03/30/22 Toxicology of Toxicology of the Skin the Skin Leena A. Nylander-French, Ph.D., CIH 159 Rosenau Tel: 966.3826 E-mail: [email protected] Science that studies adverse skin effects and the substances that produce them
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Toxicology of the SkinToxicology of the Skin
Leena A. Nylander-French, Ph.D., CIH159 RosenauTel: 966.3826E-mail: [email protected]
Science that studies adverse skin effects and the substances that
produce them
Prevalence of Skin DiseasePrevalence of Skin Disease
Occupational skin diseases are the second most common types of occupational disease
45,000 reported cases of occupational skin disease in 2002
15% of all occupational diseases in the US 1983-1994 occupational skin diseases
increased by 26% and 75% of workers with occupational skin disease developed a chronic skin disease
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Prevalence of Skin DiseasePrevalence of Skin Disease
Greatest number of occupational skin disease cases occur in the agricultural and manufacturing industries
Occupational skin diseases are believed to be severely underreported and the true rate may be many fold higher
Estimated total annual costs (including lost work days and loss of productivity) associated with occupational skin disease may reach $1 billion
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Acetone 600 µmol Ethyl Acrylate
60 µmol TPGDA 1.25 µmol TPA
Introduction to:Introduction to:
Structure and function of the skin Percutaneous absorption Metabolism Allergic contact dermatitis
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Functions of the Skin Functions of the Skin
Environmental barrier– diffusion barrier
– metabolic barrier Mechanical support Neurosensory reception
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Functions of the SkinFunctions of the Skin
Physiologically, skin participates directly in– thermal regulation
regulation of blood flow, hair and fur, sweating
– metabolism keratin, collage, melanin, lipids, and vitamin D
synthesis, respiration and biotransformation
– electrolyte and hormonal regulation apocrine/eccrine/sebaceous glandular secretion endocrine function
– immune regulation
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HormonesHormones Hormones (chemical messengers) secret into
blood or extracellular fluid by one cell that affect the functioning of other cells
Endocrine action– distribution in blood and binding to a distant target
Paracrine action– acts locally by diffusing from
its source to target cells in the neighborhood
Autocrine action– acts on the same cell that produces it
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Structure of the SkinStructure of the Skin
Dermal surface area 1.5-2 m2
Two major components, separated with a basement membrane– epidermis (outer layer)
– dermis (underlying epidermis)
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Dermis
Hypodermis
Epidermis
The Major Structures of the SkinThe Major Structures of the Skin
04/21/23Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.
Diagram of a Cross Section of Human Diagram of a Cross Section of Human SkinSkin
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EpidermisEpidermis
Stratified squamous epithelium Keratinocytes the major cell type
– > 90% of all cells Programmed process of differentiation Divided into several layers based on the state
of keratinocyte differentiation
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Structure of the EpidermisStructure of the Epidermis
04/21/23Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.
Schematic of the Stratum CorneumSchematic of the Stratum Corneum
04/21/23Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.
Cell Types in Epidermis Cell Types in Epidermis
Keratinocytes Merkel cells
– type I mechanoreseptor (sensory reception) Melanocytes
– pigment-producing (melanin granules) cells that originate in the neural crest
Langerhan’s cells– bone marrow derived antigen presenting cells that
are localized in the viable epidermis
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DermisDermis
Largest fraction of the skin– approximately 90%
Provides structural strength– high content of collagen and elastin
Nerve and vascular networks and appendages required to support the epidermis
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The Major Structures of the SkinThe Major Structures of the Skin
04/21/23Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.
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Eccrine GlandEccrine Gland
Thermoregulation Eccrine unit consists of
– intraepiermal spiralled duct– coiled and straight intradermal duct– secretory coiled gland
Highest density on palms, soles, and axillae Clear sells secrete glycogen, water, and
electrolytes Dark cells secrete sialomucin
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Apocrine GlandApocrine Gland
Function unclear– acne
Sialomucin More viscous and produced
less than eccrine sweat Apocrine unit consists of
– secretory coiled gland– straight duct which traverses the
dermis and empties into the isthmus of a hair follicle
1. Papillary Layer1. Papillary Layer
Underlies the epidermis Fibroblasts Major synthetic product is type III collagen Organized into small fiber bundles that
contrast with the larger type I collagen fiber bundles found in the reticular dermis
Collagenase activity
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2. Reticular Layer2. Reticular Layer
Superficial to the hypodermis Composed primarily of type I collagen;
organized in large fibrillar bundles Contains large, fully matured elastic bundles
that extend between the collagen fiber bundles
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Cell Types in Dermis Cell Types in Dermis
Fibroblast Macrophages
– phagocytize and neutralize foreign cells and chemicals
– process and present antigen to immunocompetent lymphoid cells
Mast cells– respond to light, cold, acute trauma, vibration, and
pressure
– initiate chemotaxis or vasodilation
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HypodermisHypodermis Layer of mesenchymally derived adipose cells
that form the connective tissue layer of the reticular epidermis
Innermost layer of the skin Provides cushion between the external skin
layers and the internal structures such as bone and muscle
Energy reserve Allows for skin mobility and molds body
contours Insulates the body
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Metabolism of XenobioticsMetabolism of Xenobiotics
Most foreign compounds are lipophilic and able to penetrate lipid membranes and to be transported by lipoproteins in the blood
These lipophilic compounds are substrates for biotransforming enzymes
Epidermis is the major site in the skin for metabolism of xenobiotics, steroids, and vitamins
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Metabolism of XenobioticsMetabolism of Xenobiotics
After invasion, the xenobiotic substance is first chemically activated (usually by oxidation)– phase I metabolic reaction, where a polar reactive
group is introduced into the molecule, rendering it a suitable substrate for phase II metabolism
– cytochrome P-450 isoenzymes localized mainly in the endoplasmic reticulum (microsomal
fraction) activities about 1-5% of those in the liver
Pre-carcinogenic chemicals can be converted to carcinogenic metabolites
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Metabolism of XenobioticsMetabolism of Xenobiotics
Activated metabolite is transformed by phase II enzymes (transferases, reductases) to highly hydrophilic metabolites, which are more readily excreted– all major transferases are found in the skin (about
10% of hepatic activities)
– NAD(P)H-quinone reductase (NQR)
– epoxide hydrolase
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Metabolism of XenobioticsMetabolism of Xenobiotics
Some compounds (e.g., electrophiles that undergo nuclear substitution) are not transformed by phase I enzymes but react directly at the site of contact; ultimately eliminated by phase II enzymes– e.g., mono- and multifunctional acrylates
Skin metabolizing enzymes differ both quantitatively and qualitatively from those in the liver, particularly by their relative proportions, composition, and interactions
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Schematic of Metabolism of Xenobiotics in the SkinSchematic of Metabolism of Xenobiotics in the Skin
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DrugOr
Xenobiotic
Active Xenobiotic(e.g., epoxides)
Elimination
Binding to Macromolecules(e.g., membranes, proteins, DNA, RNA)
Chemocarcinogenesis, Mutagenesis,Teratogenesis, Sensitization
Transferases,Epoxyhydrase,
NQRP-450
Marzulli, F.N. and Maibach, H.I., 1996. Dermatotoxicology, 5th ed. Taylor & Francis, Washington, DC.