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DERMAL TOXICITY
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DERMAL TOXICITY
SKIN: STRUCTURE, IMPORTANCE
DERMAL ABSORPTION OF TOXICANTS
RESPONSE OF SKIN TO INJURY : CLINICAL
SIGNS
MANIFESTATION/ TYPES OF DERMAL TOXICITYand TOXIC AGENTS
EVALUATION OF CUTANEOUS TOXICITY
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SKIN
Multilayer , heterogeneous organ, external covering.
Largest organ.
10
20% of total body weight.
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Basic Functions/Physiology of skin
Thermoregulation
Preventing insensible water loss
Metabolic, immunological and neurosensory.
Protect the body against a variety of
toxicological insults. (Animals: less protectivecompared to humans)
Directly contacts environmental, chemical and
other pollutant exposure
Exhibit symptoms of dermal toxicity when thethreshold limit is passed.
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Structurally Three
components:
Superficial lining ofepithelial cells:
epidermis
Subepithelial
connective tissuestroma and
vasculature: dermis
Layer of
subcutaneous fat ofvarying thickness:
hypodermis.
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Epidermis (consists ofkerationocytes and non-keratinocytes)
Most important barrier
stratum corneum stratum lucidum stratum granulosum stratum spinosum
stratum basale.
Approximate cell turnoverand self-replacement timein normal human skin is 28days.( differs widely
across species) Mechanical or chemical
injuries can increase themitotic rate of basal cells.
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EPIDERMIS
In general, rodents and cats have a thin
epidermis, only 2 3 cell layers thick
Dogs and horses - thicker epidermis
Pigs have the thickest
General thumb rule: More sparsely-haired a species: Thicker
its epidermis will be, in particular thehorny keratin layer.
Marine mammals-whales: Exceedinglythick, up to ten cell layers or more
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Cross section
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Stratum basale. single layer of cuboidal or columnar cells resting on basal
lamina ; viable layer of cells in the epidermis; mitotically
active, keeping the epidermis replenishedStratum spinosum Layers of irregular polyhedral cells. Cells have numerous tonofilaments and small membrane bound organelles (lamellar granules).
Stratum granulosum Layers of flattened cells ; irregularly shaped, non-membrane
bound and electrondense keratohyalin granules. Keratinization and maintaining the barrier functions Lamellar granules contain several types of lipids (ceramides,
cholesterol, fatty acids) and hydrolytic enzymes includingproteases, acid phosphatases, lipases and glycosidases
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Stratum lucidum : Thin layer , in very thick areas : palmer and plantar
surfaces.Startum Corneum: Outermost layer of epidermis Several layers of completely keratinized dead cells
(corneocytes) embedded in an extracellular lipid matrix. Brick and mortar model where keratinized cells, the
bricks, are embedded in the lipid mortar. The dead keratinized cells-highly water absorbent; keep
the skin moist and soft. The water holding capacity of epidermis: maintained by
sebum (natural oil covering the skin) secretion from
glandular structures of the skin. The mature cells. gradually shed from the surface and
replaced from beneath
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Stratum Corneum:
The primary barrier of skin
Provides up to 1000 times the resistance to
exogenous compounds as compared to the layers
beneath it.
Consists of approximately 40% protein and40%water; the rest is mainly lipid.
Lipophilic substances, : organic solvents and OPC
insecticides (e.g., parathion, penetrate readily.
Disruption : by physical (tape striping) or bychemical means: Adversely affect barrier properties.
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Specialized cells of epidermis :Not involved in barrier
functions of skin
Melanocytes: involved in skin ; stimulated by UVlight to produce melanin
granules.
Merkel cells
act as mechanoreceptors for touchLangerhans cells
play a major role in the skin immune response.
Other specialized regions of the epidermis:
Skin appendages (ADNEXA) : Hair, sweat and sebaceousglands, hoof, claw, nail, feathers and horn.
.
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DERMIS:
Dense irregular connective tissue with collagen, elastic and
reticular fibers in a mucopolysaccharides ground substance Fibroblasts, mast cells and macrophages: predominant cells
High content of collagen and elastin secreted by scattered
fibroblasts, provide the skin with elastic properties.
Impregnated within the epidermis and dermis are specializedadnexa : Sweat glands, sebaceous glands, hair follicles and
erector pili muscles are located
A layer of adipocytes, accumulation of fat : cushioning action
Capillaries located in the rete ridges at the dermalepidermaljunction; supply to the bulbs of the hair follicles and the
secretory cells of the sweat glands.
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DERMAL ABSORPTION OF TOXICANTS By passive diffusion or by active transport.
