Toxicology of the Skin

1. 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 • 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

3. Prevalence 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

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

9. Introduction to: • Structure and function of the skin • Percutaneous absorption • Metabolism • Allergic contact dermatitis

10. Functions of the Skin • Environmental barrier • diffusion barrier • metabolic barrier • Mechanical support • Neurosensory reception

11. Functions 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

12. Hormones • 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

13. Epidermis Dermis Hypodermis Structure of the Skin • Dermal surface area 1.5-2 m2 • Two major components, separated with a basement membrane • epidermis (outer layer) • dermis (underlying epidermis)

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

15. Diagram of a Cross Section of Human Skin

16. Epidermis • 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

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

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

19. 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

20. Dermis • 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

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

22. Eccrine 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

23. Apocrine 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

24. 1. 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

25. 2. 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

26. 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

27. Hypodermis • 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

28. Metabolism 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

29. Metabolism 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

30. Metabolism 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

31. Metabolism 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

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