Toxicological Pathology TOX*4100

Lect 19: Lab 9: Lect 20: Lect 21: Lab 10: Lect 22: Lect 23: Lab 11: Lect 24: Respiratory system Respiratory system Immunotoxic responses Teratogenesis Urinary system Urinary Skin Skin Review

Q 1: What is the difference between corrosive and irritant dermatitis in response to topical exposure?
Corrosive dermatitis Irritant dermatitis

Edema

Necrosis of dermal vessels

Final Exam: 1130-1330 Saturday 14 April, Room 1813

Primary necrosis at the surface Secondary inflammation in dermis

Primary injury in dermis Secondary necrosis of epidermis

Q 1: What enables the skin to exclude the following:

Reactive chemicals? Lipid soluble substances? Macromolecular allergens? Dead cells on surface -SH rich binding proteins Skin is permeable Intact impermeable barriers Hydrophobic lipids

Q 2: What is meant by the term hand eczema?

Common chronic inflammatory skin disease (dematitis) affecting the hands Occupational health problem Multifactorial causation Allergies Barrier damage Exposure

Exfoliation Lipids Dead cells

Q 3: How does hand washing exacerbate the severity of immune-mediated dermatitis?

Q 4: How does skin irritation exacerbate the severity of immune-mediated dermatitis?

Lf2 Allergic dermatitis

Loss of Surface keratin

Hyperplasia (acanthosis)

Increases permeability to antigens

Detergents remove lipids from epidermis Overhydration softens the keratin barrier Some chemicals are keratolytic or necrogenic Inflamed skin is more permable and fragile Inflammation in dermis Inflammation alters structural integrity of the epidermis Increases likelihood of absorption of allergenic substances

Q 5: What is the normal role of filaggrin and how do defects in in this contribute to immune-mediated dermatitis?

Filaggrin functions and deficiencies

Main component of keratohyalin granules Binds to and aggregates the keratin cytoskeleton Genetic defects increase permeability to water, allergens and irritants leading to atopic dermatitis, hand eczema, etc
1 in 10-12 Caucasians have impaired filaggrin function 1 in 400 have complete deficiency (congenital ichthyosis)

Irvine AD, McLean WH J Invest Dermatol (2006) 126, 12001202

Q 6: How are hair and toenails useful for analysis of exposure to arsenic?

Cutaneous and adnexal residues

Arsenical tonic recipe

Melbourne museum

Arsenic in Phar-Laps Hair

Death of Napoleon
http://www.napoleon-series.org/ins/ weider/c_assassination_w.html

Many reactive agents bind thiol-rich proteins in hair, hoof etc High stability of keratin proteins in dead cells Period of exposure can be determined from location in hair etc

Q 6: Describe the pathogenesis of urticaria

Q 7: What is photosensitization?
Skin photosensitivity to UV-A or visible >320 nm Hyper-reactive to sunlight Involves photoactive substances in the skin Sensitization implies an allergic component

Physical Damage

Histamine Fluid leakage Hyperemia

Mast cell release of histamine and cytokines Vascular permeability and acute skin swelling (hives) Allergic (IgE) and non-allergic mechanisms

Photoactive Chemical Light energy Excited Chemical Triplet state Free radicals

Q 8: Describe the pathogenesis of photoallergic dermatitis

Allergic contact dermatitis to photoactivated antigen

Singlet oxygen

Energy to component

Oxidation

Adducts

Tissue damage
O. Yamamoto, Y. Tokura: J. Dermatol Sci (2003) 32,85

Q 8: Describe the pathogenesis of photoallergic dermatitis

Irritant contact dermatitis Allergic contact dermatitis Photoallergic dermatitis

Dermatitis at contact locations Not allergic nor photodermatitis Type IV allergic dermatitis Dermatitis elicited by allergens that are activated by UVA/vis

Q 9: How does nickel cause allergic contact dermatitis

Barrier Cell death
Neutrophils
Macrophages

5. Allergic dermatitis
Irritants Hapten Epidermis Hapten-Protein in Langerhans cells
NLRP3 TLR2 TLR4 Immunostimulatory cytokines Pro-inflammatory Cytokines (IL-1, etc) Adjuvant Effect

Cell death DAMPs

ATP Nickel

Fas Granzymes Perforin FasLigand

Cytokines TNF, IL1, IFN

Hyaluronic acid

Th1

Th2

T-lymphocytes

B-lymphocytes

Activated CD8+ Cytotoxic T-lymphocytes (CTLs)

Activated CD4+ T-lymphocytes

CD4+ CD8+ Antibodies Macophage activation Cytotoxic (CTLs)

Immune-mediated inflammation targetted at hapten

Q 10: Describe the condition of toxic epidermal necrolysis (TEN)?

Q 11: Describe the typical effects of arsenic on the skin ?

Hyperkeratosis
From University of Erlangen Website

Arsenic residues in keratinized tissues Skin cancer

Toxic epidermal necrolysis is a life-threatening skin disorder characterized by cell death, blistering and peeling of the epidermis, usually over large areas of the body

Q 12: What is parakeratosis and hos is it associated with scaly skin

Incomplete cross-linking No keratohyalin

Q 13: Compare the pathogenesis of: Chloracne Acne vulgaris

Keratin plugging Altered differentiation Sebaceous atrophy Squamous metaplasia etc

Sebum plugging in follicles Sebaceous hyperplasia

Q 14 Why are the extremities more susceptible to ergot toxicity? What is ergot ?
Ergots are sclerotia of Claviceps spp Fungi grow in various grains

Q 14 Why are the extremities more susceptible to ergot toxicity? Vasotoxic

Contrict arterial smooth muscle Ischemia of extremities Exacerbated by cold Therapeutic uses of vasoconstrictive Ergotamine Migraines Uterine hemorrhage Necrosis of the tip of the ear of a pig

What are ergot alkaloids?

Mycotoxins of ergot Indole alkaloids from tryptophan Lysergic acid and Ergotamine classes
Schiff PL. Ergot and its alkaloids. Am J Pharm Educ. 2006 70:98.
http://www.flickr.com/photos/dougcwaylett/ 2890999682/#/photos/dougcwaylett/ 2890999682/lightbox/

See Schiff PL. Ergot and its alkaloids. Am J Pharm Educ. 2006 70:98.

Q 15: How does ultraviolet radiation influence the development of malignant skin neoplasms?

Actinic keratosis, basal cell adenoma and carcinoma

Actinic keratosis (a preneoplastic epidermal proliferation)

Basal cell carcinoma the most common skin cancer in humans

Malignant melanoma

The most aggressive skin cancer, associated with sunburn and high UV-B exposure