide resistance against external shearing forces.
Dermis
The dermis is an integrated system of fibrous cellular and acellular matrices that accommodates nervous and vascular structures as well as epidermally derived appendages. Many cell types reside in the dermis including fibroblasts, macrophages, mast cells, and circulating immune cells. The dermis is responsible for skin elasticity, pliability, and tensile strength. It provides protection against mechanical injury, retains water, and aids in thermal regulation. It also contains and supports receptors of sensory stimuli and is a key element in wound healing (7).
Hypodermis
The hypodermis is primarily composed of adipose tissue, which insulates the body and serves as a reserve energy supply. It cushions and protects the skin and supports nerves, vessels, and lymphatics located within the septa, supplying the overlying region.
Skin Appendages
Skin appendages include nails, hair, sebaceous glands, eccrine (sweat) glands, and apocrine glands. They have two distinct components: superficial and deeper components in the dermis, which are downgrowths of the epidermis. The dermal component regulates differentiation of the appendage. During embryonic development, dermal–epidermal interactions are critical for the induction and differentiation of these structures.
Skin as a Route of Entry
The SC is 3–20 μm in thickness, composed of 15–25 layers of corneocytes. It provides an effective barrier against transcutaneous water loss and entry of exogenous materials.
Extracellular lipids contribute to the barrier function and the route taken through the SC by all molecules. Arrangement of extracellular lipids, their hydrophobicity, their composition, and distribution of key components (ceramides, cholesterol, and free fatty acids) provide more barrier function (8). Skin absorption varies between different body parts and between individuals; these regional intra- and inter-individual variations are partly related to variations in lipid composition and SC thickness (8). A range of biological factors can influence the rate and extent of percutaneous penetration including the anatomical site, age, appendageal density, SC morphology, and composition. Routes through which chemicals can cross the SC (Figure 3.2) include the following (9):
• Intercellular (or extracellular), in which chemicals pass exclusively through the lipid matrix
• Intracellular or transcellular, in which chemicals pass both through the lipid matrix and through the corneocytes themselves
FIGURE 3.2 Schematic pathways of penetration into the skin with arrangement of corneocytes in a brick-and-mortar model.
• Through skin appendages
• Mechanical methods to remove SC such as stripping, ablation, and microneedles
In vivo measurement of skin absorption to quantify and rate the extent of absorption is of fundamental importance in the risk assessment of compounds that are active via the dermal route of entry, although the details are beyond the scope of this chapter. The skin as part of the somatosensory system is reviewed in the following chapter.
Measuring the Skin
Measuring the physical characteristics of the skin using biophysical instruments provides key information about various skin parameters. Many noninvasive techniques and equipment are available with increasing applications within dermatotoxicology, allowing the study of the skin in real time and providing objective, quantitative data, which can also be used in the evaluation of individuals affected by sensitive skin.
Parameters measured with these techniques provide information about a particular aspect of the skin. Using multiple parameters measured simultaneously, along with clinical assessment, provides more of a comprehensive analysis. Histological studies may be used to complement these analyses. Few parameters and techniques are briefly introduced in this chapter, and additional texts are available for comprehensive study (10,11). Raman spectroscopy is discussed in detail later in the book.
Skin Surface pH
Skin pH is normally acidic, ranging in pH values of 4–6, while the pH in the internal environment of the body is near neutral, ranging from 7 to 9 (12). The term acid mantle refers to the inherent acidic nature of the SC. Skin pH affects barrier function and SC cohesion. The elevation of pH in the normal skin creates a disturbed barrier (13). Measurement of skin surface pH is used to assess the acidity of the surface of the skin, which can vary according to the time of the day, the skin site, and between individuals. There are several instruments available for the measurement of skin pH; basically, any standard, portable pH meter with a planar electrode should suffice.
Sebum
Sebum is a light yellow viscous fluid, composed of triglycerides, free fatty acids, squalene, wax and sterol esters, and free sterols. Sebum is produced by sebaceous glands and contributes to moisture balance in the SC. Sebum production is mainly influenced by androgens and varies among individuals and races, but its average rate in adults is approximately 1 mg/10 cm2 every 3 hours (14). Sebum production less than 0.5 mg/10 cm2 every 3 hours is associated with dry skin, and values of 1.5–4.0 mg/10 cm2 every 3 hours are associated with seborrhea (15
