1. 11/14/2015 Toxicology of the Skin Leena A. Nylander-French, Ph.D., CIH 159 Rosenau Tel: 966.3826 E-mail: leena_french@unc.edu Science that studies adverse skin effects and the substances that produce them

2. Prevalence of Skin Disease l Occupational skin diseases are the second most common types of occupational disease l 45,000 reported cases of occupational skin disease in 2002 l 15% of all occupational diseases in the US l 1983-1994 occupational skin diseases increased by 26% and 75% of workers with occupational skin disease developed a chronic skin disease 11/14/2015

3. Prevalence of Skin Disease l Greatest number of occupational skin disease cases occur in the agricultural and manufacturing industries l Occupational skin diseases are believed to be severely underreported and the true rate may be many fold higher l Estimated total annual costs (including lost work days and loss of productivity) associated with occupational skin disease may reach $1 billion 11/14/2015

8. Acetone 600 µmol Ethyl Acrylate 60 µmol TPGDA 1.25 µmol TPA

9. Introduction to: l Structure and function of the skin l Percutaneous absorption l Metabolism l Allergic contact dermatitis 11/14/2015

10. Functions of the Skin l Environmental barrier –diffusion barrier –metabolic barrier l Mechanical support l Neurosensory reception 11/14/2015

11. Functions of the Skin l Physiologically, skin participates directly in –thermal regulation l regulation of blood flow, hair and fur, sweating –metabolism l keratin, collage, melanin, lipids, and vitamin D synthesis, respiration and biotransformation –electrolyte and hormonal regulation l apocrine/eccrine/sebaceous glandular secretion l endocrine function –immune regulation 11/14/2015

12. Hormones l Hormones (chemical messengers) secret into blood or extracellular fluid by one cell that affect the functioning of other cells l Endocrine action –distribution in blood and binding to a distant target l Paracrine action –acts locally by diffusing from its source to target cells in the neighborhood l Autocrine action –acts on the same cell that produces it 11/14/2015

13. Structure of the Skin l Dermal surface area 1.5-2 m 2 l Two major components, separated with a basement membrane –epidermis (outer layer) –dermis (underlying epidermis) 11/14/2015 Dermis Hypodermis Epidermis

14. The Major Structures of the Skin 11/14/2015 Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.

15. Diagram of a Cross Section of Human Skin 11/14/2015

16. Epidermis l Stratified squamous epithelium l Keratinocytes the major cell type –> 90% of all cells l Programmed process of differentiation l Divided into several layers based on the state of keratinocyte differentiation 11/14/2015

17. Structure of the Epidermis 11/14/2015 Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.

18. Schematic of the Stratum Corneum 11/14/2015 Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.

19. Cell Types in Epidermis l Keratinocytes l Merkel cells –type I mechanoreseptor (sensory reception) l Melanocytes –pigment-producing (melanin granules) cells that originate in the neural crest l Langerhan’s cells –bone marrow derived antigen presenting cells that are localized in the viable epidermis 11/14/2015

20. Dermis l Largest fraction of the skin –approximately 90% l Provides structural strength –high content of collagen and elastin l Nerve and vascular networks and appendages required to support the epidermis 11/14/2015

21. The Major Structures of the Skin 11/14/2015 Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.

22. 11/14/2015 Eccrine Gland l Thermoregulation l Eccrine unit consists of –intraepiermal spiralled duct –coiled and straight intradermal duct –secretory coiled gland l Highest density on palms, soles, and axillae l Clear sells secrete glycogen, water, and electrolytes l Dark cells secrete sialomucin

23. 11/14/2015 Apocrine Gland l Function unclear –acne l Sialomucin l More viscous and produced less than eccrine sweat l Apocrine unit consists of –secretory coiled gland –straight duct which traverses the dermis and empties into the isthmus of a hair follicle

24. 1. Papillary Layer l Underlies the epidermis l Fibroblasts l Major synthetic product is type III collagen l Organized into small fiber bundles that contrast with the larger type I collagen fiber bundles found in the reticular dermis l Collagenase activity 11/14/2015

25. 2. Reticular Layer l Superficial to the hypodermis l Composed primarily of type I collagen; organized in large fibrillar bundles l Contains large, fully matured elastic bundles that extend between the collagen fiber bundles 11/14/2015

26. Cell Types in Dermis l Fibroblast l Macrophages –phagocytize and neutralize foreign cells and chemicals –process and present antigen to immunocompetent lymphoid cells l Mast cells –respond to light, cold, acute trauma, vibration, and pressure –initiate chemotaxis or vasodilation 11/14/2015

27. Hypodermis l Layer of mesenchymally derived adipose cells that form the connective tissue layer of the reticular epidermis l Innermost layer of the skin l Provides cushion between the external skin layers and the internal structures such as bone and muscle l Energy reserve l Allows for skin mobility and molds body contours l Insulates the body 11/14/2015

28. Metabolism of Xenobiotics l Most foreign compounds are lipophilic and able to penetrate lipid membranes and to be transported by lipoproteins in the blood l These lipophilic compounds are substrates for biotransforming enzymes l Epidermis is the major site in the skin for metabolism of xenobiotics, steroids, and vitamins 11/14/2015

29. Metabolism of Xenobiotics l 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 l localized mainly in the endoplasmic reticulum (microsomal fraction) l activities about 1-5% of those in the liver l Pre-carcinogenic chemicals can be converted to carcinogenic metabolites 11/14/2015

30. Metabolism of Xenobiotics l 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 11/14/2015

31. Metabolism of Xenobiotics l 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 l Skin metabolizing enzymes differ both quantitatively and qualitatively from those in the liver, particularly by their relative proportions, composition, and interactions 11/14/2015

32. Schematic of Metabolism of Xenobiotics in the Skin 11/14/2015 Drug Or Xenobiotic Active Xenobiotic (e.g., epoxides) Elimination Binding to Macromolecules (e.g., membranes, proteins, DNA, RNA) Chemocarcinogenesis, Mutagenesis, Teratogenesis, Sensitization Transferases, Epoxyhydrase, NQR P-450 Marzulli, F.N. and Maibach, H.I., 1996. Dermatotoxicology, 5th ed. Taylor & Francis, Washington, DC.