Exam 2 Flashcards
Lecture 12 Liver and GI tract 1
Toxicity: Liver and Gastrointestinal Tract
Describe the functional unit of the liver and how the zones within this unit vary relative to potential for toxicity
Hepatic lobule (based on anatomical location)
-Centrilobular zone
-Midzonal
-Periportal
Portal lobule
-Based on biliary flow: opposite to blood flow
Portal Triad
-Hepatic artery
-Hepatic vein
-Bile Canniculi/duct
Hepatic Acinus (Based on Flow)
-Zone 1: Periportal (9-13% oxygenated)
-Zone 2: Midzonal (or “Transitional”)
-Zone 3: Centrilobular (4-5% oxygenated)
Blood supply
-Portal vein 60-80% deoxygenated (functional supply)
-Hepatic artery 20-40% (nutritional supply)
Factors for Hepatic Toxicity
-Zone 1: highest oxygen, lowest metabolism. Periportal
-Zone 3: Lowest oxygen, highest metabolism. Centrilobular
-Blood flow: Zone 1 to Zone 3 Central vein.
-Uptake and concentration: Fist pass effect, Close contact with circulation, accumulate metals and vitamins, Iron Homeostasis (high levels produce lipid per oxidation in Zone 1).
Copper homeostasis: Bedlington terriers, West highland white terries, Skye terriers, Dalmatians, Doberman pinschers, Labrador retrievers, Anatolian shepherds, Cocker spaniels, Poodles.
-Bioactivation and Metabolism
Types of Toxicant Induced Liver Injury
- Focal: randomly distributed and involves individual or small cluster of hepatocytes
- Zonal: usually zone 3, higher level of phase I enzymes
- Bridging : confluent zones of necrosis that extend between zones of the lobule and between lobules
- Massive: denotes hepatocytes loss throughout the lobule with loss of lobular architecture
Describe the mechanism of toxicity of pyrrolidine alkaloids, mushroom mycotoxins, and cycads and some example plants that carry these toxins
Pyrrolizidine Alkaloids
-Not all toxic
-Only those that are unsaturated at the 1,2-position e.g., Senecionine
-MOA: Potent electrophiles that react with neucleophilic substrate (DNA, Protein, AAs) and soluble nucleophiles (Glutathione); liver damage.
Plant families
- Boraginacea
- Composite
- Leguminosae
Senecio and Crotalaria spp.
-Cause irreversible liver damage, impaired liver function
-Small herbivores are resistant to PA toxicity
CROTALARIA spp., Showy Rattlebox
-Legume that supports nitrogen fixing bacteria “soil Builder”
-Toxic principle: monocrotaline and spectabiline
Crotalaria intoxication leads to pulmonary damage as a primary effect; hepatic secondary and less prominent
Tansy ragwort, SENECIO
-Majority found in the Western States
-Young plant contains highest concentrations of alkaloids
-Liver necrosis and death in cattle 4-6% of body weight consumed for several days.
-Some PA activated to more reactive, toxic compounds and others being detoxified
C/S
-Acute intoxication show signs of liver failure, including anorexia, depression, icterus and edema.
-Chronically: photosensitivity, icterus and increased susceptibility to other liver insults.
-No specific treatment available
-DDx: high levels of bilirubin and bile salts
-Prognosis: poor
Mushrooms
Mycotoxins
- MOA: Inhibition of Nuclear RNA Polymerase: loss of MRNA; no proteins; cell death. (Hepatocytes but also renal tubules and GIT)
-Orellanine
-Coprine
-Ibotenic acid
-Muscimol
-Arbitol
-Ergotamine
Cyclopeptides: Phallotoxins & amatoxins
Amita phalloides mushrooms
-“Death Cap” or “Death Angel”
-Most dangerous
-Toxic principle: Cyclopeptides (amatoxins and phallotoxins)
Amita mascara mushrooms
-Contain parasympathomimetic agent MUSCARINE.
-MOA: inhibit nuclear RNA polymerase, resulting in decrease protein synthesis. Hepatocytes, renal tubular cells, Gi epithelium most vulnerable.