For polar toxicants the diffusional resistance of the SC is large
compared to that presented by the viableepidermis and dermis.
For lipophilic toxicants the resistance of the SC is smaller.
Generally, topical absorption A sequence ofevents that include partitioning of the moleculeinto the SC from the applied vehicle phase,diffusion through the SC, partitioning from theSC into the viable epidermis, diffusion
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Penetration pathways:
1 The intercellular/para-cellular path: Via the tortuous but
continuous intercellular lipids.2 The transcellular path : The toxicants transfer sequentially
and repeatedly through the bricks and mortar.
3 The transappendageal path via hair follicles, sweat pores, etc.
Most molecules follow the first penetration pathway The absorption of certain compounds can take place via
transfollicular path or sweat pores, often resulting in skin
penetration (residing within skin) rather than true absorption
(systemic exposure).
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Factors affecting the dermal toxicity in animals.
Species,Breed : Epidermal thickness, epidermal cell size, number
of cell layers and blood flow patterns can vary between species as
well as within the species Age and Health status : Young and emaciated animals are more
prone to dermal intoxication than are adults or healthy animals
Skin condition (dryness, hairiness or thickness)
Local environment (weather, humidity, temperature).
Type/Nature: lipophilicity chemical/drug/plant
Direct/Indirectexposure/concentration
The ionization state of the penetrant
Electrolytes in aqueous solution have poor penetrability, and the
ionization of a weak electrolyte notably reduces its permeability (e.g.,salicylic acid as opposed to sodiumsalicylate). Ions such as Na , K , Al and
Br penetrate very slowly
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Skin occlusion with fabric or transdermal patches, creams,
and ointments: increase epidermal hydration, which can
increase permeability
The molecular size of the penetrant: Molecules of smallerweight penetrate more rapidly
Skin occlusion raises the local temperature, important factor
that enhances permeability
Organic solvents-methanol, acetone, hexane, and ether. They produce delipidization of the skin, generating
interstices that transform the tissue
Anionic and cationic surfactants (soaps, detergents),: alter
the lipid pathway by fluidization,delipidization of lipids, andproteins within the keratinocytes-denatured. (anionic
surfactants than non-ionic surfactants)
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Regional variations in areas of the body : Dependenton differences in the thickness of the stratumcorneum - will affect absorption.
The rate of penetration is in the following order:
Scrotal > Forehead > Axilla >Scalp > Back =Abdomen > Palm and plantar.(Highly cornified; 100
to 400 times thicker than other regions)
Physical integrity of the horny layer (skin diseases thebarrier function is notably diminished (e.g., psoriaticskin).
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Percutaneous absorption driven by passive diffusiondown a concentration gradient described at steadystate by Ficks law of diffusion
Flux = [(D PC SA)/H](x)
where Dis the diffusion coefficientPCis the partition coefficient,SA is the applied surface area,H is membrane thickness (or more precisely theintercellular path length)
x is the concentration gradient across themembrane
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RESPONSE OF SKIN TO INJURY
Fundamental Cutaneous Non-neoplasticLesions
The extent and degree of involvement of eachcomponent will depend on
The agent itself,
severity of the exposure. factors such as dose,concentration,pH, length of exposure, numberof exposures, and time between exposures.
Epidermal lesions
Dermal
Adnexal
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EPIDERMAL LESIONS Degree of epidermal damage or destruction. ;
vary from very focal keratinocyte swelling (intracellular edema or ballooningdegeneration) to extensive epidermalcoagulative necrosis.
Spongiosis or intercellular edema of thespinous layer: characterized by increasedspace between keratinocyte
Hydropic or vacuolar degeneration of the
basal layer Individual or focal cell necrosis, also usually
in the basal layer.
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EPIDERMAL LESIONS: NECROSIS
Visualised as: devitalized, hypereosinophilic and
hyalinized epithelial layers with pyknotic nuclei thatloosely line the dermis.
Necrotic epithelium : sloughed off, leaving a denuded
dermal surface exposed to the environment
When the dermis is not compromised and only the
epidermis is affected, the lesion is called Erosion.
When the epidermis is sloughed and the dermis is
involved, the lesion is called anUlcer.
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Epidermis responds with a series of reactive or progressive
changes that usually include increased proliferation of cells
(hyperplasia), and increased cell volume /size(hypertrophy)-
the Usual pattern of response to chronic or protracted toxicant
exposure of moderate intensity
Associated with edema and spongiosis,-as an increased number
of spinous keratinocytes (acanthosis).
An increased thickness of the epidermis, and is frequently
accompanied by an increased production of superficial
anucleated squames in the stratum corneum
(hyperkeratosis).
