DERMAL TOXICITY SKIN: STRUCTURE, IMPORTANCE DERMAL ABSORPTION OF TOXICANTS
RESPONSE OF SKIN TO INJURY : CLINICAL SIGNS
MANIFESTATION/ TYPES OF and TOXIC AGENTS DERMAL TOXICITY
EVALUATION OF CUTANEOUS TOXICITY
SKIN Multilayer , heterogeneous organ, external covering.
Largest organ. 10–20% of total body weight.
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 protective compared to humans) Directly contacts environmental, chemical and other pollutant exposure Exhibit symptoms of dermal toxicity when the threshold limit is passed.
Structurally Three components: Superficial lining of epithelial cells: epidermis Subepithelial connective tissue stroma and vasculature: dermis Layer of subcutaneous fat of varying thickness: hypodermis.
Epidermis (consists of kerationocytes and nonkeratinocytes) Most important barrier
stratum corneum stratum lucidum stratum granulosum stratum spinosum stratum basale. Approximate cell turnover and self-replacement time in normal human skin is 28 days.( differs widely across species) Mechanical or chemical injuries can increase the mitotic rate of basal cells.
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 the horny keratin layer. Marine mammals-whales: Exceedingly thick, up to ten cell layers or more
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 replenished Stratum 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 including proteases, acid phosphatases, lipases and glycosidases
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
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 and 40%water; the rest is mainly lipid. Lipophilic substances, : organic solvents and OPC insecticides (e.g., parathion, penetrate readily. Disruption : by physical (tape striping) or by chemical means: Adversely affect barrier properties.
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 touch Langerhans cells play a major role in the skin immune response. Other specialized regions of the epidermis: Skin appendages (ADNEXA) : Hair, sweat and sebaceous glands, hoof, claw, nail, feathers and horn. .
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 specialized ‘adnexa : 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 dermal–epidermal junction; supply to the bulbs of the hair follicles and the secretory cells of the sweat glands.
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 viable epidermis and dermis. For lipophilic toxicants the resistance of the SC is smaller.
Generally, topical absorption A sequence of events that include partitioning of the molecule into the SC from the applied vehicle phase, diffusion through the SC, partitioning from the SC into the viable epidermis, diffusion
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).
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/Indirect exposure/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
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 smaller weight 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, and proteins within the keratinocytes-denatured. (anionic surfactants than non-ionic surfactants)
Regional variations in areas of the body : Dependent on differences in the thickness of the stratum corneum - 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 the barrier function is notably diminished (e.g., psoriatic skin).
Percutaneous absorption driven by passive diffusion down a concentration gradient described at steady state by Fick’s law of diffusion Flux = [(D • PC • SA)/H](Δx)
where D is the diffusion coefficient PC is the partition coefficient, SA is the applied surface area, H is membrane thickness (or more precisely the intercellular path length) Δx is the concentration gradient across the membrane
RESPONSE OF SKIN TO INJURY Fundamental Cutaneous Non-neoplastic Lesions The extent and degree of involvement of each component will depend on The agent itself, severity of the exposure. factors such as dose, concentration,pH, length of exposure, number of exposures, and time between exposures. Epidermal lesions Dermal Adnexal
EPIDERMAL LESIONS Degree of epidermal damage or destruction. ; vary from very focal keratinocyte swelling (“ intracellular edema” or “ ballooning degeneration”) to extensive epidermal coagulative necrosis. Spongiosis or intercellular edema of the spinous layer: characterized by increased space between keratinocyte Hydropic or vacuolar degeneration of the basal layer Individual or focal cell necrosis, also usually in the basal layer.
EPIDERMAL LESIONS: NECROSIS Visualised as: devitalized, hypereosinophilic and hyalinized epithelial layers with pyknotic nuclei that loosely 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 an Ulcer.
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 of cells or number of epidermal layers (epidermal atrophy /hypotrophy).
DERMAL LESIONS Diffusion through dermal capillaries of a systemicallycirculating toxicant; Direct penetration of the toxicant through 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.
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 scar tissue. Severe injury can cause adnexal atrophy or hypotrophy. Conversely, some agents are able to induce hyperplasia of sebaceous glands and hair follicles
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 of the 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 ulceration affecting high friction areas: paws ; face,ears, ventrum, perineum, and mucocutaneous junctions.
Mechanism: Interfere with the incorporation of cysteine into keratins Interfere with energy metabolism of proliferating hair bulb cells, -premature telogen,shedding of the affected hairs. Other telogenic compounds: iodine (cranial alopecia in horses), propanolol, triparanol, and some anticoagulants, such as heparin and coumarin, and oral contraceptives. In general, unless there is severe damage to the follicle, toxic alopecia is reversible once exposure ceases or the toxicant is metabolized and detoxified
ACNE Affliction of the pilosebaceous units in the face, upper chest and upper back. Blockage of the sebaceous duct leading from the gland to the hair follicle, resulting in retention of sebum and enlargement of the gland.