-Short half life 1 hr or less
-C/S: Asymptomatic latency 0-6 hrs. GI symptoms nausea, vomiting, bloody diarrhea 6-24 hrs. Lag period several hours to several days appears to have recovered. After 36-48 hours, signs of liver, kidney, and other organs failure
Other Mushroom Toxicities
-Gyromitra spp: monomethylhydrazine = hemolysis of RBCs
-Cortinarius spp: orellanine = destroys the kidney tubules
-Psilocybe spp: psilocybin = physcoactive compounds (hallucinogens) many species, various compounds, GI distress.
Sago Palm (CYCADS)
-Native to Japan, landscape use throughout Southern US.
-Toxic principle: Cyasin
causes hepatic necrosis and GI irritation. Beta-methylamino L-alanine (BMAA) is neurotoxic amino acid, causing muscle weakness, paralysis and seizures. Unidentified third toxin causes axonal degeneration.
-Signs of toxicity appear 12-24 hrs
-MOA: not well understood, mutagenic, carcinogenic, teratogenic as well as hepatotoxic.
-C/S: cattle develop muscle weakness and or other neurological symptoms but must consume the plant for extended periods.
Zamia integrifolia (CYCADS)
Hepatotoxic Plants
Cocklebur (Xanthium strumarium)
-Toxic principle: Carboxyactractyloside (CAT)
-MOA: inhibits ADP translocate on the cytosolic side of the mitochondrial membrane
-Seeds are highly toxic
-Early, 2 leaf plant, highly toxic then lose toxicity
Present in fields, get in bailed hay
-Species affected: pigs, ruminants, horses
-C/S: weakness, vomiting, twisted neck, weak pulse. Characteristic histologic lesion is severe, diffuse, centrilobular hepatocellular necrosis.
Mycotoxins Review
Describe the mechanisms of aflatoxins and copper excess
Aflatoxins
-Aspergillus (A. flavus, A. parasiticus)
-Penicillium
**Aflatoxin B1 and B2 produced by Aspergillus **
G1 and G2: produced by Group II A. flavus and A. parasiticus
Toxic level in dog 100-300 ppb requires continuous exposure for a few weeks.
Turkey extremely susceptible <50 ppb
-MOA: Lipid accumulation and massive centrilobular necrosis in the liver. Also can be carcinogenic and teratogenic.
Alsike and Red Clover (Trifolium)
-Species: primarily in horses
-MOA: unknown mechanism
-Chronic liver failure
-More prevalent in NW US and Canada
Sheep seldom survive
Copper Toxicosis
-MOA: copper accumulates in liver, hepatocellular damage releases copper. Ex: Stressful incident. Copper into blood damaging RBCs/Hemolysis. It goes into kidneys, causing renal damage
-Dogs: genetic
-Sheep: diet issue such as Molybdeum deficiency.
Lecture 13 Liver and GI tract 2
Describe the toxicity risk associated with Xylitol sweetener
a.k.a Sorbitol, Burch sugar, Beach sugar.
What are the clinical signs?
How soon can hypoglycemia develop?
How soon does liver failure occur?
What species are affected?
C/S
Vomiting, weakness, ataxia, depression, hypokalemia, seizures, and coma.
Hypoglycemia within 30 minutes
Liver injury may occur >24-48 hours after ingestion
Only occurs in canids, possibly ferrets.
Describe the toxic agents and mechanisms of GI toxicity of plant oxalates, castor bean plant, Ranunculus plants, Colchicine, Salframine mycotoxin and some example plants that carry these
What plant is a traditional Appalachian food?
What is the most toxic seed in the world?
What is a powerful vesicant precursor and which plant contains it?
Which plants causes myelosuppression in surviving animals?
Oxalates Toxicity
Locally: Calcium oxalate crystals produce physical damage to skin and mucous membranes they contact.
Systemically: oxalate can produce hypocalcemia and crystallize in renal tubules resulting in kidney damage.
MOA: Chewing the leaves and stems causes sharp crystals (Raphides) to be forcibly ejected fro, idioblastic cells in the plant. The crystals don’t dissolve.
C/S
-Hypocalcemia, renal tubular damage.
-Pain in the mouth, head shaking, intense salivation, unusual vocalization.
-Nausea, vomiting, diarrhea may occur.
Toxic principle: Raphides (sharp crystals).