Occasionally Epidermis responds by a decrease in the size ofcells or number of epidermal layers (epidermal atrophy
/hypotrophy).
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DERMAL LESIONS
Diffusion through dermal capillaries of a systemically-
circulating toxicant; Direct penetration of the toxicantthrough the epidermis to cause direct damage to the dermis.
Subepidermal mononuclearinflammatory cell infiltrates at the
dermal epidermal interface (lichenoid pattern), or with
focal perivascular infiltrates of lymphocytes, histiocytic
macrophages and mast cells.
Secondary infection: leading to a suppurative or
pyogranulomatous reaction if opportunistic bacteria or fungi,
respectively, colonize the area.
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ADNEXAL LESIONS
Cutaneous adnexa (appendages) undergo dynamic changes of
degeneration, proliferation, inflammation and repair.
Typical destructive and involutional changes (e.g., focal
necrosis, edema, hypertrophy and hyperplasia)
Partial or total destruction of the structures or the supporting
stroma may result in disappearance of the appendages from
the exposed area, due to replacement by less-functional scartissue.
Severe injury can cause adnexal atrophy or hypotrophy.
Conversely, some agents are able to induce hyperplasia of
sebaceous glands and hair follicles
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HAIR LESIONS: TOXIC ALOPECIA
Hair follicles in a specific phase of the hair Cycle: Anagen(actively growing) or Telogen (stationary) phase.
Anagen Toxicity Effect becomes evident within days or weeks of toxic
exposure
interference with the rapid mitotic activity at the base ofthe hair follicle (hair bulb)
Eg: cancer chemotherapeutic agents ( doxorubicin -dog,and antigout agent colchicine
Telogen toxicity
slower and occurs over months of exposure.
Heavy metals Eg: chronic arsenic, mercury, selenium,thallium toxicity (in dogs ,cats): alopecia and ulcerationaffecting high friction areas: paws ; face,ears, ventrum,perineum, and mucocutaneous junctions.
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Mechanism: Interfere with the incorporation of cysteine into
keratins
Interfere with energy metabolism of proliferatinghair bulb cells, -premature telogen,shedding ofthe affected hairs.
Other telogenic compounds: iodine (cranial
alopecia in horses), propanolol, triparanol, andsome anticoagulants, such as heparin andcoumarin, and oral contraceptives.
In general, unless there is severe damage to
the follicle, toxic alopecia is reversible onceexposure ceases or the toxicant ismetabolized and detoxified
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ACNE
Affliction of the
pilosebaceous units inthe face, upper chest and
upper back.
Blockage of thesebaceous duct leading
from the gland to the hair
follicle, resulting in
retention of sebum andenlargement of the gland.
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ACNE VULGARIS Androgen stimulation at puberty leads to excess sebum
production and as a result of the high local fatty acidconcentration.
Excessive cornification of the ductal cells to plug the
orifice.
Proliferation of resident bacteria and inflammation
typically result.
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CHLORACNE
Occupational dermatosis: Exp. To Halogenated hydrocarbons
(polyhalogenated naphthalenes, biphenyls, dibenzofurans,and contaminants of herbicides, such as polychlorophenol
and dichloroaniline),
characterized by an acneiform lesion, on face and behind
the ear
Comedones ( blackheads ) are located in these regions,
external genitalia, in the axillae, shoulders, chest, back,
abdomen
Histologically, comedones: dilations of the infundibular or
suprafollicular area of the hair follicle, with accumulation of
keratin and sebaceous gland secretion causing cystic dilation
of the upper third of the hair follicles.
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PIGMENTARY DISTURBANCES
LEUKODERMA or VITILIGO (HYPOPIGMENTATION)
Melanocytes protect the skin from harmful effects ofultraviolet light by producing melanin.
An autoimmune origin, : Loss of melanocytes
Acquired condition of generalized pigmentation loss
has a genetic basis.
Exposure to phenols, catechols, quinones, and
related compounds, environmental influences,
chemicalsHYPERPIGMENTATION: UV Light, hypoadrenalism,
chemicals-Hg,Pb,Bi, zidovudine, bleomycin
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URTICARIA (HIVES)
Wheal and flare reactions, produced by topical exposure to a
variety of topical agents, especially biogenic polymers
released from plants and insects.
The response occurs within one hour of exposure and
involves the local release of vasoactive substances including
histamine.
Generally disappearing within hours and rarely lasting longerthan a day or two.
