Download Dermal Toxicology

Toxicology of the Skin
Science that studies adverse skin effects
and the substances that produce them
Leena A. Nylander-French, Ph.D., CIH
159 Rosenau
Tel: 966.3826
E-mail: [email protected]
4/28/2017
Prevalence of Skin Disease
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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 Disease
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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
60 µmol TPGDA
600 µmol Ethyl Acrylate
1.25 µmol TPA
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Introduction to:
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Structure and function of the skin
Percutaneous absorption
Metabolism
Allergic contact dermatitis
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Functions of the Skin
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Environmental barrier
– diffusion barrier
– metabolic barrier
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Mechanical support
Neurosensory reception
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Functions of the Skin
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Physiologically, skin participates directly in
– thermal regulation
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regulation of blood flow, hair and fur, sweating
– metabolism
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keratin, collage, melanin, lipids, and vitamin D
synthesis, respiration and biotransformation
– electrolyte and hormonal regulation
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apocrine/eccrine/sebaceous glandular secretion
endocrine function
– immune regulation
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Hormones
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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
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Paracrine action
– acts locally by diffusing from
its source to target cells in the
neighborhood
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Autocrine action
– acts on the same cell that produces it
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Structure of the Skin
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Dermal surface area
1.5-2 m2
Two major
components, separated
with a basement
membrane
– epidermis (outer layer)
– dermis (underlying
epidermis)
Epidermis
Dermis
Hypodermis
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The Major Structures of the Skin
Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.
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Diagram of a Cross Section of Human Skin
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Epidermis
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Stratified squamous epithelium
Keratinocytes the major cell type
– > 90% of all cells
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Programmed process of differentiation
Divided into several layers based on the state
of keratinocyte differentiation
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Structure of the Epidermis
Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.
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Schematic of the Stratum Corneum
Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.
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Cell Types in Epidermis
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Keratinocytes
Merkel cells
– type I mechanoreseptor (sensory reception)
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Melanocytes
– pigment-producing (melanin granules) cells that
originate in the neural crest
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Langerhan’s cells
– bone marrow derived antigen presenting cells that
are localized in the viable epidermis
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Dermis
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Largest fraction of the skin
– approximately 90%
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Provides structural strength
– high content of collagen and elastin
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Nerve and vascular networks and appendages
required to support the epidermis
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The Major Structures of the Skin
Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.
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Eccrine Gland
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Thermoregulation
Eccrine unit consists of
– intraepiermal spiralled duct
– coiled and straight intradermal duct
– secretory coiled gland
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Highest density on palms, soles, and axillae
Clear sells secrete glycogen, water, and
electrolytes
Dark cells secrete sialomucin
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Apocrine Gland
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Function unclear
– acne
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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
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1. Papillary Layer
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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 Layer
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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
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Fibroblast
Macrophages
– phagocytize and neutralize foreign cells and chemicals
– process and present antigen to immunocompetent
lymphoid cells
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Mast cells
– respond to light, cold, acute trauma, vibration, and
pressure
– initiate chemotaxis or vasodilation
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Hypodermis
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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 Xenobiotics
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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 Xenobiotics
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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
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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 Xenobiotics
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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 Xenobiotics
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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
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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 Skin
P-450
Drug
Or
Xenobiotic
Active Xenobiotic
(e.g., epoxides)
Transferases,
Epoxyhydrase,
NQR
Elimination
Binding to Macromolecules
(e.g., membranes, proteins, DNA, RNA)
Chemocarcinogenesis, Mutagenesis,
Teratogenesis, Sensitization
Marzulli, F.N. and Maibach, H.I., 1996. Dermatotoxicology, 5th ed. Taylor & Francis, Washington, DC.
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