* Toxicology of the Skin Leena A. Nylander-French, Ph.D., CIH

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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

05/02/23Mukhtar, 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

05/02/23Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.

Schematic of the Stratum CorneumSchematic of the Stratum Corneum

05/02/23Mukhtar, 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

05/02/23Mukhtar, 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.