Result from degranulation of cutaneous mast cells by liganded
IgE, leading to release of histamine and other vasoactive
substances. Bites,stings, Medications,Chemicals (such as turpentine or crude oil),
Intestinal parasites. Inhaled or ingested allergens, Food allergies Major
Causes
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Neoplastic Lesions
Papillomas (Warts):
Cauliflower-like structures, with
either a narrow or a broad base,
consisting of a series of folds
united by common stalks to the
underlying skin
Each of the folds : a centralconnective tissue core covered
by an epidermis-like epithelium.
The epithelium: thick, with
numerous mitoses in the
germinative layers, a thick,usually fully-keratinized
(orthokeratotic) horny layer.
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In domestic animals : typically virally-induced, and
generally do not progress to carcinoma, as can
happen with chemically-induced papillomas inrodent models.
Papilloma virus infection can act as a cocarcinogen,
especially with concomitant solar keratosis.
Chemically-induced papillomas appear to arise from
metaplastic or hyperplastic hair follicles, especially
from the infundibular area.
Papillomas may regress or continue theirprogression toward carcinomas.
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Wheals / UrticariaSharply circumscribed, flat elevations produced byedema of corium.
VesiclesCircumscribed elevation s of the epidermis producedby accumulation of fluids, either serum or blood
Blebs/ bullaeLarger counterparts of vesicles are bleb or bullae
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Wheals
Vesicles
Cyst
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Pustules:Simple and very superficial abcesses / natural
sequence of vesiclesScales:Bran like flakes of imperfectly corn-fed superficiallayer of the epidermis
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Pustules
Scales
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Treatment is based on the principles.
Removal of the source of the poison
Preventing further exposure
Delaying further absorption
Hastening elimination of the absorbed poison Providing supportive therapy
Use of specific antidotes
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GENERAL LINE OF TREATMENT FOR DERMAL TOXICITY
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REMOVAL OF THE SOURCE OF THE POISON ( DERMAL)
Washing well with plenty of lukewarm water; Drying thoroughly
and keeping the animal warm
Clipping of the hair or wool.
Epidermal structures (wings, nails, claws, feathers, fur): cleaned
with the greatest care, attention to areas such as the ears,toes etc.
The cleaning should be undertaken quickly to avoid licking and to
limit cutaneous absorption. Soapy water rinsing with copious tepid water; repeating as often
as necessary and dyring carefully.
Organic solvents (alcohol, white spirit etc.) or oily substances,
which may actually increase percutaneous absorption of toxicant.:
Should never be used
Avoid Rubbing the area vigorously.
The eyes should be flushed with water or normal saline
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THERAPY OF CUTANEOUS LESIONS
TOPICAL/ SYSTEMIC ADMINISTRATIONOF Antibiotics, Antiseptics
Antiinflammatories
Antihistaminics Dermatologicals: antipruitics,antiseborrhoeics, keratolytics,demulcents, astringents etc
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THREE main Types of ( dermal ) toxicity to skin:
Direct damage produced by the toxic agent or
its metabolitesEg: Allergy, Burns, Irritation (with or without cell
death) and Genotoxicity
Immune-mediated Toxic effects : Immune
mediated syndromes
Phototoxic and photoallergic effects.-photosensitization: Drugs, chemicals and plants
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DIRECT DAMAGE TO SKIN11/29/2012 46
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IMMUNE MEDIATED TOXICITY11/29/2012 47
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PHOTO TOXIC EFFECTS
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DIRECT DAMAGE TO SKIN
Topical: Second most frequent route by which chemicalsenter the body of animals.
Liquid chemicals are generally absorbed well through
the skin if they can partition into the SC lipids.
Chemicals in the forms of solids, gases and vapors areonly absorbed through the skin if they are first dissolved
in the moist layer at the surface of the skin.
Major target for gaseous and liquid pollutants.
Allergic or Irritant/ inflammatory conditions of skin :eczema, atopic dermatitis or acne
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CHEMICAL BURNS
Direct toxicity : chemical burns produced by accidental
exposure to strong acids, alkali agents, or oxidizing agents
ACIDS: Coagulate cellular and intercellular proteins in the
Epidermis/dermis .