Plant examples:
Dieffenbachia (dumbcane) spp.,
-Philodendron
-Elephant’s ear
-Calla lily
-Caladium
-Shunk cabbage
-Jack in the pulpit
-Peace lily
Pokeweed (Phylotacca americana).
-Saponins and oxalates; phytolaccotoxin.
MOA: Irritation of mucosal surfaces. Roots and seeds highest amounts
Traditionally a southern Appalachian food
C/S
-Oral irritation, excessive salivation, vomiting, colic, bloody diarrhea, depression, prostration, and death.
-Mild to severe gastroenteritis with ulceration of the gastric mucosa.
Castor Bean (Ricinus communis) Tick-like seed
MOA: Ricin is transported into cells by endocytosis and once in the cytoplasm they migrate into the ER where it DEPURINATES the 28S ribosomes in rRNA.
Considered the most toxic in the world, 4 seeds can be lethal to a human
Toxic principle: Ricin
C/S
-Intoxication signs appear within 6 hours
-Effects intestinal mucosa, vomiting, diarrhea, decreased nutritional absorption, increased bacterial infections, hemorrhagic gastroenteritis.
Buttercup (Ranunculus spp).
MOA: Proteoanemonin is a potent vesicant that irritates mucous membranes of the GI. When severe, it affects the kidney.
Toxic principle: Ranunculin (glycoside) precursor converted to Proteoanemonin. Dried plant non-toxic
C/S
-Irritation of the mouth and upper GI tract, swelling of the muzzle and lips along with diarrhea, vomiting and colic reported.
Autumn crocus (Crocus autumnale) family Colchicaceae
MOA: Colchicine interferes with the spindle formation in normally dividing cells; rapidly dividing cells such as epithelium are most affected.
Toxicant principle: Colchicine
C/S
-Multiple organ systems affected. Vomiting, diarrhea, Gi hemorrhage are often seen.
-Myelosuppression seen in animals that survive
Slaframine Toxicity
Toxic principle: Slaframine and swainsonine (Mycotoxin)
Source: Fungus Rhizoctonia leguminicola from Red Clover causes black patch disease in the plants
C/S
-Generally salivation (slobbers disease) in most animals.
Describe the mechanisms of NSAID toxicity and the role of COX-1 and COX-2 selective agents.
Which are approved for cats and what administration?
Which are approved for cats and dogs?
Which are approved for horses?
Which is the constitutive isoform?
Often multi-treatment; Steroids + NSAIDs
-Phenylbutazone
-Flunixin (Banamine)
-Dexamethasone
NSAIDs Toxicity
-They all inhibit Cyclooxygenase, resulting in PG synthesis inhibition = GIT damage (dyspepsia, gastritis)
-Analgesic: non-PG related effects, CNS and peripheral effects
-Antipyretic: CNS effect
-Anti-inflammatory (except acetaminophen): PG inhibition
-Some shown to inhibit activation, aggregation, and adhesion of neutrophils and release of lysosomal enzymes.
Cats: Meloxicam, Robenacoxib
Horses/Cattle: Flunixin meglumine, Ketoprofen, Firocoxib
Constitutive isoform: COX 1 needed for homeostatic functions
Second Isoform: COX 2 responds to cytokines from site of inflammation
Currently, Most are selective for COX-1
Arachidonic Acid Cascade
-Cyclooxygenase is involved in the AAC and creates prostaglandins. Some homeostatic functions of prostaglandins include the production of Bicarb and Mucus to protect GI, and PGE2-PGI2 vasodilation in kidney (GFR).
What are some of the adverse effects from NSAIDs toxicity?
-Platelet dysfunction
-Gastritis and peptic ulceration with bleeding
-Acute renal failure is susceptible
-Sodium and water retention, edema
-Analgesic nephropathy
-Prolongation of gestation and inhibition of labor
-Hypersensitivity due to PG inhibition
-GIT bleeding and perforation
What chemical is found in old pressure treated wood that can be released from burn piles, causes hemorrhagic gastroenteritis? The harmful smoke leads to sudden death in cattle.
Arsenic
C/S
-Hemorrhagic gastroenteritis
-Watery diarrhea
-Cramping, bloating
Lecture 14 Renal System Toxicity
List the mechanisms by which nephrotoxicants may injure the kidney
> 90% of Acute renal failures are considered a result of?
