Dermatological Toxicity

7/30/2019 Dermatological Toxicity

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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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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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Dermatological Toxicity

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