ACNE VULGARIS Androgen stimulation at puberty leads to excess sebum production and as a result of the high local fatty acid concentration.
Excessive cornification of the ductal cells to plug the orifice. Proliferation of resident bacteria and inflammation typically result.
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.
PIGMENTARY DISTURBANCES LEUKODERMA or VITILIGO (HYPOPIGMENTATION) Melanocytes protect the skin from harmful effects of ultraviolet 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, chemicals HYPERPIGMENTATION: UV Light, hypoadrenalism, chemicals-Hg,Pb,Bi, zidovudine, bleomycin
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 longer than 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
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 central connective 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.
In domestic animals : typically virally-induced, and generally do not progress to carcinoma, as can happen with chemically-induced papillomas in rodent 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 their progression toward carcinomas.
Wheals / Urticaria Sharply circumscribed, flat elevations produced by edema of corium. Vesicles Circumscribed elevation s of the epidermis produced by accumulation of fluids, either serum or blood Blebs/ bullae Larger counterparts of vesicles are bleb or bullae
Wheals Cyst Vesicles
Pustules: Simple and very superficial abcesses / natural sequence of vesicles Scales: Bran like flakes of imperfectly corn-fed superficial layer of the epidermis
GENERAL LINE OF TREATMENT FOR DERMAL TOXICITY
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
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
THERAPY OF CUTANEOUS LESIONS
TOPICAL/ SYSTEMIC ADMINISTRATIONOF Antibiotics, Antiseptics Antiinflammatories Antihistaminics Dermatologicals: antipruitics, antiseborrhoeics, keratolytics, demulcents, astringents etc
THREE main Types of ( dermal ) toxicity to skin: Direct damage produced by the toxic agent or its metabolites
Eg: Allergy, Burns, Irritation (with or without cell death) and Genotoxicity
Toxic effects :
Phototoxic and photoallergic effects.photosensitization: Drugs, chemicals and plants
DIRECT DAMAGE TO SKIN
IMMUNE MEDIATED TOXICITY
PHOTO TOXIC EFFECTS
DIRECT DAMAGE TO SKIN
Topical: Second most frequent route by which chemicals enter 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 are only 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
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 colonization
Classification of Burns
1st Degree Burns - injures only the top layer of the skin (epidermis) Common Causes: Sunburns, Scalds – burns caused by hot liquids or steam (water, oil) Symptoms: - Redness of the skin - Mild pain - Dry - Blanching - Wash with cool water for several minutes DO NOT: - Directly apply ice - Use toothpaste, ointment or any topical creams unless prescribed
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
3rd Degree Burns Injures all layers of the skin and causes permanent tissue damage Destroys nerve endings on the skin causing numbness May extend to the muscles and bones May require skin grafting Requires IMMEDIATE medical treatment
Third degree burns
3rd Degree Burns First Aid: -If clothes are caught on fire – STOP, DROP AND ROLL -Remove any tight clothing, jewelleries, - Cool the burn using a wet towel Cover with sterile pad/cloth or clean cloth - If hands, legs, feet or head is burned, elevate them higher from the heart - Remove clothing in contact with the burned skin -Submerge large burned areas in cool water
CONTACT DERMATITIS: Allergic : ACD Irritation : ICD Involve inflammatory processes Clinically : Erythema (redness), induration (thickening and firmness), scaling (flaking) and vesiculation (blistering) in areas of direct contact with the chemical.
IRRITANT CONTACT DERMATITIS
An inflammatory process of the skin (dermatitis) that is not mediated by the immune system (non immunological).
Result of acute or chronic exposure to a large number of unrelated 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 perineal areas, (where a protective hair coat that would otherwise impair contact is sparse, epidermis is thinner)
Direct interaction of the toxic compound with immune system
effectors without intervention of an antigen – antibody reaction
Three levels of interaction with immunoeffectors
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 increase prostaglandin synthesis. Eg: aspirin, nonsteroidal anti-inflammatory agents, and phorbol esters. Keratolysis,Lipid and membrane disruption, Protein denaturation, Cytotoxicity Pathology: PMN margination, Epidermal necrosis, Dermal inflammation
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
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.
Allergic Contact Dermatitis
Chronic phase : Thickening of the epidermis: acanthosis, parakeratosis (abnormal keratinization with retention of keratinocyte nuclei), hyperkeratosis. Dermis: chronic superficial perivascular infiltrate that ranges from a small perivascular ring of lymphocytes to massive dermal infiltration by lymphocytes, eosinophils, and mast cells If associated with tissue destruction: dermal fibroblastic proliferation changes: Fibrovascular proliferation or granulation tissue, usually culminate in increased collagen content in the papillary and reticular dermis (fibrosis or scarring,)
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.