> 90% acute renal failure due to Ischemia/reperfusion and neprhotoxicosis.
The 5 general mechanisms of Nephrotoxicity
- Direct injury to renal tubular epithelium (epithelial cell necrosis by debris)
- Detachment of lethally injured cells from basement membrane, resulting in back leakage of filtrate.. causing lumen obstruction
- Renal vasoconstriction, hypoxia, ischemic necrosis of renal structures
4 & 5. Damage to the glomerular filtration barrier, and impairment of renal healing and repair.
C/S
Polydipsia, nausea, vomiting, lethargy, weakness, dehydration, polyuria/oliguria/anuria.
Describe the common findings in cases of cholecalciferol poisoning including common sources and possible treatments
MOA: Underlying mechanism = dystrophic mineralization
Sources: modern rodenticides (Bromethalin, Cholcalciferal)
Treatment: hormonal therapies to block Ca release from bone, block Ca uptake at GI
Low Ca diet.
Describe the mechanism of toxicity of ochratoxins, aminoglycoside antibiotics and NSAIDs
What are sources of Ochratoxins?
Ochratoxin (mycotoxin) toxicity
Source: Penicillum and Aspergillus micro fungi molds, which grow at high temperatures and high moisture during harvest, handling, storage and transport.
-Cereal grains, cottonseed, nuts, dried beans and coffee beans.
Cattle thought to be resistant due to degradation in the rumen, though pre-rumen calves susceptible
Pigs are the most sensitive
MOA: Not fully understood.
-Inhibition of protein synthesis and energy production
-Induction of oxidative stress
-DNA adduct formation
-Apoptosis/necrosis and cell arrest.
Aminoglycoside antibiotics toxicity
Drug examples:
-Neomacin»Gentamicin»Streptomycin»Kanamycin
MOA: Concentration beyond a threshold level, endosomal membranes become disrupted and the drug leaks into the cytosol where it activates the intrinsic apoptotic pathway, increases production of reactive oxygen intermediates and interacts with mitochondria to interrupt the respiratory chain.
C/S
-Cats: vestibular damage, renal damage
-Dogs: renal damage, vestibular damage
NSAIDs drugs
-see image
Describe the renal toxicity associated with Pigweed, Lyly spp., grapes/raisins, oaks, and ethylene glycol.
Pigweed (Amaranthus spp.) red root
-Renal injury with peri-renal edema and widespread degeneration of PT and DT
Toxic principle: unknown, but it contains oxalates and accumulate nitrates at low levels.
Nephrotoxicity
Pyrrolizine alkaloids
Plants examples:
-Amsinckia
-Crotoloria
-Cynoglossum
-Echium
Species: predominantly cattle, pigs, horses.
-Tubular degeneration and Necrosis
-Megalocytosis of tubular and glomerular cells
-Hepatic lesions more prominent
-Secondary photosensitization
-Hepatic encephalopathy
Oxalic acid, soluble oxalates
Plants examples:
-Halogetonglomeratus
-Sarcobatusverniculatus
-Rheum rhaponicum
-Rumex spp.
-Chenopodium spp.
Rhubarb, Lambs quarter, Dock
Species: ruminants and pigs most common
-Tubular degeneration and necrosis
-Intra-tubular calcium oxalate crystals
-Hypocalcemic tetany possible
Red Maple (Ace rubrum)
Species: horses
-Acute tubular degeneration and necrosis
-Hemoglobin casts in tubules
Bracken Fern
Toxic principle: hypovitaminosis B1 (horses), Ptaquiloside (cattle).
C/S
-Epistaxis, melena, hemorrhage (cattle), enzootic hematuria a.k.a Red water disease.
Lilium spp. and Hemerocallis spp.
Toxic principle: consumption of any part of the plant, specific not identified
Species: Cats affected most, renal toxicity in other species not substantiated.
MOA: unknown, but severe damage to renal tubular epithelium and sloughing of cells.
-Polyuric renal failure followed by dehydration and anuric stage
Raisins/Grapes (Vitis spp.)
Species: dogs, cats, and ferrets
Toxic principle: Tartaric acid
C/S
-Vomiting, diarrhea, within 12 hours
-Elevated serum calcium and phosphorus, golden brown pigment within tubular lumen.
Oak (Quercus spp.)
Species: Cattle most affected, rarely horses, pigs, goats, sheep.
Toxic principle: Tannic acid and pyrogallol
MOA: compounds react with cell proteins to denature them, with resulting cell death.
C/S
-kidneys, liver, digestive severe lesions.
Ethylene glycol
- Initial CNS depression due to alcohol like effect: 30 min to 12 hours
-CNS signs, vomiting, PU/PD - Acidosis phase: from 8 hrs on
-Vomiting, depression, anorexia, weakness, coma - Renal failure phase: 24 hors on (sooner in cats)
-Vomiting anorexia, abdominal pain, azotemia, anuria, cristalleria.
Clinical findings
-Oxalate Crystals in urine after 6 hrs
Treatment
-Fomepizole injection
-Calculate dose of alcohol infusion to compete with the toxin for metabolic pathways and stall its activation (buy some time for renal clearance)
-At a minimum provide lots of IV fluids to try to flush out the remaining toxin.
Lecture 15 Reproductive Toxicity
What are the mechanisms of adverse effects in reproductive function?
-Any manifestation of xenobiotic exposure reflecting adverse effect on physiological processes and associated behaviors/anatomical structures in animal reproduction or development.
Developmental toxicity
-Any adverse effect on the developing organism associated with either pre-conception parental exposures to toxicants or post-conception xenobiotic exposures to the embryo, fetus or pre-pubertal offspring.
Teratogenesis
-Specifically to developmental defects induced by toxicant exposure occurring between conception and birth
Mechanisms
- Toxicant-induced cellular dysregulation
- Alterations in cellular maintenance
- Endocrine disruption
Endocrine disruptors
What are some reproductive toxicants - female, male?
-Effects are mediated directly by interactions between the xenobiotic and an endogenous hormone
-Example: xenobiotic functions as aligned for an endogenous receptor and a receptor-ligand complex is formed.
-Includes adverse effects that alter hormonal functions without direct interactions between the toxicant and endogenous receptor
Reproductive Toxicants Female
DES: diethylstilbestrol (treat female incontinence)
DDT: pesticide
PCBs: polychlorinated biphenyls - similar to dioxin, used in electrical grid, now banned.
Bisphenol A - plasticizer
Nonylphenol: commercial chemical, can arise from nontoxynol
Ketone: insecticide
TCDD: Dioxin
Phyestrogens, what are they classified as?
What are the signs of clover disease?
Classified as ISOFLAVONES
Toxic principle: Coumestrol (alfalfa)
Toxic principle: Genestein and Formononetin (clover).
Plant sources:
-Subterranean clover
-Red clover
-White Clover
-Alsike clover
-Alfalfa: Coumestrol,
-Soybean
MOA: estrogenic activity. Estrogenic activity decreases during drying process of hay.
Clover disease Phytoestrogen-induced
C/S
-Precocoius mammary development
-Infertility
-Abnormal estrous cycles
-Structural and functional changes in the cervix
-Alteration in ovine cervical mucus interfere with the slow, sustained transport of motile spermatozoa from the cervical reservoirs.
Photosensitization
What characteristics make some animals more susceptible?
How fast can the reaction start after contact?
How does it compare to sunburn?
What HAs are susceptible to light-mediated oxygenation?
Defined as severe dermatitis that results from a heightened reactivity of skin cells and associated dermal tissues upon exposure to sunlight, following ingestion or contact with plant pigments or secondary products that are UV or light reactive.
-It can occur within minutes of exposure to the toxic substance by direct contact, within hours (contact or ingestion) of deposition of the primary photosensitizing agent, or days after exposure due to activation of secondary photosensitizes (following liver damage and deposition of phytoporphyrin into skin).
-The presence of light reactive compounds produced by higher plants can result in considerable damage to sensitive dermal tissues
-Irritation, tissue abrasion, secondary skin infections, even death.
-Damage is through generation of ROS.
NOT SUNBURN: UV rays exceed blocking ability of melanin; reaches the stratum basal and causes DNA damage, edema, blistering.
-Light colored animals more susceptible
-Most common in areas of skin that remains hairless, such as mammary glands, tail, hoof wall area, skin around the eyes, face, muzzle, etc.
-Deeper layers of integument, the dermis and hypodermic, offer limited to no protection from penetrating substances nor light.
-Darker skin contains melanin or pigment also serves as protection to prevent additional photosensitization.
Photosensitizer and light
-Tryptophan, Tyrosine, Histidine, Methionine, Cystine (proteins) AAs in animal skin experience light-mediated oxygenation, eventually inflammatory response, blood vessels affected and tissue necrosis.
Photosensitization type 1
-Activated sensitizer reacts with the acceptor, in one-electron transfer reaction to produce a radical ion in both.
-Acceptor (substrate) donates electron to sensitizer, resulting in acceptor radical cation (acceptor +) and sensitizer radical anion (sensitizer -).
Phototoxic plants-produced compounds or metabolites become bioavailable within animal after ingestion or cellular layers of skin*
=DNA adducts/crosslinking, cell death/dysfunction
Type 2
-Activated sensitizer transfers energy to ground state molecular oxygen, producing excited state singlet oxygen and generating the ground-start sensitizer.
-Singlet oxygen then reacts with the acceptor to produce oxidized metabolites. The sensitizer is not consumed.
Results from the accumulation of the photodynamic compound phytoporphyrin, which is a microbial-produced metabolite of chlorophyll. May occur as a result of acute or chronic liver damage and derivatives not cleared by liver.
=Hepatotoxins, hematogenous photosensitization. DNA adducts/crosslinkin, cell death/dysfunction.
Lecture 17 Toxicants Venomous Animals
- List the venomous arthropods and snakes of concern in the US and Canada
- Explain the wide variation in clinical signs seen with snakebites, including situations where snakebites are most dangerous
- List clinical signs possible with pit viper envenomations
- Describe the appropriate treatments for snake bite victims
Venemous Snakes
Elapidae
- Micrurus - Coral snake
-Fixed fangs (proteroglyphic), have to bite and chew, less of a problem - Other: Cobras, Kraits, Death Adder.
Crotalus
- Rattlesnakes, many species.
-Eastern, Western Diamondbacks, Timber, etc. - Sistrutus Rattlesnakes
-Massassauga (largest)
-Pygmy (smallest) Rattlesnakes - Agkistrodon: NO RATTLES “TN baddies”
-Copperhead
-Water Moccasins (cottonmouth)
Venom: Proteins and peptides. Inorganic ions (Na, Ca, K, Mn2). Trace amounts of Zn, Fe, Co, Mg, Ni.
Other components: Carbohydrates (glycoproteins) lipids, biogenic amines, free amino acids.
Typical characteristics of a venomous snake
-Their nose: pits on nose (thermal receptors).
-Their eye: vertical pupils
-Their heads: triangular heads
Toxicology of Crotalids
-Direct tissue damage and necrosis
-Alterations in blood vessel resistance
-Changes in RBCs and blood coagulation
-Alterations of NS function
-Changes in metabolism and respiration
-Hypotension - shock
**A venomous snake may bite and not inject venom (dry bites occur 20-30% of pet viper bites and 50% of all coral snake bites)
Snakebites presentation
-Swelling and bruising around the bites site
-Most swelling resolves within 48 hours unless infection sets in
-Sometimes you can still see the puncture wounds
Horses
-Airway patency
-Severe local fissure damage that spreads from the bites site. The tissue becomes markedly discolored within a few minutes, dark, bloody fluid may ooze from fang wound if not prevented by swelling.
-Cardiovascular and hemolytic effects
Treatment
-Intensive therapy, irreversible effects of venom begins immediately after envenomation
-Bites site should be shaved, wounds cleansed throughly with germicidal soap.
-Crotalids bites, mark on the skin leading edge of swelling to monitor the spread of tissue injury.
-Monitor closely for a minimum of 24 to 48 hours for development of clinical signs.
May include
-Antivenins
-Opioid analgesics
-Blood replacement
-Heparin or Warfarin
-Antibiotics only if severe necrosis
Prognosis
-Depends on the type and species of snake, location of the bite, size of the snake and victim, degree of envenomation, and the time interval between the bite and the institution of treatment.
-Animals that survive elapid bites generally make full recover
-Depends on promptness and aggressiveness of treatment instituted.