The coagulated necrotic tissue can form a barrier (eschar)
that inhibits further penetration and damage by the acidic
chemical
ALKALIS: Saponify lipids and denature proteins, Producing
liquefactive necrosis, allowing for deeper penetration of the
damaging hydroxyl ions, - Greater extent and duration of
damage. Greater the degree of tissue destruction, and the greater the
depth of the injury, => secondary inflammatory reaction,:
increased likelihood- bacterial or fungal colonization50
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Classification of Burns
1st Degree Burns- injures only the top layer of the skin (epidermis)Common Causes: Sunburns, Scalds burns causedby hot liquids or steam (water, oil)
Symptoms:- Redness of the skin- Mild pain
- Dry- Blanching - Wash with cool water for severalminutes
DO NOT:- Directly apply ice
- Use toothpaste, ointment or any topical creamsunless prescribed
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2nd Degree Burns: Injures the top layer of the skin and down to the lower
layer of the skin (dermis)
Common causes: - Skin contact with flame or very hot surfaces
- High concentration chemicals strong bases and acids (hydrofluoric acid,sodium hydroxide)
First Aid: Cool the area using wet towel or dipping the burned area in cool
water - Apply sterile pad or if not available
- Loosely cover with clean cloth
DO NOT: - Pierce the blisters; - Remove burnt dead skin
- Pull away the clothing in contact with the burn
-Directly apply ice
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Third degree burns
3rd Degree Burns- Injures all layers of the
skin and causes
permanent tissuedamage- Destroys nerve endings
on the skin causingnumbness
- May extend to themuscles and bones- May require skin
grafting- Requires IMMEDIATE
medical treatment
Common Causes:
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3rd Degree BurnsFirst Aid:
-If clothes are caught onfire STOP, DROP ANDROLL-Remove any tightclothing, jewelleries,- Cool the burn using awet towel- Cover with sterile
pad/cloth or clean cloth- If hands, legs, feet orhead is burned, elevatethem higher from theheart- Remove clothing in
contact with the burnedskin-Submerge large burnedareas in cool water
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CONTACT DERMATITIS:
Allergic : ACD
Irritation : ICD Involve inflammatory processes
Clinically : Erythema (redness), induration
(thickening and firmness), scaling (flaking) andvesiculation (blistering) in areas of direct contact
with the chemical.
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IRRITANT CONTACT DERMATITIS
An inflammatory process of the skin (dermatitis) that is notmediated by the immune system (non immunological).
Result of acute or chronic exposure to a large number ofunrelated compounds- acids, alkali agents, organic solvents,keratolytic agents, and oxidizing and reducing agents.
Chemical concentration is high and the exposure time long
enough. Most common in horses and dogs, generally involving
glabrous skin surfaces such as the ventrum and perinealareas, (where a protective hair coat that would otherwiseimpair contact is sparse, epidermis is thinner)
Direct interaction of the toxic compound with immune systemeffectors without intervention of an antigen antibody reaction
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Three levels of interaction with immunoeffectors
1. Interaction with mast cells to release histamine,serotonin,
leukotrienes, and other mediators of inflammation. Eg: polymixin
B, dimethyl sulfoxide, and biogenic polymers that are released by
plants-nettles; animals- caterpillars and jellyfish.
2. Activation of complement in the absence of antibody (i.e., via the
alternate pathway). Eg: radiocontrast media.
3. Alteration of arachidonic acid metabolism to increaseprostaglandin synthesis. Eg: aspirin, nonsteroidal anti-inflammatory
agents, and phorbol esters.
Keratolysis,Lipid and membrane disruption, Protein denaturation,
Cytotoxicity
Pathology: PMN margination, Epidermal necrosis, Dermalinflammation
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CELL-MEDIATED IMMUNOTOXIC REACTIONS:
IgE-dependent Reactions
The anaphylactic( Atopic or type I) : mediated by IgE antibodies, .
Eg: foods, inhaled allergens, or injected therapeutic agents (e.g.,
penicillin, tetracycline, Vitamin K, and vaccines).
The cytotoxic hypersensitivity reaction (type II), the basis for some
autoimmune diseases, not demonstrated in immunotoxicologic
reactions of the skin.Immunocomplex-mediated Reactions (Type III reaction)
Arthus reaction -: antigen antibody complex mediated
hypersensitivity reactions.
The immunoglobulins : Complement-fixing IgG or IgM.
Eg: Large variety of antigens, most often drugs such as penicillin,
aminosalicylic acid, and streptomycin
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ALLERGIC CONTACT DERMATITIS
Acute allergic reactions which follow after local or
systemic administration of toxicants Delayed Skin Hypersensitivity (Type IV hypersensitivity)
Most common drug-associated immunologic condition in
man and domestic animals, with dogs, then horses, being
most often affected.
Typical signs : pruritus (itchiness) and a papular eruption (red
bumps).
The paws and muzzle commonly affected in animals, and
sometimes, the insides of the ears are affected, in dogs.
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Allergic Contact Dermatitis
Chronic phase : Thickening of theepidermis: acanthosis, parakeratosis
(abnormal keratinization withretention of keratinocyte nuclei),hyperkeratosis.
Dermis: chronic superficialperivascular infiltrate that rangesfrom a small perivascular ring oflymphocytes to massive dermalinfiltration by lymphocytes,eosinophils, and mast cells
If associated with tissuedestruction: dermal fibroblastic
proliferation changes: Fibrovascularproliferation or granulation tissue,usually culminate in increasedcollagen content in the papillary andreticular dermis (fibrosis or scarring,)
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Substances that have been documented to produce delayed
hypersensitivity.(ACD)
Flea collars, poison ivy/oak/sumac, rubber products,dichromates (in cement), and nickel compounds.
Therapeutic agents such as ethyl minobenzoate and
neomycin, various dyes and preservatives.
Chemicals found in soaps, flea collars, shampoos, wool and
synthetic fibers, leather, plastic and rubber dishes, grasses
and pollens
Insecticides, petrolatum, paint, carpet dyes, and rubber and
wood preservatives.
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Diagnosis and Testing Patch testing
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Diagnosis and Testing Patch testing
PATCH TEST:
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PATCH TEST:
To find the allergic cause in skin reactions.
A range of suspected allergens is prepared in soft white paraffin
(e.g. vaseline) and placed onto a metal disc or strip (about 1cm indiameter). These are then taped to the patients back.
The skin is marked appropriately and the patient is asked to keep
the skin dry.
The patches are left in place for 48 hours. After this time the discs
are removed and the skin is examined to see if any red inflamedareas (wheals) have appeared.
If no reaction is seen, then another 48 hours (without the patch) is
given before the area is re-examined to see if a delayed reaction
has occurred.
Steroid creams need to be stopped for 3-4 weeks before testing as
they may suppress the test response.
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ACD
Identify Allergen
Prevent furtherexposure
Topical antibiotic
ointment Antihistaminics
Topical and oralcorticosteroids
Immunosuppressants
ICD
Antibiotics Antihistaminics
Antipruritics
Demulcents
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TREATMENT
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ERYTHEMA MULTIFORME (EM) AND TOXIC EPIDERMAL NECROLYSIS(TEN)
Rare immune-mediated diseases
Linked to the inappropriate activation of cytotoxic (CD8 ) T-cells
against keratinocyte components in the epidermis.
Binding of cytotoxic T-cells to the offending keratinocytes results in
apoptosis : erythema, superficial vesiculation blistering) of the
epidermis, and lymphocytic migration into the epidermis
(exocytosis) and along the epidermal-dermal junction (interfacedermatitis) in EM.; Necrosis of large areas ofepidermis in EM
Excessive production and release of cytokines, such as tumor
necrosis factor- and interleukin-6: in TEN
TEN: Due to the large areas of skin affected, its fulminating nature
and the full thickness necrosis of the epidermis, often life-threatening.
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EM and TEN : Humans,dogs, cats,horses, and monkeys.
sulfonamides, penicillins, andcephalosporins,
EM Ivermectin, aurothioglucose,griseofulvin, propylthiouracil
TEN : Levamisole,D-limonene-based fleadips, Anticonvulsants and NSAIDS
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PHOTOTOXICITY
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PHOTOTOXICITY
Direct immediate reaction involving interaction of incidentlight of a particular wavelength passing through the skin,
resulting in either release of free electrons/ enhancedexcitement state for electrons in the photosensitizing
compound.
As the electrons return to a less excited state, they release
energy which can cleave certain molecules to produce free
radicals. This release of energy, or collision with free electrons themselves,
often leads to the generation of highly reactive singlet oxygen,
with the free radicals, especially from unsaturated membrane lipid.
The free radicals in turn interact with and damage proteins,
membrane lipids (especially unsaturated ones), and nucleic acids
via chain reactions - more tissue free radicals, : leading to cell injury
and death.
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Phototoxicity : (Primary)
Therapeutic agents- phenothiazine, tetracyclines, sulfonamides,
chlorpromazine, and nalidixic acid.
Others- acridine, anthracene, phenanthrenes, linear fluorocoumarins(psoralens). ( used for therapeutic purposes in the treatment of psoriasis
with UV light).
by endogenous compounds,:
Porphyria.- Results from a disturbance in the metabolism ofporphyrins, with accumulation of photoactive byproducts in
the plasma and tissues. (enzyme abnormalities disrupt the
biosynthetic pathways) skin lesions : due to absorption of visible light by the porphyrin molecules,
subsequent generation of free radicals
Hereditary or Others- related to hepatotoxicity or exposure to agents such
as polychlorinated compounds (e.g., hexachlorobenzene), lead, or alcohol
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PHOTOSENSITIZATION
Severe dermatitis resulting from a complex reaction induced
by plant pigments /photodynamic substances exposed toultraviolet (UV) sunlight in the skin of animals that have eaten
certain plants/photodynamic substances
Associated with Primary/ Secondary- liver damage.
Non-pigmented skin : the most severe reaction where thesereactive compounds are directly exposed to UV light, most
likely secondary to light enhanced photooxidation.
The amino acids susceptible to oxidation (histidine, tyrosine andtryptophan) once oxidized evoke an intense inflammatory response in the
blood vessels and surrounding cells resulting in tissue necrosis
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Mechanism
In ruminants, the photoactive compound phylloerythin isformed from chlorophyll by anaerobic bacteria in therumen.
Phylloerythrin is readily absorbed into bloodstream, butalso readily excreted by the liver into the bile.
Even moderate liver damage, however, especially if the
biliary system is involved, leads to phylloerythrindeposition in other organs, including the skin.
Triggers a photosensitization reaction :erythema, edema,exudation, and eventual necrosis of sparsely haired non-
pigmented light/ sun-exposed areas. Damage and inflammation centered round the biliary
tract, interfering with excretion of phylloerythrin.
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Phototoxicity in domestic animals (Horses cattle sheep and pigs )
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Phototoxicity in domestic animals (Horses, cattle, sheep, and pigs )
Photodynamic substances: Plant pigments: pyrrolizidine alkaloids (PAs).
(Senecio, Crotolaria, Cynoglossum , Lantana)
Fungal toxins (mycotoxin- sporidesmin); drugs
Much less common (SECONDARY> Primary)
Fewer photosensitizing drugs used
Heavy hair coats and generally more heavily-pigmented skin limits the
areas of potential damage to sparsely haired, less pigmented regions such
as conjunctiva, ventrum, perineum, nares, teats, and ear tips. Grazing animals, however, can ingest photosensitizing compounds while
feeding.
Plants such as
Buckwheat ( Fagopyrum ) and St. Johns wort ( Hypericum ) contain photoactive
red helianthrone pigments, while spring parsley ( Cymopterus ), bishops weed (
Ammi ) andDutchmansbreeches ( Thamnosma ) contain furocoumarins. ; rape
(Brassica), alfalfa and alsike clover
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PHOTOALLERGY
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PHOTOALLERGY
A special form of Delayed hypersensitivity.( Type IV)
Photoallergen elicits an allergic response by forming a complete
antigen upon absorbing ultraviolet or visible light. Light appears to modify or convert the hapten to a complete
antigen, by covalently linking the hapten to cellular proteins in the
epidermis.
Unlike photosensitization, where the response is immediate,
the onset is delayed, generally taking 48 hours to manifest.
Examples : sulfonamide, phenothiazides, coumarin derivatives,
glycerylp -aminobenzoic acid, andplant products (e.g., ragweed).
Light stimulates the chemical either to assume an excited state
that can bind directly to a carrier protein or to yield a stablephotoproduct that becomes conjugated to a carrier.
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PHOTOALLERGY
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PHOTOALLERGY
Upon recurrent exposure to an exogenous chemical and light,
a delayed hypersensitivity (Type IV) reaction ensues, leading
typically to eczema (erythema, vesiculation and itching). Light sensitivity usually subsides within days but may persist
for several weeks if the chemical is retained in the epidermis.
Chemicals causing phototoxicity may also be photoallergenic.
Phototoxic molds Ergot alkaloids (Claviceps purpurea.) can induce gangrene
in all species of animals if ingested over a period of several
days or weeks.
Serotoxins (trichothecene toxin T-2)
Fusarium tricinctum is diacetoxyscirpenol. It may causedermalnecrosis and gangrene in cattle fed on moldy corn.
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CLINICAL SIGNS
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CLINICAL SIGNS
Photophobic immediately when exposed to sunlight and squirm in
apparent discomfort.
They scratch or rub lightly pigmented, exposed areas of skin (eg,ears, eyelids, muzzle).
Typical skin lesions, even in black-coated animals. : Erythema
develops rapidly and is soon followed by edema. If exposure to light
stops at this stage, the lesions soon resolve.
When exposure is prolonged, serum exudation, scab formation, andskin necrosis are marked.
In cattle: Exposure of the tongue while licking may result in glossitis,
characterized by ulceration and deep necrosis.
Hepatogenous photosensitivity: icterus may be present.
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Di i
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Diagnosis
History and Clinical signs (but are similar to the primary actinic
effects of sunburn in early or mild cases) .
Evaluation of serum liver enzymes and liver biopsies may benecessary to confirm the presence of hepatic disease.
Examination of blood, feces, and urine for porphyrins
Treatment:
Mostly palliative measures: shaded fully or, preferably,
housed;allowed to graze only during darkness. Corticosteroids, given parenterally; demulcenrs in the early stages
Basic wound management techniques, and fly strike prevention,
liver protectants
The prognosis and eventual productivity: depends on the site and
severity of the primary lesion and/or hepatic disease, and to thedegree of resolution
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S C C S
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SKIN CANCERS
Skin cancer is the most
common neoplasm in
humans, accounting for
nearly one-third of all
cancers.
Sunlight, which damages
epidermal cell DNA.
The p53 tumor suppressor
gene is a major target in
which damage occurs earlyand is detectable in:
squamous cell carcinomas.
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K t th
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Keratoacanthomas
Morphologically very similar
Appear after exposure to UV radiation or complete carcinogens
starts as an intradermal growth of epithelial prolongationsoriginating in the hair follicles.
It usually acquires a cup-shaped architecture, with a central horny
crater that has a papillomatous exophytic component and an
endophytic component of deeply-penetrating epithelial cords that
usually do not invade the subcutaneous tissue.Squamous cell carcinoma and Basal cell carcinomas:
(common in dogs and cats)
UV exposure, most commonly : chronic exposure toarsenic and PAHs
Histologically, squamous cell carcinomas are usually well-differentiated, often with abundant amounts of keratinproduction
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DERMATOLOGIC TOXICITY OF CHEMOTHERAPEUTIC
AGENTS
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AGENTS
TOPICAL CHEMICALS CAUSING DERMAL TOXICITY
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TOPICAL CHEMICALS CAUSING DERMAL TOXICITY
PAHs:
VOCs:
Pesticides
Detergents, solvents, corrosives and other household
preparations
SYSTEMIC COMPOUNDS CAUSING DERMAL TOXICITY :
Heavy metals.
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P l li ti h d b (PAC)
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Polycyclic aromatic hydrocarbons (PAC)
PAHs:Coal tar, Chlorinated PAHs,
polychlorodibenzodioxines and polychlorofuranes
Inert chemically, but tend to accumulate in membranes
and thus perturb cell function if they were not removed.
Hydroxylated by a number of cytochrome P450isozymes, primarily 1A1 and 1B1 in epidermal cells and
conjugated for disposal from the body.
Oxidative biotransformation, produces electrophilicepoxides that can form DNA adducts.
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VOLATILE ORGANIC COMPOUNDS (VOC)
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VOLATILE ORGANIC COMPOUNDS (VOC)
Hydrocarbons, ketones, aldehydes, solvents
(benzene, fluorocarbons) and gases (methane) aregenerated from automobiles and industries.
Highly genotoxic, inducing cancers in various
tissues.
Precancerous lesions in the lungs and in the skin
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PESTICIDES
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PESTICIDES 97% of all pesticide exposures are
dermal.(other : inhalational, oral ocular)
Common : Hands and forearms(humans).
Dermatitis : Most common reported symptom
associated with exposure.
OPC,OCC,Pyrethroids, Rodenticides,Weedicides
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H t l
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Heavy metals Highly Toxic: Arsenic, lead, cadmium,
chromium , Ni Moderately toxic : iron,zinc, selenium, Hg,Cu.
Redistribution of metals
Act directly or indirectly on intracellular proteinsin the skin
Chelation
Interference in energy production, metabolism
Exposure in drinking water is linked to skin,
bladder and lung cancer.
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EVALUATION OF CUTANEOUS TOXICITY
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EVALUATION OF CUTANEOUS TOXICITY
Assessment methods (Invivomodels)
To assess the dermal uptake of topically applied toxicants
Cutaneous microdialysis
Tape stripping
Skin surface biopsies
Skin Irritation Tests : Designed to differentiate between
Agents that produce minor and reversible inflammatory
changes (minor irritants)
Those that induce severe inflammation (major irritants)
Those that cause massive destruction or necrosis of
cutaneous structures (corrosive agents).
Draize Technique:
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DRAIZE technique:
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Applying 0.5 g of the test substance under a gauze pad to the skin of rats/
rabbits or guinea pigs.
Young adult animals (same sex), rats between 8 and 12 weeks old, rabbits
at least 12 weeks and guinea pigs between 5 and 6 weeks old at thebeginning of dosing should be used.
The weight variation of animals used in a test should be within 20 percent of
the mean weight for each sex.
Semifluids and liquids can be applied directly; solids should be dissolved
or moistened with adequate solvents.
Each animal can be used for four (guinea pig) or six (rabbit) patch tests;
six animals should be used to test each substance.
The Draize procedure can be modified to use abraded skin for substances
that might come in direct contact with the
dermis.
The grossly observable skin reaction: at 4, 24, and 72 hours after
application, and scored according to Draizes scale
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