Diagnosis and Testing Patch testing
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 in diameter). These are then taped to the patient’s 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 inflamed areas (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.
ACD Identify Allergen Prevent further exposure Topical antibiotic ointment Antihistaminics Topical and oral corticosteroids Immunosuppressants
ICD Antibiotics Antihistaminics Antipruritics Demulcents
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 (interface dermatitis) in EM.; Necrosis of large areas of epidermis in EM Excessive production and release of cytokines, such as tumor necrosis factor- α 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 lifethreatening.
EM and TEN : Humans,dogs, cats, horses, and monkeys. sulfonamides, penicillins, and cephalosporins, EM Ivermectin, aurothioglucose, griseofulvin, propylthiouracil TEN : Levamisole,D-limonene-based flea dips, Anticonvulsants and NSAIDS
Direct immediate reaction involving interaction of incident light of a particular wavelength passing through the skin, resulting in either release of free electrons/ enhanced excitement 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.
Phototoxicity : (Primary) Therapeutic agents Others-
phenothiazine, tetracyclines, sulfonamides,
chlorpromazine, and nalidixic acid. 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 of porphyrins, 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
PHOTOSENSITIZATION Severe dermatitis resulting from a complex reaction induced by plant pigments /photodynamic substances exposed to ultraviolet (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 these reactive compounds are directly exposed to UV light, most likely secondary to light enhanced photooxidation.
The amino acids susceptible to oxidation (histidine, tyrosine and tryptophan) once oxidized evoke an intense inflammatory response in the blood vessels and surrounding cells resulting in tissue necrosis
Mechanism In ruminants, the photoactive compound phylloerythin is formed from chlorophyll by anaerobic bacteria in the rumen. Phylloerythrin is readily absorbed into bloodstream, but also readily excreted by the liver into the bile. Even moderate liver damage, however, especially if the biliary system is involved, leads to phylloerythrin deposition in other organs, including the skin. Triggers a photosensitization reaction :erythema, edema, exudation, and eventual necrosis of sparsely haired nonpigmented light/ sun-exposed areas. Damage and inflammation centered round the biliary tract, interfering with excretion of phylloerythrin.
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. John’s wort ( Hypericum ) contain photoactive red helianthrone pigments, while spring parsley ( Cymopterus ), bishop’s weed ( Ammi ) and Dutchman’s breeches ( Thamnosma ) contain furocoumarins. ; rape (Brassica), alfalfa and alsike clover
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, glyceryl p -aminobenzoic acid, and plant 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 stable photoproduct that becomes conjugated to a carrier.
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 cause dermal necrosis and gangrene in cattle fed on moldy corn.
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, and skin 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.
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 be necessary 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 the degree of resolution
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.
p53 tumor suppressor gene is a major target in which damage occurs early and is detectable in: squamous cell carcinomas.
Keratoacanthomas Morphologically very similar Appear after exposure to UV radiation or complete carcinogens starts as an intradermal growth of epithelial prolongations originating 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 to arsenic and PAHs Histologically, squamous cell carcinomas are usually welldifferentiated, often with abundant amounts of keratin production
DERMATOLOGIC TOXICITY OF CHEMOTHERAPEUTIC AGENTS
TOPICAL CHEMICALS CAUSING DERMAL TOXICITY
PAHs: VOCs: Pesticides Detergents, solvents, corrosives and other household preparations
SYSTEMIC COMPOUNDS CAUSING DERMAL TOXICITY : Heavy metals.
Polycyclic aromatic hydrocarbons (PAC)
tar, Chlorinated PAHs, polychlorodibenzodioxines and polychlorofuranes
chemically, but tend to accumulate in membranes and thus perturb cell function if they were not removed. by a number of cytochrome P450 isozymes, primarily 1A1 and 1B1 in epidermal cells and conjugated for disposal from the body. biotransformation, produces epoxides that can form DNA adducts.
VOLATILE ORGANIC COMPOUNDS (VOC) Hydrocarbons, ketones, aldehydes, solvents (benzene, fluorocarbons) and gases (methane) are generated from automobiles and industries. Highly genotoxic, inducing cancers in various tissues. Precancerous lesions in the lungs and in the skin
PESTICIDES 97% of all pesticide exposures dermal.(other : inhalational, oral ocular)
Common : Hands and forearms(humans).
Dermatitis : Most common reported symptom associated with exposure. OPC,OCC,Pyrethroids, Weedicides Rodenticides,
Highly Toxic: Arsenic, lead, cadmium, chromium , Ni Moderately toxic : iron,zinc, selenium, Hg,Cu. Redistribution of metals Act directly or indirectly on intracellular proteins in the skin Chelation Interference in energy production, metabolism Exposure in drinking water is linked to skin, bladder and lung cancer.
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:
DRAIZE technique: 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 the beginning 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 Draize’